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HCQ for COVID-19: real-time meta analysis of 422 studies

 
0 0.5 1 1.5+ All studies 26% 422 535,118 Improvement, Studies, Patients Relative Risk Mortality 25% 253 381,319 RCTs 19% 61 27,461 RCTs PrEP 25% 13 6,982 RCTs Early 34% 11 3,475 RCT cases 23% 17 11,660 Early 66% 39 57,678 Early Mortality 76% 17 53,681 Early Hosp. 41% 16 50,759 PrEP 33% 106 190,589 PEP 30% 8 6,157 Late 20% 269 285,312 HCQ for COVID-19 c19hcq.org April 2024 after exclusions FavorsHCQ Favorscontrol
18% 50% 54% Late treatment   Early treatment   Prophylaxis   c19hcq.orgApril 2024 Percentage of HCQ RCTsnot reporting results
Abstract
Early treatment shows 66% [54‑74%] lower risk with pooled effects in 39 studies. Results are similar for higher quality studies and for peer-reviewed studies. The 17 mortality and 16 hospitalization results show 76% [61‑85%] lower mortality and 41% [28‑51%] lower hospitalization.
Late treatment is less successful, with 20% [16‑24%] lower risk from 269 studies. Very late treatment may be harmful, especially with excessive dosages.
Randomized Controlled Trials show 19% [6‑30%] lower risk, or 25% [11‑37%] when excluding late treatment.
0 0.5 1 1.5+ All studies 26% 422 535,118 Improvement, Studies, Patients Relative Risk Mortality 25% 253 381,319 RCTs 19% 61 27,461 RCTs PrEP 25% 13 6,982 RCTs Early 34% 11 3,475 RCT cases 23% 17 11,660 Early 66% 39 57,678 Early Mortality 76% 17 53,681 Early Hosp. 41% 16 50,759 PrEP 33% 106 190,589 PEP 30% 8 6,157 Late 20% 269 285,312 HCQ for COVID-19 c19hcq.org April 2024 after exclusions FavorsHCQ Favorscontrol
18% 50% 54% Late treatment   Early treatment   Prophylaxis   c19hcq.orgApril 2024 Percentage of HCQ RCTsnot reporting results
There is substantial bias towards publishing negative results. Prospective studies show higher efficacy. Negative RCTs received priority treatment at top journals, while positive trials report difficulty publishing. There is a strong geographical bias, with significantly more negative studies from North America.
Results are missing for 53% of early treatment and prophylaxis RCTs, compared to 18% for late treatment, consistent with the higher prevalence of positive studies for early treatment and prophylaxis, and bias against publishing positive results.
No treatment or intervention is 100% effective. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, which may be significantly more effective. Lung pharmacokinetics show high inter-individual variability Ruiz.
All data to reproduce this paper and the sources are in the appendix. Multiple other meta analyses show efficacy for early treatment or prophylaxis García-Albéniz, Ladapo, Landsteiner de Sampaio Amêndola, Prodromos, Risch, Risch (B), Stricker.
Evolution of COVID-19 clinical evidence HCQ p<0.0000000001 early treatment prophylaxis Acetaminophen p=0.00000029 2020 2021 2022 2023 2024 Effective Harmful c19hcq.org April 2024 meta analysis results (pooled effects) 100% 50% 0% -50%
Highlights
HCQ reduces risk for COVID-19 with very high confidence for mortality, hospitalization, cases, viral clearance, and in pooled analysis.
1st treatment shown effective with ≥3 clinical studies in March 2020, now with p < 0.00000000001 from 422 studies, and recognized in 42 countries.
We show outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor for COVID-19.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 69 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Gautret 66% 0.34 [0.17-0.68] 2.4g viral+ 6/20 14/16 Improvement, RR [CI] Dose (4d) Treatment Control Esper 64% 0.36 [0.15-0.87] 2g hosp. 8/412 12/224 CT​2 Ashraf 68% 0.32 [0.10-1.10] 1.6g death 10/77 2/5 Huang (ES) 59% 0.41 [0.26-0.64] 2g (c) viral time 32 (n) 37 (n) CQ​3 Guérin 61% 0.39 [0.02-9.06] 2.4g death 0/20 1/34 CT​2 Derwand 79% 0.21 [0.03-1.47] 1.6g death 1/141 13/377 CT​2 Smith (RCT) 64% 0.36 [0.02-7.70] 2g hosp. 0/7 1/9 Mitjà (RCT) 16% 0.84 [0.35-2.03] 2g hosp. 8/136 11/157 Skipper (RCT) 37% 0.63 [0.21-1.91] 3.2g death/hosp. 5/231 8/234 OT​1 Hong 65% 0.35 [0.13-0.72] n/a viral+ 42 (n) 48 (n) Bernabeu-Wittel 94% 0.06 [0.01-0.31] 2g death 24/139 37/83 CT​2 Yu (ES) 85% 0.15 [0.03-0.74] 1.6g death 1/73 238/2,604 Ly 56% 0.44 [0.26-0.75] 2.4g death 18/116 29/110 CT​2 Ip 55% 0.45 [0.11-1.85] n/a death 2/97 44/970 Heras 96% 0.04 [0.02-0.09] n/a death 8/70 16/30 CT​2 Kirenga 26% 0.74 [0.47-1.17] n/a recov. time 29 (n) 27 (n) Sulaiman 64% 0.36 [0.16-0.80] 2g death 7/1,817 54/3,724 Guisado-Vasco (ES) 67% 0.33 [0.05-1.55] n/a death 2/65 139/542 Szente Fonseca 64% 0.36 [0.20-0.67] 2g hosp. 25/175 89/542 Cadegiani 81% 0.19 [0.01-3.88] 1.6g death 0/159 2/137 Simova 94% 0.06 [0.01-0.57] 2.4g hosp. 0/33 2/5 CT​2 Q-PROTECT Omrani (RCT) 12% 0.88 [0.26-2.94] 2.4g hosp. 7/304 4/152 CT​2 Agusti 68% 0.32 [0.06-1.67] 2g progression 2/87 4/55 Su 85% 0.15 [0.04-0.57] 1.6g progression n/a n/a Amaravadi (RCT) 60% 0.40 [0.13-1.28] 3.2g no recov. 3/15 6/12 Roy 2% 0.98 [0.45-2.20] n/a recov. time 14 (n) 15 (n) Mokhtari 70% 0.30 [0.20-0.45] 2g death 27/7,295 287/21,464 Corradini (ES) 67% 0.33 [0.14-0.78] n/a death 641 (n) 102 (n) Million 83% 0.17 [0.06-0.48] 2.4g death 5/8,315 11/2,114 CT​2 Sobngwi (RCT) 52% 0.48 [0.09-2.58] 1.6g no recov. 2/95 4/92 OT​1 Rodrigues (RCT) -200% 3.00 [0.13-71.6] 3.2g hosp. 1/42 0/42 CT​2 Sawanpanyalert 42% 0.58 [0.18-1.91] varies progression n/a n/a CT​2 Atipornwan.. (RCT) -150% 2.50 [0.10-59.6] 1.6g progression 1/60 0/30 OT​1 CT​2 Chechter 95% 0.05 [0.00-0.96] 2g hosp. 0/60 3/12 CT​2 Rouamba (ES) 73% 0.27 [0.09-1.02] 2.4g progression 23/399 4/33 Avezum (RCT) 1% 0.99 [0.29-3.41] 2g death 5/687 5/682 Roy-García (RCT) -100% 2.00 [0.19-20.9] 1.6g progression 2/31 1/31 Rathod 73% 0.27 [0.09-0.83] n/a death 513 (n) 52 (n) CT​2 PROTECT Azhar (RCT) 71% 0.29 [0.09-0.90] 2.4g death 4/248 10/178 OT​1 Early treatment 66% 0.34 [0.26-0.46] 207/22,697 1,051/34,981 66% lower risk All 39 HCQ COVID-19 early treatment studies c19hcq.org April 2024 Tau​2 = 0.46, I​2 = 71.2%, p < 0.0001 Effect extraction pre-specified, see appendix 1 OT: comparison with other treatment3 CQ: study uses chloroquine 2 CT: study uses combined treatment Favors HCQ Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Gautret 66% viral- Improvement Relative Risk [CI] Esper 64% hospitalization Ashraf 68% death Huang (ES) 59% viral- Guérin 61% death Derwand 79% death Smith (RCT) 64% hospitalization Mitjà (RCT) 16% hospitalization Skipper (RCT) 37% death/hosp. Hong 65% viral- Bernabeu-Wittel 94% death Yu (ES) 85% death Ly 56% death Ip 55% death Heras 96% death Kirenga 26% recovery Sulaiman 64% death Guisado-Vasco (.. 67% death Szente Fonseca 64% hospitalization Cadegiani 81% death Simova 94% hospitalization Q-PROTECT Omrani (RCT) 12% hospitalization Agusti 68% progression Su 85% progression Amaravadi (RCT) 60% recovery Roy 2% recovery Mokhtari 70% death Corradini (ES) 67% death Million 83% death Sobngwi (RCT) 52% recovery Rodrigues (RCT) -200% hospitalization Sawanpanyalert 42% progression Atipornwa.. (RCT) -150% progression Chechter 95% hospitalization Rouamba (ES) 73% progression Avezum (RCT) 1% death Roy-García (RCT) -100% progression Rathod 73% death PROTECT Azhar (RCT) 71% death Early treatment 66% 66% lower risk All 39 HCQ C19 early treatment studies c19hcq.org April 2024 Tau​2 = 0.46, I​2 = 71.2%, p < 0.0001 Effect extraction pre-specifiedRotate device for details Favors HCQ Favors control
B
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Ashraf 68% 0.32 [0.10-1.10] 1.6g 10/77 2/5 Improvement, RR [CI] Dose (4d) Treatment Control Guérin 61% 0.39 [0.02-9.06] 2.4g 0/20 1/34 Derwand 79% 0.21 [0.03-1.47] 1.6g 1/141 13/377 Bernabeu-Wittel 94% 0.06 [0.01-0.31] 2g 24/139 37/83 Yu (ES) 85% 0.15 [0.03-0.74] 1.6g 1/73 238/2,604 Ly 56% 0.44 [0.26-0.75] 2.4g 18/116 29/110 Ip 55% 0.45 [0.11-1.85] n/a 2/97 44/970 Heras 96% 0.04 [0.02-0.09] n/a 8/70 16/30 Sulaiman 64% 0.36 [0.16-0.80] 2g 7/1,817 54/3,724 Guisado-Vasco (ES) 67% 0.33 [0.05-1.55] n/a 2/65 139/542 Cadegiani 81% 0.19 [0.01-3.88] 1.6g 0/159 2/137 Mokhtari 70% 0.30 [0.20-0.45] 2g 27/7,295 287/21,464 Corradini (ES) 67% 0.33 [0.14-0.78] n/a 641 (n) 102 (n) Million 83% 0.17 [0.06-0.48] 2.4g 5/8,315 11/2,114 Avezum (RCT) 1% 0.99 [0.29-3.41] 2g 5/687 5/682 Rathod 73% 0.27 [0.09-0.83] n/a 513 (n) 52 (n) PROTECT Azhar (RCT) 71% 0.29 [0.09-0.90] 2.4g 4/248 10/178 Early treatment 76% 0.24 [0.14-0.41] 114/20,473 888/33,208 76% lower risk All 17 HCQ COVID-19 mortality early treatment results c19hcq.org April 2024 Tau​2 = 0.73, I​2 = 80.9%, p < 0.0001 Favors HCQ Favors control
C
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Esper 64% 0.36 [0.15-0.87] 2g hosp. 8/412 12/224 Improvement, RR [CI] Dose (4d) Treatment Control Derwand 82% 0.18 [0.07-0.54] 1.6g hosp. 4/141 58/377 Smith (RCT) 64% 0.36 [0.02-7.70] 2g hosp. 0/7 1/9 Mitjà (RCT) 16% 0.84 [0.35-2.03] 2g hosp. 8/136 11/157 Skipper (RCT) 49% 0.51 [0.15-1.66] 3.2g hosp. 4/231 8/234 Ip 37% 0.63 [0.37-0.96] n/a hosp. 21/97 305/970 Sulaiman 39% 0.61 [0.52-0.73] 2g hosp. 171/1,817 617/3,724 Szente Fonseca 64% 0.36 [0.20-0.67] 2g hosp. 25/175 89/542 Cadegiani 98% 0.02 [0.00-0.27] 1.6g hosp. 0/159 27/137 Simova 94% 0.06 [0.01-0.57] 2.4g hosp. 0/33 2/5 Q-PROTECT Omrani (RCT) 12% 0.88 [0.26-2.94] 2.4g hosp. 7/304 4/152 Mokhtari 35% 0.65 [0.59-0.71] 2g hosp. 523/7,295 2,382/21,464 Million 4% 0.96 [0.71-1.29] 2.4g hosp. 214/8,315 64/2,114 Rodrigues (RCT) -200% 3.00 [0.13-71.6] 3.2g hosp. 1/42 0/42 Chechter 95% 0.05 [0.00-0.96] 2g hosp. 0/60 3/12 Avezum (RCT) 23% 0.77 [0.52-1.12] 2g hosp. 44/689 57/683 Early treatment 41% 0.59 [0.49-0.72] 1,030/19,913 3,640/30,846 41% lower risk All 16 HCQ COVID-19 hospitalization early treatment results c19hcq.org April 2024 Tau​2 = 0.05, I​2 = 61.0%, p < 0.0001 Favors HCQ Favors control
D
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E
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Figure 1. A. Random effects meta-analysis of all early treatment studies. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported. Simplified dosages are shown for comparison, these are the total dose in the first four days. Chloroquine is indicated with (c). For details of effect extraction and full dosage information see the appendix. B. and C. Random effects meta-analysis of early treatment mortality and hospitalization results. D. Timeline of results in HCQ treatment studies. The marked dates indicate the time when efficacy was known with a statistically significant improvement of ≥10% from ≥3 studies for pooled outcomes, one or more specific outcome, pooled outcomes in RCTs, and one or more specific outcome in RCTs. Efficacy based on RCTs only was delayed by 10.8 months, compared to using all studies. Efficacy based on specific outcomes was delayed by 2.4 months, compared to using pooled outcomes. Efficacy based on specific outcomes in RCTs was delayed by 2.6 months, compared to using pooled outcomes in RCTs. E. Scatter plot of the effects reported in early treatment studies compared with all studies. Early treatment is more effective.
Introduction
SARS-CoV-2 infection primarily begins in the upper respiratory tract and may progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems, which may lead to cytokine storm, pneumonia, ARDS, neurological issues Duloquin, Hampshire, Scardua-Silva, Sodagar, Yang, cardiovascular complications Eberhardt, organ failure, and death. Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+ host and viral proteins and other factors Note A, Malone, Murigneux, Lv, Lui, Niarakis, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 7,000 compounds may reduce COVID-19 risk c19early.org, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
We analyze all significant controlled studies of HCQ (or CQ) for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random-effects meta-analysis results for all studies, studies within each treatment stage, mortality, hospitalization, cases, viral clearance, higher quality studies, and for Randomized Controlled Trials (RCTs).
Figure 2 shows stages of possible treatment for COVID-19. Pre-Exposure Prophylaxis (PrEP) refers to regularly taking medication before being infected, in order to prevent or minimize infection. In Post-Exposure Prophylaxis (PEP), medication is taken after exposure but before symptoms appear. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Preclinical Research
8 In Silico studies support the efficacy of hydroxychloroquine Alkafaas, Baildya, González-Paz, Hussein, Navya, Noureddine, Tarek, Yadav.
21 In Vitro studies support the efficacy of hydroxychloroquine Alsmadi, Andreani, Clementi, Dang, Delandre, Faísca, González-Paz, Kamga Kapchoup, Liu, Miao, Milan Bonotto, Mohd Abd Razak, Ou, Purwati, Shang, Sheaff, Wang, Wang (B), Wen, Yao, Yuan.
2 In Vivo animal studies support the efficacy of hydroxychloroquine Shu-Han Lin, Wen.
5 studies investigate novel formulations of hydroxychloroquine that may be more effective for COVID-19 Alsmadi, Faísca, Kavanagh, Klimke, Zelenko.
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
92% of early treatment studies report a positive effect, with an estimated improvement of 66% in random effects meta analysis.
Late treatment studies are mixed, with 68% showing positive effects, and an estimated improvement of 20%. Negative studies typically fall into the following categories: they show evidence of significant unadjusted confounding, including confounding by indication; usage is extremely late; or they use an excessively high dosage.
81% of PrEP studies show positive effects, with an estimated improvement of 33%. The majority of negative studies analyze systemic autoimmune disease patients and either do not adjust for the different baseline risk of these patients at all, or do not adjust for the highly variable risk within this group.
88% of PEP studies report positive effects, with an estimated improvement of 30%.
Table 1 summarizes the results for all stages combined, for Randomized Controlled Trials, with different exclusions, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3 plots individual results by treatment stage. Figure 4, 5, 6, 7, and 8 show forest plots for treatment studies with pooled effects, and for studies reporting mortality, hospitalization, case, and viral clearance results.
Table 1. Random effects meta-analysis for all stages combined, for Randomized Controlled Trials, with different exclusions, and for specific outcomes. Results show the percentage improvement with treatment and the 95% confidence interval. * p<0.05  ** p<0.01  *** p<0.001  **** p<0.0001.
Improvement Studies Patients Authors
All studies26% [23‑30%] p < 0.0001
****
422 535,118 8,711
After exclusions37% [34‑41%] p < 0.0001
****
272 318,601 6,476
Randomized Controlled TrialsRCTs19% [6‑30%] p = 0.0067
**
61 27,461 3,091
RCTs exc. late treatmentRCTs exc. late25% [11‑37%] p = 0.00099
***
28 15,682 695
Mortality25% [20‑29%] p < 0.0001
****
253 381,319 6,327
HospitalizationHosp.15% [6‑24%] p = 0.0013
**
65 96,654 1,298
Recovery17% [6‑27%] p = 0.0031
**
28 8,652 501
Cases28% [20‑35%] p < 0.0001
****
81 161,641 1,139
Viral19% [10‑28%] p = 0.00023
***
48 9,069 643
RCT mortality exc. late48% [-5‑74%] p = 0.0693 4,292 111
RCT hospitalization exc. lateRCT hosp. exc. late24% [-1‑43%] p = 0.05711 8,780 274
RCT casesRCT cases23% [10‑34%] p = 0.0008
***
17 11,660 488
Table 2. Random effects meta-analysis results by treatment stage. Results show the percentage improvement with treatment, the 95% confidence interval, and the number of studies for the stage.treatment and the 95% confidence interval. * p<0.05  ** p<0.01  *** p<0.001  **** p<0.0001.
Early treatment Late treatment Pre‑Exposure
Prophylaxis
PrEP
Post‑Exposure
Prophylaxis
PEP
All studies66%
 [54‑74%]
****
20%
 [16‑24%]
****
33%
 [26‑40%]
****
30%
 [10‑46%]
**
After exclusions66%
 [54‑75%]
****
32%
 [27‑35%]
****
41%
 [33‑49%]
****
30%
 [10‑46%]
**
Randomized Controlled TrialsRCTs34%
 [-1‑56%]
15%
 [-4‑31%]
25%
 [4‑42%]
*
21%
 [-6‑41%]
Mortality76%
 [61‑85%]
****
21%
 [16‑25%]
****
30%
 [14‑43%]
***
46%
 [-80‑84%]
HospitalizationHosp.41%
 [28‑51%]
****
-2%
 [-17‑11%]
11%
 [-1‑22%]
16%
 [-69‑58%]
Recovery35%
 [16‑50%]
**
12%
 [-1‑23%]
Cases28%
 [20‑35%]
****
25%
 [-0‑43%]
Viral32%
 [14‑47%]
**
17%
 [6‑27%]
**
RCT mortality48%
 [-76‑85%]
-3%
 [-19‑11%]
46%
 [-80‑84%]
RCT hospitalizationRCT hosp.24%
 [-5‑45%]
-18%
 [-70‑19%]
61%
 [-83‑92%]
16%
 [-69‑58%]
RCT casesRCT cases29%
 [15‑41%]
***
13%
 [-14‑34%]
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Figure 3. Results by treatment stage.
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Figure 4. Random effects meta-analysis. This plot shows pooled effects, see the specific outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. (ES) indicates the early treatment subset of a study.
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Figure 5. Random effects meta-analysis for mortality results only. (ES) indicates the early treatment subset of a study.
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Figure 6. Random effects meta-analysis for hospitalization results only.
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Figure 7. Random effects meta-analysis for case results only.
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Figure 8. Random effects meta-analysis for viral clearance results only.
Randomized Controlled Trials (RCTs)
Figure 9 compares RCT vs. other results. Meta analysis for RCTs is shown in Figure 10 and Figure 11, showing 19% [6‑30%] improvement for all RCTs, and 25% [11‑37%] improvement when excluding late treatment studies.
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Figure 9. Scatter plot of all effects comparing RCTs to non-RCTs.
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Figure 10. Random effects meta-analysis for RCTs.
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Figure 10. Random effects meta-analysis for RCTs excluding late treatment studies.
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Figure 12. Random effects meta-analysis for RCT mortality results excluding late treatment.
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Figure 13. Random effects meta-analysis for RCT hospitalization results excluding late treatment.
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Figure 14. Random effects meta-analysis for RCT case results.
RCTs help to make study groups more similar and can provide a higher level of evidence, however they are subject to many biases Jadad, and analysis of double-blind RCTs has identified extreme levels of bias Gøtzsche. For COVID-19, the overhead may delay treatment, dramatically compromising efficacy; they may encourage monotherapy for simplicity at the cost of efficacy which may rely on combined or synergistic effects; the participants that sign up may not reflect real world usage or the population that benefits most in terms of age, comorbidities, severity of illness, or other factors; standard of care may be compromised and unable to evolve quickly based on emerging research for new diseases; errors may be made in randomization and medication delivery; and investigators may have hidden agendas or vested interests influencing design, operation, analysis, reporting, and the potential for fraud. All of these biases have been observed with COVID-19 RCTs. There is no guarantee that a specific RCT provides a higher level of evidence.
RCTs are expensive and many RCTs are funded by pharmaceutical companies or interests closely aligned with pharmaceutical companies. For COVID-19, this creates an incentive to show efficacy for patented commercial products, and an incentive to show a lack of efficacy for inexpensive treatments. The bias is expected to be significant, for example Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that trials funded by for-profit organizations were 5 times more likely to recommend the experimental drug compared with those funded by nonprofit organizations. For COVID-19, some major philanthropic organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with increased ethical issues due to the urgency of treatment, increased risk due to enrollment delays, and more difficult design with a rapidly evolving evidence base. For COVID-19, the most common site of initial infection is the upper respiratory tract. Immediate treatment is likely to be most successful and may prevent or slow progression to other parts of the body. For a non-prophylaxis RCT, it makes sense to provide treatment in advance and instruct patients to use it immediately on symptoms, just as some governments have done by providing medication kits in advance. Unfortunately, no RCTs have been done in this way. Every treatment RCT to date involves delayed treatment. Among the 69 treatments we have analyzed, 63% of RCTs involve very late treatment 5+ days after onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of early treatments. They may more accurately represent results for treatments that require visiting a medical facility, e.g., those requiring intravenous administration.
RCTs have a bias against finding an effect for interventions that are widely available — patients that believe they need the intervention are more likely to decline participation and take the intervention. RCTs for hydroxychloroquine are more likely to enroll low-risk participants that do not need treatment to recover, making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments, and may be greater when the risk of a serious outcome is overstated. This bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
Evidence shows that non-RCT studies can also provide reliable results. Concato et al. found that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. Anglemyer et al. summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. Lee et al. showed that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias may have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see Deaton, Nichol.
Currently, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of these, 28 have been confirmed in RCTs, with a mean delay of 7.0 months. When considering only low cost treatments, 23 have been confirmed with a delay of 8.4 months. For the 16 unconfirmed treatments, 3 have zero RCTs to date. The point estimates for the remaining 13 are all consistent with the overall results (benefit or harm), with 10 showing >20%. The only treatments showing >10% efficacy for all studies, but <10% for RCTs are sotrovimab and aspirin.
We need to evaluate each trial on its own merits. RCTs for a given medication and disease may be more reliable, however they may also be less reliable. For off-patent medications, very high conflict of interest trials may be more likely to be RCTs, and more likely to be large trials that dominate meta analyses.
Exclusions
Many meta-analyses for HCQ have been written, most of which have become obselete due to the continuing stream of more recent studies. More recent analyses with positive conclusions include IHU Marseille which considers significant bias from an understanding of each trial, and García-Albéniz, Ladapo, Prodromos which focus on early or prophylactic use studies.
Meta analyses reporting negative conclusions focus on late treatment studies, tend to disregard treatment delay, tend to follow formulaic evaluations which overlook major issues with various studies, and end up with weighting disproportionate to a reasoned analysis of each study's contribution. For example, Axfors assigns 87% weight to a single trial, the RECOVERY trial RECOVERY Collaborative Group, thereby producing the same result. However, the RECOVERY trial may be the most biased of the studies they included, due to the excessive dosage used, close to the level shown to be very dangerous in Borba (OR 2.8), and with extremely sick late stage patients (60% requiring oxygen, 17% ventilation/ECMO, and a very high mortality rate in both arms). There is little reason to suggest that the results from this trial are applicable to more typical dosages or to earlier treatment (10/22: the second version of this study released 10/22 assigns 74% to RECOVERY and 15% to SOLIDARITY SOLIDARITY Trial Consortium, which is the only other trial using a similar excessive dosage).
We include all studies in the main analysis, however there are major issues with several studies that could significantly alter the results. Here, we present an analysis excluding studies with significant issues, including indication of significant unadjusted group differences or confouding by indication, extremely late stage usage >14 days post symptoms or >50% on oxygen at baseline, very minimal detail provided, excessive dosages which have been shown to be dangerous, significant issues with adjustments that could reasonably make substantial differences, and reliance on PCR which may be inaccurate and less indicative of severity than symptoms. The aim here is not to exclude studies on technicalities, but to exclude studies that clearly have major issues that may significantly change the outcome. We welcome feedback on improvements or corrections to this. The studies excluded are as follows, and the resulting forest plot is shown in Figure 15.
Aboulenain, substantial unadjusted confounding by indication possible.
Ader, very late stage, >50% on oxygen/ventilation at baseline.
Afşin, unadjusted results with no group details.
Alamdari, substantial unadjusted confounding by indication likely.
Albanghali, unadjusted results with no group details; substantial unadjusted confounding by indication likely.
Albani, substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Alghamdi, unadjusted results with no group details; very late stage, ICU patients.
Alghamdi (B), confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.
Alhamlan, substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Alqatari, unadjusted results with no group details.
AlShehhi, unadjusted results with no group details.
Alwafi, excessive unadjusted differences between groups.
Annie, confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.
Aparisi, unadjusted results with no group details.
Assad, unadjusted results with no group details; confounding by time possible, propensity to use HCQ changed significantly during the study period.
Awad, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely.
Azaña Gómez, unadjusted results with no group details.
Barbosa, excessive unadjusted differences between groups.
Barra, unadjusted results with no group details.
Bielza, unadjusted results with no group details.
Boari, unadjusted results with no group details.
Bosaeed, very late stage, >50% on oxygen/ventilation at baseline.
Budhiraja, excessive unadjusted differences between groups.
Cassione, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Chari, unadjusted results with no group details.
Chechter, unadjusted results with no group details.
Choi, excessive unadjusted differences between groups.
Coll, unadjusted results with no group details.
Cortez, unadjusted results with no group details.
Cravedi, substantial unadjusted confounding by indication likely.
Cárdenas-Jaén, unadjusted for baseline differences with no group details.
de Gonzalo-Calvo, unadjusted results with no group details.
de la Iglesia, not fully adjusting for the different baseline risk of systemic autoimmune patients.
De Luna, unadjusted results with no group details; substantial unadjusted confounding by indication likely.
Erden, unadjusted results with no group details.
Fernández-Cruz, unadjusted results with no group details.
Fitzgerald, not fully adjusting for the baseline risk differences within systemic autoimmune patients.
Fried, excessive unadjusted differences between groups; substantial unadjusted confounding by indication likely.
Fung, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Gadhiya, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely.
Gautret, excessive unadjusted differences between groups; results only for PCR status which may be significantly different to symptoms.
Geleris, significant issues found with adjustments.
Gendebien, not fully adjusting for the baseline risk differences within systemic autoimmune patients.
Gendelman, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Gianfrancesco, not fully adjusting for the baseline risk differences within systemic autoimmune patients.
Goldman, unadjusted results with no group details.
Guillaume, statistical analysis shows significant mismatch with prior research, potential overfitting.
Gupta, very late stage, >50% on oxygen/ventilation at baseline.
Gómez, unadjusted results with no group details.
Hall, unadjusted results with no group details.
Ho, excessive unadjusted differences between groups.
Hraiech, very late stage, ICU patients.
Huang, significant unadjusted confounding possible.
Huh, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Izoulet, excessive unadjusted differences between groups.
Jacobs, unadjusted results with no group details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Juneja, excessive unadjusted differences between groups.
Kamran, excessive unadjusted differences between groups.
Kamstrup, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Karruli, unadjusted results with no group details.
Kelly, substantial unadjusted confounding by indication likely.
Konig, not fully adjusting for the baseline risk differences within systemic autoimmune patients; unadjusted results with no group details.
Krishnan, unadjusted results with no group details.
Kuderer, substantial unadjusted confounding by indication likely.
Küçükakkaş, minimal details of groups provided.
Lamback, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Laplana, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Lecronier, very late stage, >50% on oxygen/ventilation at baseline.
Lotfy, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely.
Luo, substantial unadjusted confounding by indication likely.
Lyashchenko, substantial unadjusted confounding by indication likely.
Macias, not fully adjusting for the baseline risk differences within systemic autoimmune patients.
Mahale, unadjusted results with no group details.
Mahto, unadjusted results with no group details.
Maldonado, treatment or control group size extremely small.
Malundo, unadjusted results with no group details.
Martin-Vicente, unadjusted results with no group details; treatment or control group size extremely small.
Martinez-Lopez, unadjusted results with no group details.
McGrail, excessive unadjusted differences between groups.
Menardi, excessive unadjusted differences between groups; substantial unadjusted confounding by indication likely.
Mitchell, excessive unadjusted differences between groups.
Mohandas, substantial unadjusted confounding by indication likely; unadjusted results with no group details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Mulhem, substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Niwas, excessive unadjusted differences between groups.
Oztas, not adjusting for the different baseline risk of systemic autoimmune patients; excessive unadjusted differences between groups.
Pasquini, unadjusted results with no group details.
Patel, unadjusted results with no group details.
Peters, excessive unadjusted differences between groups.
Psevdos, unadjusted results with no group details; no treatment details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely.
Qin, unadjusted results with no group details.
Ramírez-García, excessive unadjusted differences between groups; substantial unadjusted confounding by indication likely.
Rangel, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Rao, unadjusted results with minimal group details.
RECOVERY Collaborative Group, excessive dosage in late stage patients, results do not apply to typical dosages.
Rentsch, not fully adjusting for the baseline risk differences within systemic autoimmune patients; medication adherence unknown and may significantly change results.
Rodriguez, unadjusted results with no group details.
Rodriguez-Nava, substantial unadjusted confounding by indication likely; excessive unadjusted differences between groups; unadjusted results with no group details.
Roger, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Roig, unadjusted results with no group details.
Roomi, substantial unadjusted confounding by indication likely.
Rosenthal, confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.
Roy, no serious outcomes reported and fast recovery in treatment and control groups, there is little room for a treatment to improve results.
Rubio-Sánchez, unadjusted results with no group details.
Saib, substantial unadjusted confounding by indication likely.
Said, unadjusted results with no group details.
Salazar, substantial unadjusted confounding by indication likely; unadjusted results with no group details.
Saleemi, substantial unadjusted confounding by indication likely.
Salehi, unadjusted results with no group details.
Salesi, unadjusted results with no group details.
Salvarani, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Samajdar, minimal details provided; unadjusted results with no group details; results may be significantly affected by survey bias.
Sammartino, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Sands, includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons; substantial unadjusted confounding by indication likely.
Santos, unadjusted results with no group details.
Santos, unadjusted results with no group details.
Sarfaraz, substantial unadjusted confounding by indication likely; significant unadjusted confounding possible; unadjusted results with no group details.
Sarhan, very late stage, >50% on oxygen/ventilation at baseline; significant unadjusted differences between groups.
Satti, unadjusted results with no group details.
Sbidian, significant issues found with adjustments.
Schmidt, confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.
Shamsi, unadjusted results with no group details.
Shoaibi, unadjusted results with no group details.
Singer, not fully adjusting for the baseline risk differences within systemic autoimmune patients.
Singh, confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.
Smith, immortal time bias may significantly affect results.
Solh, very late stage, >50% on oxygen/ventilation at baseline; substantial unadjusted confounding by indication likely.
SOLIDARITY Trial Consortium, excessive dosage in late stage patients, results do not apply to typical dosages; very late stage, >50% on oxygen/ventilation at baseline.
Sosa-García, very late stage, >50% on oxygen/ventilation at baseline; substantial unadjusted confounding by indication likely.
Soto, unadjusted results with no group details; substantial unadjusted confounding by indication likely; substantial confounding by time possible due to significant changes in SOC and treatment propensity near the start of the pandemic.
Soto-Becerra, substantial unadjusted confounding by indication likely; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Souza-Silva, substantial unadjusted confounding by indication likely; authors discussion of prior research exhibits strong bias, raising concern for bias in analysis.
Stewart, substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Stewart (B), substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Stewart (C), substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Stewart (D), substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Stewart (E), substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Stewart (F), substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Stewart (G), substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons.
Tamura, substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Tehrani, substantial unadjusted confounding by indication likely; unadjusted results with no group details.
Texeira, unadjusted results with no group details; no treatment details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely.
Trefond, not fully adjusting for the different baseline risk of systemic autoimmune patients; significant unadjusted confounding possible; excessive unadjusted differences between groups.
Tu, unadjusted results with no group details.
Ubaldo, substantial unadjusted confounding by indication likely; very late stage, ICU patients; unadjusted results with no group details.
Ulrich, very late stage, >50% on oxygen/ventilation at baseline.
Vernaz, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely.
Vivanco-Hidalgo, not fully adjusting for the different baseline risk of systemic autoimmune patients.
Wang (C), confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline.
Xia, minimal details provided.
Yegerov, unadjusted results with no group details.
Çivriz Bozdağ, substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically.
Çiyiltepe, treatment group only includes patients where treatment failed resulting in ICU admission.
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Figure 15. Random effects meta-analysis excluding studies with significant issues. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found below. (ES) indicates the early treatment subset of a study.
Heterogeneity
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours McLean, Treanor. Baloxavir studies for influenza also show that treatment delay is critical — Ikematsu et al. report an 86% reduction in cases for post-exposure prophylaxis, Hayden et al. show a 33 hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for treatment within 24-48 hours, and Kumar et al. report only 2.5 hours improvement for inpatient treatment.
Table 3. Studies of baloxavir for influenza show that early treatment is more effective.
Treatment delayResult
Post-exposure prophylaxis86% fewer cases Ikematsu
<24 hours-33 hours symptoms Hayden
24-48 hours-13 hours symptoms Hayden
Inpatients-2.5 hours to improvement Kumar
Figure 16 shows a mixed-effects meta-regression of efficacy as a function of treatment delay in HCQ COVID-19 studies, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
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Figure 16. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 HCQ studies.
Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results, for example as in López-Medina et al.
Efficacy may depend critically on the distribution of SARS-CoV-2 variants encountered by patients. Risk varies significantly across variants Korves, for example the Gamma variant shows significantly different characteristics Faria, Karita, Nonaka, Zavascki. Different mechanisms of action may be more or less effective depending on variants, for example the degree to which TMPRSS2 contributes to viral entry can differ across variants Peacock, Willett.
Effectiveness may depend strongly on the dosage and treatment regimen.
The use of other treatments may significantly affect outcomes, including supplements, other medications, or other interventions such as prone positioning. Treatments may be synergistic Alsaidi, Andreani, De Forni, Fiaschi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Said (B), Thairu, Wan, therefore efficacy may depend strongly on combined treatments.
The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. Williams et al. analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. Xu et al. analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.
Across all studies there is a strong association between different outcomes, for example improved recovery is strongly associated with lower mortality. However, efficacy may differ depending on the effect measured, for example a treatment may be more effective against secondary complications and have minimal effect on viral clearance.
The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though early treatment is very effective. All meta analyses combine heterogeneous studies, varying in population, variants, and potentially all factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we expect the estimated effect size from meta analysis to be less than that for the optimal case. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations. While we present results for all studies, we also present treatment time and individual outcome analyses, which may be more informative for specific use cases.
HCQ studies vary widely in all the factors above. We find a significant effect based on treatment delay. Early treatment shows consistently positive results, while late treatment results are very mixed. Closer analysis may identify factors related to efficacy among this group, for example treatment may be more effective in certain popuations, or more fine-grained analysis of treatment delay may identify a point after which treatment is ineffective.
Pooled Effects
For COVID-19, delay in clinical results translates into additional death and morbidity, as well as additional economic and societal damage. Combining the results of studies reporting different outcomes is required. There may be no mortality in a trial with low-risk patients, however a reduction in severity or improved viral clearance may translate into lower mortality in a high-risk population. Different studies may report lower severity, improved recovery, and lower mortality, and the significance may be very high when combining the results. "The studies reported different outcomes" is not a good reason for disregarding results.
We present both specific outcome and pooled analyses. In order to combine the results of studies reporting different outcomes we use the most serious outcome reported in each study, based on the thesis that improvement in the most serious outcome provides comparable measures of efficacy for a treatment. A critical advantage of this approach is simplicity and transparency. There are many other ways to combine evidence for different outcomes, along with additional evidence such as dose-response relationships, however these increase complexity.
Another way to view pooled analysis is that we are using more of the available information. Logically we should, and do, use additional information. For example dose-response and treatment delay-response relationships provide significant additional evidence of efficacy that is considered when reviewing the evidence for a treatment.
Trials with high-risk patients may be restricted due to ethics for treatments that are known or expected to be effective, and they increase difficulty for recruiting. Using less severe outcomes as a proxy for more serious outcomes allows faster collection of evidence.
For many COVID-19 treatments, a reduction in mortality logically follows from a reduction in hospitalization, which follows from a reduction in symptomatic cases, which follows from a reduction in PCR positivity. We can directly test this for COVID-19.
Analysis of the the association between different outcomes across studies from all 69 treatments we cover confirms the validity of pooled outcome analysis for COVID-19. Figure 17 shows that lower hospitalization is very strongly associated with lower mortality (p < 0.000000000001). Similarly, Figure 18 shows that improved recovery is very strongly associated with lower mortality (p < 0.000000000001). Considering the extremes, Singh (B) et al. show an association between viral clearance and hospitalization or death, with p = 0.003 after excluding one large outlier from a mutagenic treatment, and based on 44 RCTs including 52,384 patients. Figure 19 shows that improved viral clearance is strongly associated with fewer serious outcomes. The association is very similar to Singh (B) et al., with higher confidence due to the larger number of studies. As with Singh (B) et al., the confidence increases when excluding the outlier treatment, from p = 0.0000031 to p = 0.0000000067.
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Figure 17. Lower hospitalization is associated with lower mortality, supporting pooled outcome analysis.
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Figure 18. Improved recovery is associated with lower mortality, supporting pooled outcome analysis.
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Figure 17. Improved viral clearance is associated with fewer serious outcomes, supporting pooled outcome analysis.
Currently, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 88% of these have been confirmed with one or more specific outcomes, with a mean delay of 4.7 months. When restricting to RCTs only, 54% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 5.5 months. Figure 20 shows when treatments were found effective during the pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
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Figure 20. The time when studies showed that treatments were effective, defined as statistically significant improvement of ≥10% from ≥3 studies. Pooled results typically show efficacy earlier than specific outcome results. Results from all studies often shows efficacy much earlier than when restricting to RCTs. Results reflect conditions as used in trials to date, these depend on the population treated, treatment delay, and treatment regimen.
Pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but has no effect on viral clearance may show no efficacy if most studies only examine viral clearance. In practice, it is rare for a non-antiviral treatment to report viral clearance and to not report clinical outcomes; and in practice other sources of heterogeneity such as difference in treatment delay is more likely to hide efficacy.
Analysis validates the use of pooled effects and shows significantly faster detection of efficacy on average. However, as with all meta analyses, it is important to review the different studies included. We also present individual outcome analyses, which may be more informative for specific use cases.
Publication of clinical trials is often biased based on conflicts of interest. One way to examine potential bias is to compare prospective and retrospective studies. Prospective trials that involve significant effort are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.
For HCQ, 78.0% of prospective studies report positive effects, compared to 72.6% of retrospective studies, suggesting a bias toward publishing negative results. Prospective studies show 33% [23‑41%] improvement in meta analysis, compared to 26% [22‑29%] for retrospective studies. Figure 21 shows a scatter plot of results for prospective and retrospective studies.
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Figure 21. Prospective vs. retrospective studies. The diamonds show the results of random effects meta-analysis.
Figure 22 shows the results by region of the world, for all regions that have > 5 studies. Studies from North America are 2.4 times more likely to report negative results than studies from the rest of the world combined, 47.8% vs. 19.9%, two-tailed z test -5.34, p = 0.0000000942. Berry performed an independent analysis which also showed bias toward negative results for US-based research.
86.7% 83.8% 81.6% 76.1% 63.6% 52.2% Africa Asia Europe MiddleEast SouthAmerica NorthAmerica c19hcq.org Apr 2024
Figure 22. Percentage of studies reporting positive effects by region.
HCQ treatment became highly politicized and widely restricted. In many cases, physicians recommending treatment based on clinical evidence lost employment, licenses, and careers. There is a strong bias towards publishing negative results, with negative RCTs receiving priority handling at top journals, and scientists reporting difficulty publishing positive results Boulware, Meeus, Meneguesso. Meeus, for example, report that their paper with 4,000 patients reporting favourable outcomes for HCQ+AZ was rejected without peer review from the editors of four different journals.
News organizations show a similar bias. Although 309 studies show positive results, The New York Times, for example, has only written articles for studies that claim HCQ is not effective The New York Times, The New York Times (B), The New York Times (C). As of September 10, 2020, The New York Times still claims that there is clear evidence that HCQ is not effective for COVID-19 The New York Times (D). As of October 9, 2020, the United States National Institutes of Health recommends against HCQ for both hospitalized and non-hospitalized patients United States National Institutes of Health.
38 HCQ RCTs have not reported their results, with results missing for 50% of early treatment RCTs and 54% of prophylaxis RCTs, compared to 18% for late treatment RCTs. This is consistent with the higher prevalence of positive studies for early treatment and prophylaxis, and bias against publishing positive results.
18% 50% 54% Late treatment   Early treatment   Prophylaxis   c19hcq.orgApril 2024 Percentage of HCQ RCTsnot reporting results
Figure 23. Many RCTs have not reported their results, mostly those for early treatment and prophylaxis.
The RCTs with missing results are shown in the RCT forest plots, and do not include 65 RCTs that report terminating prior to enrolling 30 patients. The missing trials report a total of 25,399 patients, with 12 trials having actual enrollment of 8,139, and the remainder only reporting estimated numbers. Most trials are known to have started enrollment, while several may have been terminated early. A few trials may have been terminated before enrollment started. This analysis is based on the US clinicaltrials.gov registry. There may be additional missing RCTs not registered in the US. Fincham et al. found 70% of 187 HCQ trials had not reported results as of October 2022. Their analysis includes additional trials that were not registered in clinicaltrials.gov.
Unpublished results are unethical. Future patients are deprived of the ability to make informed decisions. Moreover, RCT participants make a potentially lethal sacrifice for the good of humanity. For existing medications with known efficacy and safety data, patients forego the best treatment choice based on current data. For COVID-19, they know that they may die, depending on their random assignment.
The reasons for lack of publication differ, and may be out of control of the authors. Some RCTs were submitted for publication, but have been caught in journal politicization (authors should release preprints in this case). Others may be held due to decisions of associated organizations, or decisions of only a subset of authors. Most missing RCTs have associations with organizations and/or physicians that restricted HCQ — publication would highlight their liability. Note that in many cases, trials may have been started prior to the extreme politicization.
Table 4 shows the reported results of physicians that use early treatments for COVID-19, compared to the results for a non-treating physician (this physician reportedly prescribed early treatment for themself, but not for patients medicospelavidacovid19.com.br). The treatments used vary between physicians. Almost all report using ivermectin and/or HCQ, and most use additional treatments in combination. These results are subject to selection and ascertainment bias and more accurate analysis requires details of the patient populations and followup, however results are consistently better across many teams, and consistent with the extensive controlled trial evidence that shows a significant reduction in risk with many early treatments, and improved results with the use of multiple treatments in combination.
Table 4. Physician results with early treatment protocols compared to no early treatment. (*) Dr. Uip reportedly prescribed early treatment for himself, but not for patients medicospelavidacovid19.com.br.
LATE TREATMENT
Physician / TeamLocationPatients HospitalizationHosp. MortalityDeath
Dr. David Uip (*) Brazil 2,200 38.6% (850) Ref. 2.5% (54) Ref.
EARLY TREATMENT - 39 physicians/teams
Physician / TeamLocationPatients HospitalizationHosp. ImprovementImp. MortalityDeath ImprovementImp.
Dr. Roberto Alfonso Accinelli
0/360 deaths for treatment within 3 days
Peru 1,265 0.6% (7) 77.5%
Dr. Mohammed Tarek Alam
patients up to 84 years old
Bangladesh 100 0.0% (0) 100.0%
Dr. Oluwagbenga Alonge Nigeria 310 0.0% (0) 100.0%
Dr. Raja Bhattacharya
up to 88yo, 81% comorbidities
India 148 1.4% (2) 44.9%
Dr. Flavio Cadegiani Brazil 3,450 0.1% (4) 99.7% 0.0% (0) 100.0%
Dr. Alessandro Capucci Italy 350 4.6% (16) 88.2%
Dr. Shankara Chetty South Africa 8,000 0.0% (0) 100.0%
Dr. Deborah Chisholm USA 100 0.0% (0) 100.0%
Dr. Ryan Cole USA 400 0.0% (0) 100.0% 0.0% (0) 100.0%
Dr. Marco Cosentino
vs. 3-3.8% mortality during period; earlier treatment better
Italy 392 6.4% (25) 83.5% 0.3% (1) 89.6%
Dr. Jeff Davis USA 6,000 0.0% (0) 100.0%
Dr. Dhanajay India 500 0.0% (0) 100.0%
Dr. Bryan Tyson & Dr. George Fareed USA 20,000 0.0% (6) 99.9% 0.0% (4) 99.2%
Dr. Raphael Furtado Brazil 170 0.6% (1) 98.5% 0.0% (0) 100.0%
Dr. Heather Gessling USA 1,500 0.1% (1) 97.3%
Dr. Ellen Guimarães Brazil 500 1.6% (8) 95.9% 0.4% (2) 83.7%
Dr. Syed Haider USA 4,000 0.1% (5) 99.7% 0.0% (0) 100.0%
Dr. Mark Hancock USA 24 0.0% (0) 100.0%
Dr. Sabine Hazan USA 1,000 0.0% (0) 100.0%
Dr. Mollie James USA 3,500 1.1% (40) 97.0% 0.0% (1) 98.8%
Dr. Roberta Lacerda Brazil 550 1.5% (8) 96.2% 0.4% (2) 85.2%
Dr. Katarina Lindley USA 100 5.0% (5) 87.1% 0.0% (0) 100.0%
Dr. Ben Marble USA 150,000 0.0% (4) 99.9%
Dr. Edimilson Migowski Brazil 2,000 0.3% (7) 99.1% 0.1% (2) 95.9%
Dr. Abdulrahman Mohana Saudi Arabia 2,733 0.0% (0) 100.0%
Dr. Carlos Nigro Brazil 5,000 0.9% (45) 97.7% 0.5% (23) 81.3%
Dr. Benoit Ochs Luxembourg 800 0.0% (0) 100.0%
Dr. Ortore Italy 240 1.2% (3) 96.8% 0.0% (0) 100.0%
Dr. Valerio Pascua
one death for a patient presenting on the 5th day in need of supplemental oxygen
Honduras 415 6.3% (26) 83.8% 0.2% (1) 90.2%
Dr. Sebastian Pop Romania 300 0.0% (0) 100.0%
Dr. Brian Proctor USA 869 2.3% (20) 94.0% 0.2% (2) 90.6%
Dr. Anastacio Queiroz Brazil 700 0.0% (0) 100.0%
Dr. Didier Raoult France 8,315 2.6% (214) 93.3% 0.1% (5) 97.6%
Dr. Karin Ried
up to 99yo, 73% comorbidities, av. age 63
Turkey 237 0.4% (1) 82.8%
Dr. Roman Rozencwaig
patients up to 86 years old
Canada 80 0.0% (0) 100.0%
Dr. Vipul Shah India 8,000 0.1% (5) 97.5%
Dr. Silvestre Sobrinho Brazil 116 8.6% (10) 77.7% 0.0% (0) 100.0%
Dr. Unknown Brazil 957 1.7% (16) 95.7% 0.2% (2) 91.5%
Dr. Vladimir Zelenko USA 2,200 0.5% (12) 98.6% 0.1% (2) 96.3%
Mean improvement with early treatment protocols 237,521 HospitalizationHosp. 94.1% MortalityDeath 94.7%
Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 24 plot A shows a funnel plot for a simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all showing p < 0.05 Egger, Harbord, Macaskill, Moreno, Peters (B), Rothstein, Rücker, Stanley. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.
Figure 24. Example funnel plot analysis for simulated perfect trials.
Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts of interest, standard of care, and other factors. We provide analyses for specific outcomes and by treatment delay, and we aim to identify key characteristics in the forest plots and summaries. Results should be viewed in the context of study characteristics.
Some analyses classify treatment based on early or late administration, as done here, while others distinguish between mild, moderate, and severe cases. Viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.
Details of treatment delay per patient is often not available. For example, a study may treat 90% of patients relatively early, but the events driving the outcome may come from 10% of patients treated very late. Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in the studies performed, for example dose, variants, and conflicts of interest. Trials with conflicts of interest may use designs better suited to the preferred outcome.
In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.
Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy than individual treatments alone Alsaidi, Andreani, De Forni, Fiaschi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Said (B), Thairu, Wan. Therefore standard of care may be critical and benefits may diminish or disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on submissions. Accuracy benefits from widespread review and submission of updates and corrections from reviewers. Less popular treatments may receive fewer reviews.
No treatment or intervention is 100% available and effective for all current and future variants. Efficacy may vary significantly with different variants and within different populations. All treatments have potential side effects. Propensity to experience side effects may be predicted in advance by qualified physicians. We do not provide medical advice. Before taking any medication, consult a qualified physician who can compare all options, provide personalized advice, and provide details of risks and benefits based on individual medical history and situations.
Many reviews cover hydroxychloroquine for COVID-19, presenting additional background on mechanisms, formulations, and related results, including Al-Bari, Brouqui, Colson, Derwand, Gao, Goldstein, Hecel, IHU, Kaur, Li, Loo, Matada, Roussel, Sahraei, Todaro, Vigbedor.
We focus here on the question of whether HCQ is effective or not for COVID-19. Studies vary significantly in terms of treatment delay, treatment regimen, patients characteristics, and (for the pooled effects analysis) outcomes, as reflected in the high degree of heterogeneity. However, early treatment consistently shows benefits. 92% of early treatment studies report a positive effect, with an estimated improvement of 66% (p < 0.0001).
Generally, it is easy to choose inclusion criteria and assign biased risk evaluations in order to produce any desired outcome in a meta analysis.
COVID-19 treatment studies have many sources of heterogeneity which affect the results, including treatment delay (time from infection or the onset of symptoms), patient population (age, comorbidities), the effect measured and details of the measurement, distribution of SARS-CoV-2 variants, dosage/regimen, and other treatments (anything from supplements, other medications, or other kinds of treatment like prone positioning).
If a treatment is effective early, there is no reason to expect it will also work late. Antivirals are typically only considered effective when used within a short timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective McLean, Treanor. For HCQ, the overwhelming majority of trials involve treatment not only after 48 hours but after 5 days - results from these trials are not relevant to earlier usage.
Authors desiring to produce a negative outcome for HCQ need only focus on late treatment studies. For example, Axfors assigns 89% weight to the RECOVERY and SOLIDARITY trials, producing the same negative result. These trials used excessively high non-patient-customized dosage in very sick late stage patients, dosages comparable to those known to be harmful in that context Borba. The results are not generalizable to typical dosage or treatment of earlier stage hospitalized patients, and certainly not applicable to early treatment, i.e., at first glance we can see that this meta analysis is of no relevance to early treatment.
This paper also does not appear to have been done very carefully. For example, authors include Borba which is assigned 97% weight for CQ. This study has no control group, comparing two different dosages of CQ, which is clear from the abstract of the study.
Axfors approximate early treatment with outpatient use, where they list 5 trials. This is misleading because authors ignore all outcomes other than mortality, and only one of the 5 trials has mortality events, so in reality only one trial is included. Table 1 shows the 5 trials, only one with mortality. The text says something different: "among the five studies on outpatients, there were three deaths, two occurring in the one trial of 491 relatively young patients with few comorbidities and one occurring in a small trial with 27 patients". We do not know what the missing 27 patient trial is, none of the 5 outpatient trials in Table 1 show 27 patients. There is an outpatient trial with 27 patients Amaravadi, however that trial reports no mortality. It does appear in the meta analysis, but is reported as being an inpatient trial with zero mortality (in reality it was a remotely conducted trial of patients quarantined at home). The supplementary appendix has another different version for outpatient trials, with only 4 trials in Table S3 and Figure S2B (only one with mortality).
Therefore, of the 39 early treatment trials, authors have included data from only one, which contains only 1 death in each of the treatment and control groups. If we read the actual study Skipper, we find that the death in the treatment group was a non-hospitalized patient, suggesting that the death was not caused by COVID-19, or at a minimum the patient did not receive standard care and the comparison here is therefore not valid.
SARS-CoV-2 infection and replication involves a complex interplay of 50+ host and viral proteins and other factors Lui, Lv, Malone, Murigneux, Niarakis, providing many therapeutic targets. Over 7,000 compounds have been predicted to reduce COVID-19 risk c19early.org, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications. Figure 25 shows an overview of the results for hydroxychloroquine in the context of multiple COVID-19 treatments, and Figure 26 shows a plot of efficacy vs. cost for COVID-19 treatments.
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Figure 25. Scatter plot showing results within the context of multiple COVID-19 treatments. Diamonds shows the results of random effects meta-analysis. 0.6% of 7,000+ proposed treatments show efficacy c19early.org (B).
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Figure 26. Efficacy vs. cost for COVID-19 treatments.
Direct clinical measurement shows that HCQ reaches therapeutic concentrations in COVID-19 patients Ruiz, and analysis of lung cells from COVID-19 patients shows inhibition in early target cell types Chaudhary.
Analysis of 422 controlled clinical studies shows that HCQ reduces risk for COVID-19. Treatment is more effective when used early. Meta analysis using the most serious outcome reported shows 66% [54‑74%] lower risk for the 39 early treatment studies. Results are similar for higher quality studies and peer-reviewed studies. Restricting to the 11 early treatment RCTs shows 34% [-1‑56%] lower risk, the 17 mortality results shows 76% [61‑85%] lower mortality, and the 16 hospitalization results show 41% [28‑51%] lower risk. Very late stage treatment is not effective and may be harmful, especially when using excessive dosages.
Most HCQ studies are inconsistent with the logical use of antivirals, with the majority of studies using late treatment. This makes it easy to generate meta analyses showing poor efficacy by including large late treatment studies Axfors, although the results are not relevant for recommended usage.
HCQ was the first treatment confirmed effective c19early.org (B), however alternatives may offer advantages. Lung pharmacokinetics show high inter-individual variability Ruiz; dosage is relatively challenging, with cholesterol dependence Yuan, delayed attainment of therapeutic concentrations, and a relatively narrow range of regimens showing efficacy while limiting side effects; and ~2.5% Million of patients may have contraindications. Longer-term use of endosomal acidification modifiers for prophylaxis raises concern for potential off-target effects, including disruption of cellular processes, impaired lysosomal function, reduced immune response Kowatsch, and altered cellular signaling. Fake tablets are common in some locations Tchounga. Usage of oral tables may be less relevant for the now typical lower severity cases, when infection does not spread far. Direct nasopharyngeal/oropharyngeal administration may be more appropriate, as it is whenever infection can be stopped at the source in the upper respiratory tract before further progression.
This paper is data driven, all graphs and numbers are dynamically generated. Please submit updates and corrections at the bottom of this page.Please submit updates and corrections at https://c19hcq.org/meta.html.
3/27: Updated discussion of pooled outcomes.
3/12: We updated the discussion of pre-exposure prophylaxis studies.
2/23: We added Piñana.
2/13: We added Liu (B).
1/25: We added Chouhdari.
1/24: We added Fincham and updated the introduction.
1/3/2024: We added Salesi.
12/14: We added Huang (D).
11/27: We added Rabe.
10/9: We added Souza-Silva.
9/28: We added Meeus (B).
9/28: We added Burhan.
9/23: We updated Sobngwi to the journal version.
8/29: We added Shamsi.
8/22: We added details of RCTs where the results have not been reported.
8/16: We added Afşin.
8/10: We added Klebanov.
7/24: We updated the conclusions.
6/30: We added Finkelstein.
6/24: We added McCullough.
6/20: We added Cárdenas-Jaén.
6/20: We added de Gonzalo-Calvo.
6/18: We added a forest plot for RCT case results.
6/9: We added Dulcey.
5/23: We added Said.
5/16: We added Yilgwan.
5/14: We added AlQadheeb.
4/27: We added Sen.
4/8: We added Chevalier, Ho.
4/5: We added Aweimer.
3/2: We added Spivak.
3/1: We added Llanos-Cuentas, Mathew.
2/21: We added Delgado.
2/17: We added Alshamrani.
2/1: We added Nasri.
1/25: We corrected Polo which had a duplicate entry.
1/9/2023: We added Dhibar.
12/31: We added Higgins, Shukla.
12/22: We added Alosaimi.
12/20: We updated the discussion of heterogeneity and RCTs.
12/8: We added Shahrin.
11/28: We added Assad.
11/18: We added Bubenek-Turconi.
11/17: We added Sukumar.
11/11: We added Fernández-Cruz.
10/26: We added Isnardi.
10/16: We added Gómez.
9/28: We added Obrișcă.
9/27: We added Go.
9/22: We added Núñez-Gil.
9/19: We added Babayigit.
9/15: We added Pablos.
9/14: We added Santos.
9/13: We added Sahebari.
9/8: We added Osawa.
9/7: We added Oku.
8/29: We added Lyashchenko, Yadav (B).
8/20: We corrected an error where Self was listed twice.
8/18: We added Loucera.
8/14: We added Becetti.
8/10: We added Strangfeld.
8/6: We added Polo.
7/16: We added Malundo, Patel.
7/4: We added Raabe.
6/5: We added Tu.
6/1: We added Satti.
5/21: We added Shaw.
5/21: We added Silva.
5/11: We added Niwas.
5/9: We added Uyaroğlu.
5/6: We added Hong.
5/3: We updated Kadnur to the journal version.
5/2: We added MacFadden.
4/17: We added a section on preclinical research.
4/16: We added Roy-García.
4/13: We added Rosenthal.
4/9: We added Hafez.
3/31: We added Avezum.
3/26: We added Salehi.
3/26: We added Oztas.
3/26: We added Schmidt.
3/25: We added AlQahtani.
3/23: We added Opdam.
3/21: We added Arabi.
3/19: We added Ebongue.
3/10: We added Azaña Gómez.
3/8: We added Cortez.
3/6: We added Khoubnasabjafari.
3/5: We added Tsanovska.
3/4: We added Soto (B).
3/3: We added Lavilla Olleros.
3/3: We updated Beltran Gonzalez to the journal version.
3/1: We added Alwafi.
2/26: We added Rouamba.
2/22: We updated Ader with the new results released 2/21/2022.
2/23: We added Omma.
2/22: We added Tamura (B).
2/21: We added Cordtz, Ugarte-Gil.
2/20: We added Mahale.
2/16: We added Mahto.
2/14: We added Beaumont.
2/7: We added Karruli.
2/6: We added Belmont.
2/5: We added Erden.
2/4: We added Albanghali.
1/30: We added Haji Aghajani.
1/24: We added Corradini.
1/21: We added AbdelGhaffar.
1/14: We added Juneja.
1/13: We added Atipornwanich. We added identification for combined treatment, comparison with other treatments, and use of CQ in Figure 1.
1/10/2022: We updated Syed to the journal version.
12/23: We added McKinnon.
12/14: We noted that the majority of the PrEP studies reporting negative effects are studies where all or most patients were autoimmune disorder patients Crawford.
12/12: We added Rao.
12/11: We added Calderón.
12/5: We added Ferreira.
12/4: We added Ahmed.
12/4: We updated Grau-Pujol to the journal version.
11/18: We added Samajdar.
11/7: We added Chechter.
11/3: We added Guglielmetti (B), Sarhan.
10/19: We added a summary plot for all results.
10/12: We added Menardi.
10/10: We added Luo (B).
10/4: We added Fung.
10/4: We added Babalola.
9/29: We corrected a display error causing some points to be missing in Figure 3.
9/27: We added Uygen, and updated Million (B) to the journal version.
9/19: We added Alotaibi, Çivriz Bozdağ.
9/17: We added Çiyiltepe.
9/15: We added Agarwal.
9/14: We added Sawanpanyalert.
9/14: We added Mulhem.
9/12: We added Küçükakkaş.
9/9: We added Alhamlan.
9/7: Discussion updates.
8/28: We added Patil.
8/27: We added Rodrigues.
8/25: We added Naggie.
8/21: We added Gadhiya.
8/20: We corrected the event counts in Berenguer.
8/17: We added De Luna.
8/16: We added Turrini.
8/12: We added Shabani.
8/10: We added Rogado.
8/8: We added Di Castelnuovo.
8/7: We added Datta, Kadnur.
8/6: We added Yadav (C).
8/5: We added Bhatt.
8/4: We added Alghamdi.
8/3: We added Barra.
7/30: We updated Bosaeed to the journal version, and added Sobngwi.
7/19: We added analysis restricted to hospitalization results.
7/15: We added Jacobs.
7/14: We added Roger.
7/13: We added Barrat-Due.
7/11: We added Krishnan.
7/8: We updated Cadegiani to the journal version.
7/2: We added Taieb.
6/22: We added Schwartz.
6/21: We added Ramírez-García.
6/16: We added Saib.
6/12: We added Sivapalan.
6/8: We added Burdick, Singh (C).
6/7: We added Badyal.
6/6: We added Lagier.
6/4: We added Byakika-Kibwika, Korkmaz.
6/2: We added Kamstrup, Smith.
5/28: We added Million (B).
5/17: We added Syed.
5/16: We added Rojas-Serrano. We corrected the group sizes for Skipper, and we excluded hospitalizations that were reported as not being related to COVID-19.
5/15: We added Sammartino.
5/14: We added more discussion of heterogeneity.
5/12: We added De Rosa.
5/10: We added additional information in the abstract.
5/8: We added Réa-Neto.
5/7: We added Kokturk.
5/3: We added an explanation of how some meta analyses produce negative results.
5/4: We added Aghajani.
5/1: We added Bosaeed.
4/29: We added Mohandas.
4/23: We added Reis.
4/20: We added Alegiani, Alzahrani.
4/14: We added Seet.
4/9: We updated Dubee to the journal version.
4/6: We added Mokhtari.
4/4: We updated Mitjà for 11 control hospitalizations. There is conflicting data, table S2 lists 12 control hospitalizations, while table 2 shows 11. A previous version of this paper also showed some values corresponding to 12 control hospitalizations in the abstract and table 2.
4/2: We added Salvarani.
4/1: We added Alghamdi (B).
3/29: We added Barry.
3/28: We added Stewart.
3/27: We added Hraiech, and we corrected an error in effect extraction for Self.
3/24: We added Dev.
3/13: We added Roy.
3/9: We added Vivanco-Hidalgo.
3/8: We added Martin-Vicente.
3/7: We added Salvador.
3/5: We added Lotfy.
3/3: We added Pasquini.
3/2: We added Pham.
2/28: We added Rodriguez.
2/26: We added Amaravadi.
2/23: We added Beltran Gonzalez.
2/25: We added Bae.
2/20: We added Lamback.
2/18: We added Awad.
2/17: We added Purwati (B).
2/16: We added Albani.
2/15: We added Lora-Tamayo.
2/10: We added Roig, Ubaldo.
2/9: We added Ouedraogo.
2/7: We added Johnston.
2/6: We added Fitzgerald.
2/5: We added Hernandez-Cardenas.
2/2: We added Bernabeu-Wittel.
2/1: We added Trefond.
1/24: We added Desbois, Psevdos. We moved the analysis with exclusions and mortality analysis to the main text.
1/21: We added Li (B).
1/16: We added the effect measured for each study in the forest plots.
1/15: We updated Ip to the published version.
1/12: We added Li (C).
1/11: We added Rangel.
1/9: We added Texeira, Yegerov.
1/7: We added direct links to the study details in the chronological plots.
1/6: We added direct links to the study details in the forest plots.
1/5: We added Sarfaraz.
1/4: We added Vernaz.
1/3: We added dosage information for early treatment studies.
1/2: We added the number of patients to the forest plots.
1/1/2021: We added Sands.
12/31: We added additional details about the studies in the appendix.
12/29: We added Güner, Salazar.
12/28: We added Auld, Cordtz (B).
12/27: We added the total number of authors and patients.
12/25: We added Chari.
12/24: We added Su.
12/23: We added Cangiano.
12/22: We added Taccone.
12/21: We added Matangila.
12/20: We added Gönenli, Huh.
12/17: We added Signes-Costa.
12/16: We added Alqassieh, Naseem, Orioli, Sosa-García, Tan.
12/15: We added Kalligeros, López.
12/13: We added Bielza.
12/11: We added Jung.
12/9: We added Agusti, Guglielmetti (B).
12/8: We added Barnabas.
12/7: We added Maldonado.
12/4: We added Modrák, Ozturk, Peng.
12/2: We added Rodriguez-Gonzalez.
12/1: We added Capsoni.
11/30: We added Abdulrahman.
11/28: We added Lambermont.
11/27: We added van Halem.
11/25: We added Qin, and we added analysis restricted to mortality results.
11/24: We added Boari.
11/23: We added Revollo.
11/20: We added Omrani.
11/19: We added Falcone.
11/18: We added Budhiraja.
11/14: We added Sheshah.
11/13: We added Núñez-Gil (B), Águila-Gordo.
11/12: We added Simova, Simova (B).
11/10: We added Mathai.
11/9: We added Self.
11/8: We added Dhibar (B).
11/4: We added Behera, Cadegiani.
11/1: We added Trullàs.
10/31: We added Frontera, Szente Fonseca, Tehrani.
10/30: We added Berenguer, Faíco-Filho.
10/28: We added Arleo, Choi.
10/26: We added Coll, Goenka, Synolaki.
10/23: We added Komissarov, Lano. The second version of the preprint for Komissarov includes a comparison with the control group (not reported in the first version). We updated Lyngbakken to use the mortality result in the recent journal version of the paper (not reported in the preprint).
10/22: We added Anglemyer, Ñamendys-Silva. We updated the discussion of Axfors for the second version of this study. We added a table summarizing RCT results.
10/21: We added studies Dubee, Martinez-Lopez, Solh. We received a report that the United States National Institutes of Health is recommending against HCQ for hospitalized and non-hospitalized patients as of October 9, and we added a reference.
10/20/2020: Initial revision.
The extreme politicization of HCQ means we must evaluate the data directly. With 422 controlled studies, 61 RCTs, and extensive supporting evidence, few people have the time and experience to analyze all or most of the evidence. Even disregarding late treatment there are still 147 studies.
One quick way to confirm efficacy is via prophylaxis RCTs. In the US HERO-HCQ RCT, authors note that combining their trial and the US COVID PREP RCT shows statistically significant efficacy: "The HERO-HCQ and COVID PREP studies are compared in Supplemental Table 3. Pooling the main results using the Mantel–Haenszel method resulted in an estimate of the common odds ratio of 0.74 (95% CI 0.55 to 1.00) with a p-value of 0.046" Naggie.
There are now 13 PrEP RCTs, showing 29% [15‑41%] lower COVID-19 cases with p = 0.00023. Non-RCT studies show a similar result, with 60 studies showing 29% [20‑36%] lower COVID-19 cases with p = 0.000000013. Forest plots are shown in Figure 27 and Figure 28.
A 2022 meta analysis of 7 RCTs by Harvard researchers confirms efficacy for prophylaxis García-Albéniz, as does a meta analysis of 20 studies on HCQ use with rheumatic disease patients Landsteiner de Sampaio Amêndola, along with our analysis of RCTs, and of all PrEP studies. All produce similar results.
Some researchers claim that reaching in vitro effective concentrations is not feasible, however direct measurement in treated patients shows that this is incorrect Chaudhary, Ruiz.
SARS-CoV-2 infection and replication involves the complex interplay of 50+ host and viral proteins and other factors Note A, Malone, Murigneux, Lv, Lui, Niarakis, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 7,000 compounds may reduce COVID-19 risk c19early.org, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications. 31 preclinical studies support the efficacy of HCQ for COVID-19 c19hcq.org, along with many additional studies because HCQ is often used as an active comparator in studies of other compounds.
HCQ was the first treatment confirmed effective c19early.org (B), however alternatives may offer advantages. Lung pharmacokinetics show high inter-individual variability Ruiz, and dosage is relatively challenging, with cholesterol dependence Yuan, delayed attainment of therapeutic concentrations, and a relatively narrow range of regimens showing efficacy while limiting side effects. Longer-term use of endosomal acidification modifiers for prophylaxis raises concern for potential off-target effects. Fake tablets are common in some locations Tchounga.
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Figure 27. Random effects meta-analysis for RCT pre-exposure prophylaxis case results.
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Figure 28. Random effects meta-analysis for non-RCT pre-exposure prophylaxis case results.
We perform ongoing searches of PubMed, medRxiv, Europe PMC, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19hcq.org, which regularly receives submissions of studies upon publication. Search terms are hydroxychloroquine or chloroquine and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all matches reviewed for inclusion. All studies regarding the use of hydroxychloroquine for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days have preference. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms are not used, the next most serious outcome with one or more events is used. For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcomes are considered more important than viral test status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available. After most or all patients have recovered there is little or no room for an effective treatment to do better, however faster recovery is valuable. If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we compute the relative risk when possible, or convert to a relative risk according to Zhang. Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported propensity score matching and multivariable regression has preference over propensity score matching or weighting, which has preference over multivariable regression. Adjusted results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed Altman, Altman (B), and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal to 1 Sweeting. Results are expressed with RR < 1.0 favoring treatment, and using the risk of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time for the control group is used. Calculations are done in Python (3.12.3) with scipy (1.13.0), pythonmeta (1.26), numpy (1.26.4), statsmodels (0.14.2), and plotly (5.21.0).
Forest plots are computed using PythonMeta Deng with the DerSimonian and Laird random effects model (the fixed effect assumption is not plausible in this case) and inverse variance weighting. Results are presented with 95% confidence intervals. Heterogeneity among studies was assessed using the I2 statistic. Mixed-effects meta-regression results are computed with R (4.1.2) using the metafor (3.0-2) and rms (6.2-0) packages, and using the most serious sufficiently powered outcome. For all statistical tests, a p-value less than 0.05 was considered statistically significant. Grobid 0.8.0 is used to parse PDF documents.
We have classified studies as early treatment if most patients are not already at a severe stage at the time of treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time of patients contributing most to the events (for example, consider a study where most patients are treated early but late treatment patients are included, and all mortality events were observed with late treatment patients). We note that a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective McLean, Treanor.
We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical companies or political parties.
A summary of study results is below. Please submit updates and corrections at the bottom of this page.
A summary of study results is below. Please submit updates and corrections at https://c19hcq.org/meta.html.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
Abayomi, 12/4/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Nigeria, peer-reviewed, trial PACTR202004801273802 (LACCTT). Estimated 800 patient RCT with results unknown and over 2 years late.
Agusti, 12/9/2020, prospective, Spain, peer-reviewed, median age 37.0, 13 authors, average treatment delay 5.0 days, dosage 400mg bid day 1, 200mg bid days 2-5. risk of progression, 68.4% lower, RR 0.32, p = 0.21, treatment 2 of 87 (2.3%), control 4 of 55 (7.3%), NNT 20, pneumonia.
Amaravadi, 2/26/2021, Double Blind Randomized Controlled Trial, USA, preprint, 20 authors, study period 15 April, 2020 - 14 July, 2020, dosage 400mg bid days 1-14. risk of not reaching lowest symptom score at day 7 mid-recovery, 60.0% lower, RR 0.40, p = 0.13, treatment 3 of 15 (20.0%), control 6 of 12 (50.0%), NNT 3.3.
risk of not reaching lowest symptom score at day 5 mid-recovery, 50.0% lower, RR 0.50, p = 0.13, treatment 5 of 15 (33.3%), control 8 of 12 (66.7%), NNT 3.0.
relative time to first occurrence of lowest symptom score, 42.9% lower, relative time 0.57, p = 0.38, treatment median 4.0 IQR 13.0 n=15, control median 7.0 IQR 10.0 n=12.
relative time to release from quarantine, 27.3% lower, relative time 0.73, p = 0.46, treatment median 8.0 IQR 15.0 n=16, control median 11.0 IQR 14.0 n=13, primary outcome.
Ashraf, 4/24/2020, retrospective, database analysis, Iran, preprint, median age 58.0, 16 authors, dosage 200mg bid daily, 400mg qd was used when combined with Lopinavir-Ritonavir. risk of death, 67.5% lower, RR 0.32, p = 0.15, treatment 10 of 77 (13.0%), control 2 of 5 (40.0%), NNT 3.7.
Aston, 12/31/2021, Randomized Controlled Trial, trial NCT04334382 (history) (HyAzOUT). Estimated 1,550 patient RCT with results unknown and over 2 years late.
Atipornwanich, 10/5/2021, Randomized Controlled Trial, Thailand, peer-reviewed, 16 authors, early treatment subset, study period 19 October, 2020 - 20 July, 2021, dosage 400mg days 1-14, 800mg/day or 400mg/day, this trial compares with another treatment - results may be better when compared to placebo, this trial uses multiple treatments in the treatment arm (combined with oseltamivir/favipiravir and duranivir/ritonavir for moderate/severe, oseltamivir and duranivir/ritonavir for mild) - results of individual treatments may vary, trial NCT04303299 (history). risk of progression, 150.0% higher, RR 2.50, p = 1.00, treatment 1 of 60 (1.7%), control 0 of 30 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), mild, early treatment result.
time to viral-, 43.3% lower, relative time 0.57, p = 0.04, treatment mean 8.9 (±6.0) n=30, control mean 15.7 (±16.7) n=30, mild, HCQ 800, primary outcome, early treatment result.
time to viral-, 36.3% lower, relative time 0.64, p = 0.09, treatment mean 10.0 (±6.9) n=30, control mean 15.7 (±16.7) n=30, mild, HCQ 400, primary outcome, early treatment result.
Avezum, 3/31/2022, Double Blind Randomized Controlled Trial, Brazil, peer-reviewed, 40 authors, study period 12 May, 2020 - 7 July, 2021, average treatment delay 4.0 days, dosage 400mg bid day 1, 200mg bid days 2-7, trial NCT04466540 (history). risk of death, 0.7% lower, RR 0.99, p = 1.00, treatment 5 of 687 (0.7%), control 5 of 682 (0.7%), NNT 18741, all-cause death.
risk of death, 56.0% higher, HR 1.56, p = 0.54, treatment 5 of 687 (0.7%), control 5 of 682 (0.7%), adjusted per study, univariate Firth's penalized likelihood.
risk of mechanical ventilation, 32.4% higher, RR 1.32, p = 0.79, treatment 8 of 687 (1.2%), control 6 of 682 (0.9%).
risk of ICU admission, 16.4% lower, RR 0.84, p = 0.61, treatment 16 of 687 (2.3%), control 19 of 682 (2.8%), NNT 219.
risk of hospitalization, 23.5% lower, RR 0.77, p = 0.18, treatment 44 of 689 (6.4%), control 57 of 683 (8.3%), NNT 51.
risk of hospitalization, 40.0% lower, RR 0.60, p = 0.15, treatment 267, control 265, <4 days.
Azhar, 3/18/2024, Randomized Controlled Trial, Pakistan, peer-reviewed, 22 authors, dosage 200mg tid days 1-5, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04338698 (history) (PROTECT). risk of death, 71.3% lower, RR 0.29, p = 0.03, treatment 4 of 248 (1.6%), control 10 of 178 (5.6%), NNT 25, HCQ arms vs. non-HCQ arms.
risk of death, 70.8% lower, RR 0.29, p = 0.05, treatment 3 of 183 (1.6%), control 10 of 178 (5.6%), NNT 25, HCQ + OS/AZ/OS+AZ vs. OS/AZ/OS+AZ.
risk of no improvement by 2 points, 4.3% lower, RR 0.96, p = 0.64, treatment 157 of 274 (57.3%), control 118 of 197 (59.9%), NNT 38, HCQ arms vs. non-HCQ arms.
risk of no viral clearance, 10.5% lower, RR 0.90, p = 0.52, treatment 66 of 274 (24.1%), control 53 of 197 (26.9%), NNT 36, HCQ arms vs. non-HCQ arms.
Bernabeu-Wittel, 8/1/2020, retrospective, Spain, peer-reviewed, 13 authors, dosage 400mg bid day 1, 200mg bid days 2-7, this trial uses multiple treatments in the treatment arm (combined with lopinavir/ritonavir, AZ, and/or antimicrobial treatments for some patients) - results of individual treatments may vary. risk of death, 93.7% lower, RR 0.06, p = 0.001, treatment 24 of 139 (17.3%), control 37 of 83 (44.6%), NNT 3.7, adjusted per study, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, active standard care.
Butler, 6/22/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial ISRCTN86534580 (PRINCIPLE). Estimated 400 patient RCT with results unknown and over 3 years late.
Cadegiani, 11/4/2020, prospective, Brazil, peer-reviewed, 4 authors, average treatment delay 2.9 days, dosage 400mg days 1-5. risk of death, 81.2% lower, RR 0.19, p = 0.21, treatment 0 of 159 (0.0%), control 2 of 137 (1.5%), NNT 68, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), control group 1.
risk of mechanical ventilation, 95.1% lower, RR 0.05, p < 0.001, treatment 0 of 159 (0.0%), control 9 of 137 (6.6%), NNT 15, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), control group 1.
risk of hospitalization, 98.3% lower, RR 0.02, p < 0.001, treatment 0 of 159 (0.0%), control 27 of 137 (19.7%), NNT 5.1, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), control group 1.
Chechter, 11/5/2021, prospective, Brazil, peer-reviewed, mean age 37.6, 14 authors, dosage 800mg day 1, 400mg days 2-5, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary, excluded in exclusion analyses: unadjusted results with no group details. risk of hospitalization, 94.7% lower, RR 0.05, p = 0.004, treatment 0 of 60 (0.0%), control 3 of 12 (25.0%), NNT 4.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Corradini, 4/24/2021, retrospective, Italy, peer-reviewed, 60 authors, early treatment subset, dosage not specified. risk of death, 67.4% lower, OR 0.33, p = 0.01, treatment 641, control 102, adjusted per study, Table S6, light condition patients, multivariable, RR approximated with OR, early treatment result.
Derwand (B), 7/3/2020, retrospective, USA, peer-reviewed, 3 authors, average treatment delay 4.0 days, dosage 200mg bid days 1-5, this trial uses multiple treatments in the treatment arm (combined with AZ and zinc) - results of individual treatments may vary. risk of death, 79.4% lower, RR 0.21, p = 0.12, treatment 1 of 141 (0.7%), control 13 of 377 (3.4%), NNT 37, odds ratio converted to relative risk.
risk of hospitalization, 81.6% lower, RR 0.18, p < 0.001, treatment 4 of 141 (2.8%), control 58 of 377 (15.4%), NNT 8.0, odds ratio converted to relative risk.
Esper, 4/15/2020, prospective, Brazil, preprint, 15 authors, average treatment delay 5.2 days, dosage 800mg day 1, 400mg days 2-7, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of hospitalization, 64.0% lower, RR 0.36, p = 0.02, treatment 8 of 412 (1.9%), control 12 of 224 (5.4%), NNT 29.
Gautret, 3/17/2020, prospective, France, peer-reviewed, 18 authors, average treatment delay 4.1 days, dosage 200mg tid days 1-10, excluded in exclusion analyses: excessive unadjusted differences between groups; results only for PCR status which may be significantly different to symptoms. risk of no virological cure at day 6, 66.0% lower, RR 0.34, p = 0.001, treatment 6 of 20 (30.0%), control 14 of 16 (87.5%), NNT 1.7.
Genton, 12/31/2022, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04385264 (history) (PROLIFIC). Estimated 800 patient RCT with results unknown and over 1 year late.
Guisado-Vasco, 10/15/2020, retrospective, Spain, peer-reviewed, median age 69.0, 25 authors, early treatment subset, dosage not specified. risk of death, 66.9% lower, RR 0.33, p = 0.19, treatment 2 of 65 (3.1%), control 139 of 542 (25.6%), NNT 4.4, adjusted per study, odds ratio converted to relative risk, multivariate.
Guérin, 5/31/2020, retrospective, France, peer-reviewed, 8 authors, dosage 600mg days 1-10, 7-10 days, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 61.4% lower, RR 0.39, p = 1.00, treatment 0 of 20 (0.0%), control 1 of 34 (2.9%), NNT 34, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
recovery time, 65.0% lower, relative time 0.35, p < 0.001, treatment 20, control 34.
Gül, 2/16/2021, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04981379 (history). 1,120 patient RCT with results unknown and over 3 years late.
Heras, 9/2/2020, retrospective, Andorra, peer-reviewed, median age 85.0, 13 authors, dosage not specified, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 95.6% lower, RR 0.04, p = 0.004, treatment 8 of 70 (11.4%), control 16 of 30 (53.3%), NNT 2.4, adjusted per study.
Hong, 7/16/2020, retrospective, South Korea, peer-reviewed, 7 authors, dosage not specified. risk of prolonged viral shedding, early vs. late HCQ, 64.9% lower, RR 0.35, p = 0.001, treatment 42, control 48, odds ratio converted to relative risk.
Huang (B), 5/28/2020, prospective, China, peer-reviewed, 36 authors, early treatment subset, dosage chloroquine 500mg days 1-10, two groups, 500mg qd and 500mg bid. time to viral-, 59.1% lower, relative time 0.41, p < 0.001, treatment 32, control 37.
Ip, 8/25/2020, retrospective, database analysis, USA, peer-reviewed, 25 authors, dosage not specified. risk of death, 54.5% lower, RR 0.45, p = 0.43, treatment 2 of 97 (2.1%), control 44 of 970 (4.5%), NNT 40.
risk of ICU admission, 28.6% lower, RR 0.71, p = 0.79, treatment 3 of 97 (3.1%), control 42 of 970 (4.3%), NNT 81.
risk of hospitalization, 37.3% lower, RR 0.63, p = 0.04, treatment 21 of 97 (21.6%), control 305 of 970 (31.4%), NNT 10, adjusted per study, odds ratio converted to relative risk.
Kara, 6/1/2021, Randomized Controlled Trial, Turkey, peer-reviewed, trial NCT04411433 (history). 1,008 patient RCT with results unknown and over 2 years late.
Kim, 4/30/2020, Randomized Controlled Trial, trial NCT04307693 (history). 65 patient RCT with results unknown and over 4 years late.
Kirenga, 9/9/2020, prospective, Uganda, peer-reviewed, 29 authors, dosage not specified. median time to recovery, 25.6% lower, relative time 0.74, p = 0.20, treatment 29, control 27.
Ly, 8/21/2020, retrospective, France, peer-reviewed, mean age 83.0, 21 authors, dosage 200mg tid days 1-10, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 55.6% lower, RR 0.44, p = 0.02, treatment 18 of 116 (15.5%), control 29 of 110 (26.4%), NNT 9.2, adjusted per study, odds ratio converted to relative risk.
Million (B), 5/27/2021, retrospective, France, peer-reviewed, 39 authors, average treatment delay 4.0 days, dosage 200mg tid days 1-10, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 83.0% lower, HR 0.17, p < 0.001, treatment 5 of 8,315 (0.1%), control 11 of 2,114 (0.5%), NNT 217, adjusted per study.
risk of ICU admission, 44.0% lower, HR 0.56, p = 0.18, treatment 17 of 8,315 (0.2%), control 7 of 2,114 (0.3%), NNT 789, adjusted per study.
risk of hospitalization, 4.0% lower, HR 0.96, p = 0.77, treatment 214 of 8,315 (2.6%), control 64 of 2,114 (3.0%), adjusted per study.
Mitjà, 7/16/2020, Randomized Controlled Trial, Spain, peer-reviewed, 46 authors, study period 17 March, 2020 - 26 May, 2020, dosage 800mg day 1, 400mg days 2-7. risk of hospitalization, 16.0% lower, RR 0.84, p = 0.64, treatment 8 of 136 (5.9%), control 11 of 157 (7.0%), NNT 89.
risk of no recovery, 34.0% lower, RR 0.66, p = 0.38, treatment 8 of 136 (5.9%), control 14 of 157 (8.9%), NNT 33.
Mokhtari, 4/6/2021, retrospective, Iran, peer-reviewed, 12 authors, dosage 400mg bid day 1, 200mg bid days 2-5. risk of death, 69.7% lower, RR 0.30, p < 0.001, treatment 27 of 7,295 (0.4%), control 287 of 21,464 (1.3%), NNT 103, adjusted per study, odds ratio converted to relative risk.
risk of hospitalization, 35.3% lower, RR 0.65, p < 0.001, treatment 523 of 7,295 (7.2%), control 2,382 of 21,464 (11.1%), NNT 25, adjusted per study, odds ratio converted to relative risk.
Okasha, 12/31/2020, Double Blind Randomized Controlled Trial, trial NCT04361318 (history). Estimated 100 patient RCT with results unknown and over 3 years late.
Omrani, 11/20/2020, Double Blind Randomized Controlled Trial, placebo-controlled, Qatar, peer-reviewed, 19 authors, study period 13 April, 2020 - 1 August, 2020, dosage 600mg days 1-6, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary, Q-PROTECT trial. risk of hospitalization, 12.5% lower, RR 0.88, p = 1.00, treatment 7 of 304 (2.3%), control 4 of 152 (2.6%), NNT 304, HCQ+AZ or HCQ vs. control.
risk of symptomatic at day 21, 25.8% lower, RR 0.74, p = 0.58, treatment 9 of 293 (3.1%), control 6 of 145 (4.1%), NNT 94, HCQ+AZ or HCQ vs. control.
risk of Ct<=40 at day 14, 10.3% higher, RR 1.10, p = 0.13, treatment 223 of 295 (75.6%), control 98 of 143 (68.5%), HCQ+AZ or HCQ vs. control.
Pineda, 12/31/2021, Double Blind Randomized Controlled Trial, trial NCT04954040 (history) (AMBUCOV). Estimated 132 patient RCT with results unknown and over 2 years late.
Rathod, 6/1/2023, retrospective, India, peer-reviewed, 6 authors, study period 28 March, 2020 - 3 June, 2020, average treatment delay 5.0 days, dosage not specified, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 73.0% lower, HR 0.27, p = 0.02, treatment 513, control 52, Cox proportional hazards.
Rodrigues, 8/25/2021, Double Blind Randomized Controlled Trial, Brazil, peer-reviewed, 8 authors, study period 12 April, 2020 - 13 May, 2020, average treatment delay 3.8 days, dosage 400mg bid days 1-7, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of hospitalization, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 42 (2.4%), control 0 of 42 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of no viral clearance, 14.4% lower, RR 0.86, p = 0.15, treatment 29 of 36 (80.6%), control 32 of 34 (94.1%), NNT 7.4, PP, day 3.
risk of no viral clearance, 13.1% lower, RR 0.87, p = 0.45, treatment 23 of 36 (63.9%), control 25 of 34 (73.5%), NNT 10, PP, day 6.
risk of no viral clearance, 23.3% lower, RR 0.77, p = 0.47, treatment 13 of 36 (36.1%), control 16 of 34 (47.1%), NNT 9.1, PP, day 9.
risk of no viral clearance, 3.1% lower, RR 0.97, p = 1.00, treatment 31 of 42 (73.8%), control 32 of 42 (76.2%), NNT 42, ITT, day 3.
risk of no viral clearance, no change, RR 1.00, p = 1.00, treatment 25 of 42 (59.5%), control 25 of 42 (59.5%), ITT, day 6.
risk of no viral clearance, 6.2% lower, RR 0.94, p = 1.00, treatment 15 of 42 (35.7%), control 16 of 42 (38.1%), NNT 42, ITT, day 9.
time to viral-, 8.8% lower, relative time 0.91, p = 0.26, treatment 36, control 34, PP.
time to viral-, 1.4% lower, relative time 0.99, p = 0.85, treatment 42, control 42, ITT.
Rouamba, 2/26/2022, retrospective, Burkina Faso, peer-reviewed, mean age 42.2, 17 authors, early treatment subset, study period 9 March, 2020 - 31 October, 2020, dosage 200mg tid days 1-10, HCQ 200mg tid daily or CQ 250mg bid daily, trial NCT04445441 (history). risk of progression, 73.0% lower, HR 0.27, p = 0.05, treatment 23 of 399 (5.8%), control 4 of 33 (12.1%), adjusted per study, outpatients, multivariable, Cox proportional hazards, early treatment result.
time to viral clearance, 21.3% lower, HR 0.79, p = 0.37, treatment 399, control 33, adjusted per study, inverted to make HR<1 favor treatment, outpatients, multivariable, Cox proportional hazards, primary outcome, early treatment result.
Roy, 3/12/2021, retrospective, database analysis, India, preprint, 5 authors, dosage not specified, excluded in exclusion analyses: no serious outcomes reported and fast recovery in treatment and control groups, there is little room for a treatment to improve results. relative time to clinical response of wellbeing, 2.4% lower, relative time 0.98, p = 0.96, treatment 14, control 15, primary outcome.
Roy-García, 4/16/2022, Double Blind Randomized Controlled Trial, Mexico, preprint, 11 authors, study period January 2021 - June 2021, average treatment delay 5.0 days, dosage 200mg bid days 1-10, trial NCT04964583 (history). risk of progression, 100% higher, RR 2.00, p = 1.00, treatment 2 of 31 (6.5%), control 1 of 31 (3.2%), supplemental oxygen.
risk of progression, 233.3% higher, RR 3.33, p = 0.06, treatment 10 of 31 (32.3%), control 3 of 31 (9.7%), pneumonia.
risk of progression, 225.0% higher, RR 3.25, p = 0.02, treatment 13 of 31 (41.9%), control 4 of 31 (12.9%), oxygen saturation less than 90%, dyspnea, or pneumonia.
Sarwar, 8/30/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04351191 (history) (PRECISE). 137 patient RCT with results unknown and over 3 years late.
Sawanpanyalert, 9/9/2021, retrospective, Thailand, peer-reviewed, 11 authors, dosage varies, this trial uses multiple treatments in the treatment arm (combined with lopinavir/ritonavir or darunavir/ritonavir) - results of individual treatments may vary. risk of death, ICU, intubation, or high-flow oxygen, 42.0% lower, OR 0.58, p = 0.37, within 4 days of symptom onset, RR approximated with OR.
Simova, 11/12/2020, retrospective, Bulgaria, peer-reviewed, 5 authors, dosage 200mg tid days 1-14, this trial uses multiple treatments in the treatment arm (combined with AZ and zinc) - results of individual treatments may vary. risk of hospitalization, 93.8% lower, RR 0.06, p = 0.01, treatment 0 of 33 (0.0%), control 2 of 5 (40.0%), NNT 2.5, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of viral+ at day 14, 95.8% lower, RR 0.04, p = 0.001, treatment 0 of 33 (0.0%), control 3 of 5 (60.0%), NNT 1.7, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Skipper, 7/16/2020, Randomized Controlled Trial, USA, peer-reviewed, 24 authors, study period 17 March, 2020 - 20 May, 2020, dosage 800mg once, followed by 600mg in 6 to 8 hours, then 600mg daily for 4 more days, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04308668 (history). risk of death/hospitalization, 36.7% lower, RR 0.63, p = 0.58, treatment 5 of 231 (2.2%), control 8 of 234 (3.4%), NNT 80, COVID-19 adjudicated hospitalization/death.
risk of hospitalization, 49.4% lower, RR 0.51, p = 0.38, treatment 4 of 231 (1.7%), control 8 of 234 (3.4%), NNT 59, COVID-19 adjudicated hospitalization.
risk of death/hospitalization, 49.4% lower, RR 0.51, p = 0.29, treatment 5 of 231 (2.2%), control 10 of 234 (4.3%), NNT 47, all hospitalization/death.
risk of hospitalization, 59.5% lower, RR 0.41, p = 0.17, treatment 4 of 231 (1.7%), control 10 of 234 (4.3%), NNT 39, all hospitalizations.
risk of no recovery at day 14, 20.0% lower, RR 0.80, p = 0.21, treatment 231, control 234.
Smith (B), 7/8/2020, Double Blind Randomized Controlled Trial, placebo-controlled, USA, preprint, 1 author, average treatment delay 5.0 days, dosage 400mg bid day 1, 200mg bid days 2-7, trial NCT04358068 (history). risk of hospitalization, 64.0% lower, RR 0.36, p = 1.00, treatment 0 of 7 (0.0%), control 1 of 9 (11.1%), NNT 9.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Sobngwi, 7/29/2021, Randomized Controlled Trial, Cameroon, peer-reviewed, mean age 39.0, 16 authors, study period 16 March, 2021 - 9 April, 2021, dosage 400mg days 1-5, this trial compares with another treatment - results may be better when compared to placebo. risk of no recovery, 51.6% lower, RR 0.48, p = 0.44, treatment 2 of 95 (2.1%), control 4 of 92 (4.3%), NNT 45, day 10.
risk of no recovery, 3.2% lower, RR 0.97, p = 1.00, treatment 18 of 95 (18.9%), control 18 of 92 (19.6%), NNT 162, day 3.
risk of no viral clearance, 3.2% lower, RR 0.97, p = 0.88, treatment 32 of 95 (33.7%), control 32 of 92 (34.8%), NNT 91, day 10.
Sow, 9/30/2020, Double Blind Randomized Controlled Trial, placebo-controlled, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04501965 (history) (PHYTCOVID-19). 231 patient RCT with results unknown and over 3 years late.
Su, 12/23/2020, retrospective, China, peer-reviewed, 9 authors, study period 20 January, 2020 - 30 April, 2020, dosage 400mg days 1-10, 400mg daily for 10-14 days. risk of progression, 84.9% lower, HR 0.15, p = 0.006, adjusted per study, binary logistic regression.
improvement time, 24.0% better, relative time 0.76, p = 0.02, adjusted per study, inverted to make RR<1 favor treatment, Cox proportional hazards.
risk of no viral clearance, 35.8% lower, HR 0.64, p = 0.001, inverted to make HR<1 favor treatment, Cox proportional hazards.
Sulaiman, 9/13/2020, prospective, Saudi Arabia, preprint, 22 authors, dosage 400mg bid day 1, 200mg bid days 2-5. risk of death, 63.7% lower, RR 0.36, p = 0.01, treatment 7 of 1,817 (0.4%), control 54 of 3,724 (1.5%), NNT 94, adjusted per study, odds ratio converted to relative risk.
risk of death/ICU, 44.4% lower, RR 0.56, p = 0.02, treatment 21 of 1,817 (1.2%), control 95 of 3,724 (2.6%), adjusted per study, odds ratio converted to relative risk.
risk of ICU admission, 36.7% lower, RR 0.63, p = 0.13, treatment 14 of 1,817 (0.8%), control 56 of 3,724 (1.5%), adjusted per study, odds ratio converted to relative risk.
risk of hospitalization, 38.6% lower, RR 0.61, p < 0.001, treatment 171 of 1,817 (9.4%), control 617 of 3,724 (16.6%), NNT 14, adjusted per study, odds ratio converted to relative risk.
Szente Fonseca, 10/31/2020, retrospective, Brazil, peer-reviewed, mean age 50.6, 10 authors, average treatment delay 4.6 days, dosage 400mg bid day 1, 400mg qd days 2-5. risk of hospitalization, 64.0% lower, RR 0.36, p < 0.001, treatment 25 of 175 (14.3%), control 89 of 542 (16.4%), adjusted per study, odds ratio converted to relative risk, HCQ vs. nothing, primary outcome.
risk of hospitalization, 50.5% lower, RR 0.49, p = 0.006, treatment 25 of 175 (14.3%), control 89 of 542 (16.4%), adjusted per study, odds ratio converted to relative risk, HCQ vs. anything else.
Yu, 8/3/2020, retrospective, China, peer-reviewed, median age 62.0, 6 authors, early treatment subset, average treatment delay 5.0 days, dosage 200mg bid days 1-10. risk of death, 85.0% lower, RR 0.15, p = 0.02, treatment 1 of 73 (1.4%), control 238 of 2,604 (9.1%), NNT 13, HCQ treatment started early vs. non-HCQ.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
AbdelGhaffar, 1/11/2022, retrospective, Egypt, peer-reviewed, 17 authors, study period April 2020 - July 2020. risk of death, 99.9% lower, RR 0.001, p < 0.001, treatment 0 of 238 (0.0%), control 900 of 3,474 (25.9%), NNT 3.9, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Abdulrahman, 11/30/2020, retrospective, propensity score matching, Bahrain, preprint, 9 authors. risk of death, 16.7% lower, RR 0.83, p = 1.00, treatment 5 of 223 (2.2%), control 6 of 223 (2.7%), NNT 223, PSM.
risk of death/intubation, 75.0% higher, RR 1.75, p = 0.24, treatment 12 of 223 (5.4%), control 7 of 223 (3.1%), adjusted per study, PSM.
Aboulenain, 11/30/2020, retrospective, USA, peer-reviewed, 13 authors, study period March 2020 - May 2020, excluded in exclusion analyses: substantial unadjusted confounding by indication possible. risk of death, 15.0% higher, HR 1.15, p = 0.72, treatment 82, control 93, Cox proportional hazards.
Ader, 10/6/2020, Randomized Controlled Trial, multiple countries, preprint, baseline oxygen required 95.4%, 59 authors, study period 22 March, 2020 - 29 June, 2020, average treatment delay 9.0 days, excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline. risk of death, 15.3% higher, RR 1.15, p = 0.70, treatment 11 of 150 (7.3%), control 13 of 149 (8.7%), adjusted per study, odds ratio converted to relative risk, day 90.
risk of death, 10.1% lower, RR 0.90, p = 0.75, treatment 15 of 150 (10.0%), control 13 of 149 (8.7%), adjusted per study, odds ratio converted to relative risk, day 28.
risk of no viral clearance, 23.8% lower, RR 0.76, p = 0.68, treatment 4 of 83 (4.8%), control 5 of 81 (6.2%), NNT 74, odds ratio converted to relative risk, Table S2, day 29.
Afşin, 8/1/2023, retrospective, Turkey, peer-reviewed, 2 authors, study period August 2020 - November 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 16.7% lower, RR 0.83, p = 0.50, treatment 15 of 36 (41.7%), control 22 of 44 (50.0%), NNT 12.
Aghajani, 4/29/2021, retrospective, Iran, peer-reviewed, 7 authors. risk of death, 19.5% lower, HR 0.81, p = 0.09, treatment 553, control 438, multivariate Cox proportional regression.
Alamdari, 9/9/2020, retrospective, Iran, peer-reviewed, 14 authors, average treatment delay 5.72 days, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 55.0% lower, RR 0.45, p = 0.03, treatment 54 of 427 (12.6%), control 9 of 32 (28.1%), NNT 6.5.
Albanghali, 2/3/2022, retrospective, Saudi Arabia, peer-reviewed, 8 authors, excluded in exclusion analyses: unadjusted results with no group details; substantial unadjusted confounding by indication likely. risk of death, 34.6% higher, RR 1.35, p = 0.46, treatment 20 of 466 (4.3%), control 11 of 345 (3.2%).
Albani, 8/30/2020, retrospective, Italy, peer-reviewed, 11 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 18.4% lower, RR 0.82, p = 0.15, treatment 60 of 211 (28.4%), control 172 of 605 (28.4%), adjusted per study, odds ratio converted to relative risk, HCQ vs. neither.
risk of death, 9.0% higher, RR 1.09, p = 0.54, treatment 60 of 211 (28.4%), control 172 of 605 (28.4%), adjusted per study, odds ratio converted to relative risk, HCQ+AZ vs. neither.
risk of ICU admission, 9.2% higher, RR 1.09, p = 0.70, treatment 73 of 211 (34.6%), control 46 of 605 (7.6%), adjusted per study, odds ratio converted to relative risk, HCQ vs. neither.
risk of ICU admission, 71.3% higher, RR 1.71, p < 0.001, treatment 73 of 211 (34.6%), control 46 of 605 (7.6%), adjusted per study, odds ratio converted to relative risk, HCQ+AZ vs. neither.
Alberici, 5/10/2020, retrospective, Italy, peer-reviewed, 31 authors, average treatment delay 4.0 days. risk of death, 42.9% lower, RR 0.57, p = 0.12, treatment 17 of 72 (23.6%), control 9 of 22 (40.9%), NNT 5.8, odds ratio converted to relative risk.
Alghamdi, 8/4/2021, retrospective, Saudi Arabia, peer-reviewed, 1 author, excluded in exclusion analyses: unadjusted results with no group details; very late stage, ICU patients. risk of death, 39.2% higher, RR 1.39, p = 0.52, treatment 29 of 128 (22.7%), control 7 of 43 (16.3%).
Alghamdi (B), 3/31/2021, retrospective, Saudi Arabia, peer-reviewed, 10 authors, excluded in exclusion analyses: confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline. risk of death, 6.9% higher, RR 1.07, p = 0.88, treatment 44 of 568 (7.7%), control 15 of 207 (7.2%).
Alhamlan, 7/16/2021, retrospective, database analysis, Saudi Arabia, preprint, 10 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 52.0% higher, HR 1.52, p = 0.57.
Almazrou, 10/1/2020, retrospective, Saudi Arabia, peer-reviewed, 5 authors. risk of mechanical ventilation, 65.0% lower, RR 0.35, p = 0.16, treatment 3 of 95 (3.2%), control 6 of 66 (9.1%), NNT 17.
risk of ICU admission, 21.0% lower, RR 0.79, p = 0.78, treatment 8 of 95 (8.4%), control 7 of 66 (10.6%), NNT 46.
Alosaimi, 11/24/2022, retrospective, Saudi Arabia, peer-reviewed, 13 authors, study period April 2020 - March 2021, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 400.0% higher, RR 5.00, p = 0.49, treatment 2 of 37 (5.4%), control 0 of 37 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), propensity score matching.
hospitalization time, 42.9% lower, relative time 0.57, p = 0.63, treatment 37, control 37, propensity score matching.
time to discharge, 28.6% lower, relative time 0.71, p = 0.74, treatment 37, control 37, propensity score matching.
Alotaibi, 9/14/2021, retrospective, Saudi Arabia, peer-reviewed, 11 authors, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 133.5% higher, RR 2.33, p = 0.05, treatment 193, control 244, multivariate.
AlQadheeb, 5/10/2023, retrospective, Saudi Arabia, peer-reviewed, mean age 55.8, 9 authors, study period March 2020 - August 2021. risk of death, 34.8% lower, RR 0.65, p < 0.001, treatment 37 of 92 (40.2%), control 466 of 756 (61.6%), NNT 4.7.
AlQahtani, 3/23/2022, Randomized Controlled Trial, Bahrain, peer-reviewed, 14 authors, study period August 2020 - March 2021, trial NCT04387760 (history). risk of ICU admission, 23.5% lower, RR 0.76, p = 1.00, treatment 3 of 51 (5.9%), control 4 of 52 (7.7%), NNT 55.
risk of no recovery, 4.1% lower, RR 0.96, p = 0.94, treatment 5 of 49 (10.2%), control 5 of 47 (10.6%), NNT 230.
risk of no viral clearance, 47.4% lower, RR 0.53, p = 0.13, treatment 7 of 38 (18.4%), control 14 of 40 (35.0%), NNT 6.0.
Alqassieh, 12/10/2020, prospective, Jordan, preprint, 10 authors. hospitalization time, 18.2% lower, relative time 0.82, p = 0.11, treatment 63, control 68.
Alshamrani, 2/15/2023, retrospective, Saudi Arabia, peer-reviewed, 3 authors, study period March 2020 - January 2021. risk of death, 50.0% lower, RR 0.50, p = 0.18, treatment 6 of 161 (3.7%), control 50 of 653 (7.7%), NNT 25, adjusted per study, odds ratio converted to relative risk, propensity score matching, multivariable.
risk of progression, 37.0% lower, RR 0.63, p = 0.21, treatment 16 of 161 (9.9%), control 100 of 653 (15.3%), NNT 19, adjusted per study, odds ratio converted to relative risk, AKI, ARDS, multi-organ failure, or mortality, propensity score matching, multivariable.
ICU time, 9.2% lower, relative time 0.91, p = 0.66, treatment 22, control 169, propensity score matching.
hospitalization time, 3.0% higher, relative time 1.03, p = 0.69, treatment 161, control 653, propensity score matching.
AlShehhi, 1/11/2024, retrospective, United Arab Emirates, peer-reviewed, 4 authors, study period 1 March, 2020 - 20 April, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of ICU admission, 42.8% lower, RR 0.57, p = 0.001, treatment 114 of 1,460 (7.8%), control 46 of 337 (13.6%), NNT 17.
Alwafi, 1/20/2022, retrospective, Saudi Arabia, peer-reviewed, 6 authors, study period 7 March, 2020 - 15 April, 2020, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of no viral clearance, 14.7% lower, RR 0.85, p = 0.65, treatment 12 of 45 (26.7%), control 15 of 48 (31.2%), NNT 22, day 5, primary outcome.
risk of no viral clearance, 25.3% lower, RR 0.75, p = 0.60, treatment 7 of 45 (15.6%), control 10 of 48 (20.8%), NNT 19, day 12.
An, 7/7/2020, retrospective, South Korea, preprint, 12 authors. time to viral clearance, 3.0% lower, HR 0.97, p = 0.92, treatment 31, control 195.
Annie, 10/12/2020, retrospective, database analysis, USA, peer-reviewed, 5 authors, excluded in exclusion analyses: confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline. risk of death, 4.3% lower, RR 0.96, p = 0.83, treatment 48 of 367 (13.1%), control 50 of 367 (13.6%), NNT 183, odds ratio converted to relative risk.
risk of death, 20.5% higher, RR 1.21, p = 0.46, treatment 29 of 199 (14.6%), control 24 of 199 (12.1%), odds ratio converted to relative risk.
Aparisi, 10/8/2020, prospective, Spain, preprint, 18 authors, average treatment delay 7.0 days, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 63.0% lower, RR 0.37, p = 0.008, treatment 122 of 605 (20.2%), control 27 of 49 (55.1%), NNT 2.9.
Arshad, 7/1/2020, retrospective, USA, peer-reviewed, 12 authors. risk of death, 51.3% lower, HR 0.49, p = 0.009, treatment 162 of 1,202 (13.5%), control 108 of 409 (26.4%), NNT 7.7.
Ashinyo, 9/15/2020, retrospective, Ghana, peer-reviewed, 16 authors. hospitalization time, 33.0% lower, relative time 0.67, p = 0.03, treatment 61, control 61.
Assad, 10/21/2022, retrospective, Iraq, peer-reviewed, 1 author, study period June 2020 - September 2020, excluded in exclusion analyses: unadjusted results with no group details; confounding by time possible, propensity to use HCQ changed significantly during the study period. risk of death, 59.7% lower, RR 0.40, p = 0.002, treatment 9 of 72 (12.5%), control 68 of 219 (31.1%), NNT 5.4, enoxaparin+HCQ vs. enoxaparin.
Atipornwanich, 10/5/2021, Randomized Controlled Trial, Thailand, peer-reviewed, 16 authors, study period 19 October, 2020 - 20 July, 2021, dosage 400mg days 1-14, 800mg/day or 400mg/day, this trial compares with another treatment - results may be better when compared to placebo, this trial uses multiple treatments in the treatment arm (combined with oseltamivir/favipiravir and duranivir/ritonavir for moderate/severe, oseltamivir and duranivir/ritonavir for mild) - results of individual treatments may vary, trial NCT04303299 (history). risk of death, 56.2% lower, RR 0.44, p = 0.07, treatment 7 of 100 (7.0%), control 16 of 100 (16.0%), NNT 11, moderate/severe, HCQ arms vs. non-HCQ arms.
risk of progression, 54.2% lower, RR 0.46, p = 0.02, treatment 11 of 100 (11.0%), control 24 of 100 (24.0%), NNT 7.7, moderate/severe, HCQ arms vs. non-HCQ arms.
time to viral-, 7.1% lower, relative time 0.93, p = 0.51, treatment mean 10.4 (±6.3) n=50, control mean 11.2 (±5.7) n=50, moderate/severe, oseltamivir arms, primary outcome.
time to viral-, 6.9% lower, relative time 0.93, p = 0.47, treatment mean 9.5 (±5.0) n=50, control mean 10.2 (±4.6) n=50, moderate/severe, favipiravir arms, primary outcome.
Auld, 4/26/2020, retrospective, USA, peer-reviewed, 14 authors. risk of death, 2.8% higher, RR 1.03, p = 1.00, treatment 33 of 114 (28.9%), control 29 of 103 (28.2%).
Awad, 2/18/2021, retrospective, USA, peer-reviewed, 4 authors, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely. risk of death, 19.1% higher, RR 1.19, p = 0.60, treatment 56 of 188 (29.8%), control 37 of 148 (25.0%).
risk of mechanical ventilation, 460.7% higher, RR 5.61, p < 0.001, treatment 64 of 188 (34.0%), control 9 of 148 (6.1%), adjusted per study, odds ratio converted to relative risk.
risk of ICU admission, 463.4% higher, RR 5.63, p < 0.001, treatment 67 of 188 (35.6%), control 9 of 148 (6.1%), adjusted per study, odds ratio converted to relative risk.
Aweimer, 3/29/2023, retrospective, Germany, peer-reviewed, median age 67.0, 19 authors, study period 1 March, 2020 - 31 August, 2021. risk of death, 40.2% lower, RR 0.60, p = 0.12, treatment 4 of 9 (44.4%), control 104 of 140 (74.3%), NNT 3.4.
Ayerbe, 9/30/2020, retrospective, database analysis, Spain, peer-reviewed, 3 authors. risk of death, 52.2% lower, RR 0.48, p < 0.001, treatment 237 of 1,857 (12.8%), control 49 of 162 (30.2%), NNT 5.7, adjusted per study, odds ratio converted to relative risk.
Azaña Gómez, 3/10/2022, retrospective, Spain, peer-reviewed, 10 authors, study period 1 March, 2020 - 1 October, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 35.8% lower, RR 0.64, p < 0.001, treatment 500 of 1,378 (36.3%), control 238 of 421 (56.5%), NNT 4.9.
Babalola, 10/1/2021, Single Blind Randomized Controlled Trial, Nigeria, peer-reviewed, 6 authors, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary, trial PACTR202108891693522. risk of no hospital discharge, 54.5% higher, RR 1.55, p = 0.20, treatment 17 of 30 (56.7%), control 11 of 30 (36.7%), day 7.
risk of no viral clearance, 9.5% lower, RR 0.90, p = 0.78, treatment 19 of 30 (63.3%), control 21 of 30 (70.0%), NNT 15, day 5 mid-recovery.
Babayigit, 8/31/2022, retrospective, Turkey, peer-reviewed, mean age 51.9, 68 authors, study period 11 March, 2020 - 18 July, 2020. risk of mechanical ventilation, 112.4% higher, RR 2.12, p = 0.21, treatment 63 of 1,378 (4.6%), control 6 of 94 (6.4%), adjusted per study, odds ratio converted to relative risk, multivariable.
risk of ICU admission, 52.8% higher, RR 1.53, p = 0.33, treatment 107 of 1,363 (7.9%), control 9 of 93 (9.7%), adjusted per study, odds ratio converted to relative risk, multivariable.
hospitalization time, 16.7% higher, relative time 1.17, p = 0.05, treatment 852, control 63.
Barbosa, 4/12/2020, retrospective, USA, preprint, 5 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of death, 147.0% higher, RR 2.47, p = 0.58, treatment 2 of 17 (11.8%), control 1 of 21 (4.8%).
Barra, 7/31/2021, retrospective, Argentina, preprint, 13 authors, average treatment delay 5.0 days, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 10.8% lower, RR 0.89, p = 1.00, treatment 2 of 18 (11.1%), control 81 of 650 (12.5%), NNT 74, unadjusted.
Barrat-Due, 7/13/2021, Double Blind Randomized Controlled Trial, Norway, peer-reviewed, 43 authors, study period 28 March, 2020 - 4 October, 2020, average treatment delay 8.0 days, trial NCT04321616 (history). risk of death, 120.0% higher, RR 2.20, p = 0.35, treatment 4 of 45 (8.9%), control 2 of 48 (4.2%), adjusted per study.
Barry, 3/23/2021, retrospective, Saudi Arabia, peer-reviewed, 14 authors. risk of death, 98.9% lower, RR 0.01, p = 0.60, treatment 0 of 6 (0.0%), control 91 of 599 (15.2%), NNT 6.6, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Bassets-Bosch, 4/30/2022, retrospective, Spain, peer-reviewed, 5 authors, study period 11 March, 2020 - 30 April, 2020, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. time to viral-, 29.2% lower, relative time 0.71, p = 0.45, treatment median 17.0 IQR 16.0 n=5, control median 24.0 IQR 21.0 n=5, onset to clearance.
Beaumont, 2/13/2022, retrospective, France, peer-reviewed, 22 authors, average treatment delay 6.0 days. risk of death/intubation, 14.1% lower, HR 0.86, p = 0.55, treatment 7 of 38 (18.4%), control 88 of 258 (34.1%), NNT 6.4, adjusted per study, odds ratio converted to relative risk, Cox proportional hazards.
Beltran Gonzalez, 2/23/2021, Double Blind Randomized Controlled Trial, Mexico, peer-reviewed, mean age 53.8, 13 authors, study period 4 May, 2020 - 6 November, 2020, average treatment delay 7.0 days, trial NCT04391127 (history). risk of death, 62.6% lower, RR 0.37, p = 0.27, treatment 2 of 33 (6.1%), control 6 of 37 (16.2%), NNT 9.8.
risk of respiratory deterioration or death, 25.3% lower, RR 0.75, p = 0.57, treatment 6 of 33 (18.2%), control 9 of 37 (24.3%), NNT 16.
risk of no hospital discharge, 12.1% higher, RR 1.12, p = 1.00, treatment 3 of 33 (9.1%), control 3 of 37 (8.1%).
Berenguer, 8/3/2020, retrospective, Spain, peer-reviewed, 8 authors, average treatment delay 7.0 days. risk of death, 18.2% lower, RR 0.82, p < 0.001, treatment 681 of 2,618 (26.0%), control 438 of 1,377 (31.8%), NNT 17.
Bernaola, 7/21/2020, retrospective, Spain, preprint, 7 authors. risk of death, 17.0% lower, HR 0.83, p < 0.001, treatment 236 of 1,498 (15.8%), control 28 of 147 (19.0%), NNT 30.
Bielza, 12/11/2020, retrospective, Spain, peer-reviewed, median age 87.0, 24 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 21.5% lower, RR 0.78, p = 0.09, treatment 33 of 91 (36.3%), control 249 of 539 (46.2%), NNT 10.
Boari, 11/17/2020, retrospective, Italy, peer-reviewed, 20 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 54.5% lower, RR 0.45, p < 0.001, treatment 41 of 202 (20.3%), control 25 of 56 (44.6%), NNT 4.1.
Bosaeed, 4/30/2021, Randomized Controlled Trial, Saudi Arabia, peer-reviewed, 30 authors, study period 21 May, 2020 - 26 January, 2021, average treatment delay 5.85 days, trial NCT04392973 (history) (FACCT), excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline. risk of death, 3.7% lower, RR 0.96, p = 0.91, treatment 14 of 125 (11.2%), control 15 of 129 (11.6%), NNT 234, 90 days.
risk of death, 28.6% lower, RR 0.71, p = 0.45, treatment 9 of 125 (7.2%), control 13 of 129 (10.1%), NNT 35, 28 days.
risk of death, 65.1% higher, RR 1.65, p = 0.68, treatment 8 of 125 (6.4%), control 5 of 129 (3.9%), 14 days.
risk of mechanical ventilation, 8.4% higher, RR 1.08, p = 0.78, treatment 21 of 125 (16.8%), control 20 of 129 (15.5%).
risk of ICU admission, 31.0% higher, RR 1.31, p = 0.24, treatment 33 of 125 (26.4%), control 26 of 129 (20.2%).
recovery time, 28.6% higher, relative time 1.29, p = 0.29, treatment 125, control 129.
hospitalization time, 12.5% higher, relative time 1.12, p = 0.42, treatment 125, control 129.
risk of no viral clearance, 2.6% lower, RR 0.97, p = 0.75, treatment 100 of 125 (80.0%), control 106 of 129 (82.2%), NNT 46.
Bousquet, 6/23/2020, prospective, France, peer-reviewed, 10 authors. risk of death, 42.8% lower, RR 0.57, p = 0.15, treatment 5 of 27 (18.5%), control 23 of 81 (28.4%), NNT 10, adjusted per study, odds ratio converted to relative risk.
Bowen, 8/25/2022, retrospective, USA, peer-reviewed, 10 authors, study period 1 March, 2020 - 31 March, 2021. risk of death, 20.0% lower, HR 0.80, p = 0.007, treatment 1,317, control 3,314, Table S2, Cox proportional hazards.
Bubenek-Turconi, 11/17/2022, prospective, Romania, peer-reviewed, 16 authors, study period March 2020 - March 2021. risk of death, 22.0% lower, OR 0.78, p = 0.01, RR approximated with OR.
Budhiraja, 11/18/2020, retrospective, India, preprint, 12 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of death, 65.4% lower, RR 0.35, p < 0.001, treatment 69 of 834 (8.3%), control 34 of 142 (23.9%), NNT 6.4.
Burdick, 11/26/2020, prospective, USA, peer-reviewed, 14 authors. risk of death, 59.0% higher, HR 1.59, p = 0.12, treatment 142, control 148, adjusted per study, all patients.
risk of death, 71.0% lower, HR 0.29, p = 0.01, treatment 26, control 17, adjusted per study, subgroup of patients where treatment is predicted to be beneficial.
Burhan, 9/25/2023, retrospective, Indonesia, peer-reviewed, 26 authors, study period January 2020 - March 2021. risk of death, 1.3% higher, RR 1.01, p = 0.91, treatment 84 of 123 (68.3%), control 294 of 436 (67.4%).
Byakika-Kibwika, 6/4/2021, Randomized Controlled Trial, Uganda, preprint, 17 authors, study period October 2020 - December 2020. recovery time, no change, relative time 1.00, p = 0.91, treatment 36, control 29.
relative improvement in Ct value, 29.3% better, RR 0.71, p = 0.47, treatment 15, control 15.
risk of no viral clearance, 2.6% higher, RR 1.03, p = 1.00, treatment 35 of 55 (63.6%), control 31 of 50 (62.0%), day 6.
risk of no viral clearance, 6.7% higher, RR 1.07, p = 0.85, treatment 27 of 55 (49.1%), control 23 of 50 (46.0%), day 10.
Calderón, 11/23/2021, retrospective, Mexico, peer-reviewed, 7 authors, dosage 200mg bid days 1-7. risk of death, 214.8% higher, RR 3.15, p = 0.38, treatment 5 of 27 (18.5%), control 1 of 17 (5.9%).
risk of mechanical ventilation, 651.9% higher, RR 7.52, p = 0.15, treatment 4 of 27 (14.8%), control 0 of 17 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of ICU admission, 145.5% higher, RR 2.45, p < 0.001, treatment 16 of 27 (59.3%), control 0 of 17 (0.0%), adjusted per study, inverted to make RR<1 favor treatment.
hospitalization time, 107.4% higher, relative time 2.07, p = 0.006, treatment 27, control 17.
Cangiano, 12/22/2020, retrospective, Italy, peer-reviewed, 14 authors. risk of death, 73.4% lower, RR 0.27, p = 0.03, treatment 5 of 33 (15.2%), control 37 of 65 (56.9%), NNT 2.4.
Capsoni, 12/1/2020, retrospective, Italy, preprint, 13 authors, average treatment delay 7.0 days. risk of mechanical ventilation, 40.0% lower, RR 0.60, p = 0.30, treatment 12 of 40 (30.0%), control 6 of 12 (50.0%), NNT 5.0.
Catteau, 8/24/2020, retrospective, database analysis, Belgium, peer-reviewed, 11 authors, average treatment delay 5.0 days. risk of death, 32.0% lower, HR 0.68, p < 0.001, treatment 804 of 4,542 (17.7%), control 957 of 3,533 (27.1%), NNT 11.
Cavalcanti, 7/23/2020, Randomized Controlled Trial, Brazil, peer-reviewed, baseline oxygen required 41.8%, 35 authors, study period 29 March, 2020 - 18 May, 2020, average treatment delay 7.0 days, trial NCT04322123 (history) (COALITION I). risk of death, 16.0% lower, RR 0.84, p = 0.77, treatment 8 of 331 (2.4%), control 5 of 173 (2.9%), NNT 211, HCQ+HCQ/AZ.
risk of hospitalization, 28.0% higher, RR 1.28, p = 0.30, treatment 331, control 173, HCQ+HCQ/AZ.
Chari, 12/24/2020, retrospective, multiple countries, peer-reviewed, median age 69.0, 25 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 33.1% lower, RR 0.67, p = 0.17, treatment 8 of 29 (27.6%), control 195 of 473 (41.2%), NNT 7.3.
Chen, 7/10/2020, Randomized Controlled Trial, Taiwan, peer-reviewed, 19 authors, study period 1 April, 2020 - 31 May, 2020, trial NCT04384380 (history). risk of no viral clearance, 24.0% lower, RR 0.76, p = 0.71, treatment 4 of 21 (19.0%), control 3 of 12 (25.0%), NNT 17, day 14.
median time to PCR-, 50.0% lower, relative time 0.50, p = 0.40, treatment 21, control 12.
Chen (B), 7/10/2020, retrospective, Taiwan, peer-reviewed, 19 authors. risk of no viral clearance, 29.0% higher, RR 1.29, p = 0.70, treatment 16 of 28 (57.1%), control 4 of 9 (44.4%), day 14.
Chen (C), 6/22/2020, Randomized Controlled Trial, China, preprint, 19 authors, study period 18 February, 2020 - 30 March, 2020, dosage 200mg bid days 1-10. time to clinical recovery, 20.0% lower, relative time 0.80, p = 0.51, treatment median 6.0 IQR 5.0 n=18, control median 7.5 IQR 11.25 n=12, HCQ.
time to clinical recovery, 26.7% lower, relative time 0.73, p = 0.36, treatment median 5.5 IQR 4.25 n=18, control median 7.5 IQR 11.25 n=12, CQ.
median time to PCR-, 71.4% lower, relative time 0.29, p < 0.001, treatment median 2.0 IQR 1.5 n=18, control median 7.0 IQR 7.0 n=12, HCQ.
median time to PCR-, 64.3% lower, relative time 0.36, p = 0.001, treatment median 2.5 IQR 1.8 n=18, control median 7.0 IQR 7.0 n=12, CQ.
Chen (D), 3/31/2020, Randomized Controlled Trial, China, preprint, 9 authors, study period 4 February, 2020 - 28 February, 2020. risk of no improvement in pneumonia at day 6, 57.0% lower, RR 0.43, p = 0.04, treatment 6 of 31 (19.4%), control 14 of 31 (45.2%), NNT 3.9.
Chen (E), 3/6/2020, Randomized Controlled Trial, China, peer-reviewed, 14 authors, study period 6 February, 2020 - 25 February, 2020, trial NCT04261517 (history). risk of radiological progression, 29.0% lower, RR 0.71, p = 0.57, treatment 5 of 15 (33.3%), control 7 of 15 (46.7%), NNT 7.5.
risk of viral+ at day 7, 100% higher, RR 2.00, p = 1.00, treatment 2 of 15 (13.3%), control 1 of 15 (6.7%).
Choi, 10/27/2020, retrospective, database analysis, South Korea, peer-reviewed, 8 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. median time to PCR-, 22.0% higher, relative time 1.22, p < 0.001, treatment 701, control 701.
Coll, 10/23/2020, retrospective, Spain, peer-reviewed, median age 61.0, 29 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 45.6% lower, RR 0.54, p < 0.001, treatment 55 of 307 (17.9%), control 108 of 328 (32.9%), NNT 6.7.
Corradini, 4/24/2021, retrospective, Italy, peer-reviewed, 60 authors, dosage not specified. risk of death, 70.2% lower, OR 0.30, p < 0.001, treatment 1,439, control 274, adjusted per study, Table S6, all patients, multivariable, RR approximated with OR.
risk of death, 76.8% lower, OR 0.23, p < 0.001, treatment 546, control 71, adjusted per study, Table S6, mild condition patients, multivariable, RR approximated with OR.
risk of death, 84.2% lower, OR 0.16, p < 0.001, treatment 184, control 64, adjusted per study, Table S6, moderate condition patients, multivariable, RR approximated with OR.
risk of death, 29.0% higher, OR 1.29, p = 0.73, treatment 68, control 37, adjusted per study, Table S6, severe condition patients, multivariable, RR approximated with OR.
Cortez, 11/11/2021, retrospective, Philippines, peer-reviewed, 29 authors, study period March 2020 - October 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 15.0% lower, RR 0.85, p = 1.00, treatment 1 of 25 (4.0%), control 12 of 255 (4.7%), NNT 142.
Cravedi, 7/10/2020, retrospective, USA, peer-reviewed, mean age 60.0, 25 authors, average treatment delay 6.0 days, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 53.0% higher, RR 1.53, p = 0.17, treatment 36 of 101 (35.6%), control 10 of 43 (23.3%).
Cárdenas-Jaén, 6/20/2023, retrospective, Spain, peer-reviewed, median age 57.0, 44 authors, study period May 2020 - September 2020, excluded in exclusion analyses: unadjusted for baseline differences with no group details. risk of severe case, 56.2% lower, RR 0.44, p = 0.13, treatment 3 of 42 (7.1%), control 126 of 787 (16.0%), NNT 11, odds ratio converted to relative risk.
D'Arminio Monforte, 7/29/2020, retrospective, Italy, peer-reviewed, 5 authors. risk of death, 34.0% lower, HR 0.66, p = 0.12, treatment 53 of 197 (26.9%), control 47 of 92 (51.1%), NNT 4.1, adjusted per study.
Davido, 8/2/2020, retrospective, France, peer-reviewed, 14 authors. risk of intubation/hospitalization, 55.0% lower, HR 0.45, p = 0.04, treatment 12 of 80 (15.0%), control 13 of 40 (32.5%), NNT 5.7.
de Gonzalo-Calvo, 6/17/2023, retrospective, Spain, peer-reviewed, median age 65.0, 46 authors, study period March 2020 - February 2021, trial NCT04457505 (history), excluded in exclusion analyses: unadjusted results with no group details. risk of death, 37.6% lower, RR 0.62, p = 0.23, treatment 6 of 32 (18.8%), control 138 of 459 (30.1%), NNT 8.8.
De Luna, 12/14/2020, retrospective, Dominican Republic, preprint, 10 authors, excluded in exclusion analyses: unadjusted results with no group details; substantial unadjusted confounding by indication likely. risk of death, 104.5% higher, RR 2.05, p = 0.69, treatment 15 of 132 (11.4%), control 1 of 18 (5.6%).
De Rosa, 5/1/2021, retrospective, Italy, peer-reviewed, 20 authors, average treatment delay 6.0 days. risk of death, 35.0% lower, RR 0.65, p = 0.02, treatment 118 of 731 (16.1%), control 80 of 280 (28.6%), NNT 8.0, adjusted per study, odds ratio converted to relative risk, multivariate logistic regression, patients alive at day 7.
Delgado, 2/20/2023, retrospective, USA, preprint, 7 authors, study period 1 March, 2020 - 31 December, 2020. risk of death, 26.0% lower, OR 0.74, p = 0.002, treatment 1,239, control 8,399, both periods combined, RR approximated with OR.
risk of death, 28.0% lower, OR 0.72, p = 0.001, treatment 1,157, control 2,064, early 2020, propensity score matching, RR approximated with OR.
risk of death, 10.0% higher, OR 1.10, p = 0.82, treatment 82, control 6,335, late 2020, propensity score matching, RR approximated with OR.
Di Castelnuovo, 1/29/2021, retrospective, Italy, peer-reviewed, 111 authors. risk of death, 40.0% lower, RR 0.60, p < 0.001, treatment 3,270, control 1,000, odds ratio converted to relative risk, multivariate Cox proportional hazards model 4, control prevalence approximated with overall prevalence.
Di Castelnuovo (B), 8/25/2020, retrospective, Italy, peer-reviewed, 106 authors. risk of death, 30.0% lower, HR 0.70, p < 0.001, treatment 386 of 2,634 (14.7%), control 90 of 817 (11.0%), adjusted per study.
Dubee, 10/21/2020, Randomized Controlled Trial, France, peer-reviewed, median age 77.0, 18 authors, study period 2 April, 2020 - 21 May, 2020, average treatment delay 5.0 days, trial NCT04325893 (history) (HYCOVID). risk of death at day 28, 46.0% lower, RR 0.54, p = 0.21, treatment 6 of 124 (4.8%), control 11 of 123 (8.9%), NNT 24.
risk of combined intubation/death at day 28, 26.0% lower, RR 0.74, p = 0.48, treatment 9 of 124 (7.3%), control 12 of 123 (9.8%), NNT 40.
Dubernet, 8/20/2020, retrospective, France, peer-reviewed, median age 66.0, 20 authors. risk of ICU admission, 87.6% lower, RR 0.12, p = 0.008, treatment 1 of 17 (5.9%), control 9 of 19 (47.4%), NNT 2.4.
Ebongue, 3/18/2022, retrospective, Cameroon, peer-reviewed, 27 authors, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 43.0% lower, HR 0.57, p = 0.04, treatment 93 of 522 (17.8%), control 36 of 58 (62.1%), NNT 2.3, adjusted per study, multivariable.
El-Sherbiny, 8/15/2020, Randomized Controlled Trial, trial NCT04477083 (history). Estimated 40 patient RCT with results unknown and over 3 years late.
Falcone, 11/19/2020, prospective, propensity score matching, Italy, peer-reviewed, 19 authors, average treatment delay 6.5 days. risk of death, 65.0% lower, RR 0.35, p = 0.20, treatment 40 of 238 (16.8%), control 30 of 77 (39.0%), NNT 4.5, adjusted per study, PSM.
risk of death, 25.0% lower, RR 0.75, p = 0.36, treatment 40 of 238 (16.8%), control 30 of 77 (39.0%), NNT 4.5, adjusted per study, multivariate Cox regression.
risk of death, 57.0% lower, RR 0.43, p < 0.001, treatment 40 of 238 (16.8%), control 30 of 77 (39.0%), NNT 4.5, adjusted per study, univariate Cox regression.
Farooq, 6/28/2020, Single Blind Randomized Controlled Trial, placebo-controlled, trial NCT04328272 (history). Estimated 75 patient RCT with results unknown and over 3 years late.
Faíco-Filho, 6/21/2020, prospective, Brazil, peer-reviewed, median age 58.0, 6 authors. Δt7-12 ΔCt improvement, 80.8% lower, RR 0.19, p = 0.40, treatment 34, control 32, mid-recovery, relative median Ct improvement, Figure 2.
Δt<7 ΔCt improvement, 24.0% lower, RR 0.76, p = 0.36, treatment 34, control 32, relative median Ct improvement, Figure 2.
Δt>12 ΔCt improvement, 15.0% higher, RR 1.15, p = 0.52, treatment 34, control 32, relative median Ct improvement, Figure 2.
Fernández-Cruz, 1/31/2022, retrospective, Spain, peer-reviewed, 10 authors, study period March 2020 - May 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 27.0% lower, RR 0.73, p = 0.47, treatment 23 of 63 (36.5%), control 4 of 8 (50.0%), NNT 7.4.
Ferreira, 11/26/2021, retrospective, Brazil, peer-reviewed, 5 authors, study period 12 March, 2020 - 8 July, 2020, average treatment delay 7.0 days, dosage not specified. risk of death, 151.5% higher, RR 2.51, p = 0.03, treatment 17 of 111 (15.3%), control 11 of 81 (13.6%), odds ratio converted to relative risk, multivariate.
risk of death/intubation, 45.9% higher, RR 1.46, p = 0.23, treatment 30 of 111 (27.0%), control 15 of 81 (18.5%).
risk of death/intubation/ICU, 61.3% higher, RR 1.61, p = 0.04, treatment 42 of 111 (37.8%), control 19 of 81 (23.5%).
Fontana, 6/22/2020, retrospective, Italy, peer-reviewed, 8 authors. risk of death, 50.0% lower, RR 0.50, p = 0.53, treatment 4 of 12 (33.3%), control 2 of 3 (66.7%), NNT 3.0.
Fried, 8/28/2020, retrospective, database analysis, USA, peer-reviewed, 11 authors, excluded in exclusion analyses: excessive unadjusted differences between groups; substantial unadjusted confounding by indication likely. risk of death, 27.0% higher, RR 1.27, p < 0.001, treatment 1,048 of 4,232 (24.8%), control 1,466 of 7,489 (19.6%).
Frontera, 10/26/2020, retrospective, propensity score matching, USA, preprint, median age 64.0, 14 authors, this trial uses multiple treatments in the treatment arm (combined with zinc) - results of individual treatments may vary. risk of death, 37.0% lower, HR 0.63, p = 0.01, treatment 121 of 1,006 (12.0%), control 424 of 2,467 (17.2%), NNT 19, adjusted per study, PSM.
risk of death, 24.0% lower, HR 0.76, p = 0.02, treatment 121 of 1,006 (12.0%), control 424 of 2,467 (17.2%), NNT 19, adjusted per study, regression.
Gadhiya, 4/8/2021, retrospective, USA, peer-reviewed, 4 authors, dosage not specified, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely. risk of death, 4.8% higher, RR 1.05, p = 0.89, treatment 22 of 55 (40.0%), control 33 of 216 (15.3%), adjusted per study, odds ratio converted to relative risk, multivariate logistic regression.
Geleris, 5/7/2020, retrospective, USA, peer-reviewed, 12 authors, excluded in exclusion analyses: significant issues found with adjustments. risk of death/intubation, 4.0% higher, HR 1.04, p = 0.76, treatment 262 of 811 (32.3%), control 84 of 565 (14.9%), adjusted per study.
Gerlovin, 6/24/2021, retrospective, USA, peer-reviewed, 21 authors. risk of death, 22.0% higher, HR 1.22, p = 0.18, treatment 90 of 429 (21.0%), control 141 of 770 (18.3%), adjusted per study, HCQ+AZ.
risk of death, 21.0% higher, HR 1.21, p = 0.33, treatment 49 of 228 (21.5%), control 141 of 770 (18.3%), adjusted per study, HCQ.
risk of mechanical ventilation, 55.0% higher, HR 1.55, p = 0.02, treatment 64 of 429 (14.9%), control 69 of 770 (9.0%), adjusted per study, HCQ+AZ.
risk of mechanical ventilation, 33.0% higher, HR 1.33, p = 0.25, treatment 32 of 228 (14.0%), control 69 of 770 (9.0%), adjusted per study, HCQ.
Go, 9/27/2022, retrospective, USA, peer-reviewed, 2 authors, study period March 2020 - June 2020, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 55.0% lower, HR 0.45, p = 0.03, adjusted per study, multivariable, Cox proportional hazards.
Goldman, 5/27/2020, retrospective, multiple countries, peer-reviewed, 26 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 22.3% lower, RR 0.78, p = 0.46, treatment 10 of 109 (9.2%), control 34 of 288 (11.8%), NNT 38.
Gonzalez, 8/21/2020, retrospective, database analysis, Spain, preprint, 25 authors. risk of death, 26.6% lower, RR 0.73, p = 0.06, treatment 1,246 of 8,476 (14.7%), control 341 of 1,168 (29.2%), NNT 6.9, adjusted per study, odds ratio converted to relative risk.
Guglielmetti, 10/25/2021, retrospective, Italy, peer-reviewed, 19 authors, study period 21 February, 2020 - 15 May, 2020. risk of death, 28.0% lower, HR 0.72, p = 0.10, treatment 474, control 126, multivariable Cox proportional hazards.
Guglielmetti (B), 12/9/2020, retrospective, Italy, peer-reviewed, 16 authors, average treatment delay 8.0 days. risk of death, 35.0% lower, RR 0.65, p = 0.22, treatment 181, control 37, adjusted per study, multivariable Cox.
Guisado-Vasco (B), 10/15/2020, retrospective, Spain, peer-reviewed, median age 69.0, 25 authors. risk of death, 20.3% lower, RR 0.80, p = 0.36, treatment 127 of 558 (22.8%), control 14 of 49 (28.6%), NNT 17, adjusted per study, odds ratio converted to relative risk.
Gupta, 7/15/2020, retrospective, USA, peer-reviewed, baseline oxygen required 87.1%, 34 authors, excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline. risk of death, 6.3% higher, RR 1.06, p = 0.41, treatment 631 of 1,761 (35.8%), control 153 of 454 (33.7%).
risk of death, 3.7% lower, RR 0.96, p = 0.53, treatment 388 of 1,117 (34.7%), control 396 of 1,098 (36.1%), NNT 75, HCQ+AZ.
Gómez, 10/13/2022, retrospective, Spain, peer-reviewed, 10 authors, study period 1 March, 2020 - 1 October, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 35.8% lower, RR 0.64, p < 0.001, treatment 500 of 1,378 (36.3%), control 238 of 421 (56.5%), NNT 4.9.
Güner, 12/29/2020, retrospective, Turkey, peer-reviewed, 23 authors. risk of ICU admission, 77.3% lower, RR 0.23, p = 0.16, treatment 604, control 100, inverted to make RR<1 favor treatment, IPTW multivariate analysis, HCQ vs. favipiravir.
Hafez, 4/8/2022, retrospective, United Arab Emirates, peer-reviewed, 6 authors. viral clearance time, 12.3% lower, HR 0.88, p = 0.59, treatment 40, control 1,446, inverted to make HR<1 favor treatment, Cox proportional hazards.
viral clearance time, 58.7% lower, HR 0.41, p = 0.09, treatment 4, control 1,446, inverted to make HR<1 favor treatment, HCQ + favipiravir + lopinavir/ritonavir, Cox proportional hazards.
Haji Aghajani, 4/29/2021, retrospective, Iran, peer-reviewed, 7 authors. risk of death, 19.5% lower, HR 0.81, p = 0.09, treatment 553, control 438, adjusted per study, Cox proportional hazards, RR approximated with OR.
Hall, 2/18/2022, retrospective, USA, peer-reviewed, 15 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 11.2% lower, RR 0.89, p = 0.31, treatment 31 of 56 (55.4%), control 280 of 449 (62.4%), NNT 14.
Hawari, 7/20/2022, Randomized Controlled Trial, trial NCT05113810 (history). Estimated 110 patient RCT with results unknown and over 1.5 years late.
Heberto, 9/12/2020, prospective, Mexico, peer-reviewed, 8 authors, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 53.9% lower, RR 0.46, p = 0.04, treatment 139, control 115, odds ratio converted to relative risk.
risk of mechanical ventilation, 65.1% lower, RR 0.35, p = 0.008, treatment 139, control 115, odds ratio converted to relative risk.
Hernandez-Cardenas, 2/5/2021, Randomized Controlled Trial, Mexico, preprint, 6 authors, study period 8 April, 2020 - 12 July, 2020, average treatment delay 7.4 days. risk of death, 12.0% lower, RR 0.88, p = 0.66, treatment 106, control 108.
risk of death, 57.0% lower, RR 0.43, p = 0.29, subgroup not intubated at baseline.
Higgins, 12/16/2022, Randomized Controlled Trial, multiple countries, peer-reviewed, 1896 authors, study period 9 March, 2020 - 22 June, 2021, trial NCT02735707 (history) (REMAP-CAP). risk of death, 51.0% higher, HR 1.51, p = 0.06, treatment 16 of 41 (39.0%), control 107 of 311 (34.4%), adjusted per study, day 180.
Ho, 3/31/2023, retrospective, Malaysia, peer-reviewed, 11 authors, average treatment delay 8.05 days, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of progression, 889.7% higher, RR 9.90, p = 0.03, treatment 4 of 91 (4.4%), control 1 of 234 (0.4%), odds ratio converted to relative risk.
Hong (B), 5/4/2022, retrospective, South Korea, peer-reviewed, 11 authors, study period 28 February, 2020 - 28 April, 2020. recovery time, 24.9% lower, HR 0.75, p = 0.45, treatment 15, control 15, inverted to make HR<1 favor treatment, propensity score matching.
hospitalization time, 12.7% higher, HR 1.13, p = 0.75, treatment 15, control 15, inverted to make HR<1 favor treatment, propensity score matching.
viral clearance time, 0.5% lower, HR 1.00, p = 0.99, treatment 15, control 15, inverted to make HR<1 favor treatment, propensity score matching.
Hraiech, 5/24/2020, retrospective, France, peer-reviewed, 8 authors, average treatment delay 7.0 days, excluded in exclusion analyses: very late stage, ICU patients. risk of death, 64.7% lower, RR 0.35, p = 0.21, treatment 2 of 17 (11.8%), control 5 of 15 (33.3%), NNT 4.6, day 38 +- 7.
risk of death, 376.5% higher, RR 4.76, p = 0.49, treatment 2 of 17 (11.8%), control 0 of 15 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 6 from ARDS.
risk of no viral clearance, 2.9% higher, RR 1.03, p = 1.00, treatment 14 of 17 (82.4%), control 8 of 10 (80.0%), day 6 from treatment.
Huang (C), 5/28/2020, prospective, China, peer-reviewed, 36 authors. time to viral-, 67.0% lower, relative time 0.33, p < 0.001, treatment 197, control 176.
time to viral-, 59.1% lower, relative time 0.41, p < 0.001, treatment 32, control 37, early treatment.
Ip (B), 5/25/2020, retrospective, database analysis, USA, peer-reviewed, 32 authors, average treatment delay 5.0 days. risk of death, 1.0% lower, HR 0.99, p = 0.93, treatment 432 of 1,914 (22.6%), control 115 of 598 (19.2%), adjusted per study.
Izoulet, 4/21/2020, retrospective, multiple countries, preprint, 1 author, dosage not specified, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of death, 85.0% lower, RR 0.15, p < 0.001.
Jacobs, 7/6/2021, prospective, USA, peer-reviewed, 14 authors, excluded in exclusion analyses: unadjusted results with no group details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 6.6% lower, RR 0.93, p = 0.74, treatment 24 of 46 (52.2%), control 86 of 154 (55.8%), NNT 27.
Johnston, 12/9/2020, Randomized Controlled Trial, USA, peer-reviewed, 30 authors, study period 15 April, 2020 - 27 July, 2020, average treatment delay 5.9 days, dosage 400mg bid day 1, 200mg bid days 2-10, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04354428 (history). risk of hospitalization, 29.9% lower, RR 0.70, p = 0.73, treatment 5 of 148 (3.4%), control 4 of 83 (4.8%), NNT 69, HCQ + folic acid and HCQ + AZ vs. vitamin C + folic acid.
risk of no recovery, 2.0% lower, RR 0.98, p = 0.95, treatment 30 of 60 (50.0%), control 34 of 72 (47.2%), adjusted per study, inverted to make RR<1 favor treatment, HCQ + folic acid vs. vitamin C + folic acid.
risk of no recovery, 9.9% higher, RR 1.10, p = 0.70, treatment 34 of 65 (52.3%), control 34 of 72 (47.2%), adjusted per study, inverted to make RR<1 favor treatment, HCQ + AZ vs. vitamin C + folic acid.
risk of no viral clearance, 38.3% lower, RR 0.62, p = 0.047, treatment 6 of 49 (12.2%), control 12 of 52 (23.1%), NNT 9.2, adjusted per study, inverted to make RR<1 favor treatment, HCQ + folic acid vs. vitamin C + folic acid.
risk of no viral clearance, 20.0% lower, RR 0.80, p = 0.49, treatment 11 of 51 (21.6%), control 12 of 52 (23.1%), adjusted per study, inverted to make RR<1 favor treatment, HCQ + AZ vs. vitamin C + folic acid.
Kalligeros, 8/5/2020, retrospective, USA, peer-reviewed, 13 authors, average treatment delay 6.0 days. risk of death, 67.0% higher, HR 1.67, p = 0.57, treatment 36, control 72.
Kamran, 8/4/2020, prospective, Pakistan, preprint, 10 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of progression, 5.0% lower, RR 0.95, p = 1.00, treatment 11 of 349 (3.2%), control 5 of 151 (3.3%), NNT 627.
risk of progression, 54.8% lower, RR 0.45, p = 0.30, treatment 4 of 31 (12.9%), control 2 of 7 (28.6%), NNT 6.4, with comorbidities.
risk of viral+ at day 14, 10.0% higher, RR 1.10, p = 0.52, treatment 349, control 151.
Karruli, 9/1/2021, retrospective, Italy, peer-reviewed, 13 authors, study period March 2020 - May 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 4.8% lower, RR 0.95, p = 1.00, treatment 20 of 28 (71.4%), control 3 of 4 (75.0%), NNT 28.
Kelly, 7/22/2020, retrospective, Ireland, peer-reviewed, 14 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 143.0% higher, RR 2.43, p = 0.03, treatment 23 of 82 (28.0%), control 6 of 52 (11.5%).
Kim (B), 5/18/2020, retrospective, South Korea, preprint, 12 authors. hospitalization time, 51.0% lower, relative time 0.49, p = 0.01, treatment 22, control 40.
time to viral-, 56.0% lower, relative time 0.44, p = 0.005, treatment 22, control 40.
Kokturk, 4/28/2021, retrospective, database analysis, Turkey, peer-reviewed, 68 authors. risk of death, 3.8% higher, RR 1.04, p = 0.97, treatment 62 of 1,382 (4.5%), control 5 of 118 (4.2%), adjusted per study, odds ratio converted to relative risk.
Komissarov, 6/30/2020, retrospective, Russia, preprint, 8 authors. risk of viral load, 25.0% higher, RR 1.25, p = 0.45, treatment 26, control 10.
Krishnan (B), 4/5/2023, retrospective, India, peer-reviewed, mean age 52.8, 48 authors, study period March 2020 - March 2021. risk of death, 40.0% lower, OR 0.60, p = 0.05, treatment 603, control 1,828, adjusted per study, case control OR, multivariable.
Krishnan, 7/20/2020, retrospective, USA, peer-reviewed, 13 authors, dosage not specified, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 20.4% lower, RR 0.80, p = 0.48, treatment 86 of 144 (59.7%), control 6 of 8 (75.0%), NNT 6.5.
Kuderer, 5/28/2020, retrospective, USA, peer-reviewed, 73 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 134.2% higher, RR 2.34, p < 0.001, treatment 45 of 181 (24.9%), control 76 of 747 (10.2%), odds ratio converted to relative risk, HCQ+AZ.
Lagier, 6/4/2021, retrospective, France, peer-reviewed, 32 authors. risk of death, 32.0% lower, HR 0.68, p = 0.004, treatment 93 of 1,270 (7.3%), control 146 of 841 (17.4%), NNT 10.0, adjusted per study, multivariable, Cox proportional hazards.
Lagier (B), 6/25/2020, retrospective, France, peer-reviewed, 22 authors, dosage 200mg tid days 1-10. risk of death, 59.0% lower, HR 0.41, p = 0.048, treatment 35 of 3,119 (1.1%), control 58 of 618 (9.4%), adjusted per study.
Lamback, 2/19/2021, retrospective, Brazil, peer-reviewed, 10 authors, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 8.9% lower, RR 0.91, p = 0.83, treatment 11 of 101 (10.9%), control 11 of 92 (12.0%), NNT 94.
risk of ICU admission, 19.9% higher, RR 1.20, p = 0.61, treatment 25 of 101 (24.8%), control 19 of 92 (20.7%).
Lambermont, 11/28/2020, retrospective, Belgium, peer-reviewed, 15 authors. risk of death, 32.3% lower, RR 0.68, p = 0.46, treatment 97 of 225 (43.1%), control 14 of 22 (63.6%), NNT 4.9, adjusted per study.
Lammers, 9/29/2020, prospective, Netherlands, peer-reviewed, 18 authors. risk of death/ICU, 32.0% lower, HR 0.68, p = 0.02, treatment 30 of 189 (15.9%), control 101 of 498 (20.3%), adjusted per study.
Lano, 10/21/2020, retrospective, France, peer-reviewed, median age 73.5, 30 authors. risk of death, 33.1% lower, RR 0.67, p = 0.28, treatment 56, control 66, adjusted per study, odds ratio converted to relative risk.
risk of death/ICU, 38.9% lower, RR 0.61, p = 0.23, treatment 17 of 56 (30.4%), control 28 of 66 (42.4%), NNT 8.3, adjusted per study, odds ratio converted to relative risk.
risk of death/ICU, 68.7% lower, RR 0.31, p = 0.11, treatment 4 of 36 (11.1%), control 11 of 31 (35.5%), NNT 4.1, not requiring O2 on diagnosis (relatively early treatment).
Lauriola, 9/14/2020, retrospective, Italy, peer-reviewed, mean age 71.8, 10 authors. risk of death, 73.5% lower, HR 0.27, p < 0.001, treatment 102 of 297 (34.3%), control 35 of 63 (55.6%), NNT 4.7, adjusted per study.
Lavilla Olleros, 1/21/2022, retrospective, Spain, peer-reviewed, 22 authors. risk of death, 36.2% lower, RR 0.64, p < 0.001, treatment 2,285 of 12,772 (17.9%), control 774 of 2,149 (36.0%), NNT 5.5, adjusted per study, odds ratio converted to relative risk, multivariable.
Lecronier, 7/11/2020, retrospective, France, peer-reviewed, baseline oxygen required 100.0%, 26 authors, HCQ vs. control, excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline. risk of death, 42.0% lower, RR 0.58, p = 0.24, treatment 9 of 38 (23.7%), control 9 of 22 (40.9%), NNT 5.8.
risk of treatment escalation, 6.0% lower, RR 0.94, p = 0.73, treatment 15 of 38 (39.5%), control 9 of 22 (40.9%), NNT 70.
risk of viral+ at day 7, 15.0% lower, RR 0.85, p = 0.61, treatment 19 of 26 (73.1%), control 12 of 14 (85.7%), NNT 7.9.
Levi, 12/11/2020, Randomized Controlled Trial, placebo-controlled, trial NCT04355052 (history) (COSTA). Estimated 250 patient RCT with results unknown and over 3 years late.
Li (B), 1/18/2021, retrospective, China, peer-reviewed, 21 authors. risk of no hospital discharge, 50.0% lower, HR 0.50, p = 0.09, treatment 14, control 14, RCT patients vs. matched sample of non-treated patients.
Li (C), 1/12/2021, retrospective, database analysis, China, preprint, 5 authors. time to viral-, 40.0% higher, relative time 1.40, p = 0.06, treatment 18, control 19.
Lora-Tamayo, 2/11/2021, retrospective, Spain, peer-reviewed, 10 authors. risk of death, 50.5% lower, RR 0.50, p < 0.001, treatment 7,192, control 1,361, odds ratio converted to relative risk, univariate, control prevalence approximated with overall prevalence.
Lotfy, 1/1/2021, retrospective, Saudi Arabia, peer-reviewed, mean age 55.0, 3 authors, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely. risk of death, 24.8% higher, RR 1.25, p = 0.76, treatment 6 of 99 (6.1%), control 5 of 103 (4.9%).
risk of mechanical ventilation, 41.2% higher, RR 1.41, p = 0.34, treatment 19 of 99 (19.2%), control 14 of 103 (13.6%).
risk of ICU admission, 16.5% higher, RR 1.17, p = 0.53, treatment 28 of 99 (28.3%), control 25 of 103 (24.3%).
Luo, 6/17/2020, retrospective, USA, peer-reviewed, 31 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 2.2% higher, RR 1.02, p = 0.99, treatment 11 of 35 (31.4%), control 4 of 13 (30.8%), odds ratio converted to relative risk.
Luo (B), 5/21/2020, retrospective, China, peer-reviewed, 9 authors. risk of death, 32.4% lower, OR 0.68, p = 0.72, treatment 19, control 264, inverted to make OR<1 favor treatment, multivariate, RR approximated with OR.
Lyashchenko, 8/12/2022, retrospective, USA, peer-reviewed, 6 authors, study period March 2020 - June 2020, average treatment delay 9.5 days, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 47.7% higher, RR 1.48, p < 0.001, treatment 389 of 1,419 (27.4%), control 341 of 1,837 (18.6%).
Lyngbakken, 7/17/2020, Randomized Controlled Trial, Norway, peer-reviewed, median age 62.0, 11 authors, average treatment delay 8.0 days, trial NCT04316377 (history). risk of death, 3.7% lower, RR 0.96, p = 1.00, treatment 1 of 27 (3.7%), control 1 of 26 (3.8%), NNT 702.
improvement in viral load reduction rate, 71.0% lower, relative rate 0.29, p = 0.51, treatment 27, control 26.
López, 11/2/2020, retrospective, Spain, peer-reviewed, 7 authors. risk of progression, 64.3% lower, RR 0.36, p = 0.02, treatment 5 of 36 (13.9%), control 14 of 36 (38.9%), NNT 4.0.
Magagnoli, 4/21/2020, retrospective, database analysis, USA, peer-reviewed, 7 authors. risk of death, 11.0% lower, HR 0.89, p = 0.74, treatment 39 of 148 (26.4%), control 18 of 163 (11.0%), adjusted per study, HCQ+AZ w/dispositions.
risk of death, 1.0% lower, HR 0.99, p = 0.98, treatment 30 of 114 (26.3%), control 18 of 163 (11.0%), adjusted per study, HCQ w/dispositions.
risk of death, 31.0% higher, HR 1.31, p = 0.28, treatment 49 of 214 (22.9%), control 37 of 395 (9.4%), adjusted per study, HCQ+AZ.
risk of death, 83.0% higher, HR 1.83, p = 0.009, treatment 38 of 198 (19.2%), control 37 of 395 (9.4%), adjusted per study, HCQ.
Mahale, 12/31/2020, retrospective, India, peer-reviewed, 22 authors, study period 22 March, 2020 - 21 May, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 28.7% lower, RR 0.71, p = 0.36, treatment 25 of 102 (24.5%), control 11 of 32 (34.4%), NNT 10.
Mahévas, 5/14/2020, retrospective, France, peer-reviewed, 34 authors, average treatment delay 7.0 days. risk of death, 20.0% higher, HR 1.20, p = 0.75, treatment 9 of 84 (10.7%), control 8 of 89 (9.0%), adjusted per study.
Maldonado, 11/5/2020, retrospective, Spain, peer-reviewed, 10 authors, excluded in exclusion analyses: treatment or control group size extremely small. risk of death, 90.9% lower, RR 0.09, p = 0.17, treatment 1 of 11 (9.1%), control 1 of 1 (100.0%), NNT 1.1.
Mallat, 5/2/2020, retrospective, United Arab Emirates, peer-reviewed, 8 authors, average treatment delay 4.0 days. time to viral-, 203.0% higher, relative time 3.03, p = 0.02, treatment 23, control 11, inverted to make RR<1 favor treatment.
Malundo, 7/14/2022, retrospective, Philippines, peer-reviewed, 16 authors, study period 12 March, 2021 - 9 September, 2021, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 24.4% higher, RR 1.24, p = 0.32, treatment 20 of 90 (22.2%), control 201 of 1,125 (17.9%).
Martin-Vicente, 3/8/2021, retrospective, Spain, preprint, 38 authors, excluded in exclusion analyses: unadjusted results with no group details; treatment or control group size extremely small. risk of death, 59.3% lower, RR 0.41, p = 0.41, treatment 37 of 91 (40.7%), control 1 of 1 (100.0%), NNT 1.7.
Martinez-Lopez, 6/30/2020, retrospective, Spain, peer-reviewed, median age 71.0, 25 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 33.0% lower, RR 0.67, p = 0.20, treatment 47 of 148 (31.8%), control 9 of 19 (47.4%), NNT 6.4.
Matangila, 12/18/2020, retrospective, DR Congo, peer-reviewed, median age 54.0, 12 authors, average treatment delay 7.0 days. risk of death, 54.9% lower, RR 0.45, p = 0.21, treatment 25 of 147 (17.0%), control 8 of 13 (61.5%), NNT 2.2, adjusted per study, odds ratio converted to relative risk.
McGrail, 7/19/2020, retrospective, USA, preprint, 2 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of death, 70.0% higher, RR 1.70, p = 0.69, treatment 4 of 33 (12.1%), control 3 of 42 (7.1%).
Meeus (B), 9/30/2023, retrospective, Belgium, peer-reviewed, 10 authors, study period 16 March, 2020 - 20 May, 2020, this trial uses multiple treatments in the treatment arm (combined with AZ) - results of individual treatments may vary. risk of death, 36.5% lower, RR 0.64, p = 0.005, treatment 59 of 352 (16.8%), control 916 of 3,533 (25.9%), NNT 11, adjusted per study, MI model.
Mehrizi, 12/18/2023, retrospective, Iran, peer-reviewed, 10 authors, study period 1 February, 2020 - 20 March, 2022. risk of death, 26.0% lower, OR 0.74, p < 0.001, RR approximated with OR.
Membrillo de Novales, 5/5/2020, retrospective, Spain, preprint, 19 authors, average treatment delay 7.0 days. risk of death, 55.1% lower, RR 0.45, p = 0.002, treatment 27 of 123 (22.0%), control 21 of 43 (48.8%), NNT 3.7.
Menardi, 9/30/2021, retrospective, Italy, peer-reviewed, 10 authors, excluded in exclusion analyses: excessive unadjusted differences between groups; substantial unadjusted confounding by indication likely. risk of death, 35.2% lower, RR 0.65, p = 0.12, treatment 32 of 200 (16.0%), control 19 of 77 (24.7%), NNT 12.
Mežnar, 7/31/2020, Randomized Controlled Trial, trial NCT04355026 (history). Estimated 90 patient RCT with results unknown and over 3 years late.
Mikami, 6/30/2020, retrospective, USA, peer-reviewed, 7 authors. risk of death, 47.0% lower, HR 0.53, p < 0.001, treatment 575 of 2,077 (27.7%), control 231 of 743 (31.1%), adjusted per study.
Modrák, 12/4/2020, retrospective, Czech Republic, preprint, 27 authors. risk of death, 59.0% lower, RR 0.41, p = 0.04, treatment 108, control 105, Cox (single).
Mohandas, 4/26/2021, retrospective, India, peer-reviewed, 6 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; unadjusted results with no group details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 81.0% higher, RR 1.81, p = 0.007, treatment 27 of 384 (7.0%), control 115 of 2,961 (3.9%).
Mordmüller, 2/26/2021, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04342221 (history). 30 patient RCT with results unknown and over 3 years late.
Mulhem, 4/7/2021, retrospective, database analysis, USA, peer-reviewed, 3 authors, dosage not specified, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 28.3% higher, RR 1.28, p = 0.10, treatment 435 of 2,496 (17.4%), control 81 of 723 (11.2%), adjusted per study, odds ratio converted to relative risk, logistic regression.
Nachega, 10/2/2020, retrospective, database analysis, DR Congo, peer-reviewed, median age 46.0, 25 authors. risk of death, 27.6% lower, RR 0.72, p = 0.17, treatment 69 of 630 (11.0%), control 28 of 96 (29.2%), NNT 5.5, adjusted per study, odds ratio converted to relative risk.
risk of no improvement, 25.8% better, RR 0.74, p = 0.13, adjusted per study, odds ratio converted to relative risk.
Naseem, 12/14/2020, retrospective, Pakistan, preprint, 5 authors. risk of death, 33.3% lower, RR 0.67, p = 0.34, treatment 77, control 1,137, multivariate Cox.
Niwas, 11/1/2020, retrospective, India, peer-reviewed, mean age 45.5, 17 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. recovery time, 29.2% lower, relative time 0.71, p = 0.008, treatment mean 6.3 (±2.7) n=12, control mean 8.9 (±2.2) n=17.
risk of no viral clearance, 183.3% higher, RR 2.83, p = 0.55, treatment 2 of 12 (16.7%), control 1 of 17 (5.9%).
Novartis, 7/27/2020, Double Blind Randomized Controlled Trial, placebo-controlled, USA, preprint, 1 author, trial NCT04358081 (history). risk of no hospital discharge, 70.6% lower, RR 0.29, p = 0.42, treatment 0 of 7 (0.0%), control 1 of 5 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), day 15.
risk of no improvement, 70.6% lower, RR 0.29, p = 0.42, treatment 0 of 7 (0.0%), control 1 of 5 (20.0%), NNT 5.0, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), clinical response, day 15.
risk of no viral clearance, 78.6% higher, RR 1.79, p = 0.56, treatment 5 of 7 (71.4%), control 2 of 5 (40.0%), day 10.
Núñez-Gil, 9/9/2022, retrospective, Spain, peer-reviewed, 32 authors. risk of death, 53.0% lower, OR 0.47, p < 0.001, treatment 581, control 581, propensity score matching, RR approximated with OR.
Núñez-Gil (B), 11/9/2020, retrospective, database analysis, multiple countries, peer-reviewed, median age 68.0, 49 authors. risk of death, 7.9% lower, RR 0.92, p = 0.005, treatment 200 of 686 (29.2%), control 100 of 268 (37.3%), adjusted per study, odds ratio converted to relative risk.
Omma, 1/31/2022, retrospective, Turkey, peer-reviewed, 11 authors, study period 1 April, 2020 - 31 December, 2020. risk of death, 28.2% lower, RR 0.72, p = 0.30, treatment 17 of 213 (8.0%), control 20 of 180 (11.1%), NNT 32.
risk of ICU admission, 50.2% lower, RR 0.50, p = 0.004, treatment 23 of 213 (10.8%), control 39 of 180 (21.7%), NNT 9.2.
hospitalization time, 16.7% lower, relative time 0.83, p = 0.007, treatment 213, control 180.
Orioli, 12/14/2020, retrospective, Belgium, peer-reviewed, 9 authors. risk of death, 12.7% lower, RR 0.87, p = 1.00, treatment 8 of 55 (14.5%), control 3 of 18 (16.7%), NNT 47.
Osawa, 7/1/2022, retrospective, Brazil, peer-reviewed, mean age 62.7, 2 authors, study period 18 March, 2020 - 26 October, 2020. risk of death, 28.6% lower, RR 0.71, p = 0.07, treatment 25 of 71 (35.2%), control 71 of 144 (49.3%), NNT 7.1.
Ouedraogo, 2/5/2021, retrospective, Burkina Faso, peer-reviewed, 14 authors. risk of death, 33.0% lower, HR 0.67, p = 0.38, treatment 397, control 59, multivariate.
risk of ARDS, 68.0% lower, OR 0.32, p = 0.001, treatment 397, control 59, multivariate, RR approximated with OR.
Ozturk, 12/4/2020, retrospective, Turkey, peer-reviewed, 71 authors. risk of death, 43.9% lower, RR 0.56, p = 0.14, treatment 165 of 1,127 (14.6%), control 6 of 23 (26.1%), NNT 8.7, CQ/HCQ.
Pablos, 8/12/2020, retrospective, Spain, peer-reviewed, mean age 63.0, 15 authors. risk of severe case, 126.0% higher, OR 2.26, p = 0.002, treatment 172, control 56, RR approximated with OR.
Paccoud, 6/18/2020, retrospective, France, peer-reviewed, 20 authors. risk of death, 11.0% lower, HR 0.89, p = 0.88, treatment 21 of 38 (55.3%), control 26 of 46 (56.5%), NNT 79, adjusted per study.
Panda, 9/30/2021, Randomized Controlled Trial, India, peer-reviewed, 13 authors, study period June 2020 - May 2021, this trial uses multiple treatments in the treatment arm (combined with ribavirin) - results of individual treatments may vary, trial CTRI/2020/06/025575. risk of death, 47.5% lower, RR 0.53, p = 0.45, treatment 3 of 20 (15.0%), control 6 of 21 (28.6%), NNT 7.4.
Pasquini, 8/23/2020, retrospective, Italy, peer-reviewed, 9 authors, average treatment delay 10.0 days, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 16.4% lower, RR 0.84, p = 0.34, treatment 23 of 33 (69.7%), control 15 of 18 (83.3%), NNT 7.3.
Peng, 12/4/2020, retrospective, China, peer-reviewed, 21 authors. risk of progression, 10.8% lower, RR 0.89, p = 0.63, treatment 29 of 453 (6.4%), control 256 of 3,567 (7.2%), NNT 129, CQ/HCQ risk of AKI.
Peters, 8/15/2020, retrospective, Netherlands, peer-reviewed, 21 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of death, 9.0% higher, HR 1.09, p = 0.57, treatment 419 of 1,596 (26.3%), control 53 of 353 (15.0%), adjusted per study.
Pinato, 8/18/2020, retrospective, multiple countries, peer-reviewed, 72 authors. risk of death, 59.0% lower, HR 0.41, p < 0.001, treatment 30 of 182 (16.5%), control 181 of 446 (40.6%), NNT 4.1.
Psevdos, 12/31/2020, retrospective, USA, peer-reviewed, 3 authors, excluded in exclusion analyses: unadjusted results with no group details; no treatment details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely. risk of death, 63.5% higher, RR 1.63, p = 0.52, treatment 17 of 52 (32.7%), control 3 of 15 (20.0%).
Purwati (B), 2/9/2021, Double Blind Randomized Controlled Trial, Indonesia, peer-reviewed, 29 authors, study period July 2020 - August 2020. risk of no viral clearance, 66.3% lower, RR 0.34, p < 0.001, treatment 38 of 121 (31.4%), control 111 of 119 (93.3%), NNT 1.6, day 7.
Qin, 11/23/2020, retrospective, China, peer-reviewed, 17 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 34.3% lower, RR 0.66, p = 0.61, treatment 3 of 43 (7.0%), control 75 of 706 (10.6%), NNT 27.
Ramírez-García, 5/31/2021, retrospective, Spain, peer-reviewed, 5 authors, excluded in exclusion analyses: excessive unadjusted differences between groups; substantial unadjusted confounding by indication likely. risk of death, 67.0% lower, RR 0.33, p < 0.001, treatment 48 of 350 (13.7%), control 22 of 53 (41.5%), NNT 3.6.
risk of ICU admission, 6.0% higher, RR 1.06, p = 1.00, treatment 35 of 350 (10.0%), control 5 of 53 (9.4%).
RECOVERY Collaborative Group, 6/5/2020, Randomized Controlled Trial, United Kingdom, preprint, baseline oxygen required 76.8%, 29 authors, study period 25 March, 2020 - 5 June, 2020, average treatment delay 9.0 days, trial NCT04381936 (history) (RECOVERY), excluded in exclusion analyses: excessive dosage in late stage patients, results do not apply to typical dosages. risk of death, 9.0% higher, RR 1.09, p = 0.15, treatment 421 of 1,561 (27.0%), control 790 of 3,155 (25.0%).
risk of mechanical ventilation, 15.0% higher, RR 1.15, p = 0.19, treatment 128 of 1,300 (9.8%), control 225 of 2,623 (8.6%).
Reis, 4/22/2021, Double Blind Randomized Controlled Trial, Brazil, peer-reviewed, 18 authors, study period 2 June, 2020 - 30 September, 2020, dosage 800mg day 1, 400mg days 2-10, trial NCT04403100 (history) (TOGETHER). risk of death, 66.0% lower, RR 0.34, p = 1.00, treatment 0 of 214 (0.0%), control 1 of 227 (0.4%), NNT 227, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of hospitalization, 24.0% lower, HR 0.76, p = 0.57, treatment 8 of 214 (3.7%), control 11 of 227 (4.8%), NNT 90, ITT, Cox proportional hazards.
risk of no viral clearance, 4.1% lower, RR 0.96, p = 0.10, treatment 97 of 185 (52.4%), control 102 of 179 (57.0%), NNT 22, adjusted per study, odds ratio converted to relative risk, ITT, mixed-effect logistic model.
Rivera, 7/22/2020, retrospective, USA, peer-reviewed, 45 authors. risk of death, 2.4% higher, RR 1.02, p = 0.92, treatment 44 of 179 (24.6%), control 59 of 327 (18.0%), adjusted per study, odds ratio converted to relative risk.
Rivera-Izquierdo, 7/9/2020, retrospective, Spain, peer-reviewed, 21 authors. risk of death, 19.0% lower, RR 0.81, p = 0.75, treatment 215, control 23.
Rodriguez, 11/9/2020, prospective, Spain, peer-reviewed, 13 authors, average treatment delay 8.0 days, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 59.0% lower, RR 0.41, p = 0.23, treatment 8 of 39 (20.5%), control 2 of 4 (50.0%), NNT 3.4.
Rodriguez-Gonzalez, 11/28/2020, retrospective, Spain, peer-reviewed, 20 authors, average treatment delay 6.0 days. risk of death, 22.8% lower, RR 0.77, p = 0.26, treatment 251 of 1,148 (21.9%), control 17 of 60 (28.3%), NNT 15.
Rodriguez-Nava, 11/5/2020, retrospective, USA, peer-reviewed, median age 68.0, 8 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; excessive unadjusted differences between groups; unadjusted results with no group details. risk of death, 6.3% higher, RR 1.06, p = 0.77, treatment 22 of 65 (33.8%), control 79 of 248 (31.9%), unadjusted.
Rogado, 5/29/2020, retrospective, Spain, peer-reviewed, 9 authors. risk of death, 91.6% lower, RR 0.08, p = 0.02, treatment 1 of 8 (12.5%), control 7 of 9 (77.8%), NNT 1.5, odds ratio converted to relative risk, multivariate logistic regression.
Roger, 7/10/2021, prospective, France, peer-reviewed, 34 authors, average treatment delay 8.0 days, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, no change, RR 1.00, p = 0.94, treatment 53 of 289 (18.3%), control 120 of 677 (17.7%), odds ratio converted to relative risk.
Roig, 1/31/2021, retrospective, Spain, peer-reviewed, 6 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 15.6% lower, RR 0.84, p = 0.76, treatment 33 of 67 (49.3%), control 7 of 12 (58.3%), NNT 11.
Roomi, 8/13/2020, retrospective, USA, peer-reviewed, 11 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death, 37.7% higher, RR 1.38, p = 0.54, treatment 13 of 144 (9.0%), control 6 of 32 (18.8%), adjusted per study, odds ratio converted to relative risk.
Rosenberg, 5/11/2020, retrospective, USA, peer-reviewed, 14 authors. risk of death, 35.0% higher, HR 1.35, p = 0.31, treatment 189 of 735 (25.7%), control 28 of 221 (12.7%), adjusted per study.
Rosenthal, 12/10/2020, retrospective, database analysis, USA, peer-reviewed, 5 authors, dosage not specified, excluded in exclusion analyses: confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline. risk of death, 8.0% higher, OR 1.08, p = 0.13, adjusted per study, multivariable, RR approximated with OR.
Rouamba, 2/26/2022, retrospective, Burkina Faso, peer-reviewed, mean age 42.2, 17 authors, study period 9 March, 2020 - 31 October, 2020, dosage 200mg tid days 1-10, HCQ 200mg tid daily or CQ 250mg bid daily, trial NCT04445441 (history). risk of death, 80.0% lower, HR 0.20, p < 0.001, treatment 20 of 336 (6.0%), control 24 of 73 (32.9%), NNT 3.7, adjusted per study, inpatients, multivariable, Cox proportional hazards.
risk of progression, 20.0% lower, HR 0.80, p = 0.43, treatment 75 of 745 (10.1%), control 19 of 118 (16.1%), adjusted per study, all patients, multivariable, Cox proportional hazards.
risk of progression, 7.0% higher, HR 1.07, p = 0.83, treatment 52 of 347 (15.0%), control 15 of 85 (17.6%), adjusted per study, inpatients, multivariable, Cox proportional hazards.
time to viral clearance, 30.6% lower, HR 0.69, p = 0.26, treatment 746, control 118, adjusted per study, inverted to make HR<1 favor treatment, all patients, propensity score matching, multivariable, Cox proportional hazards, primary outcome.
time to viral clearance, 13.0% lower, HR 0.87, p = 0.29, treatment 746, control 118, adjusted per study, inverted to make HR<1 favor treatment, all patients, without PSM, multivariable, Cox proportional hazards, primary outcome.
time to viral clearance, 13.8% lower, HR 0.86, p = 0.37, treatment 345, control 86, adjusted per study, inverted to make HR<1 favor treatment, inpatients, multivariable, Cox proportional hazards, primary outcome.
Rubio-Sánchez, 3/3/2021, retrospective, Spain, peer-reviewed, 3 authors, study period 14 March, 2020 - 5 June, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of severe case, 40.0% lower, RR 0.60, p = 0.02, treatment 51 of 161 (31.7%), control 19 of 36 (52.8%), NNT 4.7.
Réa-Neto, 4/27/2021, Randomized Controlled Trial, Brazil, peer-reviewed, 6 authors, study period 16 April, 2020 - 6 August, 2020, average treatment delay 8.0 days, trial NCT04420247 (history). risk of death, 57.0% higher, RR 1.57, p = 0.20, treatment 16 of 53 (30.2%), control 10 of 52 (19.2%).
risk of mechanical ventilation, 115.0% higher, RR 2.15, p = 0.03, treatment 53, control 52.
9-point scale clinical status, 147.0% higher, OR 2.47, p = 0.02, treatment 53, control 52, RR approximated with OR.
Saib, 6/9/2021, prospective, propensity score matching, France, peer-reviewed, 9 authors, average treatment delay 7.2 days, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. risk of death/intubation, 125.0% higher, RR 2.25, p = 0.23, treatment 9 of 52 (17.3%), control 4 of 52 (7.7%), PSM.
Said, 5/1/2023, retrospective, Saudi Arabia, peer-reviewed, 12 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 77.5% lower, RR 0.22, p < 0.001, treatment 14 of 435 (3.2%), control 58 of 405 (14.3%), NNT 9.0.
Salazar, 11/4/2020, retrospective, USA, peer-reviewed, 19 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; unadjusted results with no group details. risk of death, 37.0% higher, RR 1.37, p = 0.28, treatment 12 of 92 (13.0%), control 80 of 811 (9.9%).
Saleemi, 8/11/2020, retrospective, Saudi Arabia, preprint, 5 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely. median time to PCR-, 21.0% higher, relative time 1.21, p < 0.05, treatment 65, control 20.
Salehi, 3/11/2022, retrospective, Iran, preprint, mean age 62.0, 11 authors, study period April 2021 - September 2021, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 14.5% higher, RR 1.14, p = 0.44, treatment 53 of 86 (61.6%), control 21 of 39 (53.8%).
Salvador, 3/4/2021, prospective, Portugal, peer-reviewed, 10 authors. risk of death, 32.9% lower, RR 0.67, p = 0.10, treatment 28 of 121 (23.1%), control 58 of 124 (46.8%), NNT 4.2, odds ratio converted to relative risk, multivariate.
risk of mechanical ventilation, 447.8% higher, RR 5.48, p = 0.003, treatment 32 of 121 (26.4%), control 12 of 124 (9.7%), odds ratio converted to relative risk, multivariate.
risk of death/intubation, 16.7% lower, RR 0.83, p = 0.21, treatment 51 of 121 (42.1%), control 63 of 124 (50.8%), NNT 12, odds ratio converted to relative risk, univariate.
Sammartino, 5/10/2021, retrospective, propensity score matching, USA, peer-reviewed, 7 authors, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 240.0% higher, OR 3.40, p = 0.002, treatment 137, control 191, PSM, model 1a, RR approximated with OR.
Sands, 1/1/2021, retrospective, database analysis, USA, peer-reviewed, 10 authors, excluded in exclusion analyses: includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons; substantial unadjusted confounding by indication likely. risk of death, 69.9% higher, RR 1.70, p = 0.01, treatment 101 of 973 (10.4%), control 56 of 696 (8.0%), odds ratio converted to relative risk.
Santos, 7/27/2020, prospective, Spain, peer-reviewed, median age 78.4, mean age 75.3, 6 authors, study period 1 March, 2020 - 1 June, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 9.7% lower, RR 0.90, p = 1.00, treatment 8 of 31 (25.8%), control 2 of 7 (28.6%), NNT 36, HCQ, late treatment result.
risk of death, 50.8% lower, RR 0.49, p = 0.65, treatment 1 of 7 (14.3%), control 9 of 31 (29.0%), NNT 6.8, CQ, late treatment result.
Sarfaraz, 1/2/2021, retrospective, Pakistan, preprint, 7 authors, average treatment delay 7.0 days, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; significant unadjusted confounding possible; unadjusted results with no group details. risk of death, 45.0% higher, RR 1.45, p = 0.07, treatment 40 of 94 (42.6%), control 27 of 92 (29.3%).
Sarhan, 11/2/2021, Randomized Controlled Trial, Egypt, peer-reviewed, 8 authors, study period 1 October, 2020 - 10 March, 2021, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04779047 (history), excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline; significant unadjusted differences between groups. risk of death, 25.7% lower, RR 0.74, p = 0.39, treatment 12 of 56 (21.4%), control 15 of 52 (28.8%), NNT 13.
risk of no hospital discharge, 25.7% lower, RR 0.74, p = 0.39, treatment 12 of 56 (21.4%), control 15 of 52 (28.8%), NNT 13.
hospitalization time, 25.0% higher, relative time 1.25, p = 0.06, treatment 56, control 52.
Sbidian, 6/19/2020, retrospective, database analysis, France, preprint, 21 authors, excluded in exclusion analyses: significant issues found with adjustments. risk of death, 5.0% higher, RR 1.05, p = 0.74, treatment 111 of 623 (17.8%), control 830 of 3,792 (21.9%), adjusted per study, whole population HCQ AIPTW adjusted.
risk of no hospital discharge, 20.0% lower, RR 0.80, p = 0.002, treatment 623, control 3,792, adjusted per study, inverted to make RR<1 favor treatment, whole population HCQ AIPTW adjusted.
Schmidt, 11/12/2021, retrospective, USA, peer-reviewed, 42 authors, study period 17 March, 2020 - 11 February, 2021, excluded in exclusion analyses: confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline. risk of death, 333.0% higher, OR 4.33, p < 0.001, treatment 70, control 407, adjusted per study, propensity score matching, multivariable, RR approximated with OR.
risk of severe case, 613.0% higher, OR 7.13, p < 0.001, treatment 70, control 407, adjusted per study, propensity score matching, multivariable, RR approximated with OR.
Schwartz, 6/18/2021, Double Blind Randomized Controlled Trial, Canada, peer-reviewed, 20 authors, study period April 2020 - September 2020, average treatment delay 7.0 days, dosage 800mg day 1, 400mg days 2-5. risk of ICU admission, 133.3% higher, RR 2.33, p = 1.00, treatment 1 of 111 (0.9%), control 0 of 37 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of hospitalization, 533.3% higher, RR 6.33, p = 0.57, treatment 4 of 111 (3.6%), control 0 of 37 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of ICU admission, 141.9% higher, RR 2.42, p = 1.00, treatment 1 of 74 (1.4%), control 0 of 31 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), per-protocol.
risk of hospitalization, 141.9% higher, RR 2.42, p = 1.00, treatment 1 of 74 (1.4%), control 0 of 31 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), per-protocol.
lack of improvement ≥1 year, 37.0% lower, OR 0.63, p = 0.15, treatment 90, control 89, day 365, RR approximated with OR.
persistence ≥1 year, 14.0% lower, OR 0.86, p = 0.16, treatment 90, control 89, day 365, RR approximated with OR.
presence of symptoms, 19.0% lower, OR 0.81, p = 0.37, treatment 90, control 89, RR approximated with OR.
ongoing symptoms, 27.8% higher, RR 1.28, p = 0.64, treatment 23 of 111 (20.7%), control 6 of 37 (16.2%), day 30.
Self, 11/9/2020, Double Blind Randomized Controlled Trial, USA, peer-reviewed, 33 authors, study period 2 April, 2020 - 19 June, 2020, average treatment delay 5.0 days, trial NCT04332991 (history) (ORCHID). risk of death, 6.2% higher, RR 1.06, p = 0.85, treatment 25 of 241 (10.4%), control 25 of 236 (10.6%), NNT 455, adjusted per study, odds ratio converted to relative risk.
risk of death, 51.0% higher, RR 1.51, p = 0.28, treatment 18 of 241 (7.5%), control 14 of 236 (5.9%), adjusted per study, odds ratio converted to relative risk, day 14.
risk of 7-point scale, 3.1% higher, OR 1.03, p = 0.87, treatment 241, control 236, inverted to make OR<1 favor treatment, day 28, RR approximated with OR.
risk of 7-point scale, 2.0% lower, OR 0.98, p = 0.91, treatment 241, control 236, inverted to make OR<1 favor treatment, day 14, RR approximated with OR.
risk of 7-point scale, 39.0% lower, OR 0.61, p = 0.09, treatment 241, control 236, inverted to make OR<1 favor treatment, subgroup not on oxygen at baseline, day 14, RR approximated with OR.
Serrano, 9/22/2020, retrospective, Spain, peer-reviewed, 8 authors. risk of death, 43.0% lower, RR 0.57, p = 0.14, treatment 6 of 14 (42.9%), control 6 of 8 (75.0%), NNT 3.1.
Shabrawishi, 5/11/2020, retrospective, Saudi Arabia, preprint, mean age 43.9, 5 authors. risk of no virological cure at day 5, 14.7% lower, RR 0.85, p = 0.66, treatment 12 of 45 (26.7%), control 15 of 48 (31.2%), NNT 22.
Shamsi, 7/17/2023, retrospective, Iran, peer-reviewed, 4 authors, study period 1 March, 2020 - 1 August, 2021, dosage not specified, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 39.1% higher, RR 1.39, p = 0.51, treatment 4 of 23 (17.4%), control 20 of 160 (12.5%).
Sheshah, 11/13/2020, retrospective, Saudi Arabia, peer-reviewed, 8 authors. risk of death, 80.0% lower, RR 0.20, p < 0.001, treatment 267, control 33, odds ratio converted to relative risk.
Shoaibi, 9/24/2020, retrospective, database analysis, USA, preprint, 5 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 15.4% lower, RR 0.85, p < 0.001, treatment 686 of 5,047 (13.6%), control 3,923 of 24,404 (16.1%), NNT 40.
Signes-Costa, 12/16/2020, retrospective, multiple countries, peer-reviewed, 28 authors. risk of death, 47.0% lower, RR 0.53, p < 0.001, treatment 4,854, control 993, adjusted per study.
Silva, 5/20/2022, retrospective, Brazil, peer-reviewed, mean age 58.4, 28 authors, study period 25 March, 2020 - 21 October, 2020. risk of death, 46.1% higher, RR 1.46, p = 0.21, treatment 21, control 374, adjusted per study, odds ratio converted to relative risk, multivariable, control prevalance approximated with overall prevalence.
Singh (C), 6/8/2021, Randomized Controlled Trial, India, preprint, 13 authors, study period March 2020 - October 2020, this trial uses multiple treatments in the treatment arm (combined with ribavirin) - results of individual treatments may vary. risk of death, 47.5% lower, RR 0.53, p = 0.45, treatment 3 of 20 (15.0%), control 6 of 21 (28.6%), NNT 7.4, severe.
risk of death, 50.0% lower, RR 0.50, p = 0.48, treatment 3 of 37 (8.1%), control 6 of 37 (16.2%), NNT 12, all patients.
risk of no recovery, 14.1% lower, RR 0.86, p = 0.76, treatment 9 of 20 (45.0%), control 11 of 21 (52.4%), NNT 14, severe.
risk of no recovery, 8.3% lower, RR 0.92, p = 1.00, treatment 11 of 37 (29.7%), control 12 of 37 (32.4%), NNT 37, all patients.
Singh, 5/19/2020, retrospective, database analysis, USA, preprint, 4 authors, excluded in exclusion analyses: confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline. risk of death, 5.0% lower, RR 0.95, p = 0.72, treatment 104 of 910 (11.4%), control 109 of 910 (12.0%), NNT 182.
risk of mechanical ventilation, 19.0% lower, RR 0.81, p = 0.26, treatment 46 of 910 (5.1%), control 57 of 910 (6.3%), NNT 83.
Sivapalan, 6/3/2021, Double Blind Randomized Controlled Trial, Denmark, peer-reviewed, 32 authors, study period 6 April, 2020 - 21 December, 2020, average treatment delay 8.0 days, trial NCT04322396 (history) (ProPAC-COVID). risk of death, 92.0% lower, RR 0.08, p = 0.32, treatment 1 of 61 (1.6%), control 2 of 56 (3.6%), adjusted per study.
risk of ICU admission, 22.4% higher, RR 1.22, p = 1.00, treatment 4 of 61 (6.6%), control 3 of 56 (5.4%).
relative days alive and discharged from hospital within 14 days (inverse), 8.4% worse, RR 1.08, p = 0.36, treatment 61, control 56, adjusted per study.
Smith, 5/31/2021, retrospective, USA, preprint, 4 authors, excluded in exclusion analyses: immortal time bias may significantly affect results. risk of death, 27.2% lower, RR 0.73, p = 0.002, treatment 19 of 37 (51.4%), control 182 of 218 (83.5%), NNT 3.1, odds ratio converted to relative risk, >3g HCQ and >1g AZ, multivariable cox proportional hazard regression.
Solh, 10/20/2020, retrospective, database analysis, USA, preprint, 5 authors, excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline; substantial unadjusted confounding by indication likely. risk of death, 18.0% higher, HR 1.18, p = 0.17, treatment 131 of 265 (49.4%), control 134 of 378 (35.4%), adjusted per study.
SOLIDARITY Trial Consortium, 10/15/2020, Randomized Controlled Trial, multiple countries, peer-reviewed, baseline oxygen required 64.0%, 15 authors, study period 22 March, 2020 - 4 October, 2020, trial NCT04315948 (history) (SOLIDARITY), excluded in exclusion analyses: excessive dosage in late stage patients, results do not apply to typical dosages; very late stage, >50% on oxygen/ventilation at baseline. risk of death, 19.0% higher, RR 1.19, p = 0.23, treatment 104 of 947 (11.0%), control 84 of 906 (9.3%).
Sosa-García, 6/29/2020, retrospective, Mexico, peer-reviewed, baseline oxygen required 100.0%, 6 authors, average treatment delay 9.0 days, excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline; substantial unadjusted confounding by indication likely. risk of death, 10.5% higher, RR 1.11, p = 1.00, treatment 7 of 38 (18.4%), control 3 of 18 (16.7%).
Soto, 3/2/2022, retrospective, Peru, peer-reviewed, median age 58.0, 10 authors, study period April 2020 - August 2020, dosage not specified, excluded in exclusion analyses: unadjusted results with no group details; substantial unadjusted confounding by indication likely; substantial confounding by time possible due to significant changes in SOC and treatment propensity near the start of the pandemic. risk of death, 6.0% higher, HR 1.06, p = 0.46, treatment 292 of 590 (49.5%), control 362 of 828 (43.7%), Cox proportional hazards.
Soto-Becerra, 10/8/2020, retrospective, database analysis, Peru, preprint, median age 59.4, 4 authors, study period 1 April, 2020 - 19 July, 2020, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of death, 18.1% lower, HR 0.82, p < 0.001, treatment 346 of 692 (50.0%), control 1,606 of 2,630 (61.1%), NNT 9.0, day 54 (last day available) weighted KM.
risk of death, 84.0% higher, HR 1.84, p = 0.02, treatment 165 of 692 (23.8%), control 401 of 2,630 (15.2%), adjusted per study, day 30.
Souza-Silva, 9/30/2023, retrospective, Brazil, peer-reviewed, median age 60.0, 29 authors, study period March 2020 - September 2020, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; authors discussion of prior research exhibits strong bias, raising concern for bias in analysis. risk of death, 5.5% higher, RR 1.05, p = 0.68, treatment 135 of 673 (20.1%), control 128 of 673 (19.0%).
risk of mechanical ventilation, 21.1% higher, RR 1.21, p = 0.08, treatment 145 of 538 (27.0%), control 120 of 539 (22.3%).
risk of ICU admission, 9.5% higher, RR 1.09, p = 0.31, treatment 196 of 559 (35.1%), control 179 of 559 (32.0%).
hospitalization time, 12.5% higher, relative time 1.12, p = 0.03, treatment median 9.0 IQR 13.0 n=673, control median 8.0 IQR 10.0 n=673.
Spivak, 3/2/2023, Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, mean age 41.9, 13 authors, study period April 2020 - April 2021, dosage 800mg day 1, 400mg days 2-5, trial NCT04342169 (history). risk of hospitalization, 72.7% higher, RR 1.73, p = 0.54, treatment 7 of 152 (4.6%), control 4 of 150 (2.7%), day 28.
symptom score difference, 20.4% lower, RR 0.80, p = 0.19, treatment 167, control 165, adjusted per study, adjusted symptom score difference relative to placebo score.
viral shedding, 17.4% lower, HR 0.83, p = 0.19, treatment 185, control 182, inverted to make HR<1 favor treatment.
Stewart, 3/17/2021, retrospective, USA, peer-reviewed, 37 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of death, 18.0% higher, RR 1.18, p = 0.27, treatment 90 of 429 (21.0%), control 141 of 737 (19.1%), adjusted per study, VA, HCQ+AZ.
Stewart (B), 3/17/2021, retrospective, USA, peer-reviewed, 37 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of mechanical ventilation, 29.0% higher, RR 1.29, p = 0.09, treatment 48 of 305 (15.7%), control 95 of 1,302 (7.3%), adjusted per study, Aetion, HCQ.
Stewart (C), 3/17/2021, retrospective, USA, peer-reviewed, 37 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of death, 16.0% higher, RR 1.16, p = 0.26, treatment 428 of 1,711 (25.0%), control 123 of 688 (17.9%), adjusted per study, COTA/HMH, HCQ+AZ.
Stewart (D), 3/17/2021, retrospective, USA, peer-reviewed, 37 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of death, 90.0% higher, RR 1.90, p = 0.09, treatment 46 of 208 (22.1%), control 47 of 1,334 (3.5%), adjusted per study, Dascena, HCQ+AZ.
Stewart (E), 3/17/2021, retrospective, USA, peer-reviewed, 37 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of death, 9.0% higher, RR 1.09, p = 0.65, treatment 212 of 1,157 (18.3%), control 203 of 1,101 (18.4%), NNT 873, adjusted per study, Health Catalyst, HCQ+AZ.
Stewart (F), 3/17/2021, retrospective, USA, peer-reviewed, 37 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of death, 129.9% higher, RR 2.30, p < 0.001, treatment 32 of 108 (29.6%), control 33 of 256 (12.9%), Synapse, HCQ+AZ.
Stewart (G), 3/17/2021, retrospective, USA, peer-reviewed, 37 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; includes PCR+ patients that may be asymptomatic for COVID-19 but in hospital for other reasons. risk of death, 1.0% lower, RR 0.99, p = 0.95, treatment 66 of 578 (11.4%), control 188 of 1,243 (15.1%), adjusted per study, TriNetX, HCQ+AZ.
Synolaki, 9/5/2020, retrospective, Greece, preprint, 20 authors. risk of death, 23.6% lower, RR 0.76, p = 0.27, treatment 21 of 98 (21.4%), control 60 of 214 (28.0%), NNT 15.
Sánchez-Álvarez, 4/27/2020, retrospective, database analysis, Spain, peer-reviewed, mean age 67.0, 10 authors. risk of death, 45.9% lower, RR 0.54, p = 0.005, treatment 322, control 53, odds ratio converted to relative risk.
Taccone, 12/23/2020, retrospective, Belgium, peer-reviewed, 10 authors, average treatment delay 5.0 days. risk of death, 24.7% lower, RR 0.75, p = 0.02, treatment 449 of 1,308 (34.3%), control 183 of 439 (41.7%), NNT 14, odds ratio converted to relative risk.
Taieb, 6/30/2021, retrospective, Senegal, peer-reviewed, 29 authors, average treatment delay 6.0 days. risk of no hospital discharge, 38.7% lower, OR 0.61, p = 0.02, treatment 674, control 252, inverted to make OR<1 favor treatment, multivariate, RR approximated with OR.
Tamura, 7/13/2021, retrospective, Brazil, peer-reviewed, 4 authors, study period 10 March, 2020 - 13 November, 2020, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 299.0% higher, OR 3.99, p = 0.04, treatment 25, control 163, adjusted per study, multivariable, RR approximated with OR.
Tan, 12/14/2020, retrospective, China, peer-reviewed, 7 authors. hospitalization time, 35.2% lower, relative time 0.65, p = 0.04, treatment 8, control 277.
Tang, 4/14/2020, Randomized Controlled Trial, China, peer-reviewed, 24 authors, study period 11 February, 2020 - 19 February, 2020, average treatment delay 16.6 days. risk of no virological cure at day 21, 21.4% lower, RR 0.79, p = 0.51, treatment 11 of 75 (14.7%), control 14 of 75 (18.7%), NNT 25.
Tehrani, 10/30/2020, retrospective, Sweden, peer-reviewed, 5 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; unadjusted results with no group details. risk of death, 13.4% lower, RR 0.87, p = 0.63, treatment 16 of 65 (24.6%), control 54 of 190 (28.4%), NNT 26.
Texeira, 12/31/2020, retrospective, USA, peer-reviewed, 6 authors, excluded in exclusion analyses: unadjusted results with no group details; no treatment details; substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely. risk of death, 79.3% higher, RR 1.79, p = 0.10, treatment 17 of 65 (26.2%), control 14 of 96 (14.6%).
Trullàs, 7/14/2020, retrospective, Spain, preprint, median age 75.0, 8 authors, average treatment delay 9.0 days. risk of death, 35.6% lower, RR 0.64, p = 0.12, treatment 20 of 66 (30.3%), control 16 of 34 (47.1%), NNT 6.0.
Tsanovska, 3/3/2022, prospective, Bulgaria, peer-reviewed, 8 authors, study period 6 November, 2020 - 28 December, 2020. risk of death, 57.9% lower, RR 0.42, p = 0.03, treatment 8 of 70 (11.4%), control 19 of 70 (27.1%), NNT 6.4, propensity score matching.
risk of mechanical ventilation, 73.9% lower, RR 0.26, p < 0.001, treatment 6 of 70 (8.6%), control 23 of 70 (32.9%), NNT 4.1, propensity score matching.
risk of ICU admission, 70.4% lower, RR 0.30, p < 0.001, treatment 8 of 70 (11.4%), control 27 of 70 (38.6%), NNT 3.7, propensity score matching.
Tu, 1/13/2022, retrospective, Sierra Leone, peer-reviewed, 11 authors, study period 31 March, 2020 - 11 August, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 17.2% lower, RR 0.83, p = 0.81, treatment 6 of 37 (16.2%), control 28 of 143 (19.6%), NNT 30.
Turrini, 6/11/2021, retrospective, Italy, peer-reviewed, 16 authors. risk of death, 9.8% lower, RR 0.90, p = 0.15, treatment 103 of 160 (64.4%), control 33 of 45 (73.3%), NNT 11, adjusted per study, odds ratio converted to relative risk, multivariate.
Ubaldo, 2/1/2021, retrospective, Philippines, peer-reviewed, 3 authors, excluded in exclusion analyses: substantial unadjusted confounding by indication likely; very late stage, ICU patients; unadjusted results with no group details. risk of death, 18.4% lower, RR 0.82, p = 0.64, treatment 17 of 25 (68.0%), control 5 of 6 (83.3%), NNT 6.5, COVID-19 positive patients.
Ulrich, 9/23/2020, Randomized Controlled Trial, USA, peer-reviewed, baseline oxygen required 63.3%, mean age 66.2, 18 authors, study period 17 April, 2020 - 12 May, 2020, average treatment delay 7.0 days, trial NCT04369742 (history) (TEACH), excluded in exclusion analyses: very late stage, >50% on oxygen/ventilation at baseline. risk of death, 6.0% higher, RR 1.06, p = 1.00, treatment 7 of 67 (10.4%), control 6 of 61 (9.8%).
risk of mechanical ventilation, 51.7% higher, RR 1.52, p = 0.72, treatment 5 of 67 (7.5%), control 3 of 61 (4.9%).
risk of ICU admission, 173.1% higher, RR 2.73, p = 0.13, treatment 9 of 67 (13.4%), control 3 of 61 (4.9%).
Uyaroğlu, 3/17/2022, retrospective, propensity score matching, Turkey, peer-reviewed, 6 authors, study period 20 March, 2020 - 30 September, 2020, this trial compares with another treatment - results may be better when compared to placebo. risk of death, 200.0% higher, RR 3.00, p = 1.00, treatment 1 of 42 (2.4%), control 0 of 42 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of ICU admission, 66.7% lower, RR 0.33, p = 1.00, treatment 0 of 42 (0.0%), control 1 of 42 (2.4%), NNT 42, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
hospitalization time, 9.8% lower, relative time 0.90, p = 0.90, treatment 42, control 42.
Uygen, 9/15/2021, retrospective, Turkey, peer-reviewed, 4 authors. time to viral-, 12.2% lower, relative time 0.88, p = 0.05, treatment 15, control 25.
van Halem, 11/27/2020, retrospective, Belgium, peer-reviewed, 10 authors. risk of death, 31.6% lower, RR 0.68, p = 0.05, treatment 34 of 164 (20.7%), control 47 of 155 (30.3%), NNT 10.
Vernaz, 12/31/2020, retrospective, propensity score matching, Switzerland, peer-reviewed, 15 authors, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically; substantial unadjusted confounding by indication likely. risk of death, 15.3% lower, RR 0.85, p = 0.71, treatment 12 of 93 (12.9%), control 16 of 105 (15.2%), NNT 43, HCQ vs. SOC, PSM.
hospitalization time, 49.0% higher, relative time 1.49, p = 0.002, treatment 93, control 105, HCQ vs. SOC, PSM.
Wang (C), 6/10/2020, retrospective, database analysis, USA, preprint, 3 authors, excluded in exclusion analyses: confounding by indication is likely and adjustments do not consider COVID-19 severity at baseline. risk of death, 5.8% lower, RR 0.94, p = 0.63, treatment 1,866, control 5,726, odds ratio converted to relative risk.
WellStar, 12/7/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04429867 (history). Estimated 700 patient RCT with results unknown and over 3 years late.
Xia, 2/11/2020, retrospective, China, preprint, 1 author, excluded in exclusion analyses: minimal details provided. risk of no viral clearance, 37.5% lower, RR 0.62, p = 0.17, treatment 5 of 10 (50.0%), control 12 of 15 (80.0%), NNT 3.3.
Yegerov, 1/8/2021, retrospective, Kazakhstan, preprint, 8 authors, average treatment delay 1.0 days, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 95.3% lower, RR 0.05, p = 1.00, treatment 0 of 23 (0.0%), control 20 of 1,049 (1.9%), NNT 52, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Yilgwan, 5/11/2023, retrospective, Nigeria, peer-reviewed, 12 authors, study period 25 February, 2020 - 30 August, 2021. risk of death, 93.0% lower, OR 0.07, p < 0.001, treatment 1,039, control 2,423, adjusted per study, RR approximated with OR.
Yu (B), 8/3/2020, retrospective, China, peer-reviewed, median age 62.0, 6 authors. risk of progression to critical, 82.5% lower, RR 0.17, p = 0.049, treatment 1 of 231 (0.4%), control 32 of 1,291 (2.5%), NNT 49, baseline critical cohort reported separately in Yu et al.
risk of death, 85.0% lower, RR 0.15, p = 0.02, treatment 1 of 73 (1.4%), control 238 of 2,604 (9.1%), NNT 13, HCQ treatment started early vs. non-HCQ.
Yu (C), 5/15/2020, retrospective, China, peer-reviewed, 8 authors. risk of death, 60.5% lower, RR 0.40, p = 0.002, treatment 9 of 48 (18.8%), control 238 of 502 (47.4%), NNT 3.5.
Zhong Nanshan (钟南山), 3/26/2020, retrospective, China, preprint, 1 author. risk of no virological cure at day 10, 80.0% lower, RR 0.20, p < 0.001, treatment 5 of 115 (4.3%), control 17 of 82 (20.7%), NNT 6.1, adjusted per study.
Águila-Gordo, 11/11/2020, retrospective, Spain, peer-reviewed, mean age 84.4, 6 authors. risk of death, 67.0% lower, RR 0.33, p = 0.10, treatment 151 of 346 (43.6%), control 47 of 70 (67.1%), NNT 4.3, adjusted per study.
Çivriz Bozdağ, 9/15/2021, retrospective, Turkey, peer-reviewed, 64 authors, excluded in exclusion analyses: substantial confounding by time likely due to declining usage over the early stages of the pandemic when overall treatment protocols improved dramatically. risk of death, 399.2% higher, RR 4.99, p = 0.003, treatment 35, control 140.
Çiyiltepe, 4/30/2021, retrospective, Turkey, peer-reviewed, 5 authors, excluded in exclusion analyses: treatment group only includes patients where treatment failed resulting in ICU admission. risk of death, 3.2% lower, RR 0.97, p = 0.85, treatment 69 of 95 (72.6%), control 39 of 52 (75.0%), NNT 42.
Ñamendys-Silva, 10/21/2020, retrospective, database analysis, Mexico, peer-reviewed, mean age 57.3, 18 authors, average treatment delay 7.0 days. risk of death, 32.3% lower, RR 0.68, p = 0.18, treatment 24 of 54 (44.4%), control 42 of 64 (65.6%), NNT 4.7, HCQ+AZ vs. neither HCQ or CQ.
risk of death, 37.1% lower, RR 0.63, p = 0.09, treatment 19 of 46 (41.3%), control 42 of 64 (65.6%), NNT 4.1, CQ vs. neither HCQ or CQ.
risk of death, 34.5% lower, RR 0.66, p = 0.006, treatment 43 of 100 (43.0%), control 42 of 64 (65.6%), NNT 4.4, HCQ+AZ or CQ.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
Abella, 9/30/2020, Randomized Controlled Trial, USA, peer-reviewed, 18 authors, study period 9 April, 2020 - 14 July, 2020, PATCH trial. risk of case, 5.0% lower, RR 0.95, p = 1.00, treatment 4 of 64 (6.2%), control 4 of 61 (6.6%), NNT 325.
Agarwal, 9/14/2021, prospective, India, preprint, 17 authors. risk of hospitalization, 94.8% lower, RR 0.05, p = 0.61, treatment 0 of 29 (0.0%), control 17 of 455 (3.7%), NNT 27, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
relative severity, 26.9% better, RR 0.73, p = 0.21, treatment 29, control 455.
risk of case, 4.6% higher, RR 1.05, p = 0.81, treatment 6 of 29 (20.7%), control 90 of 455 (19.8%).
Ahmed, 11/23/2021, retrospective, Saudi Arabia, peer-reviewed, 7 authors. risk of case, 99.3% lower, OR 0.007, p = 0.08, treatment 0 of 50 (0.0%) cases, 13 of 50 (26.0%) controls, NNT 1.7, case control OR.
Ajili, 7/31/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04377646 (history) (COVID-Milit). Estimated 660 patient RCT with results unknown and over 3 years late.
Alegiani, 4/15/2021, retrospective, case control, database analysis, Italy, peer-reviewed, 16 authors. risk of death, 8.0% higher, OR 1.08, p = 0.64, HCQ vs. other cDMARDs, RR approximated with OR.
risk of hospitalization, 18.0% lower, OR 0.82, p = 0.03, HCQ vs. other cDMARDs, RR approximated with OR.
risk of death, 19.0% higher, OR 1.19, p = 0.32, HCQ vs. MTX, RR approximated with OR.
risk of hospitalization, 12.0% lower, OR 0.88, p = 0.17, HCQ vs. MTX, RR approximated with OR.
Alqatari, 6/1/2023, retrospective, Saudi Arabia, peer-reviewed, 15 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of mechanical ventilation, 89.0% lower, RR 0.11, p = 0.13, treatment 0 of 13 (0.0%), control 5 of 21 (23.8%), NNT 4.2, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of ICU admission, 64.1% lower, RR 0.36, p = 0.14, treatment 2 of 13 (15.4%), control 9 of 21 (42.9%), NNT 3.6.
critical case, 64.1% lower, RR 0.36, p = 0.14, treatment 2 of 13 (15.4%), control 9 of 21 (42.9%), NNT 3.6.
Alzahrani, 4/15/2021, retrospective, Saudi Arabia, peer-reviewed, 3 authors. risk of death, 58.7% lower, RR 0.41, p = 1.00, treatment 0 of 14 (0.0%), control 1 of 33 (3.0%), NNT 33, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of mechanical ventilation, 81.0% lower, RR 0.19, p = 0.54, treatment 0 of 14 (0.0%), control 3 of 33 (9.1%), NNT 11, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of severe case, 32.7% lower, RR 0.67, p = 0.70, treatment 2 of 14 (14.3%), control 7 of 33 (21.2%), NNT 14.
Arleo, 10/27/2020, retrospective, USA, preprint, 5 authors. risk of death, 50.0% lower, RR 0.50, p = 0.67, treatment 1 of 20 (5.0%), control 5 of 50 (10.0%), NNT 20, all patients.
risk of death, 52.0% lower, RR 0.48, p = 0.64, treatment 1 of 10 (10.0%), control 5 of 24 (20.8%), NNT 9.2, inpatients.
Badyal, 6/7/2021, prospective, India, peer-reviewed, 18 authors, study period May 2020 - September 2020. risk of case, 60.1% lower, RR 0.40, p < 0.001, treatment 247 of 617 (40.0%), control 611 of 1,473 (41.5%), adjusted per study, odds ratio converted to relative risk, ≥6 weeks.
risk of case, 35.1% lower, RR 0.65, p = 0.003, treatment 88 of 185 (47.6%), control 611 of 1,473 (41.5%), adjusted per study, odds ratio converted to relative risk, 4-5 weeks.
risk of case, 23.2% lower, RR 0.77, p = 0.03, treatment 80 of 181 (44.2%), control 611 of 1,473 (41.5%), adjusted per study, odds ratio converted to relative risk, 2-3 weeks.
Bae, 2/20/2021, retrospective, propensity score matching, South Korea, peer-reviewed, 8 authors. risk of case, 30.3% lower, RR 0.70, p = 0.18, treatment 16 of 743 (2.2%), control 91 of 2,698 (3.4%), NNT 82, odds ratio converted to relative risk, PSM.
risk of case, 19.5% lower, RR 0.81, p = 0.50, treatment 16 of 743 (2.2%), control 91 of 2,698 (3.4%), odds ratio converted to relative risk, PSM, adjusted for region.
risk of case, 30.3% lower, RR 0.70, p = 0.30, treatment 16 of 743 (2.2%), control 91 of 2,698 (3.4%), NNT 82, odds ratio converted to relative risk, PSM, adjusted for immunosuppresant use.
Becetti, 8/5/2022, retrospective, Qatar, peer-reviewed, mean age 43.2, 12 authors, study period 1 April, 2020 - 31 July, 2020. risk of case, 36.8% lower, RR 0.63, p = 0.17, treatment 26 of 314 (8.3%), control 49 of 386 (12.7%), NNT 23, adjusted per study, odds ratio converted to relative risk, multivariable.
risk of case, 52.0% lower, RR 0.48, p < 0.001, treatment 16 of 46 (34.8%), control 29 of 40 (72.5%), NNT 2.7, patients with close contact to cases, close contact.
Behera, 11/3/2020, retrospective, India, peer-reviewed, 13 authors. risk of case, 27.9% lower, RR 0.72, p = 0.29, treatment 7 of 19 (36.8%), control 179 of 353 (50.7%), NNT 7.2, adjusted per study, odds ratio converted to relative risk, model 2 conditional logistic regression.
risk of case, 26.3% lower, RR 0.74, p = 0.25, treatment 7 of 19 (36.8%), control 179 of 353 (50.7%), NNT 7.2, odds ratio converted to relative risk, matched pair analysis.
Belmont, 10/6/2021, prospective, USA, preprint, 1 author, trial NCT04354870 (history). risk of symptomatic case, 78.6% lower, RR 0.21, p = 0.21, treatment 1 of 56 (1.8%), control 2 of 24 (8.3%), NNT 15.
risk of case, 14.3% lower, RR 0.86, p = 1.00, treatment 4 of 56 (7.1%), control 2 of 24 (8.3%), NNT 84.
Bhatt, 8/4/2021, prospective, India, preprint, 4 authors. risk of case, 49.3% higher, RR 1.49, p = 0.02, treatment 167 of 731 (22.8%), control 30 of 196 (15.3%).
Bhattacharya, 6/9/2020, retrospective, India, preprint, 7 authors. risk of case, 80.7% lower, RR 0.19, p = 0.001, treatment 4 of 54 (7.4%), control 20 of 52 (38.5%), NNT 3.2.
Burney, 10/15/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04370015 (history). Estimated 374 patient RCT with results unknown and over 3 years late.
Cassione, 5/12/2020, retrospective, Italy, peer-reviewed, survey, median age 52.5, 6 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of case, 49.6% higher, RR 1.50, p = 0.59, treatment 10 of 127 (7.9%), control 2 of 38 (5.3%).
Chatterjee, 5/28/2020, retrospective, India, peer-reviewed, survey, 11 authors. risk of case, 66.8% lower, RR 0.33, p < 0.001, treatment 12 of 68 (17.6%), control 206 of 387 (53.2%), NNT 2.8, full course vs. unused.
Chauffe, 6/1/2021, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04363450 (history) (HCQPreP). Estimated 1,700 patient RCT with results unknown and over 2 years late.
Chevalier, 3/22/2023, retrospective, France, peer-reviewed, mean age 70.3, 24 authors. risk of death, 34.7% lower, RR 0.65, p = 0.19, treatment 7 of 55 (12.7%), control 109 of 535 (20.4%), NNT 13, odds ratio converted to relative risk.
risk of hospitalization, 19.1% lower, RR 0.81, p = 0.36, treatment 15 of 116 (12.9%), control 180 of 1,097 (16.4%), NNT 29, odds ratio converted to relative risk.
Chouhdari, 1/21/2024, Double Blind Randomized Controlled Trial, Iran, peer-reviewed, 14 authors, study period 20 August, 2020 - 20 October, 2020, dosage 800mg day 1, 200mg day 8, 200mg day 15, 200mg day 22, 200mg day 29, 200mg day 36, 200mg day 43, trial IRCT20200421047153N1. risk of hospitalization, 80.1% lower, RR 0.20, p = 0.25, treatment 0 of 439 (0.0%), control 2 of 432 (0.5%), NNT 216, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of case, 42.8% lower, RR 0.57, p = 0.005, treatment 36 of 439 (8.2%), control 61 of 432 (14.1%), NNT 17, adjusted per study, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, multivariable.
Connor, 8/24/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04352946 (history) (HERO). Estimated 374 patient RCT with results unknown and over 3 years late.
Cordtz, 8/27/2021, retrospective, population-based cohort, Denmark, peer-reviewed, 8 authors, study period 1 March, 2020 - 2 February, 2021. risk of hospitalization, 40.0% lower, HR 0.60, p = 0.39, treatment 1,170, control 1,363, adjusted per study.
Cordtz (B), 12/28/2020, retrospective, population-based cohort, Denmark, peer-reviewed, 10 authors. risk of hospitalization, 24.0% lower, HR 0.76, p = 0.67, treatment 3 of 2,722 (0.1%), control 38 of 26,718 (0.1%), NNT 3124, adjusted per study, time-dependent exposure model.
risk of hospitalization, 55.0% lower, HR 0.45, p = 0.28, treatment 3 of 2,722 (0.1%), control 38 of 26,718 (0.1%), adjusted per study, time-fixed exposure model.
Datta, 11/6/2020, retrospective, India, peer-reviewed, 7 authors. risk of case, 22.1% lower, RR 0.78, p = 0.47, treatment 16 of 146 (11.0%), control 19 of 135 (14.1%), NNT 32.
de la Iglesia, 9/2/2020, retrospective, database analysis, Spain, preprint, 17 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of hospitalization, 50.0% higher, RR 1.50, p = 1.00, treatment 3 of 687 (0.4%), control 2 of 688 (0.3%).
risk of case, 42.6% higher, RR 1.43, p = 0.15, treatment 42 of 648 (6.5%), control 30 of 660 (4.5%), suspected COVID-19.
risk of case, 7.8% lower, RR 0.92, p = 0.84, treatment 12 of 678 (1.8%), control 13 of 677 (1.9%), NNT 665, confirmed COVID-19.
Desbois, 7/20/2020, retrospective, France, preprint, mean age 58.8, 13 authors. risk of case, 16.9% lower, RR 0.83, p = 1.00, treatment 3 of 27 (11.1%), control 23 of 172 (13.4%), NNT 44.
Dev, 3/24/2021, retrospective, India, peer-reviewed, 5 authors. risk of case, 26.0% lower, RR 0.74, p = 0.003, treatment 260, control 499, any number of HCQ doses vs. no HCQ prophylaxis.
Dulcey, 5/31/2023, retrospective, Colombia, peer-reviewed, 8 authors. risk of case, 21.0% lower, OR 0.79, p = 0.27, treatment 322, control 645, RR approximated with OR.
Erden, 1/23/2022, retrospective, Turkey, peer-reviewed, 11 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 150.0% higher, RR 2.50, p = 1.00, treatment 1 of 6 (16.7%), control 0 of 3 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm).
risk of hospitalization, 75.0% lower, RR 0.25, p = 0.23, treatment 1 of 6 (16.7%), control 2 of 3 (66.7%), NNT 2.0.
Ferreira (B), 6/29/2020, retrospective, population-based cohort, database analysis, Portugal, peer-reviewed, 3 authors. risk of case, 47.1% lower, RR 0.53, p < 0.001, adjusted per study, odds ratio converted to relative risk.
Ferri, 8/27/2020, retrospective, Italy, peer-reviewed, survey, 29 authors. risk of COVID-19 case, 63.0% lower, RR 0.37, p = 0.01, treatment 9 of 994 (0.9%), control 16 of 647 (2.5%), NNT 64.
Finkelstein, 6/29/2023, retrospective, USA, peer-reviewed, 2 authors, study period January 2020 - September 2020. risk of case, 21.0% lower, OR 0.79, p < 0.001, treatment 13,932, control 27,864, adjusted per study, propensity score matching, multivariable, RR approximated with OR.
Fitzgerald, 2/5/2021, retrospective, USA, preprint, 34 authors, excluded in exclusion analyses: not fully adjusting for the baseline risk differences within systemic autoimmune patients. risk of case, 8.5% lower, RR 0.91, p = 0.54, treatment 65 of 1,072 (6.1%), control 200 of 3,594 (5.6%), adjusted per study, odds ratio converted to relative risk.
Fung, 10/1/2021, retrospective, population-based cohort, USA, peer-reviewed, 6 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of death, 13.0% lower, HR 0.87, p = 0.15, vs. past use (better match for systemic autoimmune diseases).
risk of hospitalization, 3.0% lower, HR 0.97, p = 0.63, vs. past use (better match for systemic autoimmune diseases).
risk of case, 9.0% lower, HR 0.91, p = 0.02, vs. past use (better match for systemic autoimmune diseases).
risk of death, 8.0% higher, HR 1.08, p = 0.26, vs. never used.
risk of hospitalization, 6.0% higher, HR 1.06, p = 0.13, vs. never used.
risk of case, 5.0% lower, HR 0.95, p = 0.03, vs. never used.
Gagneux-Brunon, 3/30/2022, Double Blind Randomized Controlled Trial, placebo-controlled, France, peer-reviewed, study period 14 April, 2020 - 30 March, 2022, trial NCT04328285 (history). 118 patient RCT with results unknown and over 2 years late.
Gendebien, 6/25/2020, retrospective, Belgium, peer-reviewed, survey, 9 authors, excluded in exclusion analyses: not fully adjusting for the baseline risk differences within systemic autoimmune patients. risk of case, 3.9% lower, RR 0.96, p = 0.93, treatment 12 of 152 (7.9%), control 6 of 73 (8.2%), NNT 308.
Gendelman, 5/5/2020, retrospective, database analysis, Israel, peer-reviewed, 5 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of case, 8.1% lower, RR 0.92, p = 0.88, treatment 3 of 36 (8.3%), control 1,314 of 14,484 (9.1%), NNT 135.
Gentry, 9/21/2020, retrospective, database analysis, USA, peer-reviewed, 6 authors. risk of death, 91.3% lower, RR 0.09, p = 0.10, treatment 0 of 10,703 (0.0%), control 7 of 21,406 (0.0%), NNT 3058, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), COVID-19 mortality within all patients.
risk of death, 90.7% lower, RR 0.09, p = 0.19, treatment 0 of 31 (0.0%), control 7 of 78 (9.0%), NNT 11, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), mortality for infected patients.
risk of case, 20.9% lower, RR 0.79, p = 0.27, treatment 31 of 10,703 (0.3%), control 78 of 21,406 (0.4%), NNT 1338, odds ratio converted to relative risk.
Gianfrancesco, 5/28/2020, retrospective, database analysis, multiple countries, peer-reviewed, 28 authors, excluded in exclusion analyses: not fully adjusting for the baseline risk differences within systemic autoimmune patients. risk of hospitalization, 3.3% lower, RR 0.97, p = 0.82, treatment 58 of 130 (44.6%), control 219 of 470 (46.6%), NNT 50, odds ratio converted to relative risk.
Goenka, 10/24/2020, retrospective, India, preprint, 11 authors. risk of IgG positive, 87.2% lower, RR 0.13, p = 0.03, treatment 1 of 77 (1.3%), control 115 of 885 (13.0%), NNT 8.6, adjusted per study, odds ratio converted to relative risk.
Granados-Montiel, 6/30/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Mexico, peer-reviewed, this trial uses multiple treatments in the treatment arm (combined with bromhexine) - results of individual treatments may vary, trial NCT04340349 (history) (ELEVATE). Estimated 214 patient RCT with results unknown and over 2 years late.
Grau-Pujol, 9/21/2020, Randomized Controlled Trial, Spain, peer-reviewed, 22 authors, study period 4 April, 2020 - 12 June, 2020. risk of case, 10.6% lower, RR 0.89, p = 1.00, treatment 1 of 142 (0.7%), control 1 of 127 (0.8%), NNT 1202.
Guillaume, 9/16/2021, retrospective, France, peer-reviewed, survey, 25 authors, study period 17 April, 2020 - 30 April, 2020, trial NCT04345159 (history), excluded in exclusion analyses: statistical analysis shows significant mismatch with prior research, potential overfitting. risk of hospitalization, 2.4% higher, RR 1.02, p = 1.00, treatment 2 of 181 (1.1%), control 3 of 278 (1.1%).
risk of case, 2.9% higher, RR 1.03, p = 0.96, treatment 6 of 181 (3.3%), control 12 of 278 (4.3%), adjusted per study, odds ratio converted to relative risk.
risk of case, 23.2% lower, RR 0.77, p = 0.63, treatment 6 of 181 (3.3%), control 12 of 278 (4.3%), NNT 100.
Gönenli, 12/16/2020, retrospective, Turkey, peer-reviewed, survey, mean age 36.0, 9 authors, study period 14 May, 2020 - 13 June, 2020. risk of pneumonia, 29.7% lower, RR 0.70, p = 0.77, treatment 3 of 148 (2.0%), control 12 of 416 (2.9%), NNT 117.
risk of case, 18.9% higher, RR 1.19, p = 0.58, treatment 8 of 148 (5.4%), control 20 of 416 (4.8%), odds ratio converted to relative risk.
Huang (D), 12/12/2023, retrospective, China, peer-reviewed, 9 authors, study period 1 January, 2023 - 28 February, 2023. risk of hospitalization, 43.4% lower, OR 0.57, p = 0.09, treatment 141, control 291, RR approximated with OR.
risk of case, 6.3% higher, RR 1.06, p = 0.25, treatment 118 of 141 (83.7%), control 229 of 291 (78.7%).
Huang, 6/16/2020, retrospective, China, peer-reviewed, 15 authors, excluded in exclusion analyses: significant unadjusted confounding possible. risk of hospitalization, 80.0% lower, RR 0.20, p < 0.001, treatment 8, control 1,247.
Huh, 12/19/2020, retrospective, database analysis, South Korea, peer-reviewed, 8 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of progression, 251.0% higher, RR 3.51, p = 0.11, treatment 5 of 8 (62.5%), control 873 of 2,797 (31.2%), adjusted per study, multivariate.
risk of case, 6.0% lower, RR 0.94, p = 0.82, treatment 17 of 122 (13.9%), control 7,324 of 43,924 (16.7%), adjusted per study, multivariate.
Isnardi, 10/6/2022, retrospective, Argentina, peer-reviewed, mean age 51.4, 198 authors, study period 13 August, 2020 - 31 July, 2021, trial NCT04568421 (history). risk of death, 33.9% lower, RR 0.66, p = 0.23, treatment 11 of 361 (3.0%), control 72 of 1,554 (4.6%), NNT 63, odds ratio converted to relative risk.
risk of severe case, 48.0% lower, RR 0.52, p = 0.02, treatment 14 of 361 (3.9%), control 117 of 1,554 (7.5%), NNT 27, odds ratio converted to relative risk.
risk of hospitalization, 17.0% lower, RR 0.83, p = 0.09, treatment 83 of 512 (16.2%), control 429 of 1,554 (27.6%), NNT 8.8, odds ratio converted to relative risk.
James, 4/30/2021, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04352933 (history) (PROLIFIC). Estimated 500 patient RCT with results unknown and over 3 years late.
Juneja, 1/7/2022, retrospective, India, peer-reviewed, 9 authors, study period 2 April, 2020 - 3 September, 2020, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of severe case, 141.8% higher, RR 2.42, p = 0.59, treatment 2 of 996 (0.2%), control 1 of 1,204 (0.1%).
risk of case, 6.4% higher, RR 1.06, p = 0.67, treatment 103 of 996 (10.3%), control 117 of 1,204 (9.7%).
Jung, 12/11/2020, retrospective, South Korea, peer-reviewed, 6 authors. risk of death, 59.3% lower, RR 0.41, p = 1.00, treatment 0 of 649 (0.0%), control 1 of 1,417 (0.1%), NNT 1417, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of case, 13.1% higher, RR 1.13, p = 0.86, treatment 15 of 649 (2.3%), control 31 of 1,417 (2.2%), adjusted per study.
Kadnur, 7/22/2020, prospective, India, peer-reviewed, mean age 31.2, 16 authors, study period 23 April, 2020 - 11 June, 2020. risk of case, 62.3% lower, RR 0.38, p = 0.01, treatment 10 of 258 (3.9%), control 15 of 100 (15.0%), NNT 9.0, odds ratio converted to relative risk, multivariate logistic regression.
Kamstrup, 6/1/2021, retrospective, population-based cohort, Denmark, peer-reviewed, 21 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of hospitalization, 44.0% higher, OR 1.44, p = 0.25, treatment 5,488, control 54,846, RR approximated with OR.
risk of case, 10.0% lower, HR 0.90, p = 0.23, treatment 188 of 5,488 (3.4%), control 2,040 of 54,846 (3.7%), NNT 340, adjusted Cox proportional hazards regression.
Khoubnasabjafari, 1/13/2021, retrospective, Iran, peer-reviewed, 10 authors. risk of case, 16.7% lower, RR 0.83, p = 0.59, treatment 34 of 1,436 (2.4%), control 12 of 422 (2.8%), NNT 210.
Khurana, 7/24/2020, retrospective, India, preprint, survey, 6 authors. risk of case, 51.0% lower, RR 0.49, p = 0.02, treatment 6 of 22 (27.3%), control 88 of 159 (55.3%), NNT 3.6, odds ratio converted to relative risk.
Klebanov, 7/1/2023, retrospective, USA, peer-reviewed, 10 authors. risk of death, 30.6% lower, RR 0.69, p = 0.80, treatment 3 of 3,074 (0.1%), control 83 of 58,995 (0.1%), NNT 2320.
risk of case, 5.9% higher, RR 1.06, p = 0.70, treatment 51 of 3,074 (1.7%), control 973 of 58,995 (1.6%), odds ratio converted to relative risk.
Konig, 5/7/2020, retrospective, database analysis, multiple countries, peer-reviewed, 11 authors, excluded in exclusion analyses: not fully adjusting for the baseline risk differences within systemic autoimmune patients; unadjusted results with no group details. risk of hospitalization, 3.0% lower, RR 0.97, p = 0.88, treatment 16 of 29 (55.2%), control 29 of 51 (56.9%), NNT 59.
Korkmaz, 6/1/2021, retrospective, Turkey, preprint, 4 authors. risk of death, 82.1% lower, RR 0.18, p = 0.19, treatment 0 of 385 (0.0%), control 2 of 299 (0.7%), NNT 150, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of case, 93.7% lower, RR 0.06, p < 0.001, treatment 2 of 395 (0.5%), control 24 of 299 (8.0%), NNT 13.
Küçükakkaş, 7/20/2021, retrospective, Turkey, preprint, 2 authors, excluded in exclusion analyses: minimal details of groups provided. risk of ICU admission, 42.9% higher, RR 1.43, p = 1.00, treatment 1 of 7 (14.3%), control 1 of 10 (10.0%).
Laplana, 9/9/2020, retrospective, Spain, peer-reviewed, survey, 3 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of case, 56.0% higher, RR 1.56, p = 0.24, treatment 17 of 319 (5.3%), control 11 of 319 (3.4%).
Liu (B), 2/5/2024, retrospective, China, peer-reviewed, 6 authors, study period December 2022 - February 2023. risk of severe case, 39.0% lower, OR 0.61, p = 0.26, treatment 55, control 246, adjusted per study, multivariable, model 2, RR approximated with OR.
Llanos-Cuentas, 2/28/2023, Randomized Controlled Trial, Peru, peer-reviewed, mean age 39.2, 10 authors, study period July 2020 - November 2020, trial NCT04414241 (history). risk of case, 69.0% higher, RR 1.69, p = 0.46, treatment 5 of 36 (13.9%), control 3 of 32 (9.4%), adjusted per study.
Loucera, 8/16/2022, retrospective, Spain, peer-reviewed, 8 authors, study period January 2020 - November 2020. risk of death, 69.3% lower, HR 0.31, p < 0.001, treatment 320, control 15,648, Cox proportional hazards, day 30.
MacFadden, 3/29/2022, retrospective, Canada, peer-reviewed, 9 authors, study period 15 January, 2020 - 31 December, 2020. risk of case, 12.0% lower, OR 0.88, p = 0.01, RR approximated with OR.
Macias, 5/16/2020, retrospective, database analysis, Spain, preprint, 12 authors, excluded in exclusion analyses: not fully adjusting for the baseline risk differences within systemic autoimmune patients. risk of hospitalization, 25.5% lower, RR 0.74, p = 1.00, treatment 1 of 290 (0.3%), control 2 of 432 (0.5%), NNT 846.
risk of case, 49.0% higher, RR 1.49, p = 0.53, treatment 5 of 290 (1.7%), control 5 of 432 (1.2%).
Mahto, 2/15/2021, retrospective, India, peer-reviewed, 6 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of IgG positive, 26.9% lower, RR 0.73, p = 0.38, treatment 9 of 89 (10.1%), control 84 of 600 (14.0%), NNT 26, unadjusted, odds ratio converted to relative risk.
Mathai, 11/6/2020, retrospective, India, peer-reviewed, 3 authors. risk of case, 89.5% lower, RR 0.10, p < 0.001, treatment 10 of 491 (2.0%), control 22 of 113 (19.5%), NNT 5.7.
risk of case, 88.5% lower, RR 0.12, p < 0.001, treatment 5 of 491 (1.0%), control 10 of 113 (8.8%), NNT 13, symptomatic.
Mathew, 2/28/2023, prospective, India, peer-reviewed, 8 authors, study period April 2020 - October 2021. risk of death, 20.0% lower, OR 0.80, p = 0.80, treatment 23, control 41, RR approximated with OR.
risk of hospitalization, no change, OR 1.00, p = 0.94, treatment 23, control 41, RR approximated with OR.
risk of severe case, 40.0% lower, OR 0.60, p = 0.37, treatment 23, control 41, RR approximated with OR.
McCullough, 8/20/2021, prospective, USA, preprint, 1 author. risk of case, 51.7% lower, RR 0.48, p = 0.01, treatment 13 of 101 (12.9%), control 32 of 120 (26.7%), NNT 7.2.
McKinnon, 12/23/2021, Double Blind Randomized Controlled Trial, USA, peer-reviewed, 10 authors, study period 7 April, 2020 - 15 December, 2020, trial NCT04341441 (history) (WHIP COVID-19). risk of symptomatic case, 2.5% lower, RR 0.98, p = 1.00, treatment 2 of 365 (0.5%), control 1 of 178 (0.6%), NNT 7219, daily and weekly HCQ combined.
risk of symptomatic case, no change, RR 1.00, p = 1.00, treatment 1 of 178 (0.6%), control 1 of 178 (0.6%), daily HCQ.
risk of symptomatic case, 4.8% lower, RR 0.95, p = 1.00, treatment 1 of 187 (0.5%), control 1 of 178 (0.6%), NNT 3698, weekly HCQ.
risk of symptomatic case, 53.3% lower, RR 0.47, p = 1.00, treatment 0 of 25 (0.0%), control 1 of 178 (0.6%), NNT 178, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), AD patients.
risk of case, 51.2% lower, RR 0.49, p = 0.60, treatment 2 of 365 (0.5%), control 2 of 178 (1.1%), NNT 174, daily and weekly HCQ combined.
risk of case, 50.0% lower, RR 0.50, p = 1.00, treatment 1 of 178 (0.6%), control 2 of 178 (1.1%), NNT 178, daily HCQ.
risk of case, 52.4% lower, RR 0.48, p = 0.61, treatment 1 of 187 (0.5%), control 2 of 178 (1.1%), NNT 170, weekly HCQ.
risk of case, 69.5% lower, RR 0.30, p = 1.00, treatment 0 of 25 (0.0%), control 2 of 178 (1.1%), NNT 89, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), AD patients.
Mitchell, 5/5/2020, retrospective, multiple countries, preprint, 2 authors, excluded in exclusion analyses: excessive unadjusted differences between groups. risk of death, 99.0% lower, RR 0.01, p < 0.001.
Moraes, 4/30/2021, Randomized Controlled Trial, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04384458 (history). Estimated 400 patient RCT with results unknown and over 3 years late.
Morales-Asencio, 4/1/2021, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04400019 (history) (PREVICHARM). Estimated 1,930 patient RCT with results unknown and over 3 years late.
Naggie, 8/25/2021, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, mean age 43.6, 23 authors, study period April 2020 - November 2020, trial NCT04334148 (history) (HERO-HCQ). risk of symptomatic case, 23.5% lower, RR 0.76, p = 0.18, treatment 41 of 683 (6.0%), control 53 of 676 (7.8%), NNT 54, odds ratio converted to relative risk, logistic regression.
risk of symptomatic case, 29.3% lower, RR 0.71, p = 0.18, treatment 41 of 683 (6.0%), control 53 of 676 (7.8%), NNT 54, odds ratio converted to relative risk, Mantel-Haenszel.
risk of symptomatic case, 50.5% lower, RR 0.49, p = 0.34, treatment 3 of 683 (0.4%), control 6 of 676 (0.9%), NNT 223, PCR confirmed.
Nanni, 9/30/2021, Randomized Controlled Trial, Italy, peer-reviewed, trial NCT04363827 (history) (PROTECT). Estimated 2,300 patient RCT with results unknown and over 2 years late.
Nasri, 1/27/2023, Randomized Controlled Trial, Iran, peer-reviewed, mean age 29.7, 11 authors, study period 11 August, 2020 - 11 November, 2020, trial IRCT20200414047076N1. risk of symptomatic case, 92.2% lower, RR 0.08, p = 0.03, treatment 0 of 70 (0.0%), control 6 of 73 (8.2%), NNT 12, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), severe cases.
risk of symptomatic case, 85.1% lower, RR 0.15, p = 0.003, treatment 2 of 70 (2.9%), control 14 of 73 (19.2%), NNT 6.1, moderate or severe cases.
risk of symptomatic case, 47.9% lower, RR 0.52, p = 0.16, treatment 7 of 70 (10.0%), control 14 of 73 (19.2%), NNT 11, all cases.
Niriella, 7/3/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial SLCTR/2020/011. 402 patient RCT with results unknown and over 3 years late.
Obrișcă, 9/28/2022, prospective, Romania, peer-reviewed, mean age 39.0, 12 authors, study period 26 February, 2020 - 1 May, 2021. risk of case, 86.7% lower, RR 0.13, p = 0.01, treatment 10 of 81 (12.3%), control 5 of 14 (35.7%), NNT 4.3, adjusted per study, odds ratio converted to relative risk, multivariable.
Oku, 9/6/2022, retrospective, Japan, peer-reviewed, 8 authors, study period 3 June, 2020 - 30 June, 2021. risk of death, 92.2% lower, RR 0.08, p = 1.00, treatment 0 of 14 (0.0%), control 11 of 206 (5.3%), NNT 19, unadjusted, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
risk of hospitalization, 11.5% lower, RR 0.88, p = 0.34, treatment 9 of 14 (64.3%), control 177 of 206 (85.9%), NNT 4.6, adjusted per study, odds ratio converted to relative risk, multivariable.
Opdam, 2/23/2022, retrospective, Netherlands, peer-reviewed, 9 authors. risk of hospitalization, 45.0% lower, OR 0.55, p = 0.18, treatment 8 of 81 (9.9%) cases, 59 of 396 (14.9%) controls, NNT 17, case control OR.
Oztas, 3/21/2022, retrospective, Turkey, peer-reviewed, 15 authors, excluded in exclusion analyses: not adjusting for the different baseline risk of systemic autoimmune patients; excessive unadjusted differences between groups. risk of hospitalization, 215.1% higher, RR 3.15, p = 0.36, treatment 3 of 317 (0.9%), control 1 of 333 (0.3%).
risk of symptomatic case, 40.1% higher, RR 1.40, p = 0.44, treatment 16 of 317 (5.0%), control 12 of 333 (3.6%).
risk of case, 5.0% higher, RR 1.05, p = 0.88, treatment 22 of 317 (6.9%), control 22 of 333 (6.6%).
Patel, 7/15/2022, retrospective, USA, preprint, mean age 60.0, 12 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of case, 46.3% lower, RR 0.54, p = 0.001, treatment 28 of 18,358 (0.2%), control 223 of 78,509 (0.3%), cases vs. total person-months, unadjusted.
Patil, 8/24/2021, prospective, India, preprint, 21 authors. risk of death, 65.9% lower, RR 0.34, p = 0.10, treatment 5,266, control 3,946.
risk of case, 9.1% lower, RR 0.91, p = 0.43, treatment 167 of 5,266 (3.2%), control 147 of 3,946 (3.7%), NNT 181, adjusted per study.
Pellegrini, 9/12/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial ACTRN12620000501943 (COVID-SHIELD). Estimated 2,250 patient RCT with results unknown and over 3 years late.
Pham, 3/2/2021, retrospective, USA, peer-reviewed, 5 authors. risk of death, 19.7% lower, RR 0.80, p = 0.77, treatment 2 of 14 (14.3%), control 5 of 28 (17.9%), NNT 28, odds ratio converted to relative risk, univariate.
risk of ICU admission, 35.5% higher, RR 1.35, p = 0.61, treatment 4 of 14 (28.6%), control 6 of 28 (21.4%), odds ratio converted to relative risk, univariate.
Piñana, 8/25/2020, retrospective, Spain, peer-reviewed, median age 64.0, 46 authors, study period 1 March, 2020 - 15 May, 2020. risk of death, 36.0% lower, OR 0.64, p = 0.11, RR approximated with OR.
Polo, 8/5/2022, Double Blind Randomized Controlled Trial, placebo-controlled, Spain, peer-reviewed, median age 38.0, 189 authors, study period 15 April, 2020 - 11 July, 2021, trial NCT04334928 (history) (EPICOS). risk of symptomatic case, 51.0% lower, RR 0.49, p = 0.79, treatment 3 of 224 (1.3%), control 5 of 211 (2.4%), NNT 97, Kaplan–Meier, primary outcome.
risk of case, 27.0% lower, RR 0.73, p = 0.31, treatment 21 of 224 (9.4%), control 23 of 211 (10.9%), Kaplan–Meier.
Raabe, 7/3/2022, prospective, USA, preprint, 7 authors, trial NCT04354870 (history). risk of symptomatic case, 82.2% lower, RR 0.18, p = 0.17, treatment 1 of 59 (1.7%), control 2 of 21 (9.5%), NNT 13.
risk of symptomatic case, 88.4% lower, RR 0.12, p = 0.07, treatment 0 of 59 (0.0%), control 2 of 21 (9.5%), NNT 10, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm), fever.
risk of case, 28.8% lower, RR 0.71, p = 0.65, treatment 4 of 59 (6.8%), control 2 of 21 (9.5%), NNT 36, seroconversion.
Rabe, 11/22/2023, retrospective, United Kingdom, peer-reviewed, mean age 45.2, 7 authors, study period 1 May, 2020 - 31 October, 2020. risk of case, 28.6% lower, RR 0.71, p = 0.22, treatment 24 of 3,248 (0.7%), control 30 of 2,897 (1.0%), NNT 337.
Rajasingham, 9/21/2020, Randomized Controlled Trial, USA, peer-reviewed, 22 authors, study period 6 April, 2020 - 13 July, 2020, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04328467 (history) (COVID PREP). risk of hospitalization, 50.1% lower, RR 0.50, p = 1.00, treatment 1 of 989 (0.1%), control 1 of 494 (0.2%), NNT 987, COVID-19.
risk of hospitalization, 39.0% lower, RR 0.61, p = 0.34, treatment 11 of 989 (1.1%), control 9 of 494 (1.8%), NNT 141, all cause.
risk of case, 27.0% lower, HR 0.73, p = 0.12, treatment 58 of 989 (5.9%), control 39 of 494 (7.9%), NNT 49.
Rangel, 1/10/2021, retrospective, USA, peer-reviewed, 5 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of death, 25.1% lower, RR 0.75, p = 0.77, treatment 4 of 50 (8.0%), control 11 of 103 (10.7%), NNT 37, from all patients.
risk of hospitalization, 22.2% lower, RR 0.78, p = 0.29, treatment 17 of 50 (34.0%), control 45 of 103 (43.7%), NNT 10.
hospitalization time, 41.2% lower, relative time 0.59, p = 0.12, treatment 21, control 54.
Rao, 12/4/2021, prospective, India, peer-reviewed, 8 authors, excluded in exclusion analyses: unadjusted results with minimal group details. risk of case, 11.0% lower, RR 0.89, p = 0.68, treatment 16 of 273 (5.9%), control 67 of 1,021 (6.6%), NNT 143.
Rentsch, 9/9/2020, retrospective, population-based cohort, database analysis, United Kingdom, peer-reviewed, 34 authors, excluded in exclusion analyses: not fully adjusting for the baseline risk differences within systemic autoimmune patients; medication adherence unknown and may significantly change results. risk of death, 3.0% higher, HR 1.03, p = 0.83, treatment 70 of 30,569 (0.2%), control 477 of 164,068 (0.3%), adjusted per study.
Revollo, 11/21/2020, retrospective, propensity score matching, Spain, peer-reviewed, 16 authors. risk of case, 23.0% lower, RR 0.77, p = 0.52, treatment 16 of 69 (23.2%), control 65 of 418 (15.6%), adjusted per study, PSM, risk of PCR+.
risk of case, 43.0% higher, RR 1.43, p = 0.42, treatment 17 of 60 (28.3%), control 62 of 404 (15.3%), adjusted per study, PSM, risk of IgG+.
Rojas-Serrano, 5/16/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Mexico, peer-reviewed, median age 31.5, 8 authors, study period 14 April, 2020 - 31 March, 2021, trial NCT04318015 (history). risk of symptomatic case, 82.0% lower, RR 0.18, p = 0.12, treatment 1 of 62 (1.6%), control 6 of 65 (9.2%), NNT 13, adjusted per study.
Sahebari, 9/7/2022, retrospective, Iran, peer-reviewed, 6 authors. risk of case, 56.0% lower, RR 0.44, p = 0.02, treatment 10 of 108 (9.3%), control 56 of 368 (15.2%), odds ratio converted to relative risk.
Salesi, 12/18/2023, retrospective, Iran, peer-reviewed, 2 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of severe case, 85.0% lower, RR 0.15, p = 0.003, treatment 2 of 44 (4.5%), control 10 of 33 (30.3%), NNT 3.9.
risk of moderate/severe case, 18.2% lower, RR 0.82, p = 0.35, treatment 24 of 44 (54.5%), control 22 of 33 (66.7%), NNT 8.2.
Salvarani, 8/6/2020, retrospective, population-based cohort, Italy, peer-reviewed, 18 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of case, 6.0% lower, OR 0.94, p = 0.75, RR approximated with OR.
Samajdar, 11/17/2021, retrospective, India, peer-reviewed, 9 authors, study period 1 September, 2020 - 31 December, 2020, dosage not specified, excluded in exclusion analyses: minimal details provided; unadjusted results with no group details; results may be significantly affected by survey bias. risk of case, 74.5% lower, RR 0.25, p < 0.001, treatment 12 of 129 (9.3%), control 29 of 81 (35.8%), NNT 3.8, odds ratio converted to relative risk, physician survey.
risk of case, 48.6% lower, RR 0.51, p = 0.03, treatment 11 of 109 (10.1%), control 39 of 200 (19.5%), NNT 11, odds ratio converted to relative risk, combined ivermectin or HCQ in community.
Santos, 7/27/2020, prospective, Spain, peer-reviewed, median age 78.4, mean age 75.3, 6 authors, study period 1 March, 2020 - 1 June, 2020, excluded in exclusion analyses: unadjusted results with no group details. risk of death, 92.5% lower, RR 0.08, p = 0.19, treatment 0 of 7 (0.0%), control 10 of 31 (32.3%), NNT 3.1, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).
Satti, 4/22/2022, retrospective, Qatar, peer-reviewed, 6 authors, excluded in exclusion analyses: unadjusted results with no group details. risk of case, 61.5% lower, RR 0.39, p = 0.04, treatment 10 of 63 (15.9%), control 7 of 17 (41.2%), NNT 4.0.
Scirocco, 10/17/2023, retrospective, Italy, peer-reviewed, mean age 48.9, 14 authors. risk of death/intubation, 41.3% lower, OR 0.59, p = 0.38, treatment 183, control 444, meta analysis of SLE and RA, RR approximated with OR.
risk of death/intubation, 65.0% lower, OR 0.35, p = 0.03, treatment 71, control 32, SLE, RR approximated with OR.
risk of death/intubation, no change, OR 1.00, p = 0.87, treatment 112, control 412, RA, RR approximated with OR.
Seet, 4/14/2021, Cluster Randomized Controlled Trial, Singapore, peer-reviewed, 15 authors, study period 13 May, 2020 - 31 August, 2020, dosage 400mg day 1, 200mg days 2-42, this trial compares with another treatment - results may be better when compared to placebo, trial NCT04446104 (history). risk of symptomatic case, 35.1% lower, RR 0.65, p = 0.047, treatment 29 of 432 (6.7%), control 64 of 619 (10.3%), NNT 28.
risk of case, 32.0% lower, RR 0.68, p = 0.009, treatment 212 of 432 (49.1%), control 433 of 619 (70.0%), NNT 4.8, adjusted per study, odds ratio converted to relative risk, model 6.
Sen, 4/24/2023, retrospective, multiple countries, peer-reviewed, survey, 8 authors, study period 31 January, 2022 - 21 May, 2022, COVAD trial. risk of PASC, 40.0% lower, OR 0.60, p = 0.08, RR approximated with OR.
Shahrin, 12/7/2022, retrospective, Bangladesh, peer-reviewed, median age 34.0, 11 authors, study period 31 March, 2020 - 12 July, 2020. risk of case, 87.8% higher, RR 1.88, p = 0.09, treatment 43 of 230 (18.7%), control 11 of 106 (10.4%), adjusted per study, odds ratio converted to relative risk, multivariable.
risk of case, 8.0% lower, OR 0.92, p = 0.89, adjusted per study, excluding the first 14 days and including participants that worked for at least 16 days, multivariable, RR approximated with OR.
Shaw, 7/1/2021, retrospective, USA, peer-reviewed, 10 authors, study period 1 March, 2020 - 15 May, 2020. risk of case, 13.0% lower, OR 0.87, p = 0.006, treatment 45, control 99, adjusted per study, propensity score matching, multivariable, RR approximated with OR.
Shukla, 12/13/2022, retrospective, India, peer-reviewed, survey, 31 authors, study period July 2021 - October 2021, trial CTRI/2021/06/034255. risk of PASC, 5.0% lower, RR 0.95, p = 0.78, treatment 22 of 76 (28.9%), control 184 of 603 (30.5%), NNT 64, odds ratio converted to relative risk.
Singer, 8/5/2020, retrospective, database analysis, USA, peer-reviewed, 3 authors, excluded in exclusion analyses: not fully adjusting for the baseline risk differences within systemic autoimmune patients. risk of case, 9.0% higher, RR 1.09, p = 0.62, treatment 55 of 10,700 (0.5%), control 104 of 22,058 (0.5%).
Strangfeld, 1/27/2021, retrospective, multiple countries, peer-reviewed, 37 authors, study period 24 March, 2020 - 1 July, 2020. risk of death, 48.0% lower, RR 0.52, p < 0.001, treatment 27 of 426 (6.3%), control 124 of 739 (16.8%), NNT 9.6, adjusted per study, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, HCQ/CQ vs. no DMARD therapy, multivariable.
Sukumar, 11/14/2022, retrospective, India, peer-reviewed, survey, 5 authors, study period July 2020 - September 2020. risk of case, 37.6% lower, OR 0.62, p = 0.30, treatment 10 of 57 (17.5%) cases, 15 of 59 (25.4%) controls, NNT 8.6, case control OR.
Syed, 5/17/2021, Randomized Controlled Trial, Pakistan, peer-reviewed, 8 authors, study period 1 May, 2020 - 25 September, 2020, trial NCT04359537 (history). risk of symptomatic case, 59.7% higher, RR 1.60, p = 0.41, treatment 10 of 48 (20.8%), control 6 of 46 (13.0%), group 1.
risk of symptomatic case, 110.5% higher, RR 2.10, p = 0.13, treatment 14 of 51 (27.5%), control 6 of 46 (13.0%), group 2.
risk of symptomatic case, 16.4% lower, RR 0.84, p = 0.77, treatment 6 of 55 (10.9%), control 6 of 46 (13.0%), NNT 47, group 3.
risk of case, 91.7% higher, RR 1.92, p = 0.12, treatment 15 of 38 (39.5%), control 7 of 34 (20.6%), group 1.
risk of case, 136.6% higher, RR 2.37, p = 0.02, treatment 19 of 39 (48.7%), control 7 of 34 (20.6%), group 2.
risk of case, 21.4% higher, RR 1.21, p = 0.77, treatment 8 of 32 (25.0%), control 7 of 34 (20.6%), group 3.
Tirupakuzhi Vijayaraghavan, 6/1/2022, Randomized Controlled Trial, India, peer-reviewed, mean age 32.1, 21 authors, study period 29 June, 2020 - 4 February, 2021, trial CTRI/2020/05/025067 (HOPE). risk of progression, 196.2% higher, RR 2.96, p = 1.00, treatment 1 of 211 (0.5%), control 0 of 203 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), ICU/HDU.
risk of hospitalization, 51.9% lower, RR 0.48, p = 0.62, treatment 1 of 211 (0.5%), control 2 of 203 (1.0%), NNT 196.
risk of case, 14.2% lower, RR 0.86, p = 0.73, treatment 11 of 211 (5.2%), control 12 of 203 (5.9%), NNT 143, adjusted per study, odds ratio converted to relative risk, confirmed cases, multivariable.
risk of case, 5.7% lower, RR 0.94, p = 0.90, treatment 12 of 211 (5.7%), control 12 of 203 (5.9%), NNT 446, adjusted per study, odds ratio converted to relative risk, multivariable.
Trefond, 1/27/2021, retrospective, France, peer-reviewed, 21 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients; significant unadjusted confounding possible; excessive unadjusted differences between groups. risk of death, 16.6% higher, RR 1.17, p = 0.80, treatment 4 of 68 (5.9%), control 12 of 183 (6.6%), adjusted per study, odds ratio converted to relative risk.
risk of death/ICU, 78.2% higher, RR 1.78, p = 0.21, treatment 8 of 71 (11.3%), control 18 of 191 (9.4%), adjusted per study, odds ratio converted to relative risk.
risk of hospitalization, 44.9% higher, RR 1.45, p = 0.12, treatment 24 of 71 (33.8%), control 53 of 191 (27.7%), adjusted per study, odds ratio converted to relative risk.
Treluyer, 6/18/2020, Randomized Controlled Trial, placebo-controlled, trial NCT04344379 (history) (PREP-COVID). 122 patient RCT with results unknown and over 3 years late.
Ugarte-Gil, 2/16/2022, retrospective, multiple countries, peer-reviewed, 58 authors. risk of severe case, 44.4% lower, OR 0.56, p = 0.007, treatment 665, control 230, adjusted per study, inverted to make OR<1 favor treatment, HCQ/CQ only vs. no SLE medication, multivariable, RR approximated with OR.
Vivanco-Hidalgo, 3/9/2021, retrospective, Spain, peer-reviewed, 8 authors, excluded in exclusion analyses: not fully adjusting for the different baseline risk of systemic autoimmune patients. risk of hospitalization, 46.0% higher, RR 1.46, p = 0.10, treatment 40 of 6,746 (0.6%), control 50 of 13,492 (0.4%), adjusted per study.
risk of case, 8.0% higher, RR 1.08, p = 0.50, treatment 97 of 6,746 (1.4%), control 183 of 13,492 (1.4%), adjusted per study.
White, 3/22/2022, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04303507 (history) (COPCOV). 4,652 patient RCT with results unknown and over 2 years late.
Yadav (B), 7/11/2022, retrospective, India, peer-reviewed, mean age 34.1, 3 authors, study period 21 August, 2020 - 20 November, 2020. risk of seropositive, 20.0% lower, OR 0.80, p = 0.10, treatment 1,255, control 969, adjusted per study, multivariable, RR approximated with OR.
Yadav (C), 9/30/2020, retrospective, India, preprint, 11 authors. risk of hospitalization, 82.4% lower, RR 0.18, p = 0.01, treatment 2 of 279 (0.7%), control 9 of 221 (4.1%), NNT 30, PCR+.
risk of IgG+, 41.8% lower, RR 0.58, p = 0.049, treatment 17 of 178 (9.6%), control 27 of 221 (12.2%), odds ratio converted to relative risk, multivariate logistic regression.
risk of IgG+, 79.0% lower, RR 0.21, p = 0.09, treatment 1 of 39 (2.6%), control 27 of 221 (12.2%), NNT 10, HCQ >10 weeks.
risk of IgG+, 52.4% lower, RR 0.48, p = 0.14, treatment 5 of 86 (5.8%), control 27 of 221 (12.2%), NNT 16, HCQ 6-10 weeks.
risk of IgG+, 69.9% higher, RR 1.70, p = 0.12, treatment 11 of 53 (20.8%), control 27 of 221 (12.2%), HCQ <6 weeks.
Zhong, 7/3/2020, retrospective, database analysis, China, peer-reviewed, 20 authors. risk of case, 91.0% lower, RR 0.09, p = 0.04, treatment 7 of 16 (43.8%), control 20 of 27 (74.1%), NNT 3.3, adjusted per study.
Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other outcomes are used in outcome specific analyses.
Abu-Helalah, 1/31/2021, Randomized Controlled Trial, trial NCT04597775 (history) (APCC-19). Estimated 93 patient RCT with results unknown and over 3 years late.
Al Ansari, 12/31/2021, Double Blind Randomized Controlled Trial, trial NCT04437693 (history) (HCQ-COVID19). Estimated 500 patient RCT with results unknown and over 2 years late.
Barnabas, 12/7/2020, Randomized Controlled Trial, USA, peer-reviewed, 30 authors, study period 31 March, 2020 - 21 August, 2020, trial NCT04328961 (history) (HCQ COVID-19 PEP). risk of hospitalization, 3.7% higher, RR 1.04, p = 1.00, treatment 1 of 407 (0.2%), control 1 of 422 (0.2%).
risk of case, 27.0% higher, HR 1.27, p = 0.33, treatment 43 of 353 (12.2%), control 33 of 336 (9.8%), adjusted per study, day 14 symptomatic mITT PCR+ AIM.
risk of case, 23.0% higher, HR 1.23, p = 0.41, treatment 40 of 317 (12.6%), control 32 of 309 (10.4%), adjusted per study, day 14 symptomatic mITT PCR+ IDWeek.
risk of case, 10.0% higher, HR 1.10, p = 0.66, treatment 53 of 353 (15.0%), control 45 of 336 (13.4%), adjusted per study, day 14 PCR+ mITT AIM.
risk of case, 1.0% lower, HR 0.99, p = 0.97, treatment 46 of 317 (14.5%), control 43 of 309 (13.9%), adjusted per study, day 14 PCR+ mITT IDWeek.
risk of case, 19.0% lower, HR 0.81, p = 0.23, treatment 82 of 387 (21.2%), control 99 of 393 (25.2%), NNT 25, adjusted per study, day 14 PCR+ ITT AIM.
Borrie, 4/30/2021, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04397328 (history). Estimated 336 patient RCT with results unknown and over 2 years late.
Boulware (B), 6/3/2020, Randomized Controlled Trial, USA, peer-reviewed, 24 authors, study period 17 March, 2020 - 6 May, 2020, this trial compares with another treatment - results may be better when compared to placebo. risk of case, 17.0% lower, RR 0.83, p = 0.35, treatment 49 of 414 (11.8%), control 58 of 407 (14.3%), NNT 41.
risk of case, 25.1% lower, RR 0.75, p = 0.22, treatment 32 of 414 (7.7%), control 42 of 407 (10.3%), NNT 39, probable COVID-19 cases.
Dhibar, 1/7/2023, Double Blind Randomized Controlled Trial, placebo-controlled, India, peer-reviewed, mean age 35.0, 14 authors, study period 22 March, 2021 - 17 June, 2021, trial NCT04858633 (history). risk of symptomatic case, 26.7% lower, RR 0.73, p = 0.32, treatment 17 of 574 (3.0%), control 24 of 594 (4.0%), NNT 93.
risk of case, 21.2% lower, RR 0.79, p = 0.21, treatment 16 of 574 (2.8%), control 21 of 594 (3.5%), NNT 134, PCR+.
risk of case, 8.0% lower, RR 0.92, p = 0.21, treatment 24 of 574 (4.2%), control 27 of 594 (4.5%), NNT 275.
Dhibar (B), 11/6/2020, prospective, India, peer-reviewed, 13 authors, trial NCT04408456 (history). risk of symptomatic case, 43.9% lower, RR 0.56, p = 0.21, treatment 6 of 132 (4.5%), control 15 of 185 (8.1%), NNT 28, adjusted per study.
risk of case, 50.0% lower, RR 0.50, p = 0.04, treatment 10 of 132 (7.6%), control 28 of 185 (15.1%), NNT 13, adjusted per study, PCR+.
risk of case, 41.0% lower, RR 0.59, p = 0.03, treatment 14 of 132 (10.6%), control 36 of 185 (19.5%), NNT 11, adjusted per study.
Ghanem-Zoubi, 6/30/2022, Randomized Controlled Trial, trial NCT04438837 (history). Estimated 582 patient RCT with results unknown and over 1.5 years late.
González, 10/31/2021, Double Blind Randomized Controlled Trial, placebo-controlled, Spain, peer-reviewed, trial NCT04410562 (history). 129 patient RCT with results unknown and over 2 years late.
Mitjà (B), 7/26/2020, Randomized Controlled Trial, Spain, peer-reviewed, 49 authors, study period 17 March, 2020 - 28 April, 2020, BCN-PEP-CoV2 trial. risk of death, 45.6% lower, RR 0.54, p = 0.39, treatment 4 of 1,196 (0.3%), control 8 of 1,301 (0.6%), NNT 357, per supplemental appendix table S7, excluding patient that did not take any study medication and had an unknown cause of death.
risk of hospitalization, 16.8% lower, RR 0.83, p = 0.71, treatment 13 of 1,196 (1.1%), control 17 of 1,301 (1.3%), NNT 455, per supplemental appendix table S7, excluding patient that did not take any study medication and had an unknown cause of death.
baseline PCR- risk of cases, 32.0% lower, RR 0.68, p = 0.27, treatment 29 of 958 (3.0%), control 45 of 1,042 (4.3%), NNT 77.
Polat, 9/30/2020, prospective, Turkey, peer-reviewed, 3 authors. risk of case, 57.0% lower, RR 0.43, p = 0.03, treatment 12 of 138 (8.7%), control 14 of 70 (20.0%), NNT 8.8.
Sarwar (B), 8/30/2020, Double Blind Randomized Controlled Trial, placebo-controlled, trial NCT04346667 (history) (PEACE). 125 patient RCT with results unknown and over 3 years late.
Shabani, 8/10/2021, prospective, Iran, peer-reviewed, 16 authors. risk of symptomatic case, 19.0% lower, RR 0.81, p = 1.00, treatment 2 of 51 (3.9%), control 3 of 62 (4.8%), NNT 109, day 7.
risk of case, 6.4% higher, RR 1.06, p = 1.00, treatment 7 of 51 (13.7%), control 8 of 62 (12.9%), day 7, PCR+ and symptomatic.
risk of case, 21.6% higher, RR 1.22, p = 0.78, treatment 7 of 51 (13.7%), control 7 of 62 (11.3%), day 7, PCR+ only.
Simova (B), 11/12/2020, retrospective, Bulgaria, peer-reviewed, 5 authors. risk of case, 92.7% lower, RR 0.07, p = 0.01, treatment 0 of 156 (0.0%), control 3 of 48 (6.2%), NNT 16, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).