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0 0.5 1 1.5 2+ Mortality 66% Improvement Relative Risk Hospitalization 24% Viral clearance 4% HCQ  TOGETHER  LATE TREATMENT  DB RCT Is late treatment with HCQ beneficial for COVID-19? Double-blind RCT 441 patients in Brazil (June - September 2020) Lower hospitalization with HCQ (not stat. sig., p=0.57) Reis et al., JAMA Network Open, April 2021 Favors HCQ Favors control

Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19 The TOGETHER Randomized Clinical Trial

Reis et al., JAMA Network Open, doi:10.1001/jamanetworkopen.2021.6468, TOGETHER, NCT04403100
Apr 2021  
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Early terminated RCT in Brazil showing lower mortality and hospitalization with HCQ, but not reaching statistical significance. Although the title includes "early treatment", treatment was relatively late, with most patients being over 5 days from the onset of symptoms. Adverse events were lower in the HCQ group compared to the control group.
This trial appears to have been terminated at 45% enrollment while showing ≥70% probability of superiority. The futility threshold was not reported, but it would be highly unusual for it to be as high as 70%
The paper indicates the placebo was talc, however the trial protocol shows the "placebo" as vitamin C, for which there are 7 COVID-19 treatment studies as of April 2021 that collectively show significant efficacy.
Results differ significantly from those reported prior to publication. Prior to publication, authors reported an RR for hospitalization or death of 1.0 [0.45-2.21]
Viral load measured by PCR may not accurately reflect infectious virus measured by viral culture. Porter show that viral load early in infection was correlated with infectious virus, but viral load late in infection could be high even with low or undetectable infectious virus. Assessing viral load later in infection may underestimate reductions in infectious virus with treatment.
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.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Reis et al., 22 Apr 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).
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Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19
MD Gilmar Reis, Eduardo Augusto Dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Gurmit Singh, Jay J H Park, Jamie I Forrest, Ofir Harari, Castilho Vitor Quirino Dos Santos, Ana Paula Figueiredo Guimarães De Almeida, Adhemar Dias De Figueiredo Neto, Leonardo Cançado Monteiro Savassi, RN Aline Cruz Milagres, Mauro Martins Teixeira, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, Rosemary Oliveira, PhD Edward J Mills
JAMA Network Open, doi:10.1001/jamanetworkopen.2021.6468
IMPORTANCE Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. OBJECTIVE To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. MAIN OUTCOMES AND MEASURES The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. RESULTS Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavirritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91
ARTICLE INFORMATION Author Contributions: Drs Reis and Mills had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Reis, E. Conflict of Interest Disclosures: None reported. Funding/Support: The trial was supported by the Bill and Melinda Gates Foundation. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Dr. Reis wishes to acknowledge particularly here the role of mayors and public health authorities in Brazil (a complete list can be found in the eAppendix of Supplement 2). The TOGETHER Investigators
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Late treatment
is less effective
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