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0 0.5 1 1.5 2+ Mortality -6% Improvement Relative Risk Mortality, day 14 -51% 7-point scale, day 28 -3% 7-point scale, day 14 2% 7-point scale, day 14 (b) 39% HCQ  ORCHID  LATE TREATMENT  DB RCT Is late treatment with HCQ beneficial for COVID-19? Double-blind RCT 477 patients in the USA (April - June 2020) No significant difference in outcomes seen Self et al., JAMA, November 2020 Favors HCQ Favors control

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial

Self et al., JAMA, doi:10.1001/jama.2020.22240, ORCHID, NCT04332991
Nov 2020  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now known with p < 0.00000000001 from 422 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Early terminated very late stage (65% on supplemental oxygen) RCT with 242 HCQ and 237 control patients showing no significant difference in outcomes.
For the subgroup not on supplemental oxygen at baseline (relatively early treatment), the odds ratio for the 7 point outcome scale is: aOR 0.61 [0.34-1.08].
Dosage may be too low:
Dose in first 24 hours - 1g (compare to Boulware et al. 2g)
Dose in 5 days - 2.4g (compare to Boulware et al. 3.8g)
Dosage note: Boulware 2g within 24 hours includes the second day dose. Note two important differences with the RECOVERY/SOLIDARITY dosage which is believed to be dangerously high - in RECOVERY/SOLIDARITY the total dose is much higher, which is problematic because the half-life of HCQ is very long, and it is given to patients that are already in very serious condition.
Note the paper reports primary outcome values with OR>1 favoring HCQ, we have converted to OR<1 favoring HCQ. Subgroup analysis is in the supplemental appendix.
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.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Self et al., 9 Nov 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).
This PaperHCQAll
Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19
MD, MPH Wesley H Self, MD; Matthew W Semler, DO; Lindsay M Leither, MD, MSc Jonathan D Casey, MD, MPH Derek C Angus, MD Roy G Brower, MD, PhD Steven Y Chang, MD; Sean P Collins, MD John C Eppensteiner, MD Michael R Filbin, D Clark Files, MD Kevin W Gibbs, MD, MPH Adit A Ginde, MD Michelle N Gong, MS Frank E Harrell Jr, PhD Douglas L Hayden, MD, MSc Catherine L Hough, MD Nicholas J Johnson, MD Akram Khan, PhD Christopher J Lindsell, MD Michael A Matthay, MD Marc Moss, MD Pauline K Park, MD Todd W Rice, MD Bryce R H Robinson, MS David A Schoenfeld, PhD Nathan I Shapiro, MD, MPH Jay S Steingrub, MD Christine A Ulysse, MS Alexandra Weissman, MD, MPH Donald M Yealy, B Taylor Thompson, MD; Samuel M Brown
JAMA, doi:10.1001/jama.2020.22240
OBJECTIVE To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). MAIN OUTCOMES AND MEASURES The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. RESULTS Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). CONCLUSIONS AND RELEVANCE Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.
Author Contributions: Drs Schoenfeld and Hayden 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. Drs Schoenfeld and Self take responsibility for the trial overall. Conflict of Interest Disclosures: Dr Self reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and personal fees from Aerpio Pharmaceuticals outside the submitted work. Dr Semler reported receiving grants from the NHLBI during the conduct of the study. Dr Leither reported receiving grants from the NHLBI during the conduct of the study. Dr Casey reported receiving grants from the NHLBI during the conduct of the study. Dr Angus reported receiving grants from the NHLBI and National Center for Advancing Translational Sciences (NCATS) during the conduct of the study and personal fees from Ferring Pharmaceuticals, Bristol-Myers Squibb, and Bayer AG and stock from Alung Technologies. Dr Angus has patents pending through Ferring Pharmaceuticals and the University of Pittsburgh. Dr Chang reported receiving grants from the NHLBI during the conduct of the study and personal fees from PureTech Health and LaJolla Pharmaceuticals outside the submitted work. Dr Collins reported receiving grants from the NHLBI and personal fees from Vir Biotechnology outside the submitted U01HL123020). The REDCap data tools used for this study were supported by a grant from NCATS..
Administrative, Self, Semler, Casey, Angus et al., Supervision: Self
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Late treatment
is less effective
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