Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial
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, average treatment delay 5.0 days, trial NCT04332991 (history)
JAMA | Original Investigation
Effect of Hydroxychloroquine on Clinical Status at 14 Days
in Hospitalized Patients With COVID-19
A Randomized Clinical Trial
Wesley H. Self, MD, MPH; Matthew W. Semler, MD; Lindsay M. Leither, DO; Jonathan D. Casey, MD, MSc; Derek C. Angus, MD, MPH;
Roy G. Brower, MD; Steven Y. Chang, MD, PhD; Sean P. Collins, MD; John C. Eppensteiner, MD; Michael R. Filbin, MD; D. Clark Files, MD;
Kevin W. Gibbs, MD; Adit A. Ginde, MD, MPH; Michelle N. Gong, MD, MS; Frank E. Harrell Jr, PhD; Douglas L. Hayden, PhD;
Catherine L. Hough, MD, MSc; Nicholas J. Johnson, MD; Akram Khan, MD; Christopher J. Lindsell, PhD; Michael A. Matthay, MD;
Marc Moss, MD; Pauline K. Park, MD; Todd W. Rice, MD; Bryce R. H. Robinson, MD, 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, MD; B. Taylor Thompson, MD;
Samuel M. Brown, MD, MS; for the National Heart, Lung, and Blood Institute PETAL Clinical Trials Network
IMPORTANCE Data on the efficacy of hydroxychloroquine for the treatment of coronavirus
disease 2019 (COVID-19) are needed.
OBJECTIVE To determine whether hydroxychloroquine is an efficacious treatment for adults
Audio and Supplemental
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..
is less effective
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