COVID-19 Evidence Alerts
from McMaster PLUSTM

Current best evidence for clinical care (more info)

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Treatment Self WH, Semler MW, Leither LM, et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020 Dec 1;324(21):2165-2176. doi: 10.1001/jama.2020.22240.

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 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.

Trial Registration: NCT04332991.

Discipline / Specialty Area Score
Intensivist/Critical Care
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Hospital Doctor/Hospitalists
Internal Medicine
Infectious Disease
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

The editorial with this article is also excellent. The naysayers will argue about adding zinc and whatever adds to HCQ. Until we see a study showing that some combo works, these studies seem like we're whipping a dead horse.

General Internal Medicine-Primary Care(US) rater

This double-blind controlled trial of hospitalized patients with COVID-19 infection showed that hydroxychloroquine is not effective in improving clinical status nor was it effective in decreasing the death rate. The trial was stopped early due to futility.

General Internal Medicine-Primary Care(US) rater

I agree with the authors that hydroxychloroquine is not beneficial for adults hospitalized with COVID-19. The patients in this trial were very sick, given that 10% were dead and 11% still in hospital at 28 days. But is there - or will there be - a trial of hydroxychloroquine in persons not needing hospitalization? If such a trial were positive, hydroxychloroquine would then be to COVID-19 what oseltamivir is to influenza.

Hospital Doctor/Hospitalists rater

Nothing new here. These data have been made available in the media and probably all practitioners know that hydroxychloroquine is not effective.

Infectious Disease rater

We've known for a long time that hydroxychloroquine is ineffective in COVID-19 hospitalized patients.

Internal Medicine rater

The authors report on HCQ in patients with severe COVID-19 infection in a well designed multicenter RCT. Clinical status did not significantly differ between groups. This trial adds to the growing body of literature that HCQ does not appear to be an effective treatment for COVID-19.

Internal Medicine rater

Good to see a decent-sized trial.

Respirology/Pulmonology rater

This multicentre RCT finds that hydroxychloroquine made no difference to death or other clinical outcomes in patients hospitalized with COVID-19. This is the first large RCT to be blinded and placebo-controlled. The study does not confirm trends to worse outcomes with hydroxychloroquine seen in some earlier trials, likely due to exclusions and careful monitoring. However, the results overall are similar to previous trials, so most clinicians likely already know this.

Respirology/Pulmonology rater

This is the pandemic of contradictions. What seemed to be useful yesterday become useless today.