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

Abstract

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: ClinicalTrials.gov: NCT04332991.

Figure 1.. Participant Flow in a Randomized Clinical Trial of Hydroxychloroquine vs Placebo in Patients Hospitalized With Respiratory Symptoms of Coronavirus Disease 2019 (COVID-19)

^aBetween April 2 and April 21, 2020, screened patients included both those with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and those with suspected SARS-CoV-2 infection. Between April 21, 2020, and the end of the trial (June 19, 2020), only patients with laboratory-confirmed SARS-CoV-2 infection were screened. ^bExclusion criteria were not mutually exclusive. ^cQTc was assessed as a study procedure during the screening process; patients must have had a QTc less than 500 ms at the time of screening to be eligible for the trial. ^dReasons for not randomizing were not mutually exclusive. ^eRandomization was stratified by enrolling hospital.

Figure 2.. Clinical Status on the Coronavirus Disease (COVID) Outcomes Scale 14 Days and 28 Days After Randomization

ECMO indicates extracorporeal membrane oxygenation. There was no significant difference between the hydroxychloroquine group and placebo group in the overall distribution of scores at 14 days (adjusted odds ratio, 1.02 [95% CI, 0.73-1.42]) or 28 days (adjusted odds ratio, 0.97 [95% CI, 0.69-1.38]).

Figure 3.. Survival and Hospital Discharge Through 28 Days Following Randomization

The survival curves are survival function (Kaplan-Meier) curves with a P value calculated by the log-rank test. Patients were followed up for death until 28 days following randomization using in-hospital records and telephone follow-up. Two patients had unknown vital status at 28 days and were not included in this analysis. The hospital discharge curves are cumulative incidence curves of hospital discharge accounting for the competing risk of death with a P value calculated by Gray test. For hospital discharge, all patients were followed up to discharge or 28 days after randomization. A patient was considered discharged from the hospital once discharged from the index hospitalization; rehospitalizations were not considered in this analysis. There was no difference between the hydroxychloroquine group and placebo group in survival (adjusted hazard ratio, 1.05 [95% CI, 0.60-1.85]) or time to discharge (adjusted hazard ratio, 1.09 [95% CI, 0.89-1.32]).