Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial

Abstract

Background: Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death.

Methods: This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data.

Results: Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety.

Interpretation: There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered.

Trial registration: ClinicalTrials.gov, no. NCT04329611.

Conflict of interest statement

Competing interests: Aravind Ganesh reports payments to his institution from the Canadian Institutes of Health Research (CIHR), the Canadian Cardiovascular Society, Alberta Innovates and Campus Alberta Neuroscience; consulting fees from MD Analytics, My Medical Panel, Atheneum, DeepBench and Research on Mind; meetings or travel support from American Academy of Neurology, Association of Indian Neurologists in America, American Heart Association and University of Calgary; and a provisional patent application for a system for patient monitoring and delivery of remote ischemic conditioning or other cuff-based therapies. He is a member of the editorial boards of Neurology: Clinical Practice, Neurology and Stroke. He has stock in SnapDx (patient monitoring and decision support technology), American Health Analytics (AHA Health Ltd.; patient monitoring) and TheRounds.com (physician social network). Bijoy Menon reports grants or contracts from CIHR, the Heart and Stroke Foundation of Canada and Alberta Innovates Health Solutions and patents from the United States Patent and Trademark Office on systems of triage in acute stroke. He is a member of and has stock in Circle NVI. Michael Hill reports that Apotex Pharma provided the drug and placebo for the current trial as an in-kind contribution to the study. He was the main contact with Apotex Pharma and has no other relationship with the company; there were no obligations attached to this donation of drug and placebo.

© 2021 CMA Joule Inc. or its licensors.

Figures

Figure 1:

Screening process. Note: AHS = Alberta Health Services, DSL = designated supportive living, LTC = long-term care. *Reasons are not mutually exclusive. †Assigned to the first exclusion identified.

Figure 2:

Consort diagram. *Five participants did not meet eligibility criteria: 3 had no risk factors for severe COVID-19 and 2 were taking a contraindicated medication. †One participant did not meet eligibility criteria (asymptomatic) and 5 participants were stopped for safety signal. ‡Two participants stopped study drug owing to COVID-19 symptoms that started before randomization.

Figure 3:

Participants who reached the outcome of symptom resolution over the course of 30 days after randomization in the intention-to-treat population (n = 124). The curves show the cumulative percentage of participants with symptom resolution over the course of 30 days after randomization. Estimates of the cumulative percentage recovered were calculated using Kaplan–Meier survival analysis. Participants were excluded if they recovered on or before randomization (n = 11), were asymptomatic (n = 1), or could not be confirmed symptomatic on randomization and had no follow-up at day 7 or day 30 and symptoms at randomization were unconfirmed (n = 12). Participants without recovery dates were administratively censored at the last follow-up with a known disposition. Participants were censored at day 1 if disposition was unknown at both day 7 and day 30 but they were confirmed to be symptomatic at randomization.