Abstract: Research Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial Ilan Schwartz MD PhD, Mari E. Boesen MSc, Graziela Cerchiaro PhD, Craig Doram BSc PEng, Brett D. Edwards MD, Aravind Ganesh MD, Jamie Greenfield MPH, Scott Jamieson BScPT MPH, Vikram Karnik MD, Carol Kenney RN, Rachel Lim MD, Bijoy K. Menon MD, Kwadwo Mponponsuo MD, Sarah Rathwell MSc, Karla J. Ryckborst RN, Breanne Stewart RN, Maryna Yaskina PhD, Luanne Metz MD, Lawrence Richer MD, Michael D. Hill MD MSc; for the ALBERTA HOPE COVID-19 Collaborators 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 E ighteen years ago, the severe acute respiratory syndrome (SARS) experience 1–5 highlighted limited knowledge of early treatments for novel pandemic respiratory viruses. With the emergence of SARS-CoV-2, early experience in Wuhan,6 the Lombardy region of Italy7,8 and New York City9 demonstrated the need to suppress severe disease to prevent health system collapse. Hydroxychloroquine, derived from the centuries-old antimalarial medicine quinine, has broad..