Abstract: ORIGINAL RESEARCH Annals of Internal Medicine Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection A Randomized Trial Ruanne V. Barnabas, MBChB, MSc, DPhil; Elizabeth R. Brown, ScD; Anna Bershteyn, PhD; Helen C. Stankiewicz Karita, MD; Christine Johnston, MD, MPH; Lorna E. Thorpe, PhD, MPH; Angelica Kottkamp, MD; Kathleen M. Neuzil, MD, MPH; Miriam K. Laufer, MD, MPH; Meagan Deming, MD, PhD; Michael K. Paasche-Orlow, MD; Patricia J. Kissinger, PhD, MPH; Alfred Luk, MD; Kristopher Paolino, MD; Raphael J. Landovitz, MD, MSc; Risa Hoffman, MD; Torin T. Schaafsma, MS; Meighan L. Krows, BA; Katherine K. Thomas, MS; Susan Morrison, MD, MPH; Harald S. Haugen, MS; Lara Kidoguchi, MPH; Mark Wener, MD; Alexander L. Greninger, MD, PhD, MS, MPhil; Meei-Li Huang, PhD; Keith R. Jerome, MD, PhD; Anna Wald, MD, MPH; Connie Celum, MD, MPH; Helen Y. Chu, MD, MPH; Jared M. Baeten, MD, PhD; for the Hydroxychloroquine COVID-19 PEP Study Team* Background: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARSCoV-2, potentially permitting its use for prevention. Objective: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection. Design: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials .gov: NCT04328961) Setting: National U.S. multicenter study. Participants: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection. Intervention: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control. hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026). Limitation: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days. Conclusion: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection. Primary Funding Source: Bill & Melinda Gates Foundation. Measurements: Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCRconfirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment. Results: Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the A s of 3 December 2020, there have been 64 million reported cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease..