Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care WorkersA Randomized Clinical Trial

Question  Does a regimen of hydroxychloroquine, 600 mg, per day, reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a pre-exposure prophylaxis strategy when taken by hospital-based health care workers?

Finding  In this double-blind, placebo-controlled randomized clinical trial that included 132 participants and was terminated early, there was not a significant difference in reverse-transcriptase polymerase chain reaction–confirmed SARS-CoV-2 incidence between hydroxychloroquine and placebo cohorts.

Meaning  Among hospital-based health care workers, daily hydroxychloroquine did not prevent SARS-CoV-2 infection, although the trial was terminated early and may have been underpowered to detect a clinically important difference.

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Results  Of the 132 randomized participants (median age, 33 years [range, 20-66 years]; 91 women [69%]), 125 (94.7%) were evaluable for the primary outcome. There was no significant difference in infection rates in participants randomized to receive hydroxychloroquine compared with placebo (4 of 64 [6.3%] vs 4 of 61 [6.6%]; P > .99). Mild adverse events were more common in participants taking hydroxychloroquine compared with placebo (45% vs 26%; P = .04); rates of treatment discontinuation were similar in both arms (19% vs 16%; P = .81). The median change in QTc (baseline to 4-week evaluation) did not differ between arms (hydroxychloroquine: 4 milliseconds; 95% CI, −9 to 17; vs placebo: 3 milliseconds; 95% CI, −5 to 11; P = .98). Of the 8 participants with positive results for SARS-CoV-2 (6.4%), 6 developed viral symptoms; none required hospitalization, and all clinically recovered.

Conclusions and Relevance  In this randomized clinical trial, although limited by early termination, there was no clinical benefit of hydroxychloroquine administered daily for 8 weeks as pre-exposure prophylaxis in hospital-based HCWs exposed to patients with COVID-19.

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Prophylaxis studies of infectious diseases are highly sensitive to disease frequency. In Pennsylvania, daily COVID-19 incidence fell during the course of enrollment (eFigure 1 in Supplement 3), starting at 14.8 cases per 100 000 population per day on April 9, 2020, and ending at 7.1 cases per 100 000 population per day on July 14, 2020.²⁰ The overall SARS-CoV-2 infection rate in the study cohort was 6.4%; it is possible that a study of similar design conducted in a community with higher disease prevalence might yield a higher HCW infection rate and possibly more power to detect a prophylactic benefit from hydroxychloroquine. Alternatively, it is possible that uniform use of PPE and hand hygiene was sufficiently effective to reduce HCW infection to low levels, as seen in our study population.