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

Abstract

Importance: Health care workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) are at risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, to our knowledge, there is no effective pharmacologic prophylaxis for individuals at risk.

Objective: To evaluate the efficacy of hydroxychloroquine to prevent transmission of SARS-CoV-2 in hospital-based HCWs with exposure to patients with COVID-19 using a pre-exposure prophylaxis strategy.

Design, setting, and participants: This randomized, double-blind, placebo-controlled clinical trial (the Prevention and Treatment of COVID-19 With Hydroxychloroquine Study) was conducted at 2 tertiary urban hospitals, with enrollment from April 9, 2020, to July 14, 2020; follow-up ended August 4, 2020. The trial randomized 132 full-time, hospital-based HCWs (physicians, nurses, certified nursing assistants, emergency technicians, and respiratory therapists), of whom 125 were initially asymptomatic and had negative results for SARS-CoV-2 by nasopharyngeal swab. The trial was terminated early for futility before reaching a planned enrollment of 200 participants.

Interventions: Hydroxychloroquine, 600 mg, daily, or size-matched placebo taken orally for 8 weeks.

Main outcomes and measures: The primary outcome was the incidence of SARS-CoV-2 infection as determined by a nasopharyngeal swab during the 8 weeks of treatment. Secondary outcomes included adverse effects, treatment discontinuation, presence of SARS-CoV-2 antibodies, frequency of QTc prolongation, and clinical outcomes for SARS-CoV-2-positive participants.

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.

Trial registration: ClinicalTrials.gov Identifier: NCT04329923.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Frank reports consulting income from Gilead. Dr Milone reports royalty income from patents licensed to Novartis that is unrelated to hydroxychloroquine. Dr Amaravadi is the scientific founder and holds equity in Pinpoint Therapeutics, Inc. He is coinventor on patents covering autophagy inhibitors for cancer and a consultant for cancer-related programs at Sprint Biosciences, Deciphera, and Immunaccel. Dr Abella has received grant funding and honoraria from Becton Dickinson. No other disclosures were reported.

Figures

Figure 1.. Participant Enrollment and Treatment Assignment

COVID-19 indicates coronavirus disease 2019; HCQ, hydroxychloroquine.

Figure 2.. Corrected QT Interval (QTc) Assessment of Study Participants, Measured at Baseline and 1 Month

The hydroxychloroquine (HCQ) and placebo arms both had 23 participants who received pretreatment and posttreament electrocardiograms. Each patient is represented with a different colored line.