Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers
MD, MPhil Benjamin S Abella, BA Eliana L Jolkovsky, MPH Barbara T Biney, MD Julie E Uspal, MD, PhD Matthew C Hyman, MD Ian Frank, PhD Scott E Hensley, MD, PhD Saar Gill, MD Dan T Vogl, MSCE Ivan Maillard, MD, PhD Daria V Babushok, MD Alexander C Huang, PhD Sunita D Nasta, MD Jennifer C Walsh, E Paul Wiletyo, PhD; Phyllis A Gimotty, MD Michael C Milone, PhD Ravi K Amaravadi
JAMA Internal Medicine, doi:10.1001/jamainternmed.2020.6319
and the Prevention and Treatment of COVID-19 With Hydroxychloroquine (PATCH) Investigators 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.
Serological testing for the presence of anti-spike protein RBD IgM and IgG and nucleocapsid protein IgG (eTable 3 in Supplement 3) demonstrated that only 2 participants had anti-nucleocapsid IgG at baseline. Both participants had a negative SARS-CoV-2 RT-P CR test result, and these participants did not possess anti-spike protein RBD IgG at baseline. At the end of the 8 weeks, there were more positive participants treated with hydroxychloroquine (4 [7.4%]) compared with placebo (2 [3.7%]) who had an IgG antibody against SARS-CoV-2 (P = .40). All participants who developed antibodies also converted to SARS-CoV-2 positive status (eTable 4 in Supplement 3). At least 1 dose of study medication was taken by 65 participants in each arm; therefore, these participants were evaluable for adverse events (Table 3 ). The mean (SD) percentage of total pill counts prescribed that were actually taken during study treatment was 97% (8%) (hydroxychloroquine) and 98% (4%) (placebo). No participants in this study experienced grade 3 or 4 adverse events on the Common Toxicity Criteria for Adverse Events scale, hospitalizations, or death. However, there was a significant increase in any adverse events in the hydroxychloroquine arm vs placebo (45% vs 26%; P = .03), with increased diarrhea in participants receiving hydroxychloroquine compared with placebo (32% vs 12%; P = .01). No cardiac events (eg, syncope and arrhythmias) were observed. There was no significant difference in the median of..
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