A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19

Abstract

Background: Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking.

Methods: We conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days.

Results: The analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported.

Conclusions: Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.).

Figure 1. Screening and Randomization.

The safety population (2497 contacts; 1197 in the hydroxychloroquine group and 1300 in the usual-care group) included all those in the intention-to-treat population (except 28 in the hydroxychloroquine group who did not receive the trial medication) plus 40 (19 in the hydroxychloroquine group and 21 in the usual-care group) who were classified as having a screening failure. The intention-to-treat population (2485 contacts; 1206 in the hydroxychloroquine group and 1279 in the usual-care group) included 2314 who had data available for analysis of the primary outcome plus 171 (90 in the hydroxychloroquine group and 81 in the usual-care group) with no available polymerase-chain-reaction (PCR) assay results at day 14 who had missing responses imputed.

Figure 2. Subgroup Analyses of the Primary Outcome, According to Epidemiologic Risk Factors (Intention-to-Treat Population).

The primary outcome was PCR-confirmed, symptomatic coronavirus disease 2019 within 14 days.