Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial

Abstract

Background: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use.

Methods and findings: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507.

Interpretation: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs.

Trial registration: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

Fig 1. COPCOV study participant flowchart.

Fig 2. Venn diagram depicting the breakdown of numbers analysed.

Those with no serology data were either those who dropped out of the study before day 30, and had no end of study samples, or had missing end of study samples, or those judged unreliable by the serology endpoint assessment committee. This group differed from the PP population, with some overlap.

Fig 3

All-cause PCR-confirmed respiratory infections (left) and PCR-confirmed COVID-19 (right) over time in the HCQ/CQ recipients (green) and placebo recipients (pink). All-cause respiratory infection was a secondary endpoint. The majority (68%, 80/117) of infections were SARS-CoV-2. Log-rank test p-values are shown. Patients are right censored at the date of last visit. COVID-19, Coronavirus Disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Fig 4. Prespecified meta-analysis of 4-aminoquinoline COVID-19 pre-exposure chemoprevention RCTs based on individual study primary endpoints according to the method of Garcia-Albeniz and colleagues [24].

Schilling 2024 refers to the current study. The size of the grey squares centred at the treatment effect estimates are proportional to the study weight. Risk ratios were determined for all studies based on the reported data, apart from Seet and colleagues, which was cluster randomised and a recalculated adjusted RR was used. See Methods A2 in S1 Appendix for further details. CQ, chloroquine; HCQ, hydroxychloroquine; RCT, randomised controlled trial; RR, risk ratio.