Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial
Authors: Schilling William H. K. , Mukaka Mavuto , Callery James J. , Llewelyn Martin J. , Cruz Cintia V. , Dhorda Mehul , Ngernseng Thatsanun , Waithira Naomi , Ekkapongpisit Maneerat , Watson James A. , Chandna Arjun , Nelwan Erni J. , Hamers Raph L. , Etyang Anthony , Beg Mohammad Asim , Sow Samba , Yavo William , Allabi Aurel Constant , Basnyat Buddha , Sharma Sanjib Kumar , Amofa-Sekyi Modupe , Yonga Paul , Adler Amanda , Yuentrakul Prayoon , Cope Tanya , Thaipadungpanit Janjira , Rienpradub Panuvit , Imwong Mallika , Abdad Mohammad Yazid , Blacksell Stuart D. , Tarning Joel , Goudjo Frejus Faustin , Dossou Ange D. , Konaté-Touré Abibatou , Assi Serge-Brice , Ouffoué Kra , Nasronudin Nasronudin , Rachman Brian Eka , Romadhon Pradana Zaky , Dewanto Didi Darmahadi , Heryana Made Oka , Novi Theresia , Pasaribu Ayodhia Pitaloka , Mutiara Mutiara , Nasution Miranda Putri Rahayu , Khairunnisa Khairunnisa , Dalimunthe Fauzan Azima , Airlangga Eka , Fahrezzy Akmal , Subronto Yanri , Ananda Nur Rahmi , Rahardjani Mutia , Rimainar Atika , Lucinde Ruth Khadembu , Timbwa Molline , Onyango Otieno Edwin , Agutu Clara , Akech Samuel , Hamaluba Mainga , Kipyego Jairus , Ngachi Obadiah , Haidara Fadima Cheick , Traoré Oumar Y. , Diarra François , Khanal Basudha , Dahal Piyush , Shrestha Suchita , Rijal Samita , Kabore Youssouf , Adehossi Eric , Guindo Ousmane , Qamar Farah Naz , Kazi Abdul Momin , Woodrow Charles J. , Laird Steven , Cheeba Maina , Ayles Helen , Cheah Phaik Yeong , Taylor Walter R. J. , Batty Elizabeth M. , Chotivanich Kesinee , Pukrittayakamee Sasithon , Phumratanaprapin Weerapong , von Seidlein Lorenz , Dondorp Arjen , Day Nicholas P. J. , White Nicholas J. ,   on behalf of the COPCOV Collaborative Group
Published: September 2024

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.