Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial
Issued Date
2024-09-01
Resource Type
ISSN
15491277
eISSN
15491676
Scopus ID
2-s2.0-85204082070
Pubmed ID
39264960
Journal Title
PLoS Medicine
Volume
21
Issue
9 September
Rights Holder(s)
SCOPUS
Bibliographic Citation
PLoS Medicine Vol.21 No.9 September (2024)
Suggested Citation
Schilling W.H.K., Mukaka M., Callery J.J., Llewelyn M.J., Cruz C.V., Dhorda M., Ngernseng T., Waithira N., Ekkapongpisit M., Watson J.A., Chandna A., Nelwan E.J., Hamers R.L., Etyang A., Beg M.A., Sow S., Yavo W., Allabi A.C., Basnyat B., Sharma S.K., Amofa-Sekyi M., Yonga P., Adler A., Yuentrakul P., Cope T., Thaipadungpanit J., Rienpradub P., Imwong M., Abdad M.Y., Blacksell S.D., Tarning J., Goudjo F.F., Dossou A.D., Konaté-Touré A., Assi S.B., Ouffoué K., Nasronudin N., Rachman B.E., Romadhon P.Z., Dewanto D.D., Heryana M.O., Novi T., Pasaribu A.P., Mutiara M., Nasution M.P.R., Khairunnisa K., Dalimunthe F.A., Airlangga E., Fahrezzy A., Subronto Y., Ananda N.R., Rahardjani M., Rimainar A., Lucinde R.K., Timbwa M., Onyango O.E., Agutu C., Akech S., Hamaluba M., Kipyego J., Ngachi O., Haidara F.C., Traoré O.Y., Diarra F., Khanal B., Dahal P., Shrestha S., Rijal S., Kabore Y., Adehossi E., Guindo O., Qamar F.N., Kazi A.M., Woodrow C.J., Laird S., Cheeba M., Ayles H., Cheah P.Y., Taylor W.R.J., Batty E.M., Chotivanich K., Pukrittayakamee S., Phumratanaprapin W., von Seidlein L., Dondorp A., Day N.P.J., White N.J. Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial. PLoS Medicine Vol.21 No.9 September (2024). doi:10.1371/journal.pmed.1004428 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/101318
Title
Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial
Author(s)
Schilling W.H.K.
Mukaka M.
Callery J.J.
Llewelyn M.J.
Cruz C.V.
Dhorda M.
Ngernseng T.
Waithira N.
Ekkapongpisit M.
Watson J.A.
Chandna A.
Nelwan E.J.
Hamers R.L.
Etyang A.
Beg M.A.
Sow S.
Yavo W.
Allabi A.C.
Basnyat B.
Sharma S.K.
Amofa-Sekyi M.
Yonga P.
Adler A.
Yuentrakul P.
Cope T.
Thaipadungpanit J.
Rienpradub P.
Imwong M.
Abdad M.Y.
Blacksell S.D.
Tarning J.
Goudjo F.F.
Dossou A.D.
Konaté-Touré A.
Assi S.B.
Ouffoué K.
Nasronudin N.
Rachman B.E.
Romadhon P.Z.
Dewanto D.D.
Heryana M.O.
Novi T.
Pasaribu A.P.
Mutiara M.
Nasution M.P.R.
Khairunnisa K.
Dalimunthe F.A.
Airlangga E.
Fahrezzy A.
Subronto Y.
Ananda N.R.
Rahardjani M.
Rimainar A.
Lucinde R.K.
Timbwa M.
Onyango O.E.
Agutu C.
Akech S.
Hamaluba M.
Kipyego J.
Ngachi O.
Haidara F.C.
Traoré O.Y.
Diarra F.
Khanal B.
Dahal P.
Shrestha S.
Rijal S.
Kabore Y.
Adehossi E.
Guindo O.
Qamar F.N.
Kazi A.M.
Woodrow C.J.
Laird S.
Cheeba M.
Ayles H.
Cheah P.Y.
Taylor W.R.J.
Batty E.M.
Chotivanich K.
Pukrittayakamee S.
Phumratanaprapin W.
von Seidlein L.
Dondorp A.
Day N.P.J.
White N.J.
Mukaka M.
Callery J.J.
Llewelyn M.J.
Cruz C.V.
Dhorda M.
Ngernseng T.
Waithira N.
Ekkapongpisit M.
Watson J.A.
Chandna A.
Nelwan E.J.
Hamers R.L.
Etyang A.
Beg M.A.
Sow S.
Yavo W.
Allabi A.C.
Basnyat B.
Sharma S.K.
Amofa-Sekyi M.
Yonga P.
Adler A.
Yuentrakul P.
Cope T.
Thaipadungpanit J.
Rienpradub P.
Imwong M.
Abdad M.Y.
Blacksell S.D.
Tarning J.
Goudjo F.F.
Dossou A.D.
Konaté-Touré A.
Assi S.B.
Ouffoué K.
Nasronudin N.
Rachman B.E.
Romadhon P.Z.
Dewanto D.D.
Heryana M.O.
Novi T.
Pasaribu A.P.
Mutiara M.
Nasution M.P.R.
Khairunnisa K.
Dalimunthe F.A.
Airlangga E.
Fahrezzy A.
Subronto Y.
Ananda N.R.
Rahardjani M.
Rimainar A.
Lucinde R.K.
Timbwa M.
Onyango O.E.
Agutu C.
Akech S.
Hamaluba M.
Kipyego J.
Ngachi O.
Haidara F.C.
Traoré O.Y.
Diarra F.
Khanal B.
Dahal P.
Shrestha S.
Rijal S.
Kabore Y.
Adehossi E.
Guindo O.
Qamar F.N.
Kazi A.M.
Woodrow C.J.
Laird S.
Cheeba M.
Ayles H.
Cheah P.Y.
Taylor W.R.J.
Batty E.M.
Chotivanich K.
Pukrittayakamee S.
Phumratanaprapin W.
von Seidlein L.
Dondorp A.
Day N.P.J.
White N.J.
Author's Affiliation
Centre Hospitalier Universitaire de Bouake
Angkor Hospital for Children
University Hospitals Sussex NHS Foundation Trust
Faculty of Tropical Medicine, Mahidol University
Mahidol Oxford Tropical Medicine Research Unit
University Hospital Coventry
Oxford University Clinical Research Unit
Brighton and Sussex Medical School
University of Zambia
Université Abdou Moumouni
University of Abomey-Calavi
Institut National de Sante Publique Abidjan
Institut Pierre Richet Bouake
B.P. Koirala Institute of Health Sciences
Universitas Sumatera Utara
Universitas Airlangga
Universitas Gadjah Mada
Universitas Indonesia, RSUPN Dr. Cipto Mangunkusumo
Universitas Indonesia
The Aga Khan University Hospital
Wellcome Trust Research Laboratories Nairobi
London School of Hygiene & Tropical Medicine
Epicentre
Nuffield Department of Medicine
John Radcliffe Hospital
University of Oxford Medical Sciences Division
Coordination of Allada Ze Toffo Health Zone
Bunda Thamrin Hospital
Husada Utama Hospital
National Public Health Laboratory
Murni Teguh Memorial Hospital
Fountain Health Care Hospital
Centre pour le Développement des Vaccins (CVD-Mali)
Dr. Sardjito Hospital
Angkor Hospital for Children
University Hospitals Sussex NHS Foundation Trust
Faculty of Tropical Medicine, Mahidol University
Mahidol Oxford Tropical Medicine Research Unit
University Hospital Coventry
Oxford University Clinical Research Unit
Brighton and Sussex Medical School
University of Zambia
Université Abdou Moumouni
University of Abomey-Calavi
Institut National de Sante Publique Abidjan
Institut Pierre Richet Bouake
B.P. Koirala Institute of Health Sciences
Universitas Sumatera Utara
Universitas Airlangga
Universitas Gadjah Mada
Universitas Indonesia, RSUPN Dr. Cipto Mangunkusumo
Universitas Indonesia
The Aga Khan University Hospital
Wellcome Trust Research Laboratories Nairobi
London School of Hygiene & Tropical Medicine
Epicentre
Nuffield Department of Medicine
John Radcliffe Hospital
University of Oxford Medical Sciences Division
Coordination of Allada Ze Toffo Health Zone
Bunda Thamrin Hospital
Husada Utama Hospital
National Public Health Laboratory
Murni Teguh Memorial Hospital
Fountain Health Care Hospital
Centre pour le Développement des Vaccins (CVD-Mali)
Dr. Sardjito Hospital
Corresponding Author(s)
Other Contributor(s)
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.