Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: a double-blind, placebo-controlled randomized clinical trial

{ 'indexed': { 'date-parts': [[2021, 11, 16]], 'date-time': '2021-11-16T10:12:12Z', 'timestamp': 1637057532222}, 'reference-count': 29, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2021, 11, 15]], 'date-time': '2021-11-15T00:00:00Z', 'timestamp': 1636934400000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2021, 11, 15]], 'date-time': '2021-11-15T00:00:00Z', 'timestamp': 1636934400000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [{'name': 'ISGlobal'}, {'name': 'Laboratoris Rubió'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'short-container-title': ['Trials'], 'published-print': {'date-parts': [[2021, 12]]}, 'abstract': '<jats:title>Abstract</jats:title><jats:sec>\n' ' <jats:title>Background</jats:title>\n' ' <jats:p>Pre-exposure prophylaxis (PrEP) is a promising strategy to break ' 'COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment and ' 'post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The aim of this study ' 'was to evaluate the efficacy and safety of PrEP with hydroxychloroquine against placebo in ' 'healthcare workers at high risk of SARS-CoV-2 infection during an epidemic period.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Methods</jats:title>\n' ' <jats:p>We conducted a double-blind placebo-controlled randomized clinical ' 'trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers screened, we ' 'included 269 participants with no active or past SARS-CoV-2 infection (determined by a ' 'negative nasopharyngeal SARS-CoV-2 PCR and a negative serology against SARS-CoV-2). ' 'Participants allocated in the intervention arm (PrEP) received 400\u2009mg of ' 'hydroxychloroquine daily for the first four consecutive days and subsequently, 400\u2009mg ' 'weekly during the study period. Participants in the control group followed the same treatment ' 'schedule with placebo tablets.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Results</jats:title>\n' ' <jats:p>52.8% (142/269) of participants were in the hydroxychloroquine arm ' 'and 47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay, only one ' 'participant in each group was diagnosed with COVID-19. The trial was stopped due to futility ' 'and our study design was deemed underpowered to evaluate any benefit regarding PrEP efficacy. ' 'Both groups showed a similar proportion of participants experiencing at least one adverse ' 'event (AE) (<jats:italic>p</jats:italic>=0.548). No serious AEs were reported. Almost all AEs ' '(96.4%, 106/110) were mild. Only mild gastrointestinal symptoms were significantly higher in ' 'the hydroxychloroquine arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), ' '<jats:italic>p</jats:italic>=0.041).</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Conclusions</jats:title>\n' ' <jats:p>Although the efficacy of PrEP with hydroxychloroquine for preventing ' 'COVID-19 could not be evaluated, our study showed that PrEP with hydroxychloroquine at low ' 'doses is safe.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Trial registration</jats:title>\n' ' <jats:p><jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ' 'ext-link-type="uri" ' 'xlink:href="http://clinicaltrials.gov">ClinicalTrials.gov</jats:ext-link><jats:ext-link ' 'xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" ' 'xlink:href="https://clinicaltrials.gov/ct2/show/NCT04331834?term=NCT04331834&amp;draw=2&amp;rank=1">NCT04331834</jats:ext-link>. ' 'Registered on April 2, 2020.</jats:p>\n' ' </jats:sec>', 'DOI': '10.1186/s13063-021-05758-9', 'type': 'journal-article', 'created': { 'date-parts': [[2021, 11, 15]], 'date-time': '2021-11-15T12:03:01Z', 'timestamp': 1636977781000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': [ 'Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: a double-blind, ' 'placebo-controlled randomized clinical trial'], 'prefix': '10.1186', 'volume': '22', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-7320-0965', 'authenticated-orcid': False, 'given': 'Berta', 'family': 'Grau-Pujol', 'sequence': 'first', 'affiliation': []}, {'given': 'Daniel', 'family': 'Camprubí-Ferrer', 'sequence': 'additional', 'affiliation': []}, {'given': 'Helena', 'family': 'Marti-Soler', 'sequence': 'additional', 'affiliation': []}, {'given': 'Marc', 'family': 'Fernández-Pardos', 'sequence': 'additional', 'affiliation': []}, {'given': 'Clara', 'family': 'Carreras-Abad', 'sequence': 'additional', 'affiliation': []}, {'given': 'Maria Velasco-de', 'family': 'Andrés', 'sequence': 'additional', 'affiliation': []}, {'given': 'Elisabet', 'family': 'Ferrer', 'sequence': 'additional', 'affiliation': []}, { 'given': 'Magdalena', 'family': 'Muelas-Fernandez', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sophie', 'family': 'Jullien', 'sequence': 'additional', 'affiliation': []}, {'given': 'Giuseppe', 'family': 'Barilaro', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sara', 'family': 'Ajanovic', 'sequence': 'additional', 'affiliation': []}, {'given': 'Isabel', 'family': 'Vera', 'sequence': 'additional', 'affiliation': []}, {'given': 'Laura', 'family': 'Moreno', 'sequence': 'additional', 'affiliation': []}, {'given': 'Eva', 'family': 'Gonzalez-Redondo', 'sequence': 'additional', 'affiliation': []}, {'given': 'Núria', 'family': 'Cortes-Serra', 'sequence': 'additional', 'affiliation': []}, {'given': 'Montserrat', 'family': 'Roldán', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ana Artes-de', 'family': 'Arcos', 'sequence': 'additional', 'affiliation': []}, {'given': 'Isabel', 'family': 'Mur', 'sequence': 'additional', 'affiliation': []}, {'given': 'Pere', 'family': 'Domingo', 'sequence': 'additional', 'affiliation': []}, {'given': 'Felipe', 'family': 'Garcia', 'sequence': 'additional', 'affiliation': []}, {'given': 'Caterina', 'family': 'Guinovart', 'sequence': 'additional', 'affiliation': []}, {'given': 'Jose', 'family': 'Muñoz', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2021, 11, 15]]}, 'reference': [ { 'issue': '8', 'key': '5758_CR1', 'doi-asserted-by': 'publisher', 'first-page': '727', 'DOI': '10.1056/NEJMoa2001017', 'volume': '382', 'author': 'N Zhu', 'year': '2020', 'unstructured': 'Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus ' 'from patients with pneumonia in China, 2019. N Engl J Med. ' '2020;382(8):727–33. https://doi.org/10.1056/NEJMoa2001017.', 'journal-title': 'N Engl J Med.'}, { 'key': '5758_CR2', 'volume-title': 'Water, sanitation, hygiene, and waste management for the COVID-19 virus', 'year': '2020', 'unstructured': 'Water, sanitation, hygiene, and waste management for the COVID-19 virus. ' 'World Health Organization; 2020 23 April 2020. Contract No.: ' 'WHO/2019-nCoV/IPC_WASH/2020.3.'}, { 'key': '5758_CR3', 'volume-title': 'Rational use of personal protective equipment (PPE) for coronavirus ' 'disease (COVID-19)', 'year': '2020', 'unstructured': 'Rational use of personal protective equipment (PPE) for coronavirus ' 'disease (COVID-19). World Health Organization; 2020 19 March 2020. ' 'Contract No.: WHO/2019-nCoV/IPC PPE_use/2020.2.'}, { 'key': '5758_CR4', 'unstructured': 'Coronavirus (COVID-19) Centers for Disease Control and Prevention 2020 ' '[updated 29 June 2020. 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' 'Preexposure Prophylaxis for the Prevention of HIV Infection: Evidence ' 'Report and Systematic Review for the US Preventive Services Task Force. ' 'JAMA. 2019;321(22):2214–30. https://doi.org/10.1001/jama.2019.2591.', 'journal-title': 'JAMA.'}, { 'key': '5758_CR10', 'unstructured': 'Clinicaltrials.gov: NIH US National Library of Medicine; [Available ' 'from: ' 'https://clinicaltrials.gov/ct2/results?cond=COVID&term=prophylaxis&cntry=&state=&city=&dist=.'}, { 'issue': '1', 'key': '5758_CR11', 'doi-asserted-by': 'publisher', 'first-page': '647', 'DOI': '10.1186/s13063-020-04577-8', 'volume': '21', 'author': 'JK Wright', 'year': '2020', 'unstructured': 'Wright JK, DHS T, Walmsley SL, Hulme J, O’Connor E, Snider C, et al. ' 'Protecting Frontline Health Care Workers from COVID-19 with ' 'Hydroxychloroquine Pre-exposure Prophylaxis: A structured summary of a ' 'study protocol for a randomised placebo-controlled multisite trial in ' 'Toronto, Canada. Trials. 2020;21(1):647. ' 'https://doi.org/10.1186/s13063-020-04577-8 PMID: 32665039; PMCID: ' 'PMC7359423.', 'journal-title': 'Trials'}, { 'issue': '1', 'key': '5758_CR12', 'doi-asserted-by': 'publisher', 'first-page': '7', 'DOI': '10.1016/j.medmal.2020.09.013', 'volume': '51', 'author': 'E Sallard', 'year': '2021', 'unstructured': 'Sallard E, Belhadi D, Lescure FX, Yazdanpanah Y, Peiffer-Smadja N. ' 'Clinical trial protocols of repurposed prophylaxis for COVID-19: A ' 'review. Infect Dis Now. 2021;51(1):7–13. ' 'https://doi.org/10.1016/j.medmal.2020.09.013 Epub 2020 Oct 3. PMID: ' '33022293; PMCID: PMC7532748.', 'journal-title': 'Infect Dis Now'}, { 'issue': '1', 'key': '5758_CR13', 'doi-asserted-by': 'publisher', 'first-page': '69', 'DOI': '10.1186/1743-422X-2-69', 'volume': '2', 'author': 'MJ Vincent', 'year': '2005', 'unstructured': 'Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, ' 'et al. Chloroquine is a potent inhibitor of SARS coronavirus infection ' 'and spread. Virol J. 2005;2(1):69. ' 'https://doi.org/10.1186/1743-422X-2-69.', 'journal-title': 'Virol J.'}, { 'issue': '3', 'key': '5758_CR14', 'doi-asserted-by': 'publisher', 'first-page': '269', 'DOI': '10.1038/s41422-020-0282-0', 'volume': '30', 'author': 'M Wang', 'year': '2020', 'unstructured': 'Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and ' 'chloroquine effectively inhibit the recently emerged novel coronavirus ' '(2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71. ' 'https://doi.org/10.1038/s41422-020-0282-0.', 'journal-title': 'Cell Res.'}, { 'issue': '1', 'key': '5758_CR15', 'doi-asserted-by': 'publisher', 'first-page': '16', 'DOI': '10.1038/s41421-020-0156-0', 'volume': '6', 'author': 'J Liu', 'year': '2020', 'unstructured': 'Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a ' 'less toxic derivative of chloroquine, is effective in inhibiting ' 'SARS-CoV-2 infection in vitro. Cell Discov. 2020;6(1):16. ' 'https://doi.org/10.1038/s41421-020-0156-0.', 'journal-title': 'Cell Discov.'}, { 'issue': '15', 'key': '5758_CR16', 'doi-asserted-by': 'publisher', 'first-page': '732', 'DOI': '10.1093/cid/ciaa237', 'volume': '71', 'author': 'X Yao', 'year': '2020', 'unstructured': 'Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral ' 'Activity and Projection of Optimized Dosing Design of Hydroxychloroquine ' 'for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 ' '(SARS-CoV-2). Clin Infect Dis. 2020;71(15):732–9.', 'journal-title': 'Clin Infect Dis'}, { 'issue': '1', 'key': '5758_CR17', 'doi-asserted-by': 'publisher', 'first-page': '688', 'DOI': '10.1186/s13063-020-04621-7', 'volume': '21', 'author': 'B Grau-Pujol', 'year': '2020', 'unstructured': 'Grau-Pujol B, Camprubí D, Marti-Soler H, Fernández-Pardos M, Guinovart ' 'C, Muñoz J. Pre-exposure prophylaxis with hydroxychloroquine for ' 'high-risk healthcare workers during the COVID-19 pandemic: A structured ' 'summary of a study protocol for a multicentre, double-blind randomized ' 'controlled trial. Trials. 2020;21(1):688. ' 'https://doi.org/10.1186/s13063-020-04621-7 PMID: 32727613; PMCID: ' 'PMC7388426.', 'journal-title': 'Trials'}, { 'issue': '2', 'key': '5758_CR18', 'doi-asserted-by': 'publisher', 'first-page': '179', 'DOI': '10.1002/sim.4780110205', 'volume': '11', 'author': 'E Lakatos', 'year': '1992', 'unstructured': 'Lakatos E, Lan KK. A comparison of sample size methods for the logrank ' 'statistic. Statistics in Medicine. 1992;11(2):179–91. ' 'https://doi.org/10.1002/sim.4780110205.', 'journal-title': 'Statistics in Medicine.'}, { 'key': '5758_CR19', 'volume-title': 'A language and environment for statistical computing. Vienna, austria', 'year': '2019', 'unstructured': 'A language and environment for statistical computing. Vienna, austria: R ' 'Core Team, R Foundation for Statistical Computing; 2019 [Available from: ' 'https://www.R-project.org/.).'}, { 'issue': '1', 'key': '5758_CR20', 'doi-asserted-by': 'publisher', 'first-page': '4740', 'DOI': '10.1038/s41467-021-24979-9', 'volume': '12', 'author': 'N Ortega', 'year': '2021', 'unstructured': 'Ortega N, Ribes M, Vidal M, Rubio R, Aguilar R, Williams S, et al. ' 'Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing ' 'antibodies to human coronaviruses. Nat Commun. 2021;12(1):4740.', 'journal-title': 'Nat Commun'}, { 'issue': '6', 'key': '5758_CR21', 'doi-asserted-by': 'publisher', 'first-page': '517', 'DOI': '10.1056/NEJMoa2016638', 'volume': '383', 'author': 'DR Boulware', 'year': '2020', 'unstructured': 'Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor ' 'EC, et al. A randomized trial of hydroxychloroquine as postexposure ' 'prophylaxis for COVID-19. N Engl J Med. 2020;383(6):517–25. ' 'https://doi.org/10.1056/NEJMoa2016638.', 'journal-title': 'N Engl J Med.'}, { 'issue': '25', 'key': '5758_CR22', 'doi-asserted-by': 'publisher', 'first-page': '2411', 'DOI': '10.1056/NEJMoa2012410', 'volume': '382', 'author': 'J Geleris', 'year': '2020', 'unstructured': 'Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. ' 'Observational study of hydroxychloroquine in hospitalized patients with ' 'COVID-19. N Engl J Med. 2020;382(25):2411–8. ' 'https://doi.org/10.1056/NEJMoa2012410.', 'journal-title': 'N Engl J Med.'}, { 'issue': '24', 'key': '5758_CR23', 'doi-asserted-by': 'publisher', 'first-page': '2493', 'DOI': '10.1001/jama.2020.8630', 'volume': '323', 'author': 'ES Rosenberg', 'year': '2020', 'unstructured': 'Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, ' 'et al. Association of treatment with hydroxychloroquine or azithromycin ' 'with in-hospital mortality in patients with COVID-19 in New York State. ' 'JAMA. 2020;323(24):2493–502. https://doi.org/10.1001/jama.2020.8630.', 'journal-title': 'JAMA.'}, { 'issue': '4', 'key': '5758_CR24', 'doi-asserted-by': 'publisher', 'first-page': 'e208857', 'DOI': '10.1001/jamanetworkopen.2020.8857', 'volume': '3', 'author': 'MGS Borba', 'year': '2020', 'unstructured': 'Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. ' 'Effect of high vs low doses of chloroquine diphosphate as adjunctive ' 'therapy for patients hospitalized with severe acute respiratory syndrome ' 'coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA ' 'Netw Open. 2020;3(4):e208857. ' 'https://doi.org/10.1001/jamanetworkopen.2020.8857.', 'journal-title': 'JAMA Netw Open.'}, { 'issue': '4', 'key': '5758_CR25', 'doi-asserted-by': 'publisher', 'first-page': '1468', 'DOI': '10.1128/AAC.00339-08', 'volume': '53', 'author': 'HS Lim', 'year': '2009', 'unstructured': 'Lim HS, Im JS, Cho JY, Bae KS, Klein TA, Yeom JS, et al. ' 'Pharmacokinetics of hydroxychloroquine and its clinical implications in ' 'chemoprophylaxis against malaria caused by Plasmodium vivax. Antimicrob ' 'Agents Chemother. 2009;53(4):1468–75. ' 'https://doi.org/10.1128/AAC.00339-08.', 'journal-title': 'Antimicrob Agents Chemother.'}, { 'issue': '6', 'key': '5758_CR26', 'doi-asserted-by': 'publisher', 'first-page': '775', 'DOI': '10.1002/acr.20133', 'volume': '62', 'author': 'F Wolfe', 'year': '2010', 'unstructured': 'Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal ' 'toxicity in patients with rheumatoid arthritis and systemic lupus ' 'erythematosus. Arthritis Care Res. 2010;62(6):775–84. ' 'https://doi.org/10.1002/acr.20133.', 'journal-title': 'Arthritis Care Res.'}, { 'issue': '5', 'key': '5758_CR27', 'doi-asserted-by': 'publisher', 'first-page': '705', 'DOI': '10.1517/14740338.2011.566555', 'volume': '10', 'author': 'C Abarientos', 'year': '2011', 'unstructured': 'Abarientos C, Sperber K, Shapiro DL, Aronow WS, Chao CP, Ash JY. ' 'Hydroxychloroquine in systemic lupus erythematosus and rheumatoid ' 'arthritis and its safety in pregnancy. Expert Opin Drug Saf. ' '2011;10(5):705–14. https://doi.org/10.1517/14740338.2011.566555.', 'journal-title': 'Expert Opin Drug Saf.'}, { 'issue': '3', 'key': '5758_CR28', 'doi-asserted-by': 'publisher', 'first-page': '411', 'DOI': '10.1080/14740338.2017.1269168', 'volume': '16', 'author': 'C Ponticelli', 'year': '2017', 'unstructured': 'Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus ' 'erythematosus (SLE). Expert Opin Drug Saf. 2017;16(3):411–9. 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Participation in this ' 'study was voluntary, and under no circumstances the clinical management of the ' 'participants was affected by the decision to participate or not in the study. ' 'The participant was free to withdraw at any time of the study.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'The authors declare that they have no competing interests.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '808'}