Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial
MD Ilan Schwartz, PhD Mari E Boesen, MSc Graziela Cerchiaro, PhD Craig Doram, MD Brett D Edwards, MD Aravind Ganesh, MPH Jamie Greenfield, Scott Jamieson, MD Vikram Karnik, Carol Kenney, MD Rachel Lim, MD Bijoy K Menon, MD Kwadwo Mponponsuo, MSc Sarah Rathwell, RN Karla J Ryckborst, RN Breanne Stewart, PhD Maryna Yaskina, MD Luanne Metz, MD Lawrence Richer, MD MSc Michael D Hill
CMAJ Open, doi:10.9778/cmajo.20210069
E ighteen years ago, the severe acute respiratory syndrome (SARS) experience 1-5 highlighted limited knowledge of early treatments for novel pandemic respiratory viruses. With the emergence of SARS-CoV-2, early experience in Wuhan, 6 the Lombardy region of Italy 7, 8 and New York City 9 demonstrated the need to suppress severe disease to prevent health system collapse. Hydroxychloroquine, derived from the centuries-old antimalarial medicine quinine, has broad antiviral effects and immunomodulatory properties, making it an attractive candidate to be repurposed for SARS-CoV-2 infection. The precise mechanisms of immunomodulation are uncertain, but the net result is inhibition of macrophage production of proinflammatory cytokines tumor necrosis factor (TNF)-α and
Ethics approval The trial was approved by health research ethics committees of the University of Calgary and the University of Alberta, and all participants provided informed consent.
Research underpowered, leading to low precision and an inability to draw conclusions about the treatment.
Conclusion There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. Despite its premature termination, this trial successfully introduced several methodological innovations in the execution of trials in Alberta. While the SARS-CoV-2 vaccines give reason for hope, challenges in production and distribution, vaccine hesitancy, and the emergence of variants mean that the original premise of our study to investigate therapies to prevent severe disease remains real and urgent. Competing interests: Aravind Ganesh reports payments to his institution from the Canadian Institutes of Health Research (CIHR), the Canadian Cardiovascular Society, Alberta Innovates and Campus Alberta Neuroscience; consulting fees from MD Analytics, My Medical Panel, Atheneum, DeepBench and Research on Mind; meetings or travel support from American Academy of Neurology, Association of Indian Neurologists in America, American Heart Association and University of Calgary; and a provisional patent application for a system for patient monitoring and delivery of remote..
References
Avendano, Derkach, Swan, Clinical course and management of SARS in health care workers in Toronto: a case series, CMAJ
Borba, Val, Sampaio, 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
Borgundvaag, Ovens, Goldman, SARS outbreak in the Greater Toronto Area: the emergency department experience, CMAJ
Boulware, Pullen, Bangdiwala, A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19, N Engl J Med
Cavalcanti, Zampieri, Rosa, Coalition COVID-19 Brazil I Investigators. Hydroxychloroquine with or without azithromycin in mild-tomoderate COVID-19, N Engl J Med
Dwosh, Hong, Austgarden, Identification and containment of an outbreak of SARS in a community hospital, CMAJ
Gautret, Lagier, Parola, Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study, Travel Med Infect Dis
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents
Grambsch, Therneau, Proportional hazards tests and diagnostics based on weighted residuals, Biometrika
Grasselli, Pesenti, Cecconi, Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response, JAMA
Grasselli, Zangrillo, Zanella, Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy, JAMA
Harris, Taylor, Thielke, Research electronic data capture (RED-Cap) -a metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform
Hoffmann, Mösbauer, Hofmann-Winkler, Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, Nature
Horby, Mafham, Linsell, Effect of hydroxychloroquine in hospitalized patients with COVID-19, N Engl J Med
Lagier, Million, Gautret, IHU COVID-19 Task force. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/ azithromycin and other regimens in Marseille, France: a retrospective analysis, Travel Med Infect Dis
Lenze, Mattar, Zorumski, Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial, JAMA
Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
Mahévas, Tran, Roumier, Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data, BMJ
Maisonnasse, Guedj, Contreras, Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates, Nature
Mehra, Desai, Ruschitzka, Retracted: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis, Lancet,
doi:10.1016/S0140-6736(20)31180-6Mehra, Ruschitzka, Patel, Retraction: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multi national registry analysis, Lancet
Mitjà, Corbacho-Monné, Ubals, BCN PEP-CoV-2 RESEARCH GROUP. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial, Clin Infect Dis,
doi:10.1093/cid/ciaa1009Mitjà, Corbacho-Monné, Ubals, BCN-PEP-CoV2 Research Group. A cluster-randomized trial of hydroxychloroquine for prevention of COVID-19, N Engl J Med
Pan, Liu, Wang, Association of public health interventions with the epidemiology of the COVID-19 outbreak in Wuhan, China, JAMA
Pan, Peto, Henao-Restrepo, Repurposed antiviral drugs for COVID-19: interim WHO Solidarity Trial results, N Engl J Med
Pastick, Okafor, Wang, Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19), Open Forum Infect Dis
Poutanen, Low, Henry, National Microbiology Laboratory, Canada; Canadian Severe Acute Respiratory Syndrome Study Team. Identification of severe acute respiratory syndrome in Canada, N Engl J Med
Rajasingham, Bangdiwala, Nicol, Hydroxychloroquine as preexposure prophylaxis for COVID-19 in healthcare workers: a randomized trial, Clin Infect Dis,
doi:10.1093/cid/ciaa1571Richardson, Hirsch, Narasimhan, Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area, JAMA
Rosenberg, Dufort, Udo, Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State, JAMA
Rosenke, Jarvis, Feldmann, Hydroxychloroquine prophylaxis and treatment is ineffective in macaque and hamster SARS-CoV-2 disease models, JCI Insight
Schrezenmeier, Dörner, Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology, Nat Rev Rheumatol
Self, Semler, Leither, Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial, JAMA
Shehab, Lovegrove, Budnitz, US hydroxychloroquine, chloroquine, and azithromycin outpatient prescription trends, October 2019 through March 2020, JAMA Intern Med
Skipper, Pastick, Engen, Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial, Ann Intern Med
Tang, Cao, Han, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ
Varia, Wilson, Sarwal, Hospital Outbreak Investigation Team. Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada, CMAJ
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Zhao, Hill, Palesch, Minimal sufficient balance -a new strategy to balance baseline covariates and preserve randomness of treatment allocation, Stat Methods Med Res
{ 'indexed': {'date-parts': [[2024, 1, 22]], 'date-time': '2024-01-22T11:39:48Z', 'timestamp': 1705923588892},
'reference-count': 39,
'publisher': 'CMA Joule Inc.',
'issue': '2',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2021, 4]]},
'DOI': '10.9778/cmajo.20210069',
'type': 'journal-article',
'created': {'date-parts': [[2021, 6, 18]], 'date-time': '2021-06-18T16:00:20Z', 'timestamp': 1624032020000},
'page': 'E693-E702',
'source': 'Crossref',
'is-referenced-by-count': 30,
'title': 'Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a '
'randomized controlled trial',
'prefix': '10.9778',
'volume': '9',
'author': [ {'given': 'Ilan', 'family': 'Schwartz', 'sequence': 'first', 'affiliation': []},
{'given': 'Mari E.', 'family': 'Boesen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Graziela', 'family': 'Cerchiaro', 'sequence': 'additional', 'affiliation': []},
{'given': 'Craig', 'family': 'Doram', 'sequence': 'additional', 'affiliation': []},
{'given': 'Brett D.', 'family': 'Edwards', 'sequence': 'additional', 'affiliation': []},
{'given': 'Aravind', 'family': 'Ganesh', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jamie', 'family': 'Greenfield', 'sequence': 'additional', 'affiliation': []},
{'given': 'Scott', 'family': 'Jamieson', 'sequence': 'additional', 'affiliation': []},
{'given': 'Vikram', 'family': 'Karnik', 'sequence': 'additional', 'affiliation': []},
{'given': 'Carol', 'family': 'Kenney', 'sequence': 'additional', 'affiliation': []},
{'given': 'Rachel', 'family': 'Lim', 'sequence': 'additional', 'affiliation': []},
{'given': 'Bijoy K.', 'family': 'Menon', 'sequence': 'additional', 'affiliation': []},
{'given': 'Kwadwo', 'family': 'Mponponsuo', 'sequence': 'additional', 'affiliation': []},
{'given': 'Sarah', 'family': 'Rathwell', 'sequence': 'additional', 'affiliation': []},
{'given': 'Karla J.', 'family': 'Ryckborst', 'sequence': 'additional', 'affiliation': []},
{'given': 'Breanne', 'family': 'Stewart', 'sequence': 'additional', 'affiliation': []},
{'given': 'Maryna', 'family': 'Yaskina', 'sequence': 'additional', 'affiliation': []},
{'given': 'Luanne', 'family': 'Metz', 'sequence': 'additional', 'affiliation': []},
{'given': 'Lawrence', 'family': 'Richer', 'sequence': 'additional', 'affiliation': []},
{'given': 'Michael D.', 'family': 'Hill', 'sequence': 'additional', 'affiliation': []}],
'member': '382',
'published-online': {'date-parts': [[2021, 6, 18]]},
'reference': [ { 'key': '2021061809002189000_9.2.E693.1',
'first-page': '1415',
'article-title': 'Identification and containment of an outbreak of SARS in a community '
'hospital',
'volume': '168',
'author': 'Dwosh',
'year': '2003',
'journal-title': 'CMAJ'},
{ 'key': '2021061809002189000_9.2.E693.2',
'first-page': '1649',
'article-title': 'Clinical course and management of SARS in health care workers in '
'Toronto: a case series',
'volume': '168',
'author': 'Avendano',
'year': '2003',
'journal-title': 'CMAJ'},
{ 'key': '2021061809002189000_9.2.E693.3',
'first-page': '285',
'article-title': 'Investigation of a nosocomial outbreak of severe acute respiratory '
'syndrome (SARS) in Toronto, Canada',
'volume': '169',
'author': 'Varia',
'year': '2003',
'journal-title': 'CMAJ'},
{ 'key': '2021061809002189000_9.2.E693.4',
'doi-asserted-by': 'publisher',
'DOI': '10.1503/cmaj.1031580'},
{ 'key': '2021061809002189000_9.2.E693.5',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa030634'},
{ 'key': '2021061809002189000_9.2.E693.6',
'doi-asserted-by': 'crossref',
'first-page': '1915',
'DOI': '10.1001/jama.2020.6130',
'article-title': 'Association of public health interventions with the epidemiology of the '
'COVID-19 outbreak in Wuhan, China',
'volume': '323',
'author': 'Pan',
'year': '2020',
'journal-title': 'JAMA'},
{ 'key': '2021061809002189000_9.2.E693.7',
'doi-asserted-by': 'crossref',
'first-page': '1574',
'DOI': '10.1001/jama.2020.5394',
'article-title': 'Baseline characteristics and outcomes of 1591 patients infected with '
'SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy',
'volume': '323',
'author': 'Grasselli',
'year': '2020',
'journal-title': 'JAMA'},
{ 'key': '2021061809002189000_9.2.E693.8',
'doi-asserted-by': 'crossref',
'first-page': '1545',
'DOI': '10.1001/jama.2020.4031',
'article-title': 'Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: '
'early experience and forecast during an emergency response',
'volume': '323',
'author': 'Grasselli',
'year': '2020',
'journal-title': 'JAMA'},
{ 'key': '2021061809002189000_9.2.E693.9',
'doi-asserted-by': 'publisher',
'DOI': '10.1001/jama.2020.6775'},
{ 'key': '2021061809002189000_9.2.E693.10',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41584-020-0372-x'},
{ 'key': '2021061809002189000_9.2.E693.11',
'doi-asserted-by': 'crossref',
'first-page': '2493',
'DOI': '10.1001/jama.2020.8630',
'article-title': 'Association of treatment with hydroxychloroquine or azithromycin with '
'in-hospital mortality in patients with COVID-19 in New York State',
'volume': '323',
'author': 'Rosenberg',
'year': '2020',
'journal-title': 'JAMA'},
{ 'key': '2021061809002189000_9.2.E693.12',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.tmaid.2020.101663'},
{'key': '2021061809002189000_9.2.E693.13'},
{ 'key': '2021061809002189000_9.2.E693.14',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.tmaid.2020.101791'},
{ 'key': '2021061809002189000_9.2.E693.15',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/ofid/ofaa130'},
{ 'key': '2021061809002189000_9.2.E693.16',
'doi-asserted-by': 'crossref',
'first-page': '1384',
'DOI': '10.1001/jamainternmed.2020.2594',
'article-title': 'US hydroxychloroquine, chloroquine, and azithromycin outpatient '
'prescription trends, October 2019 through March 2020',
'volume': '180',
'author': 'Shehab',
'year': '2020',
'journal-title': 'JAMA Intern Med'},
{ 'key': '2021061809002189000_9.2.E693.17',
'doi-asserted-by': 'publisher',
'DOI': '10.1177/0962280212436447'},
{ 'key': '2021061809002189000_9.2.E693.18',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/biomet/81.3.515'},
{ 'key': '2021061809002189000_9.2.E693.19',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.jbi.2008.08.010'},
{ 'key': '2021061809002189000_9.2.E693.20',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/S0140-6736(20)31180-6'},
{'key': '2021061809002189000_9.2.E693.21'},
{ 'key': '2021061809002189000_9.2.E693.22',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2016638'},
{ 'key': '2021061809002189000_9.2.E693.23',
'doi-asserted-by': 'crossref',
'first-page': 'e208857',
'DOI': '10.1001/jamanetworkopen.2020.8857',
'article-title': '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',
'volume': '3',
'author': 'Borba',
'year': '2020',
'journal-title': 'JAMA Netw Open'},
{ 'key': '2021061809002189000_9.2.E693.24',
'doi-asserted-by': 'publisher',
'DOI': '10.1136/bmj.m1844'},
{ 'key': '2021061809002189000_9.2.E693.25',
'doi-asserted-by': 'publisher',
'DOI': '10.1136/bmj.m1849'},
{ 'key': '2021061809002189000_9.2.E693.26',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/cid/ciaa1571.'},
{ 'key': '2021061809002189000_9.2.E693.27',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/cid/ciaa1009.'},
{ 'key': '2021061809002189000_9.2.E693.28',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2021801'},
{ 'key': '2021061809002189000_9.2.E693.29',
'doi-asserted-by': 'publisher',
'DOI': '10.7326/M20-4207'},
{ 'key': '2021061809002189000_9.2.E693.30',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2023184'},
{ 'key': '2021061809002189000_9.2.E693.31',
'doi-asserted-by': 'crossref',
'first-page': '2041',
'DOI': '10.1056/NEJMoa2019014',
'article-title': 'Hydroxychloroquine with or without azithromycin in mild-to-moderate '
'COVID-19',
'volume': '383',
'author': 'Cavalcanti',
'year': '2020',
'journal-title': 'N Engl J Med'},
{ 'key': '2021061809002189000_9.2.E693.32',
'doi-asserted-by': 'crossref',
'first-page': '2030',
'DOI': '10.1056/NEJMoa2022926',
'article-title': 'Effect of hydroxychloroquine in hospitalized patients with COVID-19',
'volume': '383',
'author': 'Horby',
'year': '2020',
'journal-title': 'N Engl J Med'},
{ 'key': '2021061809002189000_9.2.E693.33',
'doi-asserted-by': 'crossref',
'first-page': '2165',
'DOI': '10.1001/jama.2020.22240',
'article-title': 'Effect of hydroxychloroquine on clinical status at 14 days in '
'hospitalized patients with COVID-19: a randomized clinical trial',
'volume': '324',
'author': 'Self',
'year': '2020',
'journal-title': 'JAMA'},
{ 'key': '2021061809002189000_9.2.E693.34',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41422-020-0282-0'},
{ 'key': '2021061809002189000_9.2.E693.35',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41421-020-0156-0'},
{ 'key': '2021061809002189000_9.2.E693.36',
'doi-asserted-by': 'crossref',
'first-page': '588',
'DOI': '10.1038/s41586-020-2575-3',
'article-title': 'Chloroquine does not inhibit infection of human lung cells with '
'SARS-CoV-2',
'volume': '585',
'author': 'Hoffmann',
'year': '2020',
'journal-title': 'Nature'},
{ 'key': '2021061809002189000_9.2.E693.37',
'doi-asserted-by': 'crossref',
'first-page': 'e143174',
'DOI': '10.1172/jci.insight.143174',
'article-title': 'Hydroxychloroquine prophylaxis and treatment is ineffective in macaque '
'and hamster SARS-CoV-2 disease models',
'volume': '5',
'author': 'Rosenke',
'year': '2020',
'journal-title': 'JCI Insight'},
{ 'key': '2021061809002189000_9.2.E693.38',
'doi-asserted-by': 'crossref',
'first-page': '584',
'DOI': '10.1038/s41586-020-2558-4',
'article-title': 'Hydroxychloroquine use against SARS-CoV-2 infection in non-human '
'primates',
'volume': '585',
'author': 'Maisonnasse',
'year': '2020',
'journal-title': 'Nature'},
{ 'key': '2021061809002189000_9.2.E693.39',
'doi-asserted-by': 'crossref',
'first-page': '2292',
'DOI': '10.1001/jama.2020.22760',
'article-title': 'Fluvoxamine vs placebo and clinical deterioration in outpatients with '
'symptomatic COVID-19: a randomized clinical trial',
'volume': '324',
'author': 'Lenze',
'year': '2020',
'journal-title': 'JAMA'}],
'container-title': 'CMAJ Open',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://syndication.highwire.org/content/doi/10.9778/cmajo.20210069',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 6, 18]],
'date-time': '2021-06-18T16:00:45Z',
'timestamp': 1624032045000},
'score': 1,
'resource': {'primary': {'URL': 'http://cmajopen.ca/lookup/doi/10.9778/cmajo.20210069'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 4]]},
'references-count': 39,
'journal-issue': { 'issue': '2',
'published-online': {'date-parts': [[2021, 6, 18]]},
'published-print': {'date-parts': [[2021, 4]]}},
'alternative-id': ['10.9778/cmajo.20210069'],
'URL': 'http://dx.doi.org/10.9778/cmajo.20210069',
'relation': {},
'ISSN': ['2291-0026'],
'subject': ['General Medicine'],
'container-title-short': 'cmajo',
'published': {'date-parts': [[2021, 4]]}}
