Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19
MD Gilmar Reis, Eduardo Augusto Dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Gurmit Singh, Jay J H Park, Jamie I Forrest, Ofir Harari, Castilho Vitor Quirino Dos Santos, Ana Paula Figueiredo Guimarães De Almeida, Adhemar Dias De Figueiredo Neto, Leonardo Cançado Monteiro Savassi, RN Aline Cruz Milagres, Mauro Martins Teixeira, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, Rosemary Oliveira, PhD Edward J Mills
JAMA Network Open, doi:10.1001/jamanetworkopen.2021.6468
IMPORTANCE Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. OBJECTIVE To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo.
MAIN OUTCOMES AND MEASURES The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events.
RESULTS Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavirritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91
ARTICLE INFORMATION Author Contributions: Drs Reis and Mills had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Reis, E.
Conflict of Interest Disclosures: None reported. Funding/Support: The trial was supported by the Bill and Melinda Gates Foundation.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Dr. Reis wishes to acknowledge particularly here the role of mayors and public health authorities in Brazil (a complete list can be found in the eAppendix of Supplement 2).
The TOGETHER Investigators
References
Abd-Elsalam, Esmail, Khalaf, Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study, Am J Trop Med Hyg,
doi:10.4269/ajtmh.20-0873Chan, Yao, Yeung, Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset, J Infect Dis,
doi:10.1093/infdis/jiv392Chen, Chan, Jiang, In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds, J Clin Virol,
doi:10.1016/j.jcv.2004.03.003Chu, Englund, Starita, Seattle Flu Study Investigators. Early detection of Covid-19 through a citywide pandemic surveillance platform, N Engl J Med,
doi:10.1056/NEJMc2008646Dimairo, Pallmann, Wason, The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design, BMJ,
doi:10.1136/bmj.m115Dimairo, Pallmann, Wason, The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design, Trials,
doi:10.1186/s13063-020-04334-xGillenwater, Rahaghi, Hadeh, Remdesivir for the treatment of Covid-19-preliminary report, N Engl J Med,
doi:10.1056/NEJMc2022236Harari, Hsu, Dron, Park, Thorlund et al., Utilizing Bayesian predictive power in clinical trial design, Pharm Stat,
doi:10.1002/pst.2073Hung, Lung, Tso, Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial, Lancet,
doi:10.1016/S0140-6736(20)31042-4Lee, Rayner, Forrest, Nachega, Senchaudhuri et al., The rise and fall of hydroxychloroquine for the treatment and prevention of COVID-19, Am J Trop Med Hyg,
doi:10.4269/ajtmh.20-1320Lieberman, Pepper, Naccache, Huang, Jerome et al., Comparison of commercially available and laboratory-developed assays for in vitro detection of SARS-CoV-2 in clinical laboratories, J Clin Microbiol,
doi:10.1128/JCM.00821-20Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov,
doi:10.1038/s41421-020-0156-0Mills, Department of Health Research Methods, Evidence, and Impact
Mills, None
Mitjà, Corbacho-Monné, Ubals, -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/ciaa1009Park, Decloedt, Rayner, Cotton, Mills, Clinical trials of disease stages in COVID 19: complicated and often misinterpreted, Lancet Glob Health,
doi:10.1016/S2214-109X(20)30365-XPark, Siden, Zoratti, Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols, Trials,
doi:10.1186/s13063-019-3664-1Powers, Iii, Bacci, Leidy, Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI), PLoS One,
doi:10.1371/journal.pone.0194180Rayner, Dron, Park, Accelerating clinical evaluation of repurposed combination therapies for COVID-19, Am J Trop Med Hyg,
doi:10.4269/ajtmh.20-0995Santos, Brierley, Gandhi, Cohen, Moschella et al., Repurposing therapeutics for potential treatment of SARS-CoV-2: a review, Viruses,
doi:10.3390/v12070705Silva, Silva, Quirino Dos Santos, Simplicio, Ribeiro et al., Research Division, Cardresearch-Cardiologia Assistencial e de Pesquisa
Skipper, Pastick, Engen, Hydroxychloroquine in nonhospitalized adults with early COVID-19 : a randomized trial, Ann Intern Med,
doi:10.7326/M20-4207St, Hamilton, L8s 4k1, None
Woodcock, Lavange, Master protocols to study multiple therapies, multiple diseases, or both, N Engl J Med,
doi:10.1056/NEJMra1510062Yao, Ye, Zhang, 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,
doi:10.1093/cid/ciaa237DOI record:
{
"DOI": "10.1001/jamanetworkopen.2021.6468",
"ISSN": [
"2574-3805"
],
"URL": "http://dx.doi.org/10.1001/jamanetworkopen.2021.6468",
"author": [
{
"affiliation": [
{
"name": "Research Division, Cardresearch—Cardiologia Assistencial e de Pesquisa, Brazil"
},
{
"name": "Department of Medicine, Pontifícia Universidade Católica de Minas Gerais, Brazil"
}
],
"family": "Reis",
"given": "Gilmar",
"sequence": "first"
},
{
"affiliation": [
{
"name": "Research Division, Cardresearch—Cardiologia Assistencial e de Pesquisa, Brazil"
},
{
"name": "Department of Medicine, Pontifícia Universidade Católica de Minas Gerais, Brazil"
}
],
"family": "Moreira Silva",
"given": "Eduardo Augusto dos Santos",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Research Division, Cardresearch—Cardiologia Assistencial e de Pesquisa, Brazil"
},
{
"name": "Department of Medicine, Pontifícia Universidade Católica de Minas Gerais, Brazil"
}
],
"family": "Medeiros Silva",
"given": "Daniela Carla",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada"
}
],
"family": "Thabane",
"given": "Lehana",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada"
}
],
"family": "Singh",
"given": "Gurmit",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Experimental Medicine, Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada"
},
{
"name": "Cytel Inc, Vancouver, British Columbia, Canada"
}
],
"family": "Park",
"given": "Jay J. H.",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Experimental Medicine, Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada"
},
{
"name": "Cytel Inc, Vancouver, British Columbia, Canada"
}
],
"family": "Forrest",
"given": "Jamie I.",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Cytel Inc, Vancouver, British Columbia, Canada"
}
],
"family": "Harari",
"given": "Ofir",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Research Division, Cardresearch—Cardiologia Assistencial e de Pesquisa, Brazil"
},
{
"name": "Department of Medicine, Pontifícia Universidade Católica de Minas Gerais, Brazil"
}
],
"family": "Quirino dos Santos",
"given": "Castilho Vitor",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Department of Public Health, Montes Claros State University, Montes Claros, Brazil"
}
],
"family": "Guimarães de Almeida",
"given": "Ana Paula Figueiredo",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Public Health Fellowship Program, Governador Valadares Public Health Authority, Brazil"
}
],
"family": "Figueiredo Neto",
"given": "Adhemar Dias de",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Public Health, Mental and Family Medicine Department, Ouro Preto Federal University, Ouro Preto, Brazil"
}
],
"family": "Savassi",
"given": "Leonardo Cançado Monteiro",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Public Health, Mental and Family Medicine Department, Ouro Preto Federal University, Ouro Preto, Brazil"
},
{
"name": "Public Health Care Division, City of Ibirité, Brazil"
}
],
"family": "Milagres",
"given": "Aline Cruz",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Brazil"
}
],
"family": "Teixeira",
"given": "Mauro Martins",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Research Division, Cardresearch—Cardiologia Assistencial e de Pesquisa, Brazil"
}
],
"family": "Simplicio",
"given": "Maria Izabel Campos",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Research Division, Cardresearch—Cardiologia Assistencial e de Pesquisa, Brazil"
}
],
"family": "Ribeiro",
"given": "Luciene Barra",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Research Division, Cardresearch—Cardiologia Assistencial e de Pesquisa, Brazil"
}
],
"family": "Oliveira",
"given": "Rosemary",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada"
}
],
"family": "Mills",
"given": "Edward J.",
"sequence": "additional"
},
{
"affiliation": [],
"name": "TOGETHER Investigators",
"sequence": "additional"
}
],
"container-title": "JAMA Network Open",
"container-title-short": "JAMA Netw Open",
"content-domain": {
"crossmark-restriction": false,
"domain": []
},
"created": {
"date-parts": [
[
2021,
4,
22
]
],
"date-time": "2021-04-22T22:50:49Z",
"timestamp": 1619131849000
},
"deposited": {
"date-parts": [
[
2021,
9,
17
]
],
"date-time": "2021-09-17T15:00:55Z",
"timestamp": 1631890855000
},
"indexed": {
"date-parts": [
[
2024,
3,
26
]
],
"date-time": "2024-03-26T23:17:31Z",
"timestamp": 1711495051304
},
"is-referenced-by-count": 105,
"issue": "4",
"issued": {
"date-parts": [
[
2021,
4,
22
]
]
},
"journal-issue": {
"issue": "4",
"published-print": {
"date-parts": [
[
2021,
4,
1
]
]
}
},
"language": "en",
"link": [
{
"URL": "https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2779044/reis_2021_oi_210214_1631721378.05543.pdf",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "10",
"original-title": [],
"page": "e216468",
"prefix": "10.1001",
"published": {
"date-parts": [
[
2021,
4,
22
]
]
},
"published-online": {
"date-parts": [
[
2021,
4,
22
]
]
},
"publisher": "American Medical Association (AMA)",
"reference": [
{
"DOI": "10.1056/NEJMc2022236",
"article-title": "Remdesivir for the treatment of Covid-19–preliminary report.",
"author": "Gillenwater",
"doi-asserted-by": "crossref",
"first-page": "992",
"issue": "10",
"journal-title": "N Engl J Med",
"key": "zoi210214r2",
"volume": "383",
"year": "2020"
},
{
"DOI": "10.1056/NEJMoa2021436",
"article-title": "Dexamethasone in hospitalized patients with Covid-19.",
"author": "Horby",
"doi-asserted-by": "crossref",
"first-page": "693",
"issue": "8",
"journal-title": "N Engl J Med",
"key": "zoi210214r3",
"volume": "384",
"year": "2021"
},
{
"DOI": "10.1016/S0140-6736(20)30183-5",
"article-title": "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.",
"author": "Huang",
"doi-asserted-by": "publisher",
"first-page": "497",
"issue": "10223",
"journal-title": "Lancet",
"key": "zoi210214r4",
"volume": "395",
"year": "2020"
},
{
"DOI": "10.4269/ajtmh.20-0995",
"article-title": "Accelerating clinical evaluation of repurposed combination therapies for COVID-19.",
"author": "Rayner",
"doi-asserted-by": "publisher",
"first-page": "1364",
"issue": "4",
"journal-title": "Am J Trop Med Hyg",
"key": "zoi210214r5",
"volume": "103",
"year": "2020"
},
{
"DOI": "10.1016/S2214-109X(20)30365-X",
"article-title": "Clinical trials of disease stages in COVID 19: complicated and often misinterpreted.",
"author": "Park",
"doi-asserted-by": "publisher",
"first-page": "e1249",
"issue": "10",
"journal-title": "Lancet Glob Health",
"key": "zoi210214r6",
"volume": "8",
"year": "2020"
},
{
"DOI": "10.1038/s41421-020-0156-0",
"article-title": "Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.",
"author": "Liu",
"doi-asserted-by": "publisher",
"first-page": "16",
"journal-title": "Cell Discov",
"key": "zoi210214r7",
"volume": "6",
"year": "2020"
},
{
"DOI": "10.1093/cid/ciaa237",
"article-title": "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).",
"author": "Yao",
"doi-asserted-by": "publisher",
"first-page": "732",
"issue": "15",
"journal-title": "Clin Infect Dis",
"key": "zoi210214r8",
"volume": "71",
"year": "2020"
},
{
"DOI": "10.1016/j.jcv.2004.03.003",
"article-title": "In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds.",
"author": "Chen",
"doi-asserted-by": "publisher",
"first-page": "69",
"issue": "1",
"journal-title": "J Clin Virol",
"key": "zoi210214r9",
"volume": "31",
"year": "2004"
},
{
"DOI": "10.1093/infdis/jiv392",
"article-title": "Treatment with lopinavir/ritonavir or interferon-ß1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset.",
"author": "Chan",
"doi-asserted-by": "publisher",
"first-page": "1904",
"issue": "12",
"journal-title": "J Infect Dis",
"key": "zoi210214r10",
"volume": "212",
"year": "2015"
},
{
"DOI": "10.4269/ajtmh.20-0873",
"article-title": "Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study.",
"author": "Abd-Elsalam",
"doi-asserted-by": "publisher",
"first-page": "1635",
"issue": "4",
"journal-title": "Am J Trop Med Hyg",
"key": "zoi210214r11",
"volume": "103",
"year": "2020"
},
{
"DOI": "10.1016/S0140-6736(20)32013-4",
"article-title": "Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.",
"author": "RECOVERY Collaborative Group",
"doi-asserted-by": "publisher",
"first-page": "1345",
"issue": "10259",
"journal-title": "Lancet",
"key": "zoi210214r12",
"volume": "396",
"year": "2020"
},
{
"DOI": "10.1007/s40121-020-00349-8",
"article-title": "Early treatment of COVID-19 disease: a missed opportunity.",
"author": "Forrest",
"doi-asserted-by": "publisher",
"first-page": "715",
"issue": "4",
"journal-title": "Infect Dis Ther",
"key": "zoi210214r13",
"volume": "9",
"year": "2020"
},
{
"DOI": "10.1177/1740774515626362",
"article-title": "Efficiencies of platform clinical trials: a vision of the future.",
"author": "Saville",
"doi-asserted-by": "publisher",
"first-page": "358",
"issue": "3",
"journal-title": "Clin Trials",
"key": "zoi210214r14",
"volume": "13",
"year": "2016"
},
{
"DOI": "10.1016/j.jclinepi.2020.04.025",
"article-title": "An overview of platform trials with a checklist for clinical readers.",
"author": "Park",
"doi-asserted-by": "publisher",
"first-page": "1",
"journal-title": "J Clin Epidemiol",
"key": "zoi210214r15",
"volume": "125",
"year": "2020"
},
{
"DOI": "10.1186/s13063-019-3664-1",
"article-title": "Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols.",
"author": "Park",
"doi-asserted-by": "publisher",
"first-page": "572",
"issue": "1",
"journal-title": "Trials",
"key": "zoi210214r16",
"volume": "20",
"year": "2019"
},
{
"DOI": "10.1056/NEJMra1510062",
"article-title": "Master protocols to study multiple therapies, multiple diseases, or both.",
"author": "Woodcock",
"doi-asserted-by": "publisher",
"first-page": "62",
"issue": "1",
"journal-title": "N Engl J Med",
"key": "zoi210214r17",
"volume": "377",
"year": "2017"
},
{
"DOI": "10.1136/bmj.m115",
"article-title": "The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.",
"author": "Dimairo",
"doi-asserted-by": "crossref",
"first-page": "m115",
"journal-title": "BMJ",
"key": "zoi210214r18",
"volume": "369",
"year": "2020"
},
{
"DOI": "10.1186/s13063-020-04334-x",
"article-title": "The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.",
"author": "Dimairo",
"doi-asserted-by": "publisher",
"first-page": "528",
"issue": "1",
"journal-title": "Trials",
"key": "zoi210214r19",
"volume": "21",
"year": "2020"
},
{
"DOI": "10.1056/NEJMc2008646",
"article-title": "Early detection of Covid-19 through a citywide pandemic surveillance platform.",
"author": "Chu",
"doi-asserted-by": "publisher",
"first-page": "185",
"issue": "2",
"journal-title": "N Engl J Med",
"key": "zoi210214r20",
"volume": "383",
"year": "2020"
},
{
"DOI": "10.1016/j.jclinepi.2004.11.019",
"article-title": "The Wisconsin Upper Respiratory Symptom Survey is responsive, reliable, and valid.",
"author": "Barrett",
"doi-asserted-by": "publisher",
"first-page": "609",
"issue": "6",
"journal-title": "J Clin Epidemiol",
"key": "zoi210214r21",
"volume": "58",
"year": "2005"
},
{
"DOI": "10.1371/journal.pone.0194180",
"article-title": "Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI).",
"author": "Powers",
"doi-asserted-by": "crossref",
"issue": "3",
"journal-title": "PLoS One",
"key": "zoi210214r22",
"volume": "13",
"year": "2018"
},
{
"DOI": "10.1128/JCM.00821-20",
"article-title": "Comparison of commercially available and laboratory-developed assays for in vitro detection of SARS-CoV-2 in clinical laboratories.",
"author": "Lieberman",
"doi-asserted-by": "crossref",
"issue": "8",
"journal-title": "J Clin Microbiol",
"key": "zoi210214r23",
"volume": "58",
"year": "2020"
},
{
"article-title": "Utilizing Bayesian predictive power in clinical trial design.",
"author": "Harari",
"journal-title": "Pharm Stat",
"key": "zoi210214r24",
"year": "2020"
},
{
"DOI": "10.3390/v12070705",
"article-title": "Repurposing therapeutics for potential treatment of SARS-CoV-2: a review.",
"author": "Santos",
"doi-asserted-by": "crossref",
"issue": "7",
"journal-title": "Viruses",
"key": "zoi210214r25",
"volume": "12",
"year": "2020"
},
{
"DOI": "10.4269/ajtmh.20-1320",
"article-title": "The rise and fall of hydroxychloroquine for the treatment and prevention of COVID-19.",
"author": "Lee",
"doi-asserted-by": "publisher",
"first-page": "35",
"issue": "1",
"journal-title": "Am J Trop Med Hyg.",
"key": "zoi210214r26",
"volume": "104",
"year": "2021"
},
{
"DOI": "10.1016/S0140-6736(20)31042-4",
"article-title": "Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.",
"author": "Hung",
"doi-asserted-by": "publisher",
"first-page": "1695",
"issue": "10238",
"journal-title": "Lancet",
"key": "zoi210214r27",
"volume": "395",
"year": "2020"
},
{
"article-title": "Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial.",
"author": "Mitjà",
"journal-title": "Clin Infect Dis",
"key": "zoi210214r28",
"year": "2020"
},
{
"DOI": "10.7326/M20-4207",
"article-title": "Hydroxychloroquine in nonhospitalized adults with early COVID-19 : a randomized trial.",
"author": "Skipper",
"doi-asserted-by": "publisher",
"first-page": "623",
"issue": "8",
"journal-title": "Ann Intern Med",
"key": "zoi210214r29",
"volume": "173",
"year": "2020"
},
{
"DOI": "10.1056/NEJMe2020388",
"article-title": "Hydroxychloroquine for the prevention of Covid-19 - searching for evidence.",
"author": "Cohen",
"doi-asserted-by": "publisher",
"first-page": "585",
"issue": "6",
"journal-title": "N Engl J Med",
"key": "zoi210214r30",
"volume": "383",
"year": "2020"
},
{
"article-title": "Repurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results.",
"author": "Pan",
"journal-title": "N Engl J Med",
"key": "zoi210214r31",
"year": "2020"
},
{
"DOI": "10.1056/NEJMoa2016638",
"article-title": "A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19.",
"author": "Boulware",
"doi-asserted-by": "publisher",
"first-page": "517",
"issue": "6",
"journal-title": "N Engl J Med",
"key": "zoi210214r32",
"volume": "383",
"year": "2020"
},
{
"key": "zoi210214r1",
"unstructured": "Johns Hopkins University & Medicine. Coronavirus Resource Center. September 10, 2020. Accessed November 19, 2020. https://coronavirus.jhu.edu"
},
{
"key": "zoi210214r33",
"unstructured": "Drugs for Neglected Diseases Institute. The ANTICOV trial. Accessed December 5, 2020. https://dndi.org/diseases/covid-19/"
},
{
"key": "zoi210214r34",
"unstructured": "Clincialtrials.gov. Trial of early therapies during non-hospitalized outpatient window for COVID-19 (TREATNOW). Accessed December 5, 2020. https://clinicaltrials.gov/ct2/show/NCT04372628"
}
],
"reference-count": 34,
"references-count": 34,
"relation": {},
"resource": {
"primary": {
"URL": "https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779044"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [
"General Medicine"
],
"subtitle": [
"The TOGETHER Randomized Clinical Trial"
],
"title": "Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19",
"type": "journal-article",
"volume": "4"
}
