A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19)
Cheng-Pin Chen, Yi-Chun Lin, Tsung-Chia Chen, Ting-Yu Tseng, Hon-Lai Wong, Cheng-Yu Kuo, Wu-Pu Lin, Sz-Rung Huang, Wei-Yao Wang, Jia-Hung Liao, Chung-Shin Liao, Yuan-Pin Hung, Tse-Hung Lin, Tz-Yan Chang, Chin-Fu Hsiao, Yi-Wen Huang, Wei-Sheng Chung, Chien-Yu Cheng, Shu-Hsing Cheng
PLOS ONE, doi:10.1371/journal.pone.0242763
Objective In this study, we evaluated the efficacy of hydroxychloroquine (HCQ) against coronavirus disease 2019 (COVID-19) via a randomized controlled trial (RCT) and a retrospective study.
Methods Subjects admitted to 11 designated public hospitals in Taiwan between April 1 and May 31, 2020, with COVID-19 diagnosis confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2, were randomized at a 2:1 ratio and stratified by mild or moderate illness. HCQ (400 mg
Author Contributions Conceptualization: Cheng-Pin Chen, Yi-Chun Lin, Chien-Yu Cheng, Shu-Hsing Cheng. Data curation: Yi-Chun Lin, Chin-Fu Hsiao, Shu-Hsing Cheng. Formal analysis: Cheng-Pin Chen, Yi-Chun Lin, Chin-Fu Hsiao, Chien-Yu Cheng, Shu-Hsing Cheng. Funding acquisition: Shu-Hsing Cheng. Investigation: Cheng-Pin Chen, Tsung-Chia Chen, Ting-Yu Tseng, Hon-Lai Wong, Cheng-Yu Kuo, Wu-Pu Lin, Sz-Rung Huang, Wei-Yao Wang, Jia-Hung Liao, Chung-Shin Liao, Yuan-Pin Hung, Tse-Hung Lin, Tz-Yan Chang, Yi-Wen Huang, Wei-Sheng Chung, Chien-Yu Cheng. Methodology: Chin-Fu Hsiao, Chien-Yu Cheng. Supervision: Yi-Wen Huang, Wei-Sheng Chung. Writing -original draft: Cheng-Pin Chen, Yi-Chun Lin. Writing -review & editing: Chien-Yu Cheng, Shu-Hsing Cheng.
References
Arshada, Kilgore, Chaudhry, Jacobsen, Wang et al., Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19, J Infect Dis,
doi:10.1016/j.ijid.2020.06.099.Borba, Val, Sampaio, Alexandre, Melo 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,
doi:10.1001/jamanetworkopen.2020.8857Cao, Wang, Liu, Wang, Fan, A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19, New Engl J Med,
doi:10.1056/NEJMoa2001282Chen, Hu, Zhang, Jiang, Han et al., Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial,
doi:10.1001/jama.2020.22240Chen, Liu, Liu, Liu, Xu et al., A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19), Zhejiang Da Xue Xue Bao Yi Xue Ban,
doi:10.3785/j.issn.1008-9292.2020.03.03Cheng, Chang, Chiang, Chien, Cheng et al., First case of coronavirus disease 2019 (COVID-19) pneumonia in Taiwan, J Formos Med Assoc,
doi:10.1016/j.jfma.2020.02.007Cheng, Li, Chen, Lin, Liu et al., Lopinavir/ritonavir did not shorten the duration of SARS CoV-2 shedding in patients with mild pneumonia in Taiwan, J Microbiol Infect Immunol,
doi:10.1016/j.jmii.2020.03.032Food, Drug, for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 Coronavirus Disease
Furuta, Komeno, Nakamura, Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase, Proc Jpn Acad Ser B Phys Biol Sci,
doi:10.2183/pjab.93.027Gao, Tian, Yang, Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends,
doi:10.5582/bst.2020.01047Gautret, Lagier, Parola, Hoang, Meddeb et al., Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study, Travel Med Infect Dis,
doi:10.1016/j.tmaid.2020.101663Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105949Geleris, Sun, Platt, Zucker, Baldwin et al., Observational study of hydroxychloroquine in hospitalized patients with Covid-19, New Engl J Med,
doi:10.1056/NEJMoa2012410Health, Welfare, Huang, Chen, Shin et al., Naming the coronavirus disease (COVID-19) and the viral that caused it
Holshue, Debolt, Lindquist, Lofy, Wiesman et al., First case of 2019 novel coronavirus in the United States, N Engl J Med,
doi:10.1056/NEJMoa2001191Mehra, Desai, Kuy, Henry, Patel, Retraction: cardiovascular disease, drug therapy, and mortality in Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2007621Mehra, Ruschitzka, Patel, Retraction-hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis, Lancet,
doi:10.1016/S0140-6736%2820%2931324-6Monteil, Kwon, Prado, Hagelkruys, Wimmer et al., Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2, Cell,
doi:10.1016/j.cell.2020.04.004Netea, Rovina, Akinosoglou, Antoniadou, Antonakos, Complex immune dysregulation in COVID-19 patients with severe respiratory failure, Cell Host Microbe,
doi:10.1016/j.chom.2020.04.009Rose-John, IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6, Int J Biol Sci,
doi:10.7150/ijbs.4989Sheahan, Sims, Leist, Scha ¨fer A, Won, Brown, Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV, Nat Commun,
doi:10.1038/s41467-019-13940-6Taiwan, Interim guidelines for clinical management of SARS-CoV-2 infection
Tang, Cao, Han, Wang, Chen et al., Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomized controlled trial, BMJ,
doi:10.1136/bmj.m1849Vincent, Bergeron, Benjannet, Erickson, Rollin et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J,
doi:10.1186/1743-422X-2-69Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Yao, Ye, Zhang, Cui, Huang 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,
doi:10.1093/cid/ciaa237Zhang, Xu, Sun, Zhou, Current targeted therapeutics against COVID-19: based on first-line experience in China, Pharmacol Res,
doi:10.1016/j.phrs.2020.104854{ 'DOI': '10.1371/journal.pone.0242763',
'ISSN': ['1932-6203'],
'URL': 'http://dx.doi.org/10.1371/journal.pone.0242763',
'abstract': '<jats:sec id="sec001">\n'
'<jats:title>Objective</jats:title>\n'
'<jats:p>In this study, we evaluated the efficacy of hydroxychloroquine (HCQ) against '
'coronavirus disease 2019 (COVID-19) via a randomized controlled trial (RCT) and a '
'retrospective study.</jats:p>\n'
'</jats:sec>\n'
'<jats:sec id="sec002">\n'
'<jats:title>Methods</jats:title>\n'
'<jats:p>Subjects admitted to 11 designated public hospitals in Taiwan between April 1 and May '
'31, 2020, with COVID-19 diagnosis confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2, '
'were randomized at a 2:1 ratio and stratified by mild or moderate illness. HCQ (400 mg twice '
'for 1 d or HCQ 200 mg twice daily for 6 days) was administered. Both the study and control '
'group received standard of care (SOC). Pharyngeal swabs and sputum were collected every other '
'day. The proportion and time to negative viral PCR were assessed on day 14. In the '
'retrospective study, medical records were reviewed for patients admitted before March 31, '
'2020.</jats:p>\n'
'</jats:sec>\n'
'<jats:sec id="sec003">\n'
'<jats:title>Results</jats:title>\n'
'<jats:p>There were 33 and 37 cases in the RCT and retrospective study, respectively. In the '
'RCT, the median times to negative rRT-PCR from randomization to hospital day 14 were 5 days '
'(95% CI; 1, 9 days) and 10 days (95% CI; 2, 12 days) for the HCQ and SOC groups, respectively '
'(<jats:italic>p</jats:italic> = 0.40). On day 14, 81.0% (17/21) and 75.0% (9/12) of the '
'subjects in the HCQ and SOC groups, respectively, had undetected virus '
'(<jats:italic>p</jats:italic> = 0.36). In the retrospective study, 12 (42.9%) in the HCQ '
'group and 5 (55.6%) in the control group had negative rRT-PCR results on hospital day 14 '
'(<jats:italic>p</jats:italic> = 0.70).</jats:p>\n'
'</jats:sec>\n'
'<jats:sec id="sec004">\n'
'<jats:title>Conclusions</jats:title>\n'
'<jats:p>Neither study demonstrated that HCQ shortened viral shedding in mild to moderate '
'COVID-19 subjects.</jats:p>\n'
'</jats:sec>',
'author': [ {'affiliation': [], 'family': 'Chen', 'given': 'Cheng-Pin', 'sequence': 'first'},
{'affiliation': [], 'family': 'Lin', 'given': 'Yi-Chun', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Chen', 'given': 'Tsung-Chia', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Tseng', 'given': 'Ting-Yu', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Wong', 'given': 'Hon-Lai', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Kuo', 'given': 'Cheng-Yu', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Lin', 'given': 'Wu-Pu', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Huang', 'given': 'Sz-Rung', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Wang', 'given': 'Wei-Yao', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Liao', 'given': 'Jia-Hung', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Liao', 'given': 'Chung-Shin', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Hung', 'given': 'Yuan-Pin', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Lin', 'given': 'Tse-Hung', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Chang', 'given': 'Tz-Yan', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Hsiao', 'given': 'Chin-Fu', 'sequence': 'additional'},
{ 'ORCID': 'http://orcid.org/0000-0001-6097-3910',
'affiliation': [],
'authenticated-orcid': True,
'family': 'Huang',
'given': 'Yi-Wen',
'sequence': 'additional'},
{'affiliation': [], 'family': 'Chung', 'given': 'Wei-Sheng', 'sequence': 'additional'},
{'affiliation': [], 'family': 'Cheng', 'given': 'Chien-Yu', 'sequence': 'additional'},
{ 'ORCID': 'http://orcid.org/0000-0002-6256-0527',
'affiliation': [],
'authenticated-orcid': True,
'family': 'Cheng',
'given': 'Shu-Hsing',
'sequence': 'additional'},
{ 'affiliation': [],
'name': 'on behalf of the Taiwan HCQ Study Group',
'sequence': 'additional'}],
'container-title': 'PLOS ONE',
'container-title-short': 'PLoS ONE',
'content-domain': {'crossmark-restriction': False, 'domain': ['www.plosone.org']},
'created': {'date-parts': [[2020, 12, 2]], 'date-time': '2020-12-02T19:19:35Z', 'timestamp': 1606936775000},
'deposited': { 'date-parts': [[2020, 12, 2]],
'date-time': '2020-12-02T19:21:05Z',
'timestamp': 1606936865000},
'editor': [{'affiliation': [], 'family': 'Atkin', 'given': 'Stephen L.', 'sequence': 'first'}],
'funder': [ { 'DOI': '10.13039/100008903',
'doi-asserted-by': 'publisher',
'name': 'Ministry of Health and Welfare'}],
'indexed': {'date-parts': [[2024, 3, 3]], 'date-time': '2024-03-03T01:54:12Z', 'timestamp': 1709430852425},
'is-referenced-by-count': 35,
'issue': '12',
'issued': {'date-parts': [[2020, 12, 2]]},
'journal-issue': {'issue': '12', 'published-online': {'date-parts': [[2020, 12, 2]]}},
'language': 'en',
'license': [ { 'URL': 'http://creativecommons.org/licenses/by/4.0/',
'content-version': 'vor',
'delay-in-days': 0,
'start': { 'date-parts': [[2020, 12, 2]],
'date-time': '2020-12-02T00:00:00Z',
'timestamp': 1606867200000}}],
'link': [ { 'URL': 'https://dx.plos.org/10.1371/journal.pone.0242763',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'member': '340',
'original-title': [],
'page': 'e0242763',
'prefix': '10.1371',
'published': {'date-parts': [[2020, 12, 2]]},
'published-online': {'date-parts': [[2020, 12, 2]]},
'publisher': 'Public Library of Science (PLoS)',
'reference': [ { 'key': 'pone.0242763.ref001',
'unstructured': 'World Health Organization. Naming the coronavirus disease (COVID-19) and '
'the viral that caused it [cited 2020 June 20]. Available from: '
'https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it'},
{ 'key': 'pone.0242763.ref002',
'unstructured': 'World Health Organization. Statement on the second meeting or the '
'International Health Regulations (2005) Emergency Committee regarding '
'the outbreak of novel coronavirus (2019-nCoV) [cited 2020 June 20]. '
'Available from: '
'https://www.who.int/news-room/detail/30-01-2020-statement-on-the-second-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov)'},
{ 'key': 'pone.0242763.ref003',
'unstructured': 'World Health Organization. WHO director-general’s opening remarks at the '
'media briefing on COVID-19 [cited 2020 June 20]. Available from: '
'https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020'},
{ 'key': 'pone.0242763.ref004',
'unstructured': 'World Health Organization. Novel coronavirus situation report-151. '
'Geneva, Switzerland [cited 2020 June 20]. Available from: '
'https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200619-covid-19-sitrep-151.pdf?sfvrsn=8b23b56e_2'},
{ 'DOI': '10.1016/j.jfma.2020.02.007',
'article-title': 'First case of coronavirus disease 2019 (COVID-19) pneumonia in Taiwan',
'author': 'SC Cheng',
'doi-asserted-by': 'crossref',
'first-page': '747',
'journal-title': 'J Formos Med Assoc',
'key': 'pone.0242763.ref005',
'volume': '119',
'year': '2020'},
{ 'key': 'pone.0242763.ref006',
'unstructured': 'Taiwan Centers for Disease Control. CECC confirmed 1 more imported '
'COVID-19 case; case returns to Taiwan from Bangladesh [cited 2020 June '
'20]. Accessed on: '
'https://www.cdc.gov.tw/En/Bulletin/Detail/l7L0KFRR2KRBn1JygBFPUg?typeid=158'},
{ 'DOI': '10.1056/NEJMoa2001191',
'article-title': 'First case of 2019 novel coronavirus in the United States',
'author': 'ML Holshue',
'doi-asserted-by': 'crossref',
'first-page': '926',
'journal-title': 'N Engl J Med',
'key': 'pone.0242763.ref007',
'volume': '382',
'year': '2020'},
{ 'DOI': '10.1038/s41422-020-0282-0',
'article-title': 'Remdesivir and chloroquine effectively inhibit the recently emerged '
'novel coronavirus (2019-nCoV) in vitro',
'author': 'M Wang',
'doi-asserted-by': 'crossref',
'first-page': '269',
'journal-title': 'Cell Res',
'key': 'pone.0242763.ref008',
'volume': '30',
'year': '2020'},
{ 'DOI': '10.1038/s41467-019-13940-6',
'article-title': 'Comparative therapeutic efficacy of remdesivir and combination '
'lopinavir, ritonavir, and interferon beta against MERS-CoV',
'author': 'TP Sheahan',
'doi-asserted-by': 'crossref',
'first-page': '222',
'journal-title': 'Nat Commun',
'key': 'pone.0242763.ref009',
'volume': '11',
'year': '2020'},
{ 'DOI': '10.2183/pjab.93.027',
'article-title': 'Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase',
'author': 'Y Furuta',
'doi-asserted-by': 'crossref',
'first-page': '449',
'journal-title': 'Proc Jpn Acad Ser B Phys Biol Sci',
'key': 'pone.0242763.ref010',
'volume': '93',
'year': '2017'},
{ 'article-title': 'Lopinavir/ritonavir did not shorten the duration of SARS CoV-2 shedding '
'in patients with mild pneumonia',
'author': 'CY Cheng',
'first-page': '488',
'journal-title': 'Taiwan. J Microbiol Infect Immunol. 2020',
'key': 'pone.0242763.ref011',
'volume': '53'},
{ 'DOI': '10.1056/NEJMoa2001282',
'article-title': 'A trial of lopinavir-ritonavir in adults hospitalized with severe '
'COVID-19',
'author': 'B Cao',
'doi-asserted-by': 'crossref',
'first-page': '1787',
'journal-title': 'New Engl J Med',
'key': 'pone.0242763.ref012',
'volume': '382',
'year': '2020'},
{ 'DOI': '10.1016/j.antiviral.2020.104787',
'article-title': 'The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 '
'in vitro',
'author': 'L Caly',
'doi-asserted-by': 'crossref',
'first-page': '104787',
'journal-title': 'Antiviral Res',
'key': 'pone.0242763.ref013',
'volume': '178',
'year': '2020'},
{ 'DOI': '10.1016/j.cell.2020.04.004',
'article-title': 'Inhibition of SARS-CoV-2 infections in engineered human tissues using '
'clinical-grade soluble human ACE2',
'author': 'V Monteil',
'doi-asserted-by': 'crossref',
'first-page': '905',
'journal-title': 'Cell',
'key': 'pone.0242763.ref014',
'volume': '181',
'year': '2020'},
{ 'DOI': '10.1016/j.ijantimicag.2020.105949',
'article-title': 'Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results '
'of an open-label non-randomized clinical trial',
'author': 'P Gautret',
'doi-asserted-by': 'crossref',
'first-page': '105949',
'journal-title': 'Int J Antimicrob Agents',
'key': 'pone.0242763.ref015',
'volume': '20',
'year': '2020'},
{ 'DOI': '10.1016/j.chom.2020.04.009',
'article-title': 'Complex immune dysregulation in COVID-19 patients with severe '
'respiratory failure',
'author': 'EJ Giamarellos-Bourboulis',
'doi-asserted-by': 'crossref',
'first-page': '992',
'journal-title': 'Cell Host Microbe. 2020',
'key': 'pone.0242763.ref016',
'volume': '27'},
{ 'DOI': '10.7150/ijbs.4989',
'article-title': 'IL-6 trans-signaling via the soluble IL-6 receptor: importance for the '
'pro-inflammatory activities of IL-6',
'author': 'S Rose-John',
'doi-asserted-by': 'crossref',
'first-page': '1237',
'journal-title': 'Int J Biol Sci',
'key': 'pone.0242763.ref017',
'volume': '8',
'year': '2012'},
{ 'DOI': '10.1016/S1473-3099(03)00806-5',
'article-title': 'Effects of chloroquine on viral infections: an old drug against today’s '
'diseases',
'author': 'A Savarino',
'doi-asserted-by': 'crossref',
'first-page': '722',
'journal-title': 'Lancet Infect Dis',
'key': 'pone.0242763.ref018',
'volume': '3',
'year': '2003'},
{ 'DOI': '10.1186/1743-422X-2-69',
'article-title': 'Chloroquine is a potent inhibitor of SARS coronavirus infection and '
'spread',
'author': 'MJ Vincent',
'doi-asserted-by': 'crossref',
'first-page': '69',
'journal-title': 'Virol J',
'key': 'pone.0242763.ref019',
'volume': '2',
'year': '2005'},
{ 'DOI': '10.1016/j.phrs.2020.104854',
'article-title': 'Current targeted therapeutics against COVID-19: based on first-line '
'experience in China',
'author': 'Y Zhang',
'doi-asserted-by': 'crossref',
'first-page': '104854',
'journal-title': 'Pharmacol Res',
'key': 'pone.0242763.ref020',
'volume': '157',
'year': '2020'},
{ 'key': 'pone.0242763.ref021',
'unstructured': 'U.S. Food and Drug Administration. Reply to request for emergency use '
'authorization for use of chloroquine phosphate or hydroxychloroquine '
'sulfate supplied from the strategic national stockpile for treatment of '
'2019 Coronavirus Disease [cited 2020 June 20]. Available from: '
'https://www.fda.gov/media/136534/download'},
{ 'article-title': 'Retraction: cardiovascular disease, drug therapy, and mortality in '
'Covid-19',
'author': 'MR Mehra',
'journal-title': 'N Engl J Med',
'key': 'pone.0242763.ref022',
'year': '2020'},
{ 'DOI': '10.1016/S0140-6736(20)31324-6',
'article-title': 'Retraction—hydroxychloroquine or chloroquine with or without a '
'macrolide for treatment of COVID-19: a multinational registry analysis',
'author': 'MR Mehra',
'doi-asserted-by': 'crossref',
'first-page': '1820',
'journal-title': 'Lancet',
'key': 'pone.0242763.ref023',
'volume': '395',
'year': '2020'},
{ 'key': 'pone.0242763.ref024',
'unstructured': 'World Health Organization. Diagnostic detection of 2019-nCoV by '
'real-time RT-PCR [cited 2020 June 20]. Available from: '
'https://www.who.int/docs/default-source/coronaviruse/protocol-v2-1.pdf?sfvrsn=a9ef618c_2'},
{ 'DOI': '10.5582/bst.2020.01047',
'article-title': 'Breakthrough: chloroquine phosphate has shown apparent efficacy in '
'treatment of COVID-19 associated pneumonia in clinical studies',
'author': 'J Gao',
'doi-asserted-by': 'crossref',
'first-page': '72',
'journal-title': 'Biosci Trends',
'key': 'pone.0242763.ref025',
'volume': '14',
'year': '2020'},
{ 'key': 'pone.0242763.ref026',
'unstructured': 'National Health Commission of the People’s Republic of China. National '
'recommendations for diagnosis and treatment of respiratory infections '
'caused by 2019-nCoV (6th ed) [cited 2020 June 6]. Available from: '
'http://www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc2/files/b218cfeb1bc54639af227f922bf6b817.pdf'},
{ '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',
'author': 'MGS Borba',
'doi-asserted-by': 'crossref',
'first-page': 'e208857',
'journal-title': 'JAMA Netw Open',
'key': 'pone.0242763.ref027',
'volume': '3',
'year': '2020'},
{ 'DOI': '10.1016/j.tmaid.2020.101663',
'article-title': 'Clinical and microbiological effect of a combination of '
'hydroxychloroquine and azithromycin in 80 COVID-19 patients with at '
'least a six-day follow up: an observational study',
'author': 'P Gautret',
'doi-asserted-by': 'crossref',
'first-page': '101663',
'journal-title': 'Travel Med Infect Dis',
'key': 'pone.0242763.ref028',
'volume': '34',
'year': '2020'},
{ 'article-title': 'Observational study of hydroxychloroquine in hospitalized patients with '
'Covid-19',
'author': 'J Geleris',
'journal-title': 'New Engl J Med',
'key': 'pone.0242763.ref029',
'volume': '7',
'year': '2020'},
{ 'article-title': 'Treatment with hydroxychloroquine, azithromycin, and combination in '
'patients hospitalized with COVID-19',
'author': 'S Arshada',
'first-page': '396',
'journal-title': 'J Infect Dis',
'key': 'pone.0242763.ref030',
'volume': '97',
'year': '2020'},
{ 'article-title': 'A pilot study of hydroxychloroquine in treatment of patients with '
'common coronavirus disease-19 (COVID-19)',
'author': 'J Chen',
'first-page': '215',
'journal-title': 'Zhejiang Da Xue Xue Bao Yi Xue Ban',
'key': 'pone.0242763.ref031',
'volume': '49',
'year': '2020'},
{ 'DOI': '10.1101/2020.03.22.20040758',
'article-title': 'Efficacy of hydroxychloroquine in patients with COVID-19: results of a '
'randomized clinical trial',
'author': 'Z Chen',
'doi-asserted-by': 'crossref',
'key': 'pone.0242763.ref032'},
{ 'DOI': '10.1136/bmj.m1849',
'article-title': 'Hydroxychloroquine in patients with mainly mild to moderate coronavirus '
'disease 2019: open label, randomized controlled trial',
'author': 'W Tang',
'doi-asserted-by': 'crossref',
'first-page': 'm1849',
'journal-title': 'BMJ',
'key': 'pone.0242763.ref033',
'volume': '369',
'year': '2020'},
{ 'key': 'pone.0242763.ref034',
'unstructured': 'Taiwan CDC. Interim guidelines for clinical management of SARS-CoV-2 '
'infection (5th ed.) [cited 2020 June 6]. Available from: '
'https://www.cdc.gov.tw/File/Get/-ewtg9-RCAetCPKR4_rnCw'},
{ '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': 'X Yao',
'first-page': 'ciaa237',
'journal-title': 'Clin Infect Dis',
'key': 'pone.0242763.ref035',
'year': '2020'}],
'reference-count': 35,
'references-count': 35,
'relation': { 'has-preprint': [ { 'asserted-by': 'object',
'id': '10.1101/2020.07.08.20148841',
'id-type': 'doi'}]},
'resource': {'primary': {'URL': 'https://dx.plos.org/10.1371/journal.pone.0242763'}},
'score': 1,
'short-title': [],
'source': 'Crossref',
'subject': ['Multidisciplinary'],
'subtitle': [],
'title': 'A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and '
'tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to '
'moderate coronavirus disease 2019 (COVID-19)',
'type': 'journal-article',
'update-policy': 'http://dx.doi.org/10.1371/journal.pone.corrections_policy',
'volume': '15'}
