학술논문
Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis.
Document Type
Academic Journal
Author
Di Stefano L; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.; Ogburn EL; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.; Ram M; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.; Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Scharfstein DO; Division of Biostatistics, Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Li T; University of Colorado Denver, Anschutz Medical Campus, Denver, Colorado, United States of America.; Khanal P; Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Baksh SN; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.; McBee N; Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Gruber J; Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Gildea MR; Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Clark MR; Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Goldenberg NA; Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Johns Hopkins All Children's Institute for Clinical and Translational Research, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, United States of America.; Bennani Y; Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.; University Medical Center, New Orleans, New Orleans, Louisiana, United States of America.; Brown SM; Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray, Utah, United States of America.; University of Utah, Salt Lake City, Utah, United States of America.; Buckel WR; Pharmacy Services, Intermountain Healthcare, Murray, Utah, United States of America.; Clement ME; Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.; University Medical Center, New Orleans, New Orleans, Louisiana, United States of America.; Mulligan MJ; Department of Medicine, Division of Infectious Diseases and Immunology, New York University Grossman School of Medicine, New York, New York, United States of America.; Vaccine Center, New York University Grossman School of Medicine, New York, New York, United States of America.; O'Halloran JA; Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.; Rauseo AM; Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America.; Self WH; Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.; Semler MW; Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.; Seto T; Department of Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii, United States of America.; Stout JE; Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina, United States of America.; Ulrich RJ; Department of Medicine, Division of Infectious Diseases and Immunology, New York University Grossman School of Medicine, New York, New York, United States of America.; Victory J; Bassett Research Institute, Bassett Medical Center, Cooperstown, New York, United States of America.; Bierer BE; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America.; Hanley DF; Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.; Freilich D; Department of Internal Medicine, Division of Infectious Diseases, Bassett Medical Center, Cooperstown, New York, United States of America.
Source
Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients.
Methods: We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions.
Results: Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively).
Conclusions: The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.
Competing Interests: The authors have read the journal’s policy and have the following competing interests: S.N.B., N.M., M.R.C., and D.F.H. report receiving research funding from the Department of Defense for clinical trials of convalescent plasma for COVID-19 outside the submitted work. N.A.G. reports receiving salary support from the National Institutes of Health (NIH) National Center for Advancing Translational Sciences via a Johns Hopkins Clinical and Translational Science Award outside the submitted work. Y.B. reports being a site investigator for Janssen outside the submitted work. S.M.B. reports service as chair of a data and safety monitoring board for a Hamilton clinical trial in respiratory failure; fees paid to Intermountain Healthcare from Faron Pharmaceuticals and Sedana Pharmaceuticals for steering committee service for a clinical trial in acute respiratory distress syndrome; research grants to Intermountain Healthcare from Janssen, NIH, Centers for Disease Control and Prevention, and Department of Defense; and royalties from Oxford University Press and Brigham Young University, outside the submitted work. M.E.C. reports service on a Roche advisory board and as a site investigator for Janssen outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Methods: We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions.
Results: Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively).
Conclusions: The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.
Competing Interests: The authors have read the journal’s policy and have the following competing interests: S.N.B., N.M., M.R.C., and D.F.H. report receiving research funding from the Department of Defense for clinical trials of convalescent plasma for COVID-19 outside the submitted work. N.A.G. reports receiving salary support from the National Institutes of Health (NIH) National Center for Advancing Translational Sciences via a Johns Hopkins Clinical and Translational Science Award outside the submitted work. Y.B. reports being a site investigator for Janssen outside the submitted work. S.M.B. reports service as chair of a data and safety monitoring board for a Hamilton clinical trial in respiratory failure; fees paid to Intermountain Healthcare from Faron Pharmaceuticals and Sedana Pharmaceuticals for steering committee service for a clinical trial in acute respiratory distress syndrome; research grants to Intermountain Healthcare from Janssen, NIH, Centers for Disease Control and Prevention, and Department of Defense; and royalties from Oxford University Press and Brigham Young University, outside the submitted work. M.E.C. reports service on a Roche advisory board and as a site investigator for Janssen outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.