Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial.

Background: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (COVID-19) on the basis of in vitro activity, uncontrolled data, and small randomized studies. Methods: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of hydroxychloroquine vs. usual care alone. The primary outcome was 28-day mortality. Results: 1561 patients randomly allocated to receive hydroxychloroquine were compared with 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to hydroxychloroquine were less likely to be discharged from hospital alive within 28 days (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 0.85-0.99) and those not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%; risk ratio 1.12; 95% CI 1.01-1.25). There was no excess of new major cardiac arrhythmia. Conclusions: In patients hospitalized with COVID-19, hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death.

[1]  N. White,et al.  Concentration-dependent mortality of chloroquine in overdose , 2020, medRxiv.

[2]  D. Raoult,et al.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial , 2020, International Journal of Antimicrobial Agents.

[3]  Hualiang Jiang,et al.  Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19 , 2020, Science China Life Sciences.

[4]  Jianjun Gao,et al.  Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. , 2020, Bioscience trends.

[5]  J. Fantini,et al.  Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal. , 2020, International journal of antimicrobial agents.

[6]  Kai Zhao,et al.  A pneumonia outbreak associated with a new coronavirus of probable bat origin , 2020, Nature.

[7]  E. Holmes,et al.  Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding , 2020, The Lancet.

[8]  Wu Zhong,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[9]  N. Seidah,et al.  Chloroquine is a potent inhibitor of SARS coronavirus infection and spread , 2005, Virology Journal.

[10]  H. Feldmann,et al.  Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2 , 2020, bioRxiv.

[11]  Hualiang Jiang,et al.  Erratum to: Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19 , 2020, Science China Life Sciences.

[12]  P. Ravaud,et al.  Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data , 2020, BMJ.

[13]  Ting Yu,et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study , 2020, The Lancet.

[14]  P. Woo,et al.  Phylogenetic and recombination analysis of coronavirus HKU1, a novel coronavirus from patients with pneumonia , 2005, Archives of Virology.

[15]  N. White,et al.  COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology , 2020, PLoS medicine.

[16]  Zhan Zhang,et al.  Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial , 2020, medRxiv.

[17]  Qiurong Ruan,et al.  Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China , 2020, Intensive Care Medicine.

[18]  J. Xiang,et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study , 2020, The Lancet.

[19]  S. Abate,et al.  Rate of Intensive Care Unit admission and outcomes among patients with coronavirus: A systematic review and Meta-analysis , 2020, PloS one.

[20]  Q. Bassat,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. , 2020, JAMA network open.

[21]  G. Hripcsak,et al.  Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19 , 2020, The New England journal of medicine.

[22]  Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal , 2020, International Journal of Antimicrobial Agents.

[23]  Duanqing Pei,et al.  Treating COVID-19 with Chloroquine , 2020, Journal of molecular cell biology.

[24]  Malek Okour,et al.  Evaluation of Potential Therapeutic Options for COVID‐19 , 2020, Journal of clinical pharmacology.

[25]  P. Horby,et al.  Scope, quality, and inclusivity of clinical guidelines produced early in the covid-19 pandemic: rapid review , 2020, BMJ.

[26]  Marc Van Ranst,et al.  In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine , 2004, Biochemical and Biophysical Research Communications.

[27]  J. Qu,et al.  Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial , 2020, BMJ.

[28]  S. D. Fernando,et al.  Clinical evidence for repurposing chloroquine and hydroxychloroquine as antiviral agents: a systematic review , 2020, Clinical Microbiology and Infection.

[29]  W. Tu,et al.  Clinical Features and Short-term Outcomes of 102 Patients with Corona Virus Disease 2019 in Wuhan, China , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[30]  Concentration-dependent mortality of chloroquine in overdose , 2020, eLife.

[31]  G. Gao,et al.  A Novel Coronavirus from Patients with Pneumonia in China, 2019 , 2020, The New England journal of medicine.

[32]  T. Cook,et al.  Outcomes from intensive care in patients with COVID‐19: a systematic review and meta‐analysis of observational studies , 2020, Anaesthesia.

[33]  Alexis Jacquier,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: A pilot observational study , 2020, Travel Medicine and Infectious Disease.

[34]  S. Tett,et al.  Population Pharmacokinetics of Hydroxychloroquine in Patients With Rheumatoid Arthritis , 2003, Therapeutic drug monitoring.

[35]  André Machado Siqueira,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. , 2020, JAMA network open.

[36]  D. Raoult,et al.  Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France , 2020, Travel Medicine and Infectious Disease.

[37]  C. Whittaker,et al.  Estimates of the severity of coronavirus disease 2019: a model-based analysis , 2020, The Lancet Infectious Diseases.

[38]  C. Delaugerre,et al.  No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection , 2020, Médecine et Maladies Infectieuses.

[39]  P. Horby,et al.  Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study , 2020, BMJ.

[40]  Hongzhou Lu,et al.  [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. , 2020, Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences.

[41]  Xu Liu,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) , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.