Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial
Christine Johnston, Elizabeth R Brown, Jenell Stewart, Helen C Stankiewicz Karita, Patricia J Kissinger, John Dwyer, Sybil Hosek, Temitope Oyedele, Michael K Paasche-Orlow, Kristopher Paolino, Kate B Heller, Hannah Leingang, Harald S Haugen, Tracy Q Dong, Anna Bershteyn, Arun R Sridhar, Jeanne Poole, Peter A Noseworthy, Michael J Ackerman, Susan Morrison, Alexander L Greninger, Meei-Li Huang, Keith R Jerome, Mark H Wener, Anna Wald, Joshua T Schiffer, Connie Celum, Helen Y Chu, Ruanne V Barnabas, Jared M Baeten
EClinicalMedicine, doi:10.1016/j.eclinm.2021.100773
Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%
Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.eclinm.2021.100773.
References
Beigel, Tomashek, Dodd, Remdesivir for the treatment of Covid-19 -final report, N Engl J Med
Cavalcanti, Zampieri, Rosa, Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19, N Engl J Med
Chastain, Henao-Martinez, Young, Racial disproportionality in COVID clinical trials. Reply, N Engl J Med
Chorin, Dai, Shulman, The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin, Nat Med,
doi:10.1038/s41591-020-0888-2Chu, Englund, Starita, Early detection of Covid-19 through a citywide pandemic surveillance platform, N Engl J Med
Dong, Du, Gardner, An interactive web-based dashboard to track COVID-19 in real time, Lancet Infect Dis
Furtado, Berwanger, Fonseca, Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial, Lancet
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
Gottlieb, Nirula, Chen, Effect of Bamlanivimab as monotherapy or in combination with Etesevimab on viral load in patients with mild to moderate COVID-19, JAMA
Harris, Taylor, Minor, The REDCap consortium: building an international community of software platform partners, J Biomed Inform
Harris, Taylor, Thielke, Payne, Gonzalez et al., Research electronic data capture (REDCap)Àa metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform
Hayden, Sugaya, Hirotsu, Baloxavir marboxil for uncomplicated influenza in adults and adolescents, N Engl J Med
Jean, Lee, Hsueh, Treatment options for COVID-19: the reality and challenges, J Microbiol Immunol Infect
Kim, Read, Fauci, Therapy for early COVID-19: a critical need, JAMA
Lagier, Million, Gautret, Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis, Travel Med Infect Dis
Lieberman, 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
Mitj A, Corbacho-Monn E, Ubals, Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial, Clin Infect Dis
Omrani, Pathan, Thomas, Randomized double-blinded placebocontrolled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19, EClinicalMedicine
Pastick, Okafor, Wang, Review: hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19), Open Forum Infect Dis
Powers, Bacci, Leidy, Performance of the influenza patientreported outcome (FLU-PRO) diary in patients with influenza-like illness (ILI), PLoS ONE
Scola, Bideau, Andreani, Viral RNA load as determined by cell culture as a management tool for discharge of SARS-CoV-2 patients from infectious disease wards, Eur J Clin Microbiol Infect Dis
Skipper, Pastick, Engen, Hydroxychloroquine in non-hospitalized adults with early COVID-19: a randomized trial, Ann Intern Med
The, Group, Dexamethasone in hospitalized patients with Covid-19 -preliminary report, N Engl J Med
Therneau, Grambsch, Modeling survival data: extending the cox model
Wortham, Lee, Althomsons, Characteristics of persons who died with COVID-19 -United States, February 12, MMWR Morb Mortal Wkly Rep
Wu, Mcgoogan, Characteristics of and Important Lessons From the Coronavirus Disease 2019. (COVID-19) outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention, JAMA
Yao, 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
Zhu, Zhang, Wang, A novel coronavirus from patients with pneumonia in China, 2019, N Engl J Med
