Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19
MD Caleb P Skipper, BSc Katelyn A Pastick, MS Nicole W Engen, MS Ananta S Bangdiwala, DO, MPH Mahsa Abassi, MD Sarah M Lofgren, MPH Darlisha A Williams, BSc Elizabeth C Okafor, MD Matthew F Pullen, PharmD Melanie R Nicol, PhD Alanna A Nascene, BA Kathy H Hullsiek, PhD Matthew P Cheng, MD Darlette Luke, PharmD Sylvain A Lother, MD Lauren J Mackenzie, MD, MPH Glen Drobot, MD Lauren E Kelly, PhD Ilan S Schwartz, PhD Ryan Zarychanski, MD, MSc Emily G Mcdonald, MD, MSc Todd C Lee, MD, MPH Radha Rajasingham, MD David R Boulware
Annals of Internal Medicine, doi:10.7326/m20-4207
Background: No effective oral therapy exists for early coronavirus disease 2019 . Objective: To investigate whether hydroxychloroquine could reduce COVID-19 severity in adult outpatients. Design: Randomized, double-blind, placebo-controlled trial conducted from 22 March through 20 May 2020. (ClinicalTrials .gov: NCT04308668) Setting: Internet-based trial across the United States and Canada (40 states and 3 provinces). Participants: Symptomatic, nonhospitalized adults with laboratoryconfirmed COVID-19 or probable COVID-19 and high-risk exposure within 4 days of symptom onset. Intervention: Oral hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo. Measurements: Symptoms and severity at baseline and then at days 3, 5, 10, and 14 using a 10-point visual analogue scale. The primary end point was change in overall symptom severity over 14 days. Limitation: Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.
Conclusion: Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.
References
Beigel, Tomashek, Dodd, ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 -preliminary report, N Engl J Med,
doi:10.1056/NEJMoa2007764
Boulware, Pullen, Bangdiwala, Finding the dose for hydroxychloroquine prophylaxis for COVID-19: the desperate search for effectiveness, Clin Pharmacol Ther,
doi:10.1056/NEJMoa2016638
Burke, Midgley, Dratch, Active monitoring of persons exposed to patients with confirmed COVID-19 -United States, January-February 2020,
doi:10.15585/mmwr.mm6909e115
Cheng, Papenburg, Desjardins, Diagnostic testing for severe acute respiratory syndrome-related coronavirus 2: a narrative review, Ann Intern Med,
doi:10.7326/M20-1301
Geleris, Sun, Platt, Observational study of roquine in hospitalized patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2012410
Harris, Taylor, Minor, The REDCap consortium: building an international community of software platform partners, J Biomed Inform,
doi:10.1016/j.jbi.2019.103208
Horby, Mafham, Linsell, Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv,
doi:10.1101/2020.07.15.2015185219
Kaptein, Jacobs, Langendries, Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine. bioRxiv, mBio,
doi:10.1101/2020.06.19.159053
Kucirka, Lauer, Laeyendecker, Variation in falsenegative rate of reverse transcriptase polymerase chain reactionbased SARS-CoV-2 tests by time since exposure, Ann Intern Med,
doi:10.7326/M20-1495
Lother, Abassi, Agostinis, Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomizedcontrolled trial, Can J Anaesth,
doi:10.1007/s12630-020-01684-7
Maisonnasse, Guedj, Contreras, Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in nonhuman primates,
doi:10.21203/rs.3.rs-27223/v1
Mcmichael, Currie, Clark, Public Health-Seattle and King County, EvergreenHealth, and CDC COVID-19 Investigation Team. Epidemiology of Covid-19 in a long-term care facility in King County, Washington, N Engl J Med,
doi:10.1056/NEJMoa2005412
Million, Lagier, Gautret, Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France, Travel Med Infect Dis,
doi:10.1016/j.tmaid.2020.101738
Nicholson, Aoki, Osterhaus, Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group, Lancet
Okafor ; Pullen, Nicol, Hullsiek, Mackenzie, Zarychanski et al., Critical revision of the article for important intellectual content
Pastick, Okafor, Wang, Review: hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Fo, rum Infect Dis,
doi:10.1093/ofid/ofaa130
Ross, Wilson, Papillon-Ferland, COVID-SAFER: deprescribing guidance for hydroxychloroquine drug interactions in olderadults,
doi:10.1111/jgs.1662325
Treanor, Hayden, Vrooman, Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group, JAMA
Wang, Zhang, Du, Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Lancet,
doi:10.1016/S0140-6736(20)31022-9
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)
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