A Randomized Clinical Trial Testing Hydroxychloroquine for Reduction of SARS-CoV-2 Viral Shedding and Hospitalization in Early Outpatient COVID-19 Infection
Adam M Spivak, Bradley J Barney, Tom Greene, Richard Holubkov, Cody S Olsen, Jordan Bridges, Raj Srivastava, Brandon Webb, Frances Sebahar, Ainsley Huffman, Christina F Pacchia, J Michael Dean, Rachel Hess
Microbiology Spectrum, doi:10.1128/spectrum.04674-22
Early in the COVID-19 pandemic, no effective treatment existed to prevent clinical worsening of COVID-19 among recently diagnosed outpatients. At the University of Utah, Salt Lake City, Utah, we conducted a phase 2 prospective parallel group randomized placebo-controlled trial (NCT04342169) to determine whether hydroxychloroquine given early in disease reduces the duration of SARS-CoV-2 shedding. We enrolled nonhospitalized adults ($18 years of age) with a recent positive diagnostic test for SARS-CoV-2 (within 72 h of enrollment) and adult household contacts. Participants received either 400 mg hydroxychloroquine by mouth twice daily on day 1 followed by 200 mg by mouth twice daily on days 2 to 5 or oral placebo with the same schedule. We performed SARS-CoV-2 nucleic acid amplification testing (NAAT) on oropharyngeal swabs on days 1 to 14 and 28 and monitored clinical symptomatology, rates of hospitalization, and viral acquisition by adult household contacts. We identified no overall differences in the duration of oropharyngeal carriage of SARS-CoV-2 (hazard ratio of viral shedding time comparing hydroxychloroquine to placebo, 1.21; 95% confidence interval [CI], 0.91, 1.62). Overall, 28-day hospitalization incidence was similar between treatments (4.6% hydroxychloroquine versus 2.7% placebo). No differences were seen in symptom duration, severity, or viral acquisition in household contacts between treatment groups. The study did not reach the prespecified enrollment target, which was likely influenced by a steep decline in COVID-19 incidence corresponding to the initial vaccine rollout in the spring of 2021. Oropharyngeal swabs were self-collected, which may introduce variability in these results. Placebo treatments were not identical to hydroxychloroquine treatments (capsules versus tablets) which may have led to inadvertent participant unblinding. In this group of community adults early in the COVID-19 pandemic, hydroxychloroquine did not significantly alter the natural history of early COVID-19 disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT04342169). IMPORTANCE Early in the COVID-19 pandemic, no effective treatment existed to prevent clinical worsening of COVID-19 among recently diagnosed outpatients. Hydroxychloroquine received attention as a possible early treatment; however, quality prospective studies were lacking. We conducted a clinical trial to test the ability of hydroxychloroquine to prevent clinical worsening of COVID-19.
Analyses were performed in SAS Software (version 9.4; SAS Institute Inc., Cary, NC). Two-sided P values less than 0.05 were considered significant. Multiple imputation was performed using chained equations implemented in IVEware (version 0.3; University of Michigan, Ann Arbor, MI), and results from 50 imputations were combined using standard methods (28) .
SUPPLEMENTAL MATERIAL Supplemental material is available online only. SUPPLEMENTAL FILE 1, PDF file, 0.2 MB.
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