A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19
Michael A Puskarich, Nathan W Cummins, Nicholas E Ingraham, David A Wacker, Ronald A Reilkoff, Brian E Driver, Michelle H Biros, Fernanda Bellolio, Jeffrey G Chipman, Andrew C Nelson, Kenneth Beckman, Ryan Langlois, Tyler Bold, Matthew T Aliota, Timothy W Schacker, Helen T Voelker, Thomas A Murray, Joseph S Koopmeiners, Christopher J Tignanelli
eClinicalMedicine, doi:10.1016/j.eclinm.2021.100957
Background: The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease. Methods: This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to 1:1 losartan (25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily) versus placebo for 10 days, and all patients and outcome assesors were blinded. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. (clinicatrials.gov, NCT04311177, closed to new participants) Findings: From April to November 2020, 117 participants were randomized 58 to losartan and 59 to placebo, and all were analyzed under intent to treat principles. The primary outcome did not differ significantly between the two arms based on Barnard's test [losartan arm: 3 events (5.2% 95% CI 1.1, 14.4%) versus placebo arm: 1 event (1.7%; 95% CI 0.0, 9.1%)]; proportion difference -3.5% (95% CI -13.2, 4.8%); p = 0.32]. Viral loads were not statistically different between treatment groups at any time point. Adverse events per 10 patient days did not differ signifcantly [0.33 (95% CI 0.22À0.49) for losartan vs. 0.37 (95% CI 0.25À0.55) for placebo]. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early. Interpretation: In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalizations, though assessment was limited by low event rate. Importantly, viral load was not statistically affected by treatment. This study does not support initiation of losartan for low-risk outpatients.
Declaration of Competing Interest The authors have no financial conflicts of interest to disclose. All the authors report grants from Minnesota Partnership for Biotechnology and Medical Genomics during the conduct of the study. MAP reports also grants from Bill and Melinda Gates Foundation and grants from NHLBI, outside the submitted work.
CRediT authorship contribution statement
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