Effect of Losartan on Symptomatic Outpatients with COVID-19: A Randomized Clinical Trial

Background: The SARS-CoV-2 virus enters cells via the ACE2 receptor, disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers(ARBs) may mitigate these effects, though induction of ACE2 expression 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 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 losartan versus placebo for 10 days. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. Findings: From April-November 2020, 117 participants were randomized 58 to losartan and 59 to placebo. The primary outcome did not differ significantly between the two arms based on Barnard’s test [losartan arm: 3 events (5.2%; 95% CI 1.8-14.1%) versus placebo arm: 1 event (1.7% 95% CI 0.01-9.0%); proportion difference -3.5% (95% CI -12.7-4.5%); p=0.32]. Functional status, self-reported dyspnea, maximum daily temperatures, and viral load were not significantly different between treatment groups. 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 significantly reduce hospitalizations, affect functional status or assessment of dyspnea. Viral load was not significantly affected by treatment. This study does not support initiation of losartan for low-risk outpatients. Trial Registration: The trial was conducted under the authority of the Food and Drug Administration (IND 148365), was registered on clinicaltrials.gov prior to study initialization (NCT04311177). Funding Statement: This study was supported by Minnesota Partnership for Biotechnology and Medical Genomics (CON000000076883) Declaration of Interests: The authors have no financial conflicts of interest to disclose. MAP, MHN, TWS, and CJT have received additional funding from the Bill and Melinda Gates Foundation to conduct a clinical trial of losartan in inpatients with COVID-19. Ethics Approval Statement: The protocol was approved by a central institutional review board and underwent local context review. The study was conducted following good clinical practice guidelines under the oversight of an independent data safety monitoring board (DSMB).