A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19

Abstract

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 0.22-0.49) for losartan vs. 0.37 (95% CI 0.25-0.55) 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.

Keywords: Angiotensin receptor blocker; COVID-19; Losartan; RAAS.

Conflict of interest statement

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.

© 2021 The Author(s).

Figures

Fig. 1

Study flow diagram of patient enrollments and randomization

Fig. 2

Effect of losartan on (2a) SF-12 Physical Component Score (PCS); (2b) SF-12 Mental Component Score (MCS); and (2c) PROMIS overall dyspnea, respectively. X-axis is study day and y-axis is score on the instrument. Placebo is in red lines and losartan in blue lines with 95% CIs at each assessment. Losartan did not statistically significantly affect these outcomes overall or at any time point. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.).

Fig. 3

Effect of losartan on (3a) relative viral load (log10 scale); (3b) mean cycle threshold (Ct), respectively. X-axis is study day and y-axis is relative viral load (RVL) or threshold cycle (Ct). Relative viral load (RVL) is corrected to human marker DNA to control for specimen quality. Mean cycle threshold (Ct) is inversely related to viral load (high viral loads have a low Ct). Placebo is in red lines and losartan in blue lines with 95% CIs at each assessment. Losartan did not statistically significantly affect the cycle threshold or relative viral load overall or at any time point. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Effect of losartan on mean blood pressure over study days 1–15. X-axis is day of treatment, and y-axis is mean arterial pressure (MAP) in mmHg. Placebo is in red and losartan in blue with 95% CIs at each assessment. While losartan did not statistically significantly affect these outcomes overall or at any time point, a non-significant reduction of up to 10 mmHg was observed at approximately day 5. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)