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.

Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management

“…ACE2 allows SARS-CoV-2 virus to enter cells, disrupting the renin-angiotensin-aldosterone axis and possibly contributing to lung damage [ 59 ]. The antimalarial medications, chloroquine, and hydroxychloroquine interrupt ACE2 binding and block viral entry, moreover, they also could affect endosomal and lysosomal pH, which can suppress the merging of the virus with the host cells [ 60 ].…”

“…Angiotensin receptor blockers (ARBs), such as losartan, may also alleviate some of adverse effects of ACE2 induction [ 59 ]. Losartan is currently being tested in patients with COVID-19 [ 39 , 65 ].…”

Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline

“…The compounds rutin, losartan, imatinib, saquinavir, and tenposide have been seen in other computational screens (Bello et al, 2020;Huynh et al, 2020;Pant et al, 2020;Nejat and Sadt, 2021). Losartan and imatinib have undergone clinical trials with COVID19 patients (Aman et al, 2021;Puskarich et al, 2021). Most of the metabolites found in the computational screens unfortunately were not available for purchase.…”

Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective

“…A number of clinical trials have been initiated with angiotensin receptor antagonists against COVID-19 [18]. The best-studied one is losartan (Figure 7), which unfortunately showed no reduction in the hospitalization time of patients with moderately serious disease [19]. A number of clinical trials have been initiated with angiotensin receptor antagonists against COVID-19 [18].…”