Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial

Abstract

Background COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. Findings 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. Funding Vicore Pharma AB and LifeArc, UK.

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

“…Yet, preclinical studies indicate that AT 2 receptor agonists are not suitable as a monotherapy for cardiovascular disease and that at best, AT 2 receptor agonists may be beneficial in combination with existing RAS inhibitors ( Danyel et al, 2013 ). Currently, the clinical focus of AT 2 receptor agonists (in development by Vicore Pharma) is severe lung disorders, with C21 receiving orphan drug status for idiopathic pulmonary fibrosis by the US Food and Drug Administration and the European Medicines Agency and a post hoc analysis of a recent phase 2 clinical trial, suggesting that 7-day treatment with C21 in hospitalized patients with COVID-19 reduced the requirement for oxygen at day 14 ( Tornling et al, 2021 ).…”

Comparison of Preprint Postings of Randomized Clinical Trials on COVID-19 and Corresponding Published Journal Articles

“…As of October 1, 2022, 119 preprints (78.3%) had been published in a scientific, peer-reviewed journal (Figure 2 and eTable 3 in Supplement 1). Two preprints were published in a single journal publication . The median time to publication was 186 days (range, 17-407 days).…”

Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment

“…In particular, a trial with the agonist Compound 21 (C21; Vicore Pharma, Gothenburg, Sweden) has been performed in COVID-19 hospitalized patients not requiring intensive care. Patients were treated with C21 for 7 days on top of standard of care (Angiotensin II Type Two Receptor Agonist in COVID-19 Trial (ATTRACT) study; NCT04452435) [ 122 ]. Treatment with C21 was well tolerated and safe.…”