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
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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.
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A phase 2 clinical trial early in the pandemic showed improvement of respiratory function in patients with severe COVID-19 treated with an AT2R agonist (C21).
“Indeed, results of a phase 2 clinical trial early in the pandemic showed improvement of respiratory function in patients with severe COVID-19 treated with an agonist of the AT2R (C21),22”
C21 (an activator of the AT2R) improved respiratory function in patients with severe COVID-19.
“early in the pandemic it has been reported that C21 (an activator of the AT2R) improved respiratory function in patients with severe COVID-19,22”
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The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target
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- Authors
- Tornling, G., Batta, R., Porter, J. C., Williams, B., Bengtsson, T., Parmar, K., Kashiva, R., Hallberg, A., Cohrt, A. K., Westergaard, K., Dalsgaard, C.-J., & Raud, J.
- Affiliations
- Karolinska Institutet (SE)
- Vicore Pharma (Sweden) (SE)
- University College Hospital (GB)
- National Institute for Health and Care Research (GB)
- B.J. Medical College (IN)
- Noble Hospital (IN)
- Uppsala University (SE)
- Corresponding author
- Dalsgaard, Carl-Johan
- Venue
- EClinicalMedicine
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 41
- Pages
- 101152
- ISSN
- 2589-5370 (ISSN-L)
- PMC
- PMC8542174
- OpenAlex
- W3209312055
- Cited by
- 54
- References
- 39
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 6 · 2023: 15 · 2022: 11 · 2021: 7 · 2020: 1
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EClinicalMedicine (publishedVersion, cc-by-nc-nd)
- medRxiv (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- UCLH Biomedical Research Centre
- LifeArc
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- COVID-19 pandemic, C21, angiotensin II type 2 receptor agonist, hospitalized patients, C-reactive protein, supplemental oxygen requirement, mechanical ventilation, mortality, drug safety and tolerability, cytokine storm, SARS-CoV-2, post hoc analysis, South Asia, Europe, North America, Africa, Middle East
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