Seven Days Treatment With the Angiotensin II Type 2 Receptor Agonist C21 in Hospitalized COVID-19 Patients: A Placebo-Controlled Randomized Phase 2 Trial (preprint)

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, randomized phase 2 trial to evaluate efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L (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. Findings: 106 patients were randomised (51 C21, 55 placebo). There was no significant group difference in CRP (primary endpoint). 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 (p=0.057). A post hoc analysis showed that at day 14, the proportion of patients still requiring supplemental oxygen was reduced by 90% in the C21 group compared to placebo (p=0.003). 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, there was a marked reduction of requirement for oxygen at day 14. Funding: Vicore Pharma AB and LifeArc.Clinical Trial Registration Details: The study protocol is available online at ClinicalTrials.gov, NCT04452435.Funding Information: Vicore Pharma AB and LifeArc.Declaration of Interests: Dr. Tornling reports personal fees from Vicore Pharma and Vicore Pharma shares. Dr. Batta reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stock options; in addition, Dr. Batta has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Porter has nothing to disclose. Dr. Williams has nothing to disclose. Dr. Bengtsson reports consultancy fees from Vicore Pharma. Dr. Parmar reports grants from Vicore Pharma, during the conduct of the study. Dr. Kashiva reports grants from Vicore Pharma, during the conduct of the study. Dr. Hallberg reports personal fees from Vicore Pharma. Anne Katrine Cohrt reports personal fees from Vicore Pharma and Vicore Pharma stock options. Kate Westergaard reports personal fees from Vicore Pharma. Dr. Dalsgaard reports a grant from LifeArc Medical Research Charity, during the conduct of the study; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Dalsgaard has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending. Dr. Raud reports a grant from LifeArc Medical Research Charity; personal fees from Vicore Pharma; Vicore Pharma stocks and stock options; in addition, Dr. Raud has a patent UK2004209.9 pending, a patent UK2009574.1 pending, and a patent US17/113,416 pending.Ethics Approval Statement: The protocol, patient information, patient consent form and other documents, as required, were approved by properly constituted IECs and by the national regulatory authorities.

Inhaled Budesonide in the Treatment of Early COVID-19 Illness: A Randomised Controlled Trial (preprint)

Background: Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. Methods: We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results: 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Conclusion: Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection.Trial Registration: ClinicalTrials.gov number, NCT04416399Funding: Oxford NIHR Biomedical Research Centre and AstraZenecaDeclaration of Interests: Dr. Ramakrishnan reports grants and non-financial support from Oxford Respiratory NIHR BRC, during the conduct of the study; non-financial support from AstraZeneca, personal fees from Australian Government Research Training Program, outside the submitted work; . Dr. Nicolau has nothing to disclose. Mrs Langford has nothing to disclose. Mr. Mahdi has nothing to disclose. Mrs Helen Jeffers reports personal fees from AstraZeneca, outside the submitted work; . Miss Mwasuku has nothing to disclose. Mrs Krassowska has nothing to disclose. Dr Fox has nothing to disclose. Dr Binnian has nothing to disclose. Dr Glover has nothing to disclose. Dr Bright has nothing to disclose. Dr. Butler reports grants from National Institute for Health Research (NIHR), Roche Molecular Diagnostics, Janssen Pharmaceuticals, and various public funding bodies for research related to diagnostics and infections. He has revcied personal fees from Pfizer INC, Roche Diagnostics, and Janssen Pharmaceuticals, outside the submitted work. Dr. Cane has nothing to disclose. Mr. Halner has nothing to disclose. Dr. Matthews has nothing to disclose. Dr. Donnelly reports grants from AstraZeneca, from Boehringer-Ingelheim, outside the submitted work; . Dr. Simpson has nothing to disclose. Dr Baker has nothing to disclose. Dr. Fadai has nothing to disclose. Dr. Peterson reports personal fees from AstraZeneca, outside the submitted work; . Mr. Bengtsson reports personal fees from AstraZeneca, outside the submitted work; Dr. Barnes reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, personal fees from Teva, personal fees from Covis, during the conduct of the study; Dr. Russell reports grants from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi UK, personal fees from Glaxo-SmithKline, during the conduct of the study; . Dr. Bafadhel reports grants from AstraZeneca, personal fees from AstraZeneca, Chiesi, GSK, other from Albus Health, ProAxsis, outside the submitted work; .Ethics Approval Statement: The trial was sponsored by the University of Oxford, and was approved by the Fulham London Research Ethics Committee (20/HRA/2531) and the National Health Research Authority.The ethical approval number is 20/HRA/2531.

Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial (preprint)

BackgroundMultiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. MethodsWe conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. Results146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. ConclusionEarly administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection. (Funded by Oxford NIHR Biomedical Research Centre and AstraZeneca; ClinicalTrials.gov number, NCT04416399) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe majority of interventions studied for the COVID-19 pandemic are focused on hospitalised patients. Widely available and broadly relevant interventions for mild COVID-19 are urgently needed. Added value of this studyIn this open label randomised controlled trial, inhaled budesonide, when given to adults with early COVID-19 illness, reduces the likelihood of requiring urgent care, emergency department consultation or hospitalisation. There was also a quicker resolution of fever, a known poor prognostic marker in COVID-19 and a faster self-reported and questionnaire reported symptom resolution. There were fewer participants with persistent COVID-19 symptoms at 14 and 28 days after budesonide therapy compared to usual care. Implications of all the available evidenceThe STOIC trial potentially provides the first easily accessible effective intervention in early COVID-19. By assessing health care resource utilisation, the study provides an exciting option to help with the worldwide pressure on health care systems due to the COVID-19 pandemic. Data from this study also suggests a potentially effective treatment to prevent the long term morbidity from persistent COVID-19 symptoms.

The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial (preprint)

BackgroundAlthough several therapies have been evaluated for treatment of COVID-19, the morbidity and mortality in COVID-19 are still significant, and the need for safe and effective drugs remains high even after launch of vaccine programs. MethodsWe conducted a double-blind, randomized, placebo-controlled trial with the novel oral angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients with C-reactive protein 50-150 mg/L but not needing mechanical ventilation. Patients were randomly assigned to oral C21 (100 mg twice daily) or placebo for 7 days in addition to standard of care, including glucocorticoids and remdesivir. Results106 patients underwent randomization (51 in the C21 group and 55 in the placebo group). At day 14 after start of treatment, the proportion of patients still requiring supplemental oxygen was significantly reduced by 90% in the C21 group compared to the placebo group (p=0.003). Moreover, fewer patients required mechanical ventilation (one C21 patient and four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one and three deaths in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. ConclusionsAs studied in hospitalized COVID-19 patients, C21 on top of standard of care led to a clinically beneficial improvement in respiratory function compared to placebo, paving the way for a pivotal randomised controlled trial. This study is registered at ClinicalTrials.gov with identifier NCT04452435.