Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial

BMJ, The - Trang e072175
Meg Jardine1,2, Sradha Kotwal3,4, Abhinav Bassi5, Carinna Hockham6, Mark Jones7, Arlen Wilcox2, Carol A. Pollock8,9, Louise M. Burrell10,11, James M. McGree12, Vinay Rathore13, Christine Jenkins1,4, Lalit Gupta14, Angus Ritchie1, Ashpak Bangi15, Sanjay D′Cruz16, Andrew J. McLachlan17, Simon Finfer4, Michelle M. Cummins2, Tom Snelling18, Vivekanand Jha19,20,5
1Concord Repatriation General Hospital, Concord, NSW, Australia
2NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
3Prince of Wales Hospital, Randwick, NSW. Australia
4The George Institute for Global Health, University of New South Wales, Newtown, NSW, Australia
5The George Institute for Global Health, UNSW, New Delhi, India
6The George Institute for Global Health, Imperial College, London, UK
7Sydney School of Public Health, University of Sydney, Camperdown, NSW, Australia
8Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
9Royal North Shore Hospital, St Leonards, NSW, Australia
10Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia
11Institute of Breathing and Sleep, Heidelberg, VIC, Australia
12Queensland University of Technology, Brisbane, QLD, Australia
13All India Institute of Medical Sciences, Raipur, India
14Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
15Jivanrekha Multispecialty Hospital, Pune, India
16Government Medical College and Hospital, Chandigarh, India
17Sydney Pharmacy School, The University of Sydney, Camperdown, NSW, Australia
18The Sydney Children's Hospitals Network, Westmead, NSW, Australia
19Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India
20School of Public Health, Imperial College London, UK

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Abstract Objective To determine whether disrupting the renin angiotensin system with angiotensin receptor blockers will improve clinical outcomes in people with covid-19. Design CLARITY was a pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. Setting 17 hospital sites in India and Australia. Participants Participants were at least 18 years old, previously untreated with angiotensin receptor blockers, with a laboratory confirmed diagnosis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection who had been admitted to hospital for management of covid-19. Intervention Oral angiotensin receptor blockers (telmisartan in India) or placebo (1:1) for 28 days. Main outcome measures The primary endpoint was covid-19 disease severity using a modified World Health Organization Clinical Progression Scale (WHO scale) at day 14. Secondary outcomes were WHO scale scores at day 28, mortality, intensive care unit admission, and respiratory failure. Analyses were evaluated on an ordinal scale in the intention-to-treat population. Results Between 3 May 2020 and 13 November 2021, 2930 people were screened for eligibility, with 393 randomly assigned to angiotensin receptor blockers (of which 388 (98.7%) to telmisartan 40 mg/day) and 394 to the control group. 787 participants were randomised: 778 (98.9%) from India and nine (1.1%) from Australia. The median WHO scale score at day 14 was 1 (interquartile range 1-1) in 384 participants assigned angiotensin receptor blockers and 1 (1-1) in 382 participants assigned placebo (adjusted odds ratio 1.51 (95% credible interval 1.02 to 2.23), probability of an odds ratio of >1 (Pr(OR>1)=0.98). WHO scale scores at day 28 showed little evidence of difference between groups (1.02 (0.55 to 1.87), Pr(OR>1)=0.53). The trial was stopped when a prespecified futility rule was met. Conclusions In patients admitted to hospital for covid-19, mostly with mild disease, not requiring oxygen, no evidence of benefit, based on disease severity score, was found for treatment with angiotensin receptor blockers, using predominantly 40 mg/day of telmisartan. Trial registration ClinicalTrials.gov NCT04394117 .

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