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

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

BMJ 2022; 379 doi: https://doi.org/10.1136/bmj-2022-072175 (Published 16 November 2022) Cite this as: BMJ 2022;379:e072175
  1. Meg J Jardine, professor1 2,
  2. Sradha S Kotwal, lead study clinician3 4,
  3. Abhinav Bassi, senior research fellow5,
  4. Carinna Hockham, research associate6,
  5. Mark Jones, senior biostatistician7,
  6. Arlen Wilcox, program lead1,
  7. Carol Pollock, professor of medicine8 9,
  8. Louise M Burrell, professor of medicine10 11,
  9. James McGree, professor of statistics12,
  10. Vinay Rathore, assistant professor13,
  11. Christine R Jenkins, professor of respiratory medicine2 3,
  12. Lalit Gupta, associate professor14,
  13. Angus Ritchie, clinical associate professor2,
  14. Ashpak Bangi, intensivist15,
  15. Sanjay D’Cruz, professor of general medicine16,
  16. Andrew J McLachlan, professor of pharmacy17,
  17. Simon Finfer, professorial fellow3,
  18. Michelle M Cummins, senior researcher1,
  19. Thomas Snelling, professor of statistics18,
  20. Vivekanand Jha, executive director5 19 20
  21. on behalf of the CLARITY trial investigators
    1. 1NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
    2. 2Concord Repatriation General Hospital, Concord, NSW, Australia
    3. 3The George Institute for Global Health, University of New South Wales, Newtown, NSW, Australia
    4. 4Prince of Wales Hospital, Randwick, NSW, Australia
    5. 5The George Institute for Global Health, UNSW, New Delhi, India
    6. 6The George Institute for Global Health, Imperial College London, UK
    7. 7Sydney School of Public Health, University of Sydney, Camperdown, NSW, Australia
    8. 8Royal North Shore Hospital, St Leonards, NSW, Australia
    9. 9Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia
    10. 10Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia
    11. 11Institute of Breathing and Sleep, Heidelberg, VIC, Australia
    12. 12Queensland University of Technology, Brisbane, QLD, Australia
    13. 13All India Institute of Medical Sciences, Raipur, India
    14. 14Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
    15. 15Jivanrekha Multispecialty Hospital, Pune, India
    16. 16Government Medical College and Hospital, Chandigarh, India
    17. 17Sydney Pharmacy School, The University of Sydney, Camperdown, NSW, Australia
    18. 18The Sydney Children’s Hospitals Network, Westmead, NSW, Australia
    19. 19Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India
    20. 20School of Public Health, Imperial College, London, UK
    1. Corresponding author: A Wilcox arlen.wilcox{at}sydney.edu.au (or @_ArlenWilcox on Twitter)
    • Accepted 16 September 2022

    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.

    Footnotes

    • Members of the CLARITY trial investigators are listed in the appendix (pages 1-3).

    • Contributors: MJJ contributed to conceptualisation, data curation, funding acquisition, investigation, methodology, project administration, resources, software, supervision, visualisation, writing the original draft, and writing, reviewing and editing, and is a guarantor of the study. SSK contributed to data curation, funding acquisition, investigation, methodology, project administration, writing the original draft, and reviewing and editing. AB contributed to data curation, investigation, methodology, project administration, resources, software, writing the original draft, and reviewing and editing. CH contributed to data curation, investigation, methodology, project administration, writing the original draft, and reviewing and editing. MJ contributed to formal analysis, methodology, software, visualisation, writing the original draft, and reviewing and editing. AW contributed to data curation, investigation, methodology, project administration, resources, software, writing the original draft, and reviewing and editing. CP contributed to data curation, funding acquisition, investigation, methodology, and writing, and reviewing and editing. LMB contributed to data curation, funding acquisition, investigation, methodology, writing, and reviewing and editing. JM contributed to formal analysis, funding acquisition, methodology, software, visualisation, writing the original draft, and reviewing and editing. VR contributed to investigation, resources, and writing, and reviewing and editing. CRJ contributed to data curation, funding acquisition, investigation, and writing, and reviewing and editing. LG contributed to investigation, resources, and writing, and reviewing and editing. AR contributed to data curation, funding acquisition, investigation, resources, writing, and reviewing and editing. AB and SDC contributed to investigation, resources, and writing, and reviewing and editing. AJM contributed to funding acquisition, methodology, and writing, and reviewing and editing. SF contributed to funding acquisition, and writing, and reviewing and editing. MMC contributed to project administration, visualisation, writing the original draft, and reviewing and editing. TS contributed to formal analysis, methodology, resources, software, visualisation, and writing, and reviewing and editing. VJ contributed to data curation, investigation, methodology, project administration, resources, supervision, writing the original draft, reviewing and editing, and is a guarantor of the study. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

    • Funding: The research was funded by the Australian Medical Research Future Fund Coronavirus Research Response (MRF2002277) and University of Sydney philanthropic grant funds (2021/B3027). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, or writing of the report, or decision to submit the article for publication. This publication is solely the responsibility of the authors and does not reflect the views of the Australian Commonwealth.

    • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Australian government and the University of Sydney for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years except the following: MJ is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro, and Merck Sharp and Dohme; has received advisory, steering committee or speaker fees, or both, from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, Chinook, CSL, Janssen, Medscape, Merck Sharp Dohme, Roche, and Vifor; CP serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Merck Sharp and Dohme, and Novartis; CJ serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi-Genzyme; VJ has received grants from Baxter Healthcare, Biocon, and GlaxoSmithKline, and speaker fees or on the advisory board for AstraZeneca, Baxter Healthcare, NephroPlus, Sanofi; no other relationships or activities that could appear to have influenced the submitted work.

    • The lead authors (MJJ and VJ) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned have been explained.

    • Dissemination to participants and related patient and public communities: The study convened a consumer and community engagement committee as described within the protocol publication.7 This group provided advice and feedback on the template for trial results dissemination, which was pre-approved by the ethics committee to facilitate dissemination of results to surviving participants at the conclusion of the trial. Additionally, the results of the trial will be disseminated through the consumer and community engagement committee, presentation at conferences and other appropriate forums, through relevant social media channels, and a plain English summary on the sponsors website.

    • Provenance and peer review: Not commissioned; externally peer reviewed.

    Data availability statement

    The final dataset will be under the custodianship of the chair of the trial steering committee. all individual participant data that are collected during the trial will be de-identified. The researchers intend de-identified data will contribute to global learnings through an appropriately constituted individual participant data level collaboration. Requests for data access or analysis proposals will be reviewed by the trial steering committee, who will assess proposals according to criteria based on scientific merit and contribution to global knowledge. Data sharing will be performed in compliance with local data protection laws.

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    This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.

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