Protocol for the Controlled evaLuation of Angiotensin Receptor blockers for COVID-19 respIraTorY disease (CLARITY): a randomised controlled trial

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Abstract

Background

SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solution for reducing COVID-19 respiratory outcomes.

Methods and discussion

CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020.

Trial registration

ClinicalTrials.gov, NCT04394117. Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831)

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-021-05521-0.

Related collections

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Author and article information

Contributors

Arlen Wilcox:

ORCID: http://orcid.org/0000-0003-4128-1796

arlen.wilcox@sydney.edu.au

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 28 August 2021

Publication date PMC-release: 28 August 2021

Publication date Collection: 2021

Volume: 22

Electronic Location Identifier: 573

Affiliations

[1 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, The George Institute for Global Health, , University of New South Wales, ; Sydney, Australia

[2 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, The George Institute for Global Health, , Imperial College London, ; London, UK

[3 ]GRID grid.415193.b, Prince of Wales Hospital, ; Sydney, Australia

[4 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, NHMRC Clinical Trials Centre, , University of Sydney, ; Sydney, Australia

[5 ]GRID grid.464831.c, The George Institute for Global Health, ; New Delhi, India

[6 ]GRID grid.1024.7, ISNI 0000000089150953, Queensland University of Technology, ; Brisbane, Australia

[7 ]GRID grid.412703.3, ISNI 0000 0004 0587 9093, Royal North Shore Hospital, ; Sydney, Australia

[8 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, Kolling Institute of Medical Research, , University of Sydney, ; Sydney, Australia

[9 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Medicine, , The University of Melbourne, Austin Health, ; Heidelburg, Victoria Australia

[10 ]GRID grid.413618.9, ISNI 0000 0004 1767 6103, All India Institute of Medical Sciences, ; Raipur, India

[11 ]GRID grid.414306.4, ISNI 0000 0004 1777 6366, Christian Medical College, ; Ludhiana, India

[12 ]GRID grid.414685.a, ISNI 0000 0004 0392 3935, Concord Repatriation General Hospital, ; Sydney, Australia

[13 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, The University of Sydney, ; Sydney, Australia

[14 ]GRID grid.1013.3, ISNI 0000 0004 1936 834X, Sydney School of Public Health, , University of Sydney, ; Sydney, Australia

[15 ]GRID grid.430417.5, ISNI 0000 0004 0640 6474, The Sydney Children’s Hospitals Network, ; Westmead, NSW Australia

Author information

Arlen Wilcox http://orcid.org/0000-0003-4128-1796

Article

Publisher ID: 5521

DOI: 10.1186/s13063-021-05521-0

PMC ID: 8397850

PubMed ID: 34454580

SO-VID: 131b5abb-8291-42b8-bfb9-52fe7f0a16cd

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 7 June 2021

Date accepted : 6 August 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: APP2002277

Award Recipient : Meg Jardine

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: covid-19,angiotensin receptor blockers,renin-angiotensin system,rct,bayesian adaptive design

Data availability:

ScienceOpen disciplines: Medicine

Keywords: covid-19, angiotensin receptor blockers, renin-angiotensin system, rct, bayesian adaptive design