Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease (CLARITY)

The Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY) study is a pragmatic prospective, open-label, randomised controlled trial. CLARITY aims to examine the effectiveness of angiotensin II receptor blockers (ARBs) on improving the outcomes of people who tested positive for COVID-19 disease.

Study Overview

• Status: Completed
• Conditions: COVID-19; Coronavirus Disease 2019
• Intervention / Treatment: Other: Placebo; Drug: Angiotensin Receptor Blockers

• Study Type: Interventional
• Enrollment (Actual): 787
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Campsie, New South Wales, Australia, 2194
      • Canterbury Hospital
    • Caringbah, New South Wales, Australia, 2229
      • The Sutherland Hospital
    • Concord, New South Wales, Australia, 2139
      • Concord Hospital
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • New Lambton Heights, New South Wales, Australia, 2305
      • John Hunter Hospital
    • Randwick, New South Wales, Australia, 2031
      • Prince of Wales Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
    • Wollongong, New South Wales, Australia, 2500
      • Wollongong Hospital
  • Victoria
    • Epping, Victoria, Australia, 3076
      • Northern Health
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3004
      • Alfred Health
    • St Albans, Victoria, Australia, 3021
      • Western Health
• India
  • Chandigarh, India
    • Government Medical College & Hospital
  • Chandigarh, India
    • Post Graduate Institute of Medical Education & Research
  • Delhi, India
    • Lok Nayak Jai Prakash
  • Manipal, India
    • Kasturba Medical College
  • Nabarangpur, India
    • Christian Hospital
  • Pune, India
    • Jivenrekha Hospital
  • Raipur, India
    • All India Institute of Medical Science

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Potential participants must satisfy all of the following:

1. Laboratory-confirmed* diagnosis of Severe Acute Respiratory Syndrome-Coronavirus-2 infection within 10 days prior to randomisation
2. Age ≥ 18 years
3. a) Systolic Blood Pressure (SBP) ≥ 120 mmHg OR b) SBP ≥ 115 mmHg and currently treated with a non-Renin Angiotensin Aldosterone System inhibitor Blood Pressure (BP) lowering agent that can be ceased
4. Participant and treating clinician are willing and able to perform trial procedures.

5. Either Intended for hospital admission for management of COVID-19, or (In Australia Only) Intended for management at home with one or more of the following criteria:

   1. Age≥60 years
   2. Body Mass Index ≥30kg/m2 (derived from the patient's self-report of their height and weight where these are not measured directly)
   3. Diagnosis of diabetes defined as HbA1c ≥7% and/or the consumption of glucose lowering medication
   4. History of cardiovascular disease
   5. History of chronic respiratory illness
   6. Currently treated with immunosuppression

Exclusion Criteria:

1. Currently treated with an angiotensin-converting enzyme inhibitor, Angiotensin Receptor Blocker or aldosterone antagonist, aliskiren, or angiotensin receptor-neprilysin inhibitors (ARNi)
2. Serum potassium > 5.2 mmol/L or no potassium testing within the last 3 months
3. For those intended for hospital admission, an estimated Glomerular Filtration Rate (eGFR) <30ml/min/1.73m2 or no eGFR testing within the last 3 months, or For those intended for management at home (Australia only), an eGFR <45ml/min/1.73m2 or no eGFR testing within the last 3 months
4. Known symptomatic postural hypotension
5. Known biliary obstruction, known severe hepatic impairment (Child-Pugh-Turcotte score 10-15) - see Table below
6. Intolerance of ARB

7. Pregnancy or risk of pregnancy, defined as;

   1. (In Australia only) Women younger than 51 years who have not had a negative pregnancy test during the past 3 days and/or who do not agree to use adequate contraception
   2. (In India Only) Women who are pregnant
8. Women who are currently breastfeeding
9. Individuals who are not able to take medications by mouth at enrolment, or who are not expected to be able to take medications by mouth during the first 48 hours after randomisation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Care + Angiotensin Receptor Blocker (ARB); Participants will receive an Angiotensin Receptor Blocker on top of the standard care provided by their institution.	Drug: Angiotensin Receptor Blockers; Angiotensin Receptor Blockers (ARBs) have been in clinical use for more than 30 years for their cardiac and renal protective effects. ARBs mechanism of action is through selective inhibition of angiotensin-II (Ang-II) by competitive antagonism of the angiotensin receptor. ARBs displace ang-II from the angiotensin I receptor and produce their protective effects by reducing the downstream effects of ang-II induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic response The virus causing COVID-19, SARS-CoV-2, binds to the extracellular portion of Angiotensin-Converting-Enzyme-2 (ACE2) expressed on type II alveolar cells in the lungs which is followed by internalization of ACE2 before downregulating membrane ACE2 expression. Both these components appear to require angiotensin receptor Type 1 (AT1R), and ARBs, which block the actions of AT1R, would reduce the severity of COVID-19 and reduce the duration of symptoms; Other Names: Valsartan; Losartan; Candesartan; Eprosartan; Irbesartan; Olmesartan; Telmisartan
Placebo Comparator: Standard Care + Placebo; Participants will receive a placebo on top of the standard care provided by their institution.	Other: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
7-Point National Institute of Health Clinical Health Score	To determine whether the addition of the intervention, compared to standard care, changes the clinical health score of a participant on the following scale; Not hospitalized, no limitations on activities.; Not hospitalized, limitation on activities;; Hospitalized, not requiring supplemental oxygen;; Hospitalized, requiring supplemental oxygen;; Hospitalized, on non-invasive ventilation or high flow oxygen devices;; Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);; Death;	14 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
7-Point National Institute of Health Clinical Health Score	To determine whether the addition of the intervention, compared to standard care, changes the clinical health score of a participant on the following scale; Not hospitalized, no limitations on activities.; Not hospitalized, limitation on activities;; Hospitalized, not requiring supplemental oxygen;; Hospitalized, requiring supplemental oxygen;; Hospitalized, on non-invasive ventilation or high flow oxygen devices;; Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);; Death;	28 Days
Mortality	To determine whether the addition of the intervention, compared to standard care, changes the risk of all cause mortality	28 Days
Mortality	To determine whether the addition of the intervention, compared to standard care, changes the risk of all cause mortality	90 Days
Intensive Care Unit Admission	To determine whether the addition of the intervention, compared to standard care, changes the count of all cause Intensive Care Unit admission	28 Days
Intensive Care Unit Admission	To determine whether the addition of the intervention, compared to standard care, changes the count of all cause Intensive Care Unit admission	90 Days
Intensive Care Unit Number of Days	To determine whether the addition of the intervention, compared to standard care, changes the number of days total, of intensive care unit admission	90 Days
Respiratory Failure	To determine whether the addition of the intervention, compared to standard care, changes the incidence of respiratory failure	28 Days
Dialysis Requirement	To determine whether the addition of the intervention, compared to standard care, changes the requirements for dialysis	28 Days
Hospitalisation Days	To determine whether the addition of the intervention, compared to standard care, changes the number of hospitalisation days	28 Days
Hospitalisation Days	To determine whether the addition of the intervention, compared to standard care, changes the number of hospitalisation days	90 Days
Ventilator-Free Days	To determine whether the addition of the intervention, compared to standard care, changes need for ventilation	28 Days
Dialysis Days	To determine whether the addition of the intervention, compared to standard care, changes need for dialysis	28 Days
Acute Kidney Injury	To determine whether the addition of the intervention, compared to standard care, changes risk of acute kidney injury, based on the Kidney Disease: Improving Global Outcomes definition	28 Days
Hypotension Requiring Vasopressors	To determine whether the addition of the intervention, compared to standard care, changes risk of hypotension requiring vasopressors	28 Days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hyperkalaemia	To determine whether the addition of the intervention, compared to standard care, changes risk of hyperkalaemia.	Day 28
Oxygen Saturation	To determine whether the addition of the intervention, compared to standard care, changes risk of decreased oxygen saturation	Day 28
Oxygen Saturation	To determine whether the addition of the intervention, compared to standard care, changes risk of decreased oxygen saturation	Day 14

Collaborators and Investigators

• Sponsor: The George Institute

Publications and helpful links

General Publications

• Jardine MJ, Kotwal SS, Bassi A, Hockham C, Jones M, Wilcox A, Pollock C, Burrell LM, McGree J, Rathore V, Jenkins CR, Gupta L, Ritchie A, Bangi A, D'Cruz S, McLachlan AJ, Finfer S, Cummins MM, Snelling T, Jha V; CLARITY trial investigators. Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. BMJ. 2022 Nov 16;379:e072175. doi: 10.1136/bmj-2022-072175.
• McGree JM, Hockham C, Kotwal S, Wilcox A, Bassi A, Pollock C, Burrell LM, Snelling T, Jha V, Jardine M, Jones M; CLARITY Trial Steering Committee. Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial. Trials. 2022 Apr 27;23(1):361. doi: 10.1186/s13063-022-06167-2.
• Hockham C, Kotwal S, Wilcox A, Bassi A, McGree J, Pollock C, Burrell LM, Bathla N, Kunigari M, Rathore V, John M, Lin E, Jenkins C, Ritchie A, McLachlan A, Snelling T, Jones M, Jha V, Jardine M; CLARITY Investigators. Protocol for the Controlled evaLuation of Angiotensin Receptor blockers for COVID-19 respIraTorY disease (CLARITY): a randomised controlled trial. Trials. 2021 Aug 28;22(1):573. doi: 10.1186/s13063-021-05521-0.

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2020
• Primary Completion (Actual): November 14, 2021
• Study Completion (Actual): January 17, 2022

Study Registration Dates

• First Submitted: May 18, 2020
• First Submitted That Met QC Criteria: May 18, 2020
• First Posted (Actual): May 19, 2020

Study Record Updates

• Last Update Posted (Actual): March 17, 2022
• Last Update Submitted That Met QC Criteria: March 2, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Angiotensin Receptor Blocker (ARB); Angiotensin Converting Enzyme 2 (ACE2); Coronavirus Disease 2019 (COVID-19); Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-Cov-2)
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Coronavirus Infections; Respiration Disorders; Respiratory Tract Diseases; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Valsartan; Losartan; Olmesartan; Candesartan; Telmisartan; Irbesartan; Angiotensin Receptor Antagonists; Eprosartan
• Other Study ID Numbers: 11052020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Trial data will be disseminated in the form of a publication to a relevant clinical journal and presentation at appropriate scientific conferences.

Individual participant data that underlie the results reported, after de-identification (text, tables, figures, and appendices), may be shared with Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

• IPD Sharing Time Frame: To be confirmed
• IPD Sharing Access Criteria: To be determined
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No