Trial Synopsis

Title

Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease

Short title

CLARITY

Trial Registration

ClinicalTrials.gov Identifier: NCT04394117
Clinical Trials Registry – India (CTRI) Number: CTRI/2020/07/026831

Design

Prospective, double-blind, placebo-controlled, randomised controlled trial in India.
Prospective, open-label, randomised controlled trial in Australia.

Intervention

Standard Care + Angiotensin Receptor Blocker (ARB), or Standard Care + matched placebo in India
Standard Care + ARB, or Standard Care alone in Australia.

Primary Outcome Measure

To establish evidence on the effect of ARB treatment on a 7-point ordinal score of clinical outcomes in respiratory disease, in patients recently diagnosed with SARS-CoV-2.

Inclusion criteria

Potential participants must satisfy all of the following:

1. Laboratory-confirmed diagnosis of SARS-CoV-2 infection within 10 days prior to randomisation
2. Age ≥ 18 years
3. a) Systolic Blood Pressure (SBP) ≥ 120 mmHg
4. b) SBP ≥ 115 mmHg and currently treated with a non-RAASi Blood Pressure (BP) lowering agent that can be ceased
5. Participant and treating clinician are willing and able to perform trial procedures.
6. 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. 1. Age ≥ 60 years
   2. BMI ≥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 Angiotensin-Converting Enzyme Inhibitor (ACEi), ARB 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)
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

Primary Outcome Measure

The primary endpoint is a 7-point ordinal categorical scale of the clinical status of the participant, assessed on Day 14 post-randomisation. The worse result of the day will be recorded. The scale is described as;

1. Not hospitalized, no limitations on activities.
2. Not hospitalized, limitation on activities;
3. Hospitalized, not requiring supplemental oxygen;
4. Hospitalized, requiring supplemental oxygen;
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
6. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);
7. Death.

Secondary Outcomes

1. Intensive Care Unit (ICU) admission and length of stay
2. Death
3. Rates and length of Hospitalisation
4. Ventilator requirement
5. Dialysis requirement
6. Incidence of Acute Kidney Injury (AKI)
7. Respiratory Failure
8. Incidence of Hypotension
9. Incidence of Hyperkalaemia

Randomisation

Participants will be randomised in a 1:1 ratio. Randomisation will be stratified by country and in Australia, whether the participant is planned for hospital admission or home-based care.

Sample Size

Trial will adopt a Bayesian adaptive approach to sample size calculations. The trial will continue to recruit until predefined superiority or futility rules are met.
Minimum sample size = 700, Maximum Sample size = 2200

Funding

Medical Research Future Fund, Australia