Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial

Abstract

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease) is a two-arm, multi-centre, randomised controlled trial being run in India and Australia that investigates the effectiveness of angiotensin receptor blockers in addition to standard care compared to placebo (in Indian sites) with standard care in reducing the duration and severity of lung failure in patients with COVID-19. The trial was designed as a Bayesian adaptive sample size trial with regular planned analyses where pre-specified decision rules will be assessed to determine whether the trial should be stopped due to sufficient evidence of treatment effectiveness or futility. Here, we describe the statistical analysis plan for the trial and define the pre-specified decision rules, including those that could lead to the trial being halted. The primary outcome is clinical status on a 7-point ordinal scale adapted from the WHO Clinical Progression scale assessed at day 14. The primary analysis will follow the intention-to-treat principle. A Bayesian adaptive trial design was selected because there is considerable uncertainty about the extent of potential benefit of this treatment.Trial registrationClinicalTrials.gov NCT04394117. Registered on 19 May 2020Clinical Trial Registry of India CTRI/2020/07/026831Version and revisionsVersion 1.0. No revisions.

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

“…The careful simulation planning showed a design that appeared robust to foreseen and unforeseen variations in control outcomes, albeit with differing interpretation. 8 The planned analyses meant that the trial did not continue beyond futility, hence limiting expenditure and resourcing on a therapy that indicates no benefit in the trial population. The use of modified endpoints sourced from WHO facilitated comparison with other covid-19 trials.…”

“…The primary intention-to-treat analysis used a bayesian inferential framework for all randomly assigned participants as outlined in the statistical analysis plan. 8 We regressed the WHO scale at day 14 using an ordinal cumulative logistic regression model on treatment group assignment adjusted for age, sex, comorbidity, hypertension, and oxygen requirement at baseline. Interim analyses involved evaluating prespecified futility and success rules based on the results from the joint posterior and posterior predictive distributions.…”

“…Interim analyses involved evaluating prespecified futility and success rules based on the results from the joint posterior and posterior predictive distributions. 8 Sensitivity analyses included unadjusted models, relaxation of the proportional odds assumption, and comparison with analogous frequentist models. We sampled the joint posterior distribution using Markov Chain Monte Carlo.…”

“…CLARITY (Controlled evaLuation of Angiotensin Receptor blockers for covid-19 respIraTorY disease) was a pragmatic, adaptive, multicentre, phase 3, randomised, double blinded, controlled trial conducted at 17 sites in India and Australia. The protocol and statistical analysis plan have been published 78…”

“…We regressed the WHO scale at day 14 using an ordinal cumulative logistic regression model on treatment group assignment adjusted for age, sex, comorbidity, hypertension, and oxygen requirement at baseline. Interim analyses involved evaluating prespecified futility and success rules based on the results from the joint posterior and posterior predictive distributions 8. Sensitivity analyses included unadjusted models, relaxation of the proportional odds assumption, and comparison with analogous frequentist models.…”