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.

Keywords: Adaptive sample size; Angiotensin receptor blockers; Bayesian design; Clinical trial; Coronavirus; Protocol; Statistical analysis plan.

Conflict of interest statement

JM, CH, SK, AW, AB, LB, NB, MK, VR, MJoh, EL, AR, AM, TS and MJon have no conflicts of interest to disclose.

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/advisory board from AstraZeneca, Baxter Healthcare, NephroPlus, Sanofi — all outside the submitted work. All fees paid to the organisation.

MJar is responsible for research projects that have received unrestricted funding from Amgen, Baxter, Bayer, CSL Behring, Eli Lilly, Gambro, and Merck Sharp and Dohme; has served on advisory boards sponsored by Akebia, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Merck Sharp and Dohme and Vifor; serves on the Steering Committee for trials sponsored by Chinook, CSL Behring and Janssen; serves on a Steering Committee for an investigator initiated trial in COVID-19 disease with funding support from Dimerix; spoken at scientific meetings sponsored by Amgen, Janssen, Roche and Vifor; with any consultancy, honoraria or travel support paid to the institution.

© 2022. The Author(s).

Figures

Fig. 1

Trial overview and participant schedule [11]

Fig. 2

Distribution of the posterior mean of β based on 1000 simulated data sets for a given number of enrolments and odds ratios of a 1.00, b 0.95, c 0.87 and d 0.80

Fig. 3

Estimated probability of the trial stopping for a effectiveness, b futility and c average sample sizes based on a variety of different assumptions about the odds ratio, recruitment rate and data that will be observed

Fig. 4

Empirical hazard function for patients with COVID-19 based on data from the Recovery trial (ClinicalTrials.gov, NCT04381936)

Fig. 5

Proposed hazard functions for simulation study

Fig. 6

Approximate power for given sample sizes for ψ=0.87 and the a empirical hazard function, b exponential hazard function λ=1/26 and c Weibull hazard function γ=0.8,λ=1/26 when the semi-parametric (−) and Weibull (− −) regression models were refit to the simulated data