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

The CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease) 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 CLARITY trial is a multi-centre, randomised controlled Bayesian adaptive 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.

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Enhanced PeriOperative Care and Health protection programme for the prevention of surgical site infections after elective abdominal surgery (EPO2CH): statistical analysis plan of a randomised controlled multicentre superiority trial

Trials ◽

10.1186/s13063-021-05202-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

S. W. de Jonge ◽

◽

N. Wolfhagen ◽

A. H. Zwinderman ◽

M. W. Hollmann ◽

...

Keyword(s):

Statistical Analysis ◽

Abdominal Surgery ◽

Perioperative Care ◽

Standard Care ◽

Surgical Site Infections ◽

Statistical Analysis Plan ◽

Health Protection ◽

Elective Abdominal Surgery ◽

Superiority Trial ◽

Randomised Controlled

Abstract Background Surgical site infections (SSI) are frequent complications after elective abdominal surgery. We designed the Enhanced PeriOperative Care and Health Protection programme (EPO2CH) care bundle, comprising of intraoperative high fractional inspired oxygen; intraoperative goal-directed fluid therapy; active preoperative, intraoperative and postoperative warming; glucose control and treatment of hyperglycaemia (> 10 mmol L− 1) in diabetics as well as non-diabetics; and wound irrigation before closure using an aqueous antiseptic. We hypothesise that EPO2CH added to standard care reduces the incidence of SSI compared to standard care alone for elective abdominal surgery. Methods This trial is designed as an open label, pragmatic randomised controlled parallel-group multicentre superiority trial. The primary endpoint is the incidence of SSI, defined by the Centers for Disease Control and prevention, within 30 days after surgery. The incidence of SSI is assessed using the Dutch national complication register and medical chart review. Secondary endpoints include the SSI incidence within 90 days, incidence of anastomotic leakage at 30 and 90 days, the incidence of incisional hernia within 1 year, mortality within 1 year and 5 years, quality of life, health and disability, and cost-effectiveness. Primarily, an intention-to-treat analysis will be performed to estimate the relative risk using a log binomial model. If not feasible, a logistic regression will be used to estimate the odds ratio. A per-protocol analysis will also be performed. Furthermore, the attributive effect of the distinct interventions will be explored. Discussion The results of the EPO2CH trial will determine if the EPO2CH bundle is effective to prevent SSI incidence for patients undergoing elective abdominal surgery. Details of the statistical analysis are described in this Statistical Analysis Plan (SAP). Trial registration Registration number: Dutch Trial Register Trial NL5572. Registered on March 3, 2016. SAP version: V1.0, January 8, 2020. This SAP has been written based on study protocol V10.

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

Trials ◽

10.1186/s13063-021-05521-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Carinna Hockham ◽

Sradha Kotwal ◽

Arlen Wilcox ◽

Abhinav Bassi ◽

James McGree ◽

...

Keyword(s):

Angiotensin Ii ◽

Randomised Controlled Trial ◽

Sample Size ◽

Angiotensin Receptor Blockers ◽

Controlled Trial ◽

Ordinal Scale ◽

Angiotensin Receptor ◽

Receptor Blockers ◽

Membrane Bound ◽

Randomised Controlled

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)

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