Multimodal Exercise to Prevent Post‑Stroke Cognitive Impairment: PROTECT Bayesian Adaptive Trial P

Introduction

Stroke triggers acute vascular and inflammatory mechanisms that can predispose the brain to accelerated neurodegeneration. Reported figures indicate that up to 52% of stroke survivors develop cognitive impairment within 6 months and 20% receive a clinical diagnosis of dementia within 5 years. The source text indicates an emphasis on the subacute phase as an important period for intervention, but specific details about the subacute phase were not reported in the source.

This protocol describes the PROTECT trial, which evaluates whether a 12‑week multimodal exercise training program can protect the brain from post‑stroke cognitive impairment and dementia when tested in a Phase 3, multisite, assessor‑blinded, randomized design using Bayesian adaptive methods.

Trial design and setting

PROTECT is a 12‑week, Phase 3, assessor‑blinded, multisite Bayesian adaptive randomized controlled trial. The design follows a two‑arm parallel group sequential structure with planned follow‑up visits at 6 months and 12 months after the intervention. The study is registered as NCT07445841. Specific site locations were not detailed in the source beyond multisite conduct.

Eligibility, recruitment and randomisation

Participants will be randomised to either multimodal training or a comparator using concealed allocation and permuted blocks of varying sizes. Allocation concealment and the use of permuted blocks are intended to preserve allocation balance across sites and over time. Assessors are blinded to group assignment. The source did not provide full inclusion or exclusion criteria in the excerpt provided.

Intervention and comparator overview

Participants randomised to the experimental arm will receive a 12‑week multimodal exercise training program. The comparator arm is described as a comparator but the source excerpt did not specify its content or activities. Details on exercise modalities, session frequency, intensity, progression, and supervision were not reported in the provided text.

Outcome measures and assessment schedule

Primary outcome

• The primary outcome is cognition measured using the 13‑item Alzheimer's Disease Assessment Scale‑Cognitive subscale (ADAS‑Cog‑13), assessed at baseline and post‑intervention (the primary endpoint).

Secondary outcomes

• ADAS‑Cog‑Plus.
• Structural and perfusion neuroimaging measures.
• Blood biomarkers of inflammation and neurodegeneration.

Tertiary outcomes

• Cardiorespiratory fitness, functional mobility, muscle strength, and body composition.
• Neuropsychological status and patient‑reported cognition.
• Quality of life, fatigue, and healthcare utilisation.

Assessment schedule

• Outcomes will be assessed at baseline, immediately post‑intervention (primary endpoint), and at 6‑month and 12‑month follow‑up visits.

Statistical planning and sample size rationale

Sample size estimation used Monte Carlo simulation (20,000 iterations) informed by an ADAS‑Cog effect size of Cohen's d = 0.63 derived from a previous exercise RCT. The target was to achieve ≥80% power to detect this treatment effect at a one‑sided type I error rate of 2.5%, applying a weakly informative prior centered at zero with a variance of 100.

Based on these assumptions, the minimum number of completers required was 45 per arm (N = 90). Allowing for an anticipated 25% attrition rate, the enrolment target is up to 120 participants (60 per arm).

Planned adaptive features and interim analyses

Preplanned adaptive elements of the PROTECT trial include:

• Two interim analyses scheduled when 50% and 75% of required completers have been assessed.
• Prespecified early stopping rules for both efficacy and futility to allow the trial to terminate early if strong evidence emerges for benefit or lack of effect.
• Sample size re‑estimation based on observed data at interim looks.

These Bayesian adaptive features are intended to improve trial efficiency and ethical allocation of resources while maintaining inferential control according to the protocol's predefined criteria.

Ethics, consent and dissemination

Ethical approval for the trial has been granted by the Centre de recherche interdisciplinaire en réadaptation du Montréal métropolitain (CRIR MP‑50‑2025‑2294) and the Hamilton Integrated Research Board (HIREB 19222). Any protocol amendments will be submitted to the appropriate ethics boards.

Written informed consent will be obtained from all participants by study coordinators or research assistants. Study findings will be published in peer‑reviewed journals and reported in accordance with the Adaptive Designs Consolidated Standards of Reporting Trials (CONSORT) extension.

Trial registration and reporting

The trial is registered on ClinicalTrials.gov as NCT07445841. Study results will be disseminated through peer‑reviewed publication following the Adaptive Designs CONSORT extension guidelines. The source did not provide a timeline for reporting or a data sharing plan in the excerpt provided.