Protecting the Brain From Post-Stroke Cognitive Impairment and Dementia With Multimodal Exercise Training (PROTECT)

Protecting the Brain From Post-Stroke Cognitive Impairment and Dementia With Multimodal Exercise Training: A Bayesian Adaptive Trial (PROTECT)

The rates of cognitive decline and dementia after stroke are disproportionately high. Strategies that can protect the brain early after the stroke event could reduce the future risk of cognitive decline and dementia in these patients. Although physical exercise is usually recommended after stroke, there is very little information about the protective effect of exercise implemented in early stages of recovery as a potential protective measure against cognitive decline and dementia risk in these patients. This study will investigate the effect of a multimodal exercise intervention implemented early after the stroke event on cognition and on a selected group of markers that can predict cognitive decline and dementia risk.

Study Overview

• Status: Recruiting
• Conditions: Stroke
• Intervention / Treatment: Other: Balance, Toning and Stretching; Other: Multimodal Training

Detailed Description

Rationale: Stroke triggers acute vascular and inflammatory mechanisms that predispose the brain to rapid neurodegeneration. Up to 52% of stroke survivors develop cognitive impairment within 6 months and 20% receive a clinical diagnosis of dementia within 5 years. The subacute phase (<6 months) represents a critical window in which the brain may be most responsive to neuroprotective interventions. Multimodal aerobic and resistance training improves cognition in chronic stroke, but whether it improves cognition, neuroimaging markers, and blood biomarkers of dementia risk when delivered during this early window remains unknown.

Aims: To compare the effects of 12 weeks of multimodal exercise (moderate-to-high-intensity resistance and aerobic training) versus a low-intensity community-based stroke exercise comparator on cognition, neuroimaging outcomes, blood biomarkers of cognitive decline and dementia risk in people with subacute stroke.

Sample size estimates: Sample size was estimated via 20,000 Monte Carlo simulations using an Alzheimer's Disease Assessment Scale-Cognitive assessment (ADAS-Cog) effect size of Cohen's d = 0.63 from a previous exercise RCT. The target was ≥80% power to detect this treatment effect at a one-sided Type I error rate of 2.5%, using a weakly informative prior centered at zero with a variance of 100. The minimum required was 45 completers per arm (N = 90) and accounting for 25% attrition, up to 120 participants (60 per arm) will be enrolled.

Methods and design: PROTECT is a 12-week, Phase 3, assessor-blinded, multisite Bayesian adaptive RCT following a two-arm parallel group sequential design with 6- and 12-month follow-up (NCT07445841). Participants will be randomized to multimodal training or the comparator using concealed allocation with permuted blocks of varying sizes. Pre-planned adaptive features include: (1) two interim analyses at 50% and 75% of completers; (2) early stopping for efficacy and futility; and (3) sample size re-estimation.

Study outcomes: The primary outcome is cognition, measured using the 13-item ADAS-Cog. Secondary outcomes include ADAS-Cog-Plus, structural and perfusion neuroimaging, and blood biomarkers of inflammation and neurodegeneration. Tertiary outcomes will include cardiorespiratory fitness, functional mobility, muscle strength, body composition, neuropsychological battery, patient-reported cognition, quality of life, fatigue, and healthcare utilization. Outcomes will be assessed at baseline, post-intervention (primary endpoint) and at 6- and 12-month follow-up.

Expertise: Our team includes a diverse group of physical therapists, kinesiologists, neurologists, neuroscientists, neuroimmunologists, physicists, biostatisticians and clinicians at different career stages. We have expertise in exercise RCTs post-stroke and the development of novel imaging and blood predictive biomarkers of dementia risk.

Expected outcomes: We expect that multimodal training will be more effective at improving cognition and that differences between groups will persist 12 months after training, indicating a long-lasting protective effect of multimodal training when introduced in early stages of stroke recovery. We also expect that, compared with the control condition, multimodal training will increase more significantly cerebral blood flow and reduce blood brain barrier permeability as well as the concentration of blood biomarkers of inflammation, neurodegeneration, and axonal injury. We anticipate that the identification of associations between changes in biomarkers and cognition will provide important insights about the mechanisms by which exercise can protect the brain against early neurodegeneration post-stroke.

Significance: Patients with stroke have identified the development of interventions to reduce cognitive dysfunction as the most important problem that research must address. However, cognitive post- stroke impairment is commonly neglected and there is a lack of interventions specifically designed to mitigate this problem. This project will determine if exercise implemented in early stages of recovery can reduce the burden of accelerated cognitive decline and dementia risk in these patients.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marc Roig; Phone Number: 00841 514-398-4400; Email: marc.roigpull@mcgill.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8S 1C7
      • Active, not recruiting
      • McMaster University
  • Quebec
    • Laval, Quebec, Canada
      • Recruiting
      • Jewish Rehabilitation Hospital
      • Contact: Marc Roig; Phone Number: 4217 +1 450-688-9550; Email: marc.roigpull@mcgill.ca
      • Principal Investigator: Marc Roig

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• have had a first-ever ischemic/hemorrhagic stroke confirmed by MRI/CT 0-6 months prior to participation.
• Able to independently walk at least 10 meters (assistive devices permitted) and capable of following instructions will be required.

Exclusion Criteria:

• Diagnosed with dementia
• Medications that impact cognition
• Absolute contraindications to exercise or MRI scanning
• Significant disability (modified Rankin score >3)
• Participants will be excluded if they have been engaged in a structured exercise training program outside their regular in/out-patient hospital rehabilitation since suffering the stroke.
• Co-morbidities that preclude exercise participation, pain worsened with exercise, and communication (e.g., severe aphasia) or behavioral issues limiting safe participation will also be reasons for exclusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Multimodal Exercise; Twelve weeks of combined resistance and cardiovascular training held three times per week.	Other: Multimodal Training; Training sessions, which will include resistance training followed by cardiovascular training, will start with 3 minutes of warm-up and end with 2 minutes of cool down. Resistance training (20 minutes) will involve one day of upper limb, one day of lower limb and one day of full body exercises involving major muscle groups. Workloads will be increased from moderate (50-69% 1-RM; RPE=12-13) to vigorous intensities (70-85% 1-RM; RPE=14-17) by adding movement modifications and/or increasing resistance to ensure progressive overload and maximize adaptations. The first 4 weeks of cardiovascular training will involve 20 minutes of continuous exercise at moderate intensities (40-60% HRR; RPE=12-13). The following 4 weeks, will involve 4x4 minutes (long) high intensity interval training (HIIT) at moderate to vigorous intensity (60-80% HRR; RPE=14-16). The last 4 weeks will involve 10 blocks of 1x1 minutes (short) HIIT at vigorous to maximal intensities (80-100% HRR; RPE=17-20).
Active Comparator: Balance, Toning and Stretching; Twelve weeks of low-intensity task-specific strengthening, balance, mobility, and stretching training held three times per week that is based off the Fitness and Mobility Exercise Program.	Other: Balance, Toning and Stretching; Sessions will be performed at light intensity (<40% HRR) and finalize with a 5-minute cool-down. During the 40- minute main session, exercises involving balance, toning and stretching will be performed. Participants will progress through increasingly challenging exercises (e.g., reduce base of support in balance exercises), but they will aim to maintain a HRR <40%.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognition	The primary outcome will be change in cognition immediately post-intervention (T1, primary endpoint) as measured by the ADAS-Cog-13, a 13-item cognitive assessment with scores ranging from 0 to 85, where lower scores indicate better cognition. The minimal clinical importance difference (MCID) on this scale is 2.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 12 months (T3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral Blood Flow	Resting cerebral blood flow (CBF) will be assessed using non-invasive pseudo-continuous arterial spin labelling (ASL). A T1-weighted magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) structural MRI scan will be first acquired. CBF will be calculated from the ASL control-tag volume image pair difference.	Baseline (T0), 12-week post-intervention (T1), and follow-up at 12 months (T3)
Blood Brain Barrier Permeability	Blood-Brain-Barrier permeability will be measured with a novel water-extraction with phase-contrast-arterial-spin-tagging (WEPCAST) MRI method that does not require the administration of a contrast agent.	Baseline (T0), 12-week post-intervention (T1), and follow-up at 12 months (T3)
Cerebral Blood Velocity (Middle Cerebral Artery Velocity)	A standardized cerebrovascular assessment of cerebral blood velocity (CBV) of the left and right middle cerebral artery will be conducted using Transcranial Doppler Ultrasound. CBV will be assessed in the supine resting state (~5 minutes), and in response a brief bout of resistance (~5 minutes) and aerobic exercise stimuli (~15 minutes) to evaluate the hemodynamic response to multimodal exercise. For the resistance exercise stimuli, the blood velocity response will be assessed in response to a repeated sit-to-stand maneuver at both 0.05Hz (10s squat, 10s stand) and 0.1Hz (5s squat, 5s stand) over a duration of 5 minutes. Once all systemic and cerebral hemodynamic variables have returned to resting levels, participants will then complete the aerobic exercise stimuli which will include a 10-12 minute bout of graded aerobic exercise using a validated graded exercise test.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and follow-up at 12 months (T3)
Inflammation	A multiplex assay kit will be used to analyze the blood serum concentration of a panel of inflammatory biomarkers (IL-6, IL-10, TNF-alpha, IL-1beta, IL-18, CRP, GDF-15, MPO, MCP-1) associated with vascular risk, neurodegeneration, and cognitive decline.	Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (T2), and 12 months (T3)
Neurodegeneration	Assay kits to assess blood plasma concentrations of total and β-amyloid ratios (42:40), and total and phosphorylated isoforms of tau (p-tau 181 and 217).	Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (T2), and 12 months (T3)
Axonal Injury	Blood serum samples will be taken and an immunoassay with excellent sensitivity will be used to quantify serum Nfl concentrations.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Body Composition and Anthropometrics	DEXA scan will be used to assess body composition measures: Body fat percentage, fat mass index, visceral adipose tissue, fat free mass index.	Baseline (T0), 12-week post-intervention (T1) and 12 months follow up
Strength	A composite measure of muscle strength will de derived from 1 repetition maximum (1-RM) measures obtained from various upper and lower body exercises.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Functional Mobility	The Short Physical Performance Battery (SPPB) will provide a composite measure of functional mobility. The SPPB assesses standing balance, gait speed and sit-to-stand. It generates a total score from 0 to 12, with each component contributing up to 4 points (balance 0-4, gait 0-4, chair stands 0-4). Higher scores indicate better physical function.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Self-reported Cognitive Function	Patient Reported Evaluation of Cognitive State (PRECiS): 27 core items asking about cognitive problems plus 5 additional items. Each item is scored in a 0-4 Likert scale with higher scores showing more cognitive problems	Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (T2) and 12 months (T3)
Gait Speed	Usual and fast 10m gait speed.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Cardiorespiratory Fitness	Graded exercise test measuring oxygen consumption peak capacity during an incremental test	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 12 months (T3)
Health-related Quality of Life	EuroQol 5 Dimensions, 5 Levels (EQ-5D-5L). Assesses 5 HRQoL dimensions scoring them with 5 severity levels. It also uses a 0-100 vertical VAS scale where 0 = worst imaginable health and 100 = best imaginable health.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Fatigue	Fatigue Severity Scale-7: Respondents rate 7 statements about fatigue on a 7-point Likert scale. The mean score of the t statements is stated and Higher scores = more severe fatigue.	Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (T2) and 12 months (T3)
Health Care Utilization (cost-effectiveness, cost-utility, intervention costs, and health care costs)	Participants will complete monthly health care resource use-diaries and respond to health care resource utilization questionnaires	Time Frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and follow-up at 12 months (T3)
White Matter Structure and Integrity	White Matter Structure and Integrity will be measured using diffusion-weighted MRI	Baseline (T0), 12-week post-intervention (T1), and follow-up at 12 months (T3)
Cognition	The Alzheimer's Disease Assessment Scale-Cognitive Plus Assessment (ADAS-Cog-Plus) is a secondary global cognitive outcome. This cognitive outcome is a composite score that includes the Trail Making Test Parts A and B, Digit Span Forward and Backward, Animal and Vegetable Fluency, which has been shown to be more responsive to the original ADAS-Cog and is responsive to change following exercise training in chronic stroke. The ADAS-Cog-Plus is scored via a multidimensional item response theory model that provides a global score that is calibrated with the Alzheimer's Disease Neuroimaging Initiative 1 with scores ranging from ≈-1.0 to 1.0, indicating cognitively healthy (-1.0), mild cognitive impairment (≈0.0), and dementia (≈1.0) (Mungas et al., 2013). There are no published MCIDs for the ADAS-Cog-Plus.	Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 12 months (T3)

Collaborators and Investigators

• Sponsor: McGill University
• Collaborators: McMaster University; Jewish Rehabilitation Hospital; Centre for Interdisciplinary Research in Rehabilitation of Greater Montreal; Montreal Neurological Institute and Hospital
• Investigators: Principal Investigator: Marc Roig, McGill University

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2026
• Primary Completion (Estimated): January 30, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: February 19, 2026
• First Submitted That Met QC Criteria: February 25, 2026
• First Posted (Actual): March 3, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: cognition; neurodegeneration; inflammation; cerebral blood flow; blood brain barrier permeability; subacute stroke; multimodal exercise
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Stroke; Inflammation; Nerve Degeneration
• Other Study ID Numbers: 525414

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No