An interventional study of Multimodal Training and Balance, Toning and Stretching in Stroke, sponsored by McGill University. Recruiting at 2 sites in Canada. Open to participants aged 40 Years to 80 Years. Per ClinicalTrials.gov, last updated 2026-07-06.
Sponsored by McGill University · Not applicable, Interventional, and Prevention
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.
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.
8,255 studies on the registry are indexed under Stroke; 2,056 are open to participants now.
This study's planned enrollment of 120 is above the median of 49 across 6,024 interventional studies indexed under Stroke.
Browse Stroke studies →McGill University is the lead sponsor of 249 studies on the registry; 51 are open to participants now.
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Twelve weeks of combined resistance and aerobic exercise training held three times per week.
Other: Multimodal Training
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
Training sessions, which will include resistance training followed by aerobic exercise training, will start with \~5 minutes of warm-up and end with \~5 minutes of cool down. Resistance training (20-30 minutes) will involve one day of upper limb, one day of lower limb and one day of full body exercises involving major muscle groups. Each session will include 5 exercises for 2-3 sets x 10 repetitions. Workloads will be increased from moderate to vigorous intensities (≥50-85% 1-RM; RPE≥14/20) by adding movement modifications and/or increasing resistance to ensure progressive overload. The first 4 weeks of aerobic exercise will involve 20 minutes of moderate intensity continuous training (40-60% HRR; RPE\<13/20). The following 4 weeks, will involve 3x4 minutes (long-interveral) high intensity interval training (HIIT) at ≥60-80% HRR; RPE=≥14-17. The last 4 weeks will involve 10, 1x1 minutes (short-interval) HIIT at ≥80-100% HRR; RPE≥17/20.
Sessions will be performed at light intensity (\<40% HRR) and finalize with a 5-minute cool-down. During the 40-60 minute session, 5 to 6 exercises (2-3 sets x 10 reps) 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%.
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.
Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 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, Digit Symbol Substitution, and Category Fluency (Animals and Vegetables), 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.
Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 12 months (T3)
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.
Time frame: 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.
Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 12 months (T3)
White Matter Structure and Integrity
White Matter Structure and Integrity will be measured using diffusion-weighted MRI
Time frame: 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 (\~15 minutes), and in response to a cognitive tasks (\~5 minutes), a brief bout of resistance (\~5 minutes) and aerobic exercise stimuli (\~15 minutes) to evaluate the hemodynamic response to various stimuli. 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 sit, 10s stand) and 0.1Hz (5s sit, 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 10-15 minute bout of graded aerobic exercise using a validated graded exercise test.
Time frame: 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.
Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (T2), and 12 months (T3)
Neurodegeneration
Validated assay kits to assess blood serum and plasma concentrations of total and β-amyloid ratios (42:40), total and phosphorylated isoforms of tau (p-tau 181 and 217) and klotho will be collected at all time points.
Time frame: 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.
Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Cardiorespiratory Fitness
Graded exercise test measuring peak oxygen consumption during an incremental test on a seated recumbent stepper protocol validated for subacute stroke.
Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 12 months (T3)
Physical Function
The Short Physical Performance Battery (SPPB) will provide a composite measure of physical function. 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.
Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Functional mobility
Usual and fast 10m gait speed and timed-up and go.
Time frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 (T2) and 12 months (T3)
Strength
Estimated maximal muscle strength will be derived from 10 repetition maximum (10-RM) measures obtained from various upper and lower body exercises (e.g., chest press, leg press, seated row, knee extension, etc) and from hand grip dynamometry.
Time frame: 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.
Time frame: Baseline (T0), 12-week post-intervention (T1) and 12 months follow up
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
The RBANS is a brief neuropsychological battert that measures cognition across five domains, including immediate memory, visuospatial/constructional abilities, language, attention, and delayed memory.
Time frame: Baseline (T0), 12-week post-intervention (T1), and 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
Time frame: Baseline (T0), 12-week post-intervention (T1), and follow-up at 6 (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.
Time frame: 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.
Time frame: 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: Time Frame: Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and follow-up at 12 months (T3)
Not enrolling at this site.
Plan to share: Yes — Anonymized datasets that are prepared and/or analyzed during the current study will be available in the repository of journals upon publication. We will state in the published articles that data are available upon reasonable request to corresponding author Dr. Marc Roig.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
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