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| Name | Class |
|---|---|
| Jewish Rehabilitation Hospital | OTHER |
| McMaster University | OTHER |
| Centre for Interdisciplinary Research in Rehabilitation of Greater Montreal | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Multimodal Exercise | Experimental | Twelve weeks of combined resistance and aerobic exercise training held three times per week. |
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| Balance, Toning and Stretching | Active Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Multimodal Training | Other | 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. |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiorespiratory Fitness | Graded exercise test measuring peak oxygen consumption during an incremental test on a seated recumbent stepper protocol validated for subacute stroke. | Baseline (T0), 12-week post-intervention (T1), follow-up at 6 months (T2) and 12 months (T3) |
| Physical Function |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Marc Roig | Contact | 514-398-4400 | 00841 | marc.roigpull@mcgill.ca |
| Name | Affiliation | Role |
|---|---|---|
| Marc Roig | McGill University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| McMaster University | Active, not recruiting | Hamilton | Ontario | L8S 1C7 | Canada | |
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.
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| ID | Term |
|---|---|
| D020521 | Stroke |
| D007249 | Inflammation |
| D009410 | Nerve Degeneration |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| Montreal Neurological Institute and Hospital |
| OTHER |
Two-group staggered entry parallel single blind multisite adaptive RCT
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Statistician
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| Balance, Toning and Stretching | Other | 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%. |
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| 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. | 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) |
| 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) |
| 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. | 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 | 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. | 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) |
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. |
| 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. | 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. | 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 |
| 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. | 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 | 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. | 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) |
| Jewish Rehabilitation Hospital |
| Recruiting |
| Laval |
| Quebec |
| Canada |
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| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |