The Canadian Maraviroc RCT To Augment Rehabilitation Outcomes After Stroke

Study Overview
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Brief Summary
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The CAMAROS trial is a randomized controlled phase II trial analyzing the effect of coupling a C-C chemokine receptor 5 (CCR5) antagonist, Maraviroc (Celsentri), and exercise to improve both upper and lower extremity recovery after a stroke.

Detailed Description
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After stroke, the combination of progressive skills practice in an adequate dose plus exercise for fitness augments motor and cognitive outcomes. However, sensorimotor and cognitive improvements often plateau after 12 weeks. There is an urgent need to find novel methods to drive recovery and lessen limb paralysis. Drugs that might enhance learning or neural repair, as well as other molecular and synaptic adaptations that occur during skills training and fitness exercise, might extend that recovery curve, although to date only fluoxetine has given any hint of this. Most trials have tested agents that modulate neurotransmitters. Several very recent preclinical experiments and observational studies in patients after stroke suggest that the commercially available medication, Maraviroc, may augment skills learning during rehabilitation training especially during the first three months after onset, by acting on unique molecular components for novel learning. The CAMAROS trial is a randomized, placebo-controlled, blinded phase II trial evaluating the efficacy of coupling Maraviroc (Celsentri) with exercise rehabilitation across multiple Canadian sites in 120 stroke participants. Patients will begin their participation within 6 weeks of stroke onset. Both groups will receive an exercise program in addition to standard of care rehabilitation, but only one group (the intervention group) will receive the active drug Maraviroc. Study participants will be evaluated using physical assessments, cognitive assessments, and using wrist and ankle activity sensors at baseline, after 4 weeks of taking the drug/placebo, after 8 weeks of taking the drug/placebo, and at 6-months post-stroke. While enrolled in the study, participants will be required to take part in an 8 week, daily exercise program. Participants will also perform a short motor learning assessment at each formal assessment and again within 24 hours of each formal assessment (initial test and 24-hour retention test). Evaluators and participants will be blind to the treatment administered. The trial is constructed with randomization to remove selection and allocation biases and to ensure greater validity in observed differences in the outcome measures.

Official Title
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The CAMAROS Trial: The Canadian Maraviroc RCT To Augment Rehabilitation Outcomes After Stroke

Conditions
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Stroke

Intervention / Treatment
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* Drug: Maraviroc
* Behavioral: Exercise Program
* Other: Placebo
* Device: Activity Sensor
* Behavioral: Motor Learning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary ischemic anterior circulation stroke Age ≥18 years At least 5 days after stroke but within 6 weeks of stroke on the date of medication (maraviroc or placebo) start Hemiparesis requiring inpatient rehabilitation Assistance available for daily rehabilitation training practice and for transportation when needed Adequate language skills to understand the Informed Consent and retain information during daily therapies At least one of the following: some shoulder abduction with gravity eliminated and visible extension in two or more digits OR visible hip flexion or extension Subgroup Stratification Criteria For Upper Extremity Group: Minimum Ability: MRC grade >1 for shoulder abduction AND MRC grade >1 for finger extensor on at least one digit Maximum Ability: Upper Extremity Fugl-Meyer Assessment Score >56 For Lower Extremity Group: Minimum Ability: requiring a 2-person assist Maximum Ability: walking speed <0.8m/s, no visible hip flexion or extension Exclusion Criteria: Pre-stroke modified Rankin score ≥ 2 Limited resources or illness that will not enable a return to living outside of a facility History of dementia History of hepatitis or elevated hepatic transaminases or bilirubin History of renal insufficiency or creatinine clearance (eGFR) < 60mL / min / 1.73m2 Cancer or other chronic illness that makes 1-year survival unlikely or will detract from the ability to carry out exercise and skills practice Existing pre-stroke serious disabling disease (e.g., Parkinson's disease, severe traumatic brain injury, amputation) Seizure related to stroke Acute or chronic epilepsy Currently taking any of the following anticonvulsant medications: Carbamazepine Phenobarbital Phenytoin Pregnant, breastfeeding, or positive test for pregnancy at baseline Women of childbearing potential who are not using one highly effective form of contraception or two forms of effective contraception Known HIV positivity Currently taking any of the following antifungal and/or antibacterial medications: Ketoconazole Itraconazole Voriconazole Rifampin Clarithromycin Rifabutin + Protease Inhibitor 14. Currently taking St. John's Wort

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maraviroc (Celsentri)<br>Maraviroc (Celsentri) will be administered to this group. Participants will be administered a dose of 300mg to be taken twice per day for the duration of the exercise intervention (8 weeks). | Drug: Maraviroc<br>* Half of the participants will take maraviroc for a period of 8 weeks.<br>* Other names: Celsentri;Behavioral: Exercise Program<br>* All participants will take part in an 8-week exercise program. While in-hospital, participants will undergo standard of care rehabilitation (estimated at 45 minutes each daily for PT & OT) plus a supplementary upper extremity exercise program (Graded Repetitive Arm Supplementary Program (GRASP); estimated at 1 hour daily). After discharge from inpatient care, participants will complete an at-home supplementary upper and lower extremity exercise program. This program will include 30 minutes daily walking or sit-to-stand exercises and 30 minutes daily practice using the GRASP program.<br>Device: Activity Sensor<br>* Participants will be asked to wear small activity sensors (one on each wrist and one on each ankle, total of four sensors) at the baseline, 4-week, 8-week, and 6-month assessments for 7 consecutive days. Activity related to walking, sleep, physical activity, and arm and leg movement throughout the day will be measured. The sensors will be worn for a total of 28 days throughout the study.<br>Behavioral: Motor Learning<br>* Participants will be asked to perform a computer-based motor learning assessment at the baseline, 4-week, 8-week, and 6-month assessments. A retention task, which involves shorter versions of the initial tasks, will also be completed within 24 hours of the initial assessment (initial test and 24-hour retention test).<br>|
| Placebo Comparator: Placebo<br>An over-encapsulated placebo, or sugar pill (so it appears identical to the trial drug) will be administered to this group. Participants will be administered the placebo identical to the 300mg maraviroc tablet for the duration of the exercise intervention (8 weeks). | Behavioral: Exercise Program<br>* All participants will take part in an 8-week exercise program. While in-hospital, participants will undergo standard of care rehabilitation (estimated at 45 minutes each daily for PT & OT) plus a supplementary upper extremity exercise program (Graded Repetitive Arm Supplementary Program (GRASP); estimated at 1 hour daily). After discharge from inpatient care, participants will complete an at-home supplementary upper and lower extremity exercise program. This program will include 30 minutes daily walking or sit-to-stand exercises and 30 minutes daily practice using the GRASP program.<br>Other: Placebo<br>* Half of the participants will take a placebo for a period of 8 weeks.<br>* Other names: Sugar Pill;Device: Activity Sensor<br>* Participants will be asked to wear small activity sensors (one on each wrist and one on each ankle, total of four sensors) at the baseline, 4-week, 8-week, and 6-month assessments for 7 consecutive days. Activity related to walking, sleep, physical activity, and arm and leg movement throughout the day will be measured. The sensors will be worn for a total of 28 days throughout the study.<br>Behavioral: Motor Learning<br>* Participants will be asked to perform a computer-based motor learning assessment at the baseline, 4-week, 8-week, and 6-month assessments. A retention task, which involves shorter versions of the initial tasks, will also be completed within 24 hours of the initial assessment (initial test and 24-hour retention test).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fugl-Meyer Upper Extremity Assessment Score | Difference in subscale scores on the Upper-Extremity Fugl-Meyer Assessment - both motor (max 66) and sensory (max 12) components. Higher scores indicate better outcome. | Baseline (between 5 days and 6 weeks after stroke), after 4 weeks on drug/placebo, after 8 weeks on drug/placebo, and 6-months post-stroke | 
| Change in 10-Meter Walk Test Score | A performance measure used to assess walking speed in meters per second over a short distance. It can be used to determine functional mobility, gait, and vestibular function. Faster speed indicates better function. | Baseline (between 5 days and 6 weeks after stroke), after 4 weeks on drug/placebo, after 8 weeks on drug/placebo, and 6-months post-stroke | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Action Research Arm Test (ARAT) | The ARAT assesses arm function to determine the quality of the arm movement, and the limitation of activity. The ARAT consists of 4 sub-tests; that examines and individual's grip, grasp, pinch and gross motor movement in order to determine upper extremity function. Objects of varying size, shape, and weight must be either grasped, handled or moved in a specific task in order to evaluate function. Low scores mean worse function with the minimum possible score being 0 and the highest possible score being 57 (normal function). | Baseline (between 5 days and 6 weeks after stroke), after 4 weeks on drug/placebo, after 8 weeks on drug/placebo, and 6-months post-stroke | 
| 6 Minute Walk Test | An assessment of ambulatory function by measuring the distance walked over a period of 6 minutes. Greater distance walked indicates better function. | Baseline (between 5 days and 6 weeks after stroke), after 4 weeks on drug/placebo, after 8 weeks on drug/placebo, and 6-months post-stroke | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rehabilitation, Exercise, Maraviroc, Randomized Control Trial, Activity Sensors, Motor Learning, Retention, Wearable Sensors