The Canadian Maraviroc RCT To Augment Rehabilitation Outcomes After Stroke (CAMAROS)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Stroke
• Intervention / Treatment: Drug: Maraviroc; Behavioral: Exercise Program; Device: Activity Sensor; Behavioral: Motor Learning; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mark Piitz; Phone Number: 403-944-4050; Email: mapiitz@ucalgary.ca
• Study Contact Backup: Name: Alexandra McKinnon; Phone Number: 403-944-4050; Email: alexandra.mckinnon@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Recruiting
      • University of Calgary & Foothills Medical Centre
      • Contact: Mark Piitz; Phone Number: 403-944-4050; Email: mapiitz@ucalgary.ca
      • Contact: Alexandra McKinnon; Phone Number: 403-944-4050; Email: alexandra.mckinnon@ucalgary.ca
      • Principal Investigator: Gentson Leung, MD
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 2G9
      • Not yet recruiting
      • University of British Columbia & GF Strong Rehabilitation Centre
      • Principal Investigator: Janice Eng, PhD
      • Contact: Courtney Pollock; Phone Number: 604-827-1631; Email: courtney.pollock@ubc.ca
      • Principal Investigator: Courtney Pollock, PhD
      • Principal Investigator: Jennifer Yao, MD
  • Newfoundland and Labrador
    • Saint John's, Newfoundland and Labrador, Canada, A1A 1E5
      • Not yet recruiting
      • Memorial University of Newfoundland
      • Contact: Ganesh Melam; Phone Number: 709-777-2082; Email: grmelam@mun.ca
      • Principal Investigator: Michelle Ploughman, PhD
      • Principal Investigator: Jason McCarthy, MD
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3J5
      • Not yet recruiting
      • Dalhousie University
      • Contact: Melanie Dunlop; Phone Number: 902-473-1401; Email: Melanie.Dunlop@nshealth.ca
      • Principal Investigator: Marilyn Mackay-Lyons, PhD
      • Principal Investigator: Anita Mountain, MD
  • Ontario
    • London, Ontario, Canada, N6C 0A7
      • Not yet recruiting
      • Parkwood Institute
      • Principal Investigator: Robert Teasell, MD
      • Contact: Alexandria Roa Agudelo; Email: Alexandria.RoaAgudelo@sjhc.london.on.ca
    • Toronto, Ontario, Canada, M4N 3M5
      • Not yet recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Ellen Cohen; Phone Number: 85406 416-480-6100; Email: ecohen@sri.utoronto.ca
      • Principal Investigator: Bradley MacIntosh, PhD
    • Toronto, Ontario, Canada, M5G 2A2
      • Not yet recruiting
      • Toronto Rehabilitation Institute - University Health Network
      • Contact: Evan Foster; Phone Number: 3362 416-597-3422; Email: Evan.Foster@uhn.ca
      • Principal Investigator: Mark Bayley, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Primary ischemic anterior circulation stroke
2. Age ≥18 years
3. At least 5 days after stroke but within 6 weeks of stroke on the date of medication (maraviroc or placebo) start
4. Hemiparesis requiring inpatient rehabilitation
5. Assistance available for daily rehabilitation training practice and for transportation when needed
6. Adequate language skills to understand the Informed Consent and retain information during daily therapies

7. 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

1. 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

2. 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:

1. Pre-stroke modified Rankin score ≥ 2
2. Limited resources or illness that will not enable a return to living outside of a facility
3. History of dementia
4. History of hepatitis or elevated hepatic transaminases or bilirubin
5. History of renal insufficiency or creatinine clearance (eGFR) < 60mL / min / 1.73m2
6. Cancer or other chronic illness that makes 1-year survival unlikely or will detract from the ability to carry out exercise and skills practice
7. Existing pre-stroke serious disabling disease (e.g., Parkinson's disease, severe traumatic brain injury, amputation)
8. Seizure related to stroke
9. Acute or chronic epilepsy

10. Currently taking any of the following anticonvulsant medications:

    • Carbamazepine
    • Phenobarbital
    • Phenytoin
11. Pregnant, breastfeeding, or positive test for pregnancy at baseline
12. Women of childbearing potential who are not using one highly effective form of contraception or two forms of effective contraception
13. Known HIV positivity

14. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Maraviroc (Celsentri); 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; Half of the participants will take maraviroc for a period of 8 weeks.; Other Names: Celsentri; Behavioral: Exercise Program; 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.; Device: Activity Sensor; 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.; Behavioral: Motor Learning; 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).
Placebo Comparator: Placebo; 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; 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.; Device: Activity Sensor; 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.; Behavioral: Motor Learning; 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).; Other: Placebo; Half of the participants will take a placebo for a period of 8 weeks.; Other Names: "Sugar" Pill

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fugl-Meyer Lower Extremity Assessment Score	Fugl-Meyer Lower Extremity Assessment assesses motor and sensorimotor impairment in the lower extremities. Total score is between 0 and 34. Sub-scales include: proximal (0-18), knee/ankle (0-10) and coordination/speed (0-6). Higher scores indicate better performance. Sub-scale scores are summed to calculate total score.	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
Patient Health Questionnaire 9 (PHQ-9)	A 9-question measurement used to screen for the presence and severity of depression.	Baseline (between 5 days and 6 weeks after stroke), after 8 weeks on drug/placebo, and 6-months post-stroke
Stroke Aphasia Depression Questionnaire (SADQ)	A 10-item questionnaire completed by a caregiver to quickly assess depressive symptoms in stroke patients with aphasia. Higher scores indicate a greater likelihood of depression.	BaselineBaseline (between 5 days and 6 weeks after stroke), after 8 weeks on drug/placebo, and 6-months post-stroke, 8-week assessment, and 6-month assessment
European Quality of Life Across 5 Domains (EQ-5D)	A self-completion questionnaire used to assess health-related quality of life.	Baseline (between 5 days and 6 weeks after stroke), after 8 weeks on drug/placebo, and 6-months post-stroke
Stroke Impact Scale (SIS)	Stroke-specific, self-report, health status measure. Assesses multiple domains on a 5-point Likert scale. Domains include: strength (4-20), hand function (5-25), activities of daily living/instrumental activities of daily living (10-50), mobility (9-45), communication (7-35), emotion (9-45), memory and thinking (7-35), and participation (8-40). An extra question asks that the patient rate on a scale from 0 - 100 how much they feel that he/she has recovered from his/her stroke. The 4 physical domains (strength, hand function, mobility and activities of daily living) can be summed together to create a single, physical dimension score (28-140) while all other domains should remain separate. Higher scores indicate better function.	Baseline (between 5 days and 6 weeks after stroke), after 8 weeks on drug/placebo, and 6-months post-stroke
National Institutes of Health Stroke Scale (NIHSS)	A 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. Higher scores indicate greater impairment.	Baseline (between 5 days and 6 weeks after stroke) and 6-months post-stroke
Montreal Cognitive Assessment (MoCA)	A cognitive screening test used to assess: short term memory, visuospatial abilities, executive functions, attention, concentration, working memory, language, and orientation to time and place. Higher scores indicate better function.	Baseline (between 5 days and 6 weeks after stroke) and 6-months post-stroke

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: University Health Network, Toronto; Sunnybrook Health Sciences Centre; University of British Columbia; University of California, Los Angeles; Dalhousie University; Memorial University of Newfoundland; Parkwood Hospital, London, Ontario; Riverview Health Centre Foundation; The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
• Investigators: Principal Investigator: Sean Dukelow, MD PhD FRCPC, University of Calgary, Calgary, Alberta, Canada; Study Chair: Bruce Dobkin, MD, University of California, Los Angeles, California, USA

Publications and helpful links

General Publications

• Ben Assayag E, Korczyn AD, Giladi N, Goldbourt U, Berliner AS, Shenhar-Tsarfaty S, Kliper E, Hallevi H, Shopin L, Hendler T, Baashat DB, Aizenstein O, Soreq H, Katz N, Solomon Z, Mike A, Usher S, Hausdorff JM, Auriel E, Shapira I, Bornstein NM. Predictors for poststroke outcomes: the Tel Aviv Brain Acute Stroke Cohort (TABASCO) study protocol. Int J Stroke. 2012 Jun;7(4):341-7. doi: 10.1111/j.1747-4949.2011.00652.x. Epub 2011 Nov 2.
• Duncan PW, Sullivan KJ, Behrman AL, Azen SP, Wu SS, Nadeau SE, Dobkin BH, Rose DK, Tilson JK, Cen S, Hayden SK; LEAPS Investigative Team. Body-weight-supported treadmill rehabilitation after stroke. N Engl J Med. 2011 May 26;364(21):2026-36. doi: 10.1056/NEJMoa1010790.
• Ben Assayag E, Shenhar-Tsarfaty S, Korczyn AD, Kliper E, Hallevi H, Shopin L, Auriel E, Giladi N, Mike A, Halevy A, Weiss A, Mirelman A, Bornstein NM, Hausdorff JM. Gait measures as predictors of poststroke cognitive function: evidence from the TABASCO study. Stroke. 2015 Apr;46(4):1077-83. doi: 10.1161/STROKEAHA.114.007346. Epub 2015 Feb 12.
• Ben Assayag E, Tene O, Korczyn AD, Shopin L, Auriel E, Molad J, Hallevi H, Kirschbaum C, Bornstein NM, Shenhar-Tsarfaty S, Kliper E, Stalder T. High hair cortisol concentrations predict worse cognitive outcome after stroke: Results from the TABASCO prospective cohort study. Psychoneuroendocrinology. 2017 Aug;82:133-139. doi: 10.1016/j.psyneuen.2017.05.013. Epub 2017 May 18.
• Dobkin BH. A Rehabilitation-Internet-of-Things in the Home to Augment Motor Skills and Exercise Training. Neurorehabil Neural Repair. 2017 Mar;31(3):217-227. doi: 10.1177/1545968316680490. Epub 2016 Nov 24.
• Hiragami S, Inoue Y, Harada K. Minimal clinically important difference for the Fugl-Meyer assessment of the upper extremity in convalescent stroke patients with moderate to severe hemiparesis. J Phys Ther Sci. 2019 Nov;31(11):917-921. doi: 10.1589/jpts.31.917. Epub 2019 Nov 26.
• Joy MT, Ben Assayag E, Shabashov-Stone D, Liraz-Zaltsman S, Mazzitelli J, Arenas M, Abduljawad N, Kliper E, Korczyn AD, Thareja NS, Kesner EL, Zhou M, Huang S, Silva TK, Katz N, Bornstein NM, Silva AJ, Shohami E, Carmichael ST. CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury. Cell. 2019 Feb 21;176(5):1143-1157.e13. doi: 10.1016/j.cell.2019.01.044.
• Lohse K, Bland MD, Lang CE. Quantifying Change During Outpatient Stroke Rehabilitation: A Retrospective Regression Analysis. Arch Phys Med Rehabil. 2016 Sep;97(9):1423-1430.e1. doi: 10.1016/j.apmr.2016.03.021. Epub 2016 Apr 22.
• Zhou M, Greenhill S, Huang S, Silva TK, Sano Y, Wu S, Cai Y, Nagaoka Y, Sehgal M, Cai DJ, Lee YS, Fox K, Silva AJ. CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory. Elife. 2016 Dec 20;5:e20985. doi: 10.7554/eLife.20985.

Helpful Links

• Product Monograph for Celsentri (Maraviroc)

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2022
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: March 5, 2021
• First Submitted That Met QC Criteria: March 5, 2021
• First Posted (Actual): March 9, 2021

Study Record Updates

• Last Update Posted (Estimate): January 19, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Rehabilitation; Exercise; Retention; Motor Learning; Randomized Control Trial; Maraviroc; Wearable Sensors; Activity Sensors
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Maraviroc
• Other Study ID Numbers: REB21-0258

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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