Exercise For Sub-acute Stroke Patients in Jamaica (JAMMS)

Jamaica and Maryland Mobility in Stroke

Chronic hemiparetic stroke is associated changes in body composition, skeletal muscle and cardiometabolic health; specific changes include paretic limb muscular atrophy, increased intramuscular fat deposition, elevated prevalence of impaired glucose tolerance and type 2 diabetes. This randomized intervention study compares a 6 month task oriented exercise programs versus control with both groups receiving best medical stroke care according to American Stroke Association "Get with the Guidelines". The hypothesis is that is 6 months of task-oriented exercise initiated early across the sub-acute period of stroke can prevent or ameliorate the natural course of these body composition, skeletal muscle and cardiometabolic health changes.

Study Overview

• Status: Unknown
• Conditions: Stroke
• Intervention / Treatment: Procedure: Task Oriented Exercise Training; Procedure: Stroke Care "Get with the Guidelines"

Detailed Description

Stroke leads to profound cardiovascular deconditioning and secondary abnormalities in paretic skeletal muscle that worsen cardiovascular health. Conventional rehabilitation focuses on restoration of daily function, without an adequate exercise stimulus to address deconditioning or the muscle abnormalities that may propagate insulin resistance (IR) to worsen risk for type 2 diabetes mellitus (T2DM) and recurrent stroke. By the time individuals reach chronic stroke (>6 months), we report hemiparetic body composition abnormalities including paretic leg muscular atrophy, increased intramuscular area fat, and a major shift to fast myosin heavy chain (MHC). All of these factors promote IR, which has been linked to reduced muscle protein synthesis in aging that may be reversible with exercise. We also find elevated tumor necrosis factor alpha (TNFα) in paretic leg muscle, suggesting that inflammation may affect protein synthesis and breakdown, similar to sarcopenia in aging. Yet, no prior studies have considered stroke as a catabolic syndrome modifiable by early exercise to improve muscle and cardiometabolic health.

Aim #1. Paretic (P) and non-paretic (NP) leg mixed muscle protein synthesis and breakdown in the fed and fasted state, TNFα expression, thigh muscle volume and strength.

Hypothesis 1: Paretic leg has reduced muscle protein synthesis and increased breakdown compared to non-paretic leg; TEXT will increase mixed muscle protein synthesis and reduce breakdown to increase muscle volume and strength by the mechanism(s) of reducing inflammation in the paretic leg, compared to controls.

Aim # 2. Glucose tolerance, fitness, and muscle phenotype. Hypothesis 2: TEXT will improve fitness levels, insulin and glucose response to oral glucose challenge, and increase paretic leg slow twitch (slow MHC) muscle molecular phenotype.

This randomized study investigates the hypothesis that in African-Jamaican adults with recent hemiparetic stroke, 6 months of TEXT across the sub-acute and into the chronic phase of stroke will improve paretic leg muscle and cardiometabolic health, compared to controls receiving best medical care.

Phase 1 consists of recruitment and screening of individuals with mild to moderate hemiparetic stroke from UWI Accident and Emergency Room and Neurology Stroke Clinics. Phase 2: Subjects with hemiparetic gait ≤ 8 weeks post-stroke who are not wheelchair bound or bed are approached for informed consent, medical, neurologic, blood tests, and treadmill (TM) exercise tests to determine study eligibility. Phase 3 baseline testing includes measures of fitness, oral glucose tolerance test (OGTT), body composition, bilateral vastus lateralis muscle biopsies, stable isotope measures of protein synthesis and breakdown. Phase 4: Eligible subjects are randomized to 6 months 3x/week TEXT or control group with best medical care alone that includes American Stroke Association (ASA) physical activity guideline recommendations for walking 4x/week. Randomization is stratified based on glucose tolerance (normal vs. abnormal) and gait deficit severity. Subjects have limited 3 month testing of fitness levels (VO2 peak), body composition, fasting glucose and insulin levels to document the natural history (controls) and temporal profile of exercise-mediated adaptations (TEXT) as they transition from the sub-acute into chronic phase of stroke. Phase 5 is 6-month post-intervention testing.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Richard F Macko, MD; Phone Number: 410-605-7063; Email: rmacko@grecc.umaryland.edu
• Study Contact Backup: Name: Terrence Forrester, MD; Phone Number: 876-702-4687; Email: terrence.forrester@uwimona.edu.jm

Study Locations

• Jamaica
  • Mona 7
    • Kingston, Mona 7, Jamaica
      • Recruiting
      • University of West Indies
      • Contact: Terrence Forrester, MD; Phone Number: 876-7024687; Email: terrence.forrester@uwimona.edu.jm
      • Contact: Sandra Boynes; Phone Number: 876-927-1884; Email: sandra.boyne@uwimona.edu.jm
      • Principal Investigator: Terrence Forrester, MD
      • Sub-Investigator: Sandra Boynes
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Active, not recruiting
      • University of Maryland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ischemic stroke within 8 weeks
• BMI of 18-40 kg/m2
• Able to walk 3 minutes with handrails, assistive device, or standby aid

Exclusion Criteria:

• Actively exercising for >30 minutes per day for 5 days per week
• Increased alcohol consumption (> 2 oz. liquor, 8 oz. wine, 24 oz. beer per day)
• Active abuse of other illegal and illicit drugs
• Cardiac History of: a) unstable angina, b) recent (<3 months) myocardial infarction, congestive heart failure (NYHA category II-IV), c) hemodynamically significant valvular dysfunction
• Medical History: a) peripheral arterial disease with vascular claudication making exercise challenging, b) orthopedic or chronic pain condition(s) restricting exercise, c) pulmonary or renal failure, d) active cancer, e) untreated poorly controlled hypertension measured on at least 2 occasions (greater than 160/100), f) HIV-AIDS or other known inflammatory responses, g) sickle cell anemia, h) medications: heparin, warfarin, lovenox, or oral steroids, j) currently pregnant
• Endocrine History: a) type 1 diabetes or insulin dependent type 2 diabetes, b) poorly controlled type 2 diabetes (HbA1C > 10)
• Neurological History: a) dementia (Mini-Mental Status score < 23 or < 17 if education level at or below 8th grade) and clinical confirmation by clinical evaluation, b) severe receptive or global aphasia that confounds testing and/or training, operationally defined as unable to follow 2 point commands, c) hemiparetic gait from a prior stroke preceding the index stroke defining eligibility (more than one stroke), d) neurologic disorder restricting exercise such as Parkinsons or myopathy, e) untreated major depression (CESD > 16 or clinical confirmation), f) muscular disorder (s) restricting exercise
• Muscle biopsy exclusion criteria: a) anti-coagulation therapy with heparin, warfarin, or lovenox (anit-platelet therapy is permitted), b)bleeding disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise; Task-oriented exercise training (aerobic, strength, and balance exercises)	Procedure: Task Oriented Exercise Training; Treadmill training with safety harnesses begin at 6 to 15 minutes total duration at 40-50% maximal heart rate reserve 3 times per week, increasing to 60-70% maximal heart rate reserve for 30 minutes for 6 months. Group dynamic balance exercise immediately follow the treadmill training 3 times a week. Participants also receive Best Stroke Care according to "Get with the Guidelines"
Active Comparator: Stroke Care; Best Medical Care in Jamaica adapted from the American Stroke Association "Get with the Guidelines".	Procedure: Stroke Care "Get with the Guidelines"; Post-stroke care is applied according to the recommendations of the American Stroke Association "Get with the Guidelines" adapted for Jamaica

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thigh and Abdominal muscle and fat	CT scans to determine 1) mid-thigh cross sectional area for muscle area, intramuscular and subcutaneous fat area, and quality of lean tissue mass, 2) abdominal fat area.	Baseline and 6 months
Whole body protein and skeletal muscle synthesis and breakdown	Serial blood sampling and pre-/post-muscle biopsies in the fasted and fed state	Baseline and 6 months
Muscle myosin heavy chain isoform (MHC) proportions	Analysis of muscle biopsies for MHC fiber type proportions	Baseline and 6 months
Leg Strength	1 repetitive maximum strength for leg extension, quadriceps and hamstring muscles	Baseline and 6 months
Fitness	VO2 peak testing with open circuit spirometry	Baseline and 6 months
Glucose tolerance	2 hour oral glucose tolerance test with serial blood sampling every 30 minutes for glucose and insulin	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle TNF alpha	Analysis of muscle biopsy samples for TNF levels	Baseline and 6 months
Mobility and balance	Stroke deficit profile will be indexed by NIH Stroke Scale, modified Ashworth, timed walks, Short Physical Performance Battery, Berg Balance.	Baseline and 6 months

Collaborators and Investigators

• Sponsor: Baltimore VA Medical Center
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Richard F Macko, MD, University of Maryland; Principal Investigator: Terrence Forrester, MD, University of West Indies

Publications and helpful links

General Publications

• Michael K, Goldberg AP, Treuth MS, Beans J, Normandt P, Macko RF. Progressive adaptive physical activity in stroke improves balance, gait, and fitness: preliminary results. Top Stroke Rehabil. 2009 Mar-Apr;16(2):133-9. doi: 10.1310/tsr1602-133.
• Lam JM, Globas C, Cerny J, Hertler B, Uludag K, Forrester LW, Macko RF, Hanley DF, Becker C, Luft AR. Predictors of response to treadmill exercise in stroke survivors. Neurorehabil Neural Repair. 2010 Jul-Aug;24(6):567-74. doi: 10.1177/1545968310364059. Epub 2010 May 7.
• Luft AR, Macko RF, Forrester LW, Villagra F, Ivey F, Sorkin JD, Whitall J, McCombe-Waller S, Katzel L, Goldberg AP, Hanley DF. Treadmill exercise activates subcortical neural networks and improves walking after stroke: a randomized controlled trial. Stroke. 2008 Dec;39(12):3341-50. doi: 10.1161/STROKEAHA.108.527531. Epub 2008 Aug 28.

Helpful Links

• American Stroke Association
• University of West Indies Tropical Medicine Research Unit

Study record dates

Study Major Dates

• Study Start: July 1, 2011
• Primary Completion (Anticipated): April 1, 2018
• Study Completion (Anticipated): April 1, 2018

Study Registration Dates

• First Submitted: July 11, 2011
• First Submitted That Met QC Criteria: July 11, 2011
• First Posted (Estimate): July 12, 2011

Study Record Updates

• Last Update Posted (Estimate): November 1, 2016
• Last Update Submitted That Met QC Criteria: October 28, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Inflammation; Exercise; Stroke; Insulin resistance; Fitness; Protein synthesis; Protein breakdown; Muscle atrophy; Muscle phenotype
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke
• Other Study ID Numbers: HP-00048469; R01HD068712 (U.S. NIH Grant/Contract)