Clinical trial NCT01392391: Exercise For Sub-acute Stroke Patients in Jamaica
Official title: Jamaica and Maryland Mobility in Stroke
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Stroke
Keywords: Stroke
Exercise
Protein synthesis
Protein breakdown
Muscle atrophy
Muscle phenotype
Inflammation
Insulin resistance
Fitness
Lead sponsor: Baltimore VA Medical Center
Sponsor class: FED
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2011-07-12
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Thigh and Abdominal muscle and fat
timeFrame: Baseline and 6 months
measure: Whole body protein and skeletal muscle synthesis and breakdown
timeFrame: Baseline and 6 months
measure: Muscle myosin heavy chain isoform (MHC) proportions
timeFrame: Baseline and 6 months
measure: Leg Strength
timeFrame: Baseline and 6 months
measure: Fitness
timeFrame: Baseline and 6 months
measure: Glucose tolerance
timeFrame: Baseline and 6 months
Secondary outcomes:
measure: Muscle TNF alpha
timeFrame: Baseline and 6 months
measure: Mobility and balance
timeFrame: Baseline and 6 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Kingston
country: Jamaica
facility: University of West Indies
state: Mona 7
Study officials:
affiliation: University of Maryland
name: Richard F Macko, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of West Indies
name: Terrence Forrester, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.