Mechanisms of Neuromuscular Fatigue Post Stroke

• ClinicalTrials.gov Identifier: NCT01688570
• Recruitment Status: Completed
• First Posted: September 20, 2012
• Last Update Posted: November 5, 2015
• Sponsor: Medical College of Wisconsin
• Information provided by (Responsible Party): Phillip Nelson, MD, Medical College of Wisconsin

Tracking Information

• First Submitted Date: September 12, 2012
• First Posted Date: September 20, 2012
• Last Update Posted Date: November 5, 2015
• Study Start Date: August 2011
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 16, 2012)

Force generation [ Time Frame: At time of each of 4 testing sessions (all sessions within a 2 year period). ]

Sub-maximal and maximal force measurements will be made during brief contractions during each of the four testing sessions. All sessions will occur at least one week apart and within a total time span of 2 years.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 16, 2012)

Surface electromyography (EMG)of lower leg muscles. [ Time Frame: EMG measurements will be made during each of the four sessions. ]

Sessions will occur at least a week apart and within a 2 year time span.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mechanisms of Neuromuscular Fatigue Post Stroke
• Official Title: Mechanisms of Neuromuscular Fatigue Post Stroke
• Brief Summary: While baseline weakness is clearly an important factor that contributes to disability post stroke, neuromuscular fatigue (the acute reduction in force production) of the paretic musculature likely compounds strength deficits and further exacerbates disability. The proposed study aims to improve our understanding of the mechanisms of neuromuscular fatigue in people post stroke in order to optimize strength training. In healthy individuals, both central (neural) and peripheral (muscle) factors are determinants of neuromuscular fatigue, but preliminary data from our laboratory suggests a greater contribution of central components to neuromuscular fatigue in the paretic musculature. Although cortical pathways are clearly disrupted post stroke, it is likely that brainstem pathways, known to have neuromodulatory effects on spinal motor circuitry, are more involved in the sustaining of force in the paretic leg, compared to the non-paretic and control legs. Therefore, the purpose of this proposal is to examine the role of descending neuromodulatory pathways of the brainstem in neuromuscular fatigue post stroke (Aim 1) and to correlate brainstem-related changes in neuromuscular fatigue to walking function (Aim 2). The investigators propose that stroke survivors' decreased capability to sustain force overtime results from the diminished ability of spinal motoneurons to respond to brainstem neuromodulatory inputs (serotonin (5-HT) and norepinephrine (NE)). Aim 1 will quantify stroke-related decreases in motor output sensitivity to a 5-HT and NE reuptake inhibitor (SNRI), serotonin antagonist, or placebo during sub-maximal intermittent fatiguing knee extension contractions. If motoneurons are desensitized to descending monoamines in chronic stroke patients, then they will be less sensitive to the effects of drugs that increase monoamine levels. The investigators predict that in response to the SNRI or serotonin antagonist, the paretic leg will show less change in time to task failure and a smaller reduction in strength as compared to the non-paretic and control legs. For Aim 2, the investigators predict that stroke subjects with the highest walking function will demonstrate the greatest fatigue-related changes in response to the SNRI. This proposal adopts an innovative model of motor impairment post stroke by including the role of subcortical structures in neuromuscular fatigue.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Basic Science
• Condition: Stroke

Intervention

• Drug: duloxetine
  Single dose, orally (pill), 30 mg, taken 6 hours prior to start of the testing session. Subjects will only take a single dose of duloxetine once.
  Other Name: Cymbalta
• Drug: Cyproheptadine
  Single dose, orally, 8 mg, 6 hours prior to the start of the respective testing session. Subjects will take a single dose of cyproheptadine once.
• Drug: Placebo
  Single dose, orally, 6 hours prior to the start of the respective testing session. Subjects take a single dose once.

Study Arms

• Active Comparator: Duloxetine
  Neuromuscular fatigue testing with duloxetine dose
  Intervention: Drug: duloxetine
• Active Comparator: Cyproheptadine
  Neuromuscular fatigue testing with cyproheptadine dose
  Intervention: Drug: Cyproheptadine
• Placebo Comparator: Placebo
  Neuromuscular fatigue testing with placebo dose
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 4, 2015): 27
• Original Estimated Enrollment (submitted: September 16, 2012): 26
• Actual Study Completion Date: May 2015
• Actual Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

General

• be at least 18 years of age

• Cognitively able to give informed consent Stroke

  -≥ 6 months post diagnosis of unilateral cortical stroke

• residual leg paresis

Exclusion Criteria:

General

• chronic low back or hip pain
• major psychiatric disorders (e.g. depression
• substance abuse
• head trauma
• neurodegenerative disorder
• any uncontrolled medical disorder (e.g. hypertension)
• taking any medication or supplement (e.g. St. John's Wort) that has 5-HT or NE mechanisms of action(including Monoamine oxidase inhibitors (MAO) inhibitors)
• narrow angle glaucoma
• chronic liver or kidney disorders Stroke
• history of multiple strokes
• people who are unable to follow 2 step commands
• people who cannot walk ≥ 10 ft without physical assistance.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01688570
• Other Study ID Numbers: UL1RR031973-02( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Phillip Nelson, MD, Medical College of Wisconsin
• Original Responsible Party: Same as current
• Current Study Sponsor: Medical College of Wisconsin
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Philip A. Nelson, MD; Medical College of Wisconsin

• PRS Account: Medical College of Wisconsin
• Verification Date: November 2015