<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01688570</url>
  </required_header>
  <id_info>
    <org_study_id>UL1RR031973-02</org_study_id>
    <nct_id>NCT01688570</nct_id>
  </id_info>
  <brief_title>Mechanisms of Neuromuscular Fatigue Post Stroke</brief_title>
  <official_title>Mechanisms of Neuromuscular Fatigue Post Stroke</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical College of Wisconsin</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      While baseline weakness is clearly an important factor that contributes to disability post&#xD;
      stroke, neuromuscular fatigue (the acute reduction in force production) of the paretic&#xD;
      musculature likely compounds strength deficits and further exacerbates disability. The&#xD;
      proposed study aims to improve our understanding of the mechanisms of neuromuscular fatigue&#xD;
      in people post stroke in order to optimize strength training. In healthy individuals, both&#xD;
      central (neural) and peripheral (muscle) factors are determinants of neuromuscular fatigue,&#xD;
      but preliminary data from our laboratory suggests a greater contribution of central&#xD;
      components to neuromuscular fatigue in the paretic musculature. Although cortical pathways&#xD;
      are clearly disrupted post stroke, it is likely that brainstem pathways, known to have&#xD;
      neuromodulatory effects on spinal motor circuitry, are more involved in the sustaining of&#xD;
      force in the paretic leg, compared to the non-paretic and control legs. Therefore, the&#xD;
      purpose of this proposal is to examine the role of descending neuromodulatory pathways of the&#xD;
      brainstem in neuromuscular fatigue post stroke (Aim 1) and to correlate brainstem-related&#xD;
      changes in neuromuscular fatigue to walking function (Aim 2). The investigators propose that&#xD;
      stroke survivors' decreased capability to sustain force overtime results from the diminished&#xD;
      ability of spinal motoneurons to respond to brainstem neuromodulatory inputs (serotonin&#xD;
      (5-HT) and norepinephrine (NE)). Aim 1 will quantify stroke-related decreases in motor output&#xD;
      sensitivity to a 5-HT and NE reuptake inhibitor (SNRI), serotonin antagonist, or placebo&#xD;
      during sub-maximal intermittent fatiguing knee extension contractions. If motoneurons are&#xD;
      desensitized to descending monoamines in chronic stroke patients, then they will be less&#xD;
      sensitive to the effects of drugs that increase monoamine levels. The investigators predict&#xD;
      that in response to the SNRI or serotonin antagonist, the paretic leg will show less change&#xD;
      in time to task failure and a smaller reduction in strength as compared to the non-paretic&#xD;
      and control legs. For Aim 2, the investigators predict that stroke subjects with the highest&#xD;
      walking function will demonstrate the greatest fatigue-related changes in response to the&#xD;
      SNRI. This proposal adopts an innovative model of motor impairment post stroke by including&#xD;
      the role of subcortical structures in neuromuscular fatigue.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2011</start_date>
  <completion_date type="Actual">May 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Force generation</measure>
    <time_frame>At time of each of 4 testing sessions (all sessions within a 2 year period).</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Surface electromyography (EMG)of lower leg muscles.</measure>
    <time_frame>EMG measurements will be made during each of the four sessions.</time_frame>
    <description>Sessions will occur at least a week apart and within a 2 year time span.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Stroke</condition>
  <arm_group>
    <arm_group_label>Duloxetine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Neuromuscular fatigue testing with duloxetine dose</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyproheptadine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Neuromuscular fatigue testing with cyproheptadine dose</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Neuromuscular fatigue testing with placebo dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>duloxetine</intervention_name>
    <description>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.</description>
    <arm_group_label>Duloxetine</arm_group_label>
    <other_name>Cymbalta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyproheptadine</intervention_name>
    <description>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.</description>
    <arm_group_label>Cyproheptadine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Single dose, orally, 6 hours prior to the start of the respective testing session. Subjects take a single dose once.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        General&#xD;
&#xD;
          -  be at least 18 years of age&#xD;
&#xD;
          -  Cognitively able to give informed consent Stroke&#xD;
&#xD;
             -≥ 6 months post diagnosis of unilateral cortical stroke&#xD;
&#xD;
          -  residual leg paresis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        General&#xD;
&#xD;
          -  chronic low back or hip pain&#xD;
&#xD;
          -  major psychiatric disorders (e.g. depression&#xD;
&#xD;
          -  substance abuse&#xD;
&#xD;
          -  head trauma&#xD;
&#xD;
          -  neurodegenerative disorder&#xD;
&#xD;
          -  any uncontrolled medical disorder (e.g. hypertension)&#xD;
&#xD;
          -  taking any medication or supplement (e.g. St. John's Wort) that has 5-HT or NE&#xD;
             mechanisms of action(including Monoamine oxidase inhibitors (MAO) inhibitors)&#xD;
&#xD;
          -  narrow angle glaucoma&#xD;
&#xD;
          -  chronic liver or kidney disorders Stroke&#xD;
&#xD;
          -  history of multiple strokes&#xD;
&#xD;
          -  people who are unable to follow 2 step commands&#xD;
&#xD;
          -  people who cannot walk ≥ 10 ft without physical assistance.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philip A. Nelson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical College of Wisconsin</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2015</verification_date>
  <study_first_submitted>September 12, 2012</study_first_submitted>
  <study_first_submitted_qc>September 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 20, 2012</study_first_posted>
  <last_update_submitted>November 4, 2015</last_update_submitted>
  <last_update_submitted_qc>November 4, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 5, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Phillip Nelson, MD</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>neuromuscular fatigue</keyword>
  <keyword>motor impairment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
    <mesh_term>Fatigue</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyproheptadine</mesh_term>
    <mesh_term>Duloxetine Hydrochloride</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01688570
org study id: UL1RR031973-02
nct id: NCT01688570
lead sponsor: 
has dmc: No
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Force generation
time frame: At time of each of 4 testing sessions (all sessions within a 2 year period).
description: 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.
measure: Surface electromyography (EMG)of lower leg muscles.
time frame: EMG measurements will be made during each of the four sessions.
description: Sessions will occur at least a week apart and within a 2 year time span.
arm group label: Duloxetine
arm group type: Active Comparator
description: Neuromuscular fatigue testing with duloxetine dose
arm group label: Cyproheptadine
arm group type: Active Comparator
description: Neuromuscular fatigue testing with cyproheptadine dose
arm group label: Placebo
arm group type: Placebo Comparator
description: Neuromuscular fatigue testing with placebo dose
intervention type: Drug
intervention name: duloxetine
description: 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.
arm group label: Duloxetine
other name: Cymbalta
intervention type: Drug
intervention name: Cyproheptadine
description: 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.
arm group label: Cyproheptadine
intervention type: Drug
intervention name: Placebo
description: Single dose, orally, 6 hours prior to the start of the respective testing session. Subjects take a single dose once.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Philip A. Nelson, MD
role: Principal Investigator
affiliation: Medical College of Wisconsin
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Phillip Nelson, MD
investigator title: Assistant Professor
mesh term: Stroke
mesh term: Fatigue
mesh term: Cyproheptadine
mesh term: Duloxetine Hydrochloride