xml: <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/NCT06027294</url>
    </required_header>
    <id_info>
      <org_study_id>PRO00046423</org_study_id>
      <nct_id>NCT06027294</nct_id>
    </id_info>
    <brief_title>Blood Flow Regulation and Neuromuscular Function Post-Stroke</brief_title>
    <official_title>Blood Flow Regulation and Neuromuscular Function 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>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The muscles of stroke survivors can fatigue faster compared to muscles in people who have not&#xD;
        had a stroke, which can limit how long a person with stroke can perform tasks such as&#xD;
        walking. This study will examine how blood flow is regulated to the exercising leg muscle&#xD;
        post-stroke, because if the muscle does not receive enough blood flow it will become&#xD;
        fatigued. Finally, the investigators will use a safe and simple non-invasive intervention&#xD;
        called ischemic conditioning, which has known effects to improve blood flow to exercising&#xD;
        muscle and determine the effects on muscle fatigue.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This study will examine peripheral blood flow regulation in the exercising muscle of stroke&#xD;
        survivors and determine relationships between hyperemic blood flow and the functional&#xD;
        sympatholysis magnitude with measures of muscle fatigue. In Aim 3 the investigators will&#xD;
        conduct a parallel group, randomized, controlled, double-blinded clinical trial that will&#xD;
        examine the effects of ischemic conditioning on the functional sympatholysis response, muscle&#xD;
        fatigue resistance and metrics of muscle fatigability. In total the investigators intend to&#xD;
        recruit 60 chronic stroke survivors and 20 age- and sex-matched controls. Stroke survivors&#xD;
        will be recruited from HIPAA compliant databases and from the outpatient stroke clinics&#xD;
        within the Department of Physical Medicine and Rehabilitation at the Medical College of&#xD;
        Wisconsin.&#xD;
  &#xD;
        In Aim 1 the investigators propose to recruit 20 chronic stroke survivors and 20 age- and&#xD;
        sex-matched control participants. Stroke survivors will be asked to make six visits to the&#xD;
        laboratories at Marquette University and the Medical College of Wisconsin, and the&#xD;
        investigators will perform measurements on both the paretic and non-paretic legs (three test&#xD;
        sessions on each leg). Control participants will be asked to make three visits to the&#xD;
        laboratories, and the investigators will test the dominant leg. In one visit, the functional&#xD;
        sympatholysis response will be assessed by having participants perform single leg, isometric,&#xD;
        repeated knee extensor contractions at 40% of the maximum voluntary isometric contraction&#xD;
        (MVIC) torque on a Biodex dynamometer for a total of seven minutes. During the final two&#xD;
        minutes of the exercise protocol the foot of the non-exercising leg will be placed in an ice&#xD;
        bath to increase sympathetic nervous system activity. Blood pressure and blood flow through&#xD;
        the superficial femoral artery will be continuously monitored and the magnitude of the&#xD;
        functional sympatholysis response will be calculated as a change in leg vascular conductance&#xD;
        from the exercise control condition to the exercise + ice condition. In a separate visit the&#xD;
        test leg will perform a single, isometric, sustained, fatiguing muscle contraction with the&#xD;
        knee extensor muscles equal to 30% of the MVIC. Motor unit firing rates will be continuously&#xD;
        measured during the muscle contraction using surface electromyograph (EMG). Finally, in the&#xD;
        third test session muscle metabolite accumulation will be measured during isometric knee&#xD;
        extensor contractions using 31P magnetic resonance spectroscopy (MRS). After all test&#xD;
        sessions are complete, the investigators will compare the functional sympatholysis magnitude&#xD;
        between the three test groups (paretic leg, non-paretic leg, control leg) and will examine if&#xD;
        there is a relationship between the functional sympatholysis magnitude and 1) the time to&#xD;
        muscle fatigue, 2) the change in motor unit firing rates during a fatiguing muscle&#xD;
        contraction, and 3) metabolite buildup in the muscle (peak H2PO4- concentration) during&#xD;
        fatiguing contractions.&#xD;
  &#xD;
        In Aim 2 the investigators will also recruit 20 chronic stroke survivors and 20 age- and&#xD;
        sex-matched control participants. Those participants who completed Aim 1 will also be asked&#xD;
        to complete Aim 2. Stroke survivors will be asked to make two visits to the Translational&#xD;
        Research Unit at the Medical College of Wisconsin, while control participants will be asked&#xD;
        to make one visit. During these visits the investigators will separately examine the&#xD;
        vasoactive effects of norepinephrine and acetylcholine +/- the endothelial nitric oxide&#xD;
        inhibitor L-NAME in the cutaneous microvasculature of the legs using laser Doppler flowmetry&#xD;
        with dermal microdialysis. The investigators will calculate the change in cutaneous vascular&#xD;
        conductance for each compound that is infused, and the investigators will compare the maximum&#xD;
        change between the three groups (paretic leg, non-paretic leg and control leg). The&#xD;
        investigators will also examine the relationship between the maximum change in cutaneous&#xD;
        vascular conductance during acetylcholine infusion (i.e., the maximum vasodilation) and 1)&#xD;
        the functional sympatholysis magnitude, 2) the time to muscle fatigue, 3) the change in motor&#xD;
        unit firing rates during a fatiguing muscle contraction, and 4) metabolite buildup in the&#xD;
        muscle (peak H2PO4- concentration) during fatiguing contractions.&#xD;
  &#xD;
        In Aim 3 the investigators will conduct a parallel group, randomized, controlled,&#xD;
        double-blinded clinical trial that will enroll study participants into either an ischemic&#xD;
        conditioning (IC) intervention group or an IC-Sham control group. The investigators will&#xD;
        enroll a total of 40 chronic stroke survivors (20 individuals split between two groups) and&#xD;
        the investigators will only perform testing on the paretic leg. Study participants will be&#xD;
        asked to make a total of ten visits to the laboratories at Marquette University and the&#xD;
        Medical College of Wisconsin over the course of six weeks. Participants in both groups will&#xD;
        receive a handheld sphygmomanometer and blood pressure cuff and the intervention will be&#xD;
        performed at home every other day (six total sessions). For the IC group, the cuff be placed&#xD;
        around the proximal, paretic thigh and inflated to 225 mmHg for 5 minutes with the&#xD;
        participants in a supine or semi-reclined position, then released for a 5-minute recovery&#xD;
        period. Five cycles of inflation/recovery will be performed. IC Sham will consist of the same&#xD;
        physical set-up as above, but the cuff will only be inflated to 10 mmHg. The same compliment&#xD;
        of tests described in Aim 1 will be performed at baseline, immediately after the two-week&#xD;
        intervention, and two-weeks after the end of the intervention period. The investigators will&#xD;
        determine whether the functional sympatholysis response improved in the IC group vs. the&#xD;
        IC-Sham group and examine relationships between the change in functional sympatholysis and 1)&#xD;
        the time to muscle fatigue, 2) the change in motor unit firing rates during a fatiguing&#xD;
        muscle contraction, and 3) metabolite buildup in the muscle (specifically the peak H2PO4-&#xD;
        concentration) during fatiguing contractions.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">June 30, 2028</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2028</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Functional Sympatholysis Magnitude</measure>
      <time_frame>Years 3-5</time_frame>
      <description>Functional sympatholysis will be measured as a change in leg vascular conductance (in ml/min/mmHg) from the exercise control condition to the exercise + cold pressor test condition.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Time to muscle fatigue</measure>
      <time_frame>Years 3-5</time_frame>
      <description>The time (in seconds) it takes the knee extensor muscles to fatigue in response to a sustained, isometric muscle contraction will be measured, in seconds.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in motor unit firing rates</measure>
      <time_frame>Years 3-5</time_frame>
      <description>The change in motor unit firing rates (in Hz) from the beginning to end of a fatiguing muscle contraction will be measured, in pulses per second, using surface EMG.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in muscle metabolite accumulation will include muscle pH</measure>
      <time_frame>Years 3-5</time_frame>
      <description>Changes in muscle metabolite accumulation during fatiguing knee extensor exercise will be measured.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in muscle metabolite accumulation</measure>
      <time_frame>Years 3-5</time_frame>
      <description>Changes in muscle metabolite accumulation during fatiguing knee extensor exercise will be measured. These metabolites and markers of muscle fatigue will include inorganic phosphate concentration (in mM), and diprotonated phosphate concentration (in mM).</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Stroke</condition>
    <arm_group>
      <arm_group_label>Ischemic Conditioning</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Ischemic conditioning is a well-defined, non-invasive procedure which consists of inflating a blood pressure cuff around a limb (in our study, the paretic leg), inflating the cuff to 225 mmHg to occlude blood flow to the limb for 5 minutes, releasing the cuff for 5 minutes, and repeating 5 times. In our study, participants will receive six sessions of ischemic conditioning over the course of two weeks.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Ischemic Conditioning Sham</arm_group_label>
      <arm_group_type>Sham Comparator</arm_group_type>
      <description>There will also be an IC Sham group which is identical to the IC intervention, except the cuff will only be inflated to 10 mmHg, which is not a high enough pressure to occlude arterial blood flow.</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Ischemic Conditioning</intervention_name>
      <description>A cuff will be inflated to a pressure of 225 mmHg.</description>
      <arm_group_label>Ischemic Conditioning</arm_group_label>
      <arm_group_label>Ischemic Conditioning Sham</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Be between 18-85 years of age&#xD;
  &#xD;
            -  Able to give informed consent&#xD;
  &#xD;
            -  ≥6 months post diagnosis of unilateral cortical or sub-cortical stroke&#xD;
  &#xD;
            -  English speaking&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  History of blood clots in the extremities or any condition in which compression of the&#xD;
               thigh or transient ischemia is contraindicated (e.g. wounds in the leg)&#xD;
  &#xD;
            -  Chronic pain syndrome&#xD;
  &#xD;
            -  Low back or hip pain that interferes with lower extremity motor testing&#xD;
  &#xD;
            -  History of head trauma&#xD;
  &#xD;
            -  Comorbid neurological disorder&#xD;
  &#xD;
            -  Peripheral vascular disease&#xD;
  &#xD;
            -  Myocardial infarction in the previous year&#xD;
  &#xD;
            -  Inability to follow 2 step commands&#xD;
  &#xD;
            -  Condition where fatiguing contractions or resisted leg contractions are&#xD;
               contraindicated&#xD;
  &#xD;
            -  Resting SBP ≥160 mmHg or DBP ≥ 110 mmHg&#xD;
  &#xD;
            -  Pregnancy or breastfeeding.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>85 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Matthew Durand, Ph.D.</last_name>
      <phone>4149555619</phone>
      <email>mdurand@mcw.edu</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Jennifer Nguyen, BS</last_name>
      <email>jnguyen@mcw.edu</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Medical College of Wisconsin</name>
        <address>
          <city>Milwaukee</city>
          <state>Wisconsin</state>
          <zip>53226</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Marquette University</name>
        <address>
          <city>Milwaukee</city>
          <state>Wisconsin</state>
          <zip>53233</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 30, 2023</study_first_submitted>
    <study_first_submitted_qc>September 6, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 7, 2023</study_first_posted>
    <last_update_submitted>September 6, 2023</last_update_submitted>
    <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
      <investigator_full_name>Matthew J. Durand</investigator_full_name>
      <investigator_title>Associate Professor</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Stroke</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06027294
  org study id: PRO00046423
  nct id: NCT06027294
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  The muscles of stroke survivors can fatigue faster compared to muscles in people who have not
        had a stroke, which can limit how long a person with stroke can perform tasks such as
        walking. This study will examine how blood flow is regulated to the exercising leg muscle
        post-stroke, because if the muscle does not receive enough blood flow it will become
        fatigued. Finally, the investigators will use a safe and simple non-invasive intervention
        called ischemic conditioning, which has known effects to improve blood flow to exercising
        muscle and determine the effects on muscle fatigue.
  This study will examine peripheral blood flow regulation in the exercising muscle of stroke
        survivors and determine relationships between hyperemic blood flow and the functional
        sympatholysis magnitude with measures of muscle fatigue. In Aim 3 the investigators will
        conduct a parallel group, randomized, controlled, double-blinded clinical trial that will
        examine the effects of ischemic conditioning on the functional sympatholysis response, muscle
        fatigue resistance and metrics of muscle fatigability. In total the investigators intend to
        recruit 60 chronic stroke survivors and 20 age- and sex-matched controls. Stroke survivors
        will be recruited from HIPAA compliant databases and from the outpatient stroke clinics
        within the Department of Physical Medicine and Rehabilitation at the Medical College of
        Wisconsin.
  
        In Aim 1 the investigators propose to recruit 20 chronic stroke survivors and 20 age- and
        sex-matched control participants. Stroke survivors will be asked to make six visits to the
        laboratories at Marquette University and the Medical College of Wisconsin, and the
        investigators will perform measurements on both the paretic and non-paretic legs (three test
        sessions on each leg). Control participants will be asked to make three visits to the
        laboratories, and the investigators will test the dominant leg. In one visit, the functional
        sympatholysis response will be assessed by having participants perform single leg, isometric,
        repeated knee extensor contractions at 40% of the maximum voluntary isometric contraction
        (MVIC) torque on a Biodex dynamometer for a total of seven minutes. During the final two
        minutes of the exercise protocol the foot of the non-exercising leg will be placed in an ice
        bath to increase sympathetic nervous system activity. Blood pressure and blood flow through
        the superficial femoral artery will be continuously monitored and the magnitude of the
        functional sympatholysis response will be calculated as a change in leg vascular conductance
        from the exercise control condition to the exercise + ice condition. In a separate visit the
        test leg will perform a single, isometric, sustained, fatiguing muscle contraction with the
        knee extensor muscles equal to 30% of the MVIC. Motor unit firing rates will be continuously
        measured during the muscle contraction using surface electromyograph (EMG). Finally, in the
        third test session muscle metabolite accumulation will be measured during isometric knee
        extensor contractions using 31P magnetic resonance spectroscopy (MRS). After all test
        sessions are complete, the investigators will compare the functional sympatholysis magnitude
        between the three test groups (paretic leg, non-paretic leg, control leg) and will examine if
        there is a relationship between the functional sympatholysis magnitude and 1) the time to
        muscle fatigue, 2) the change in motor unit firing rates during a fatiguing muscle
        contraction, and 3) metabolite buildup in the muscle (peak H2PO4- concentration) during
        fatiguing contractions.
  
        In Aim 2 the investigators will also recruit 20 chronic stroke survivors and 20 age- and
        sex-matched control participants. Those participants who completed Aim 1 will also be asked
        to complete Aim 2. Stroke survivors will be asked to make two visits to the Translational
        Research Unit at the Medical College of Wisconsin, while control participants will be asked
        to make one visit. During these visits the investigators will separately examine the
        vasoactive effects of norepinephrine and acetylcholine +/- the endothelial nitric oxide
        inhibitor L-NAME in the cutaneous microvasculature of the legs using laser Doppler flowmetry
        with dermal microdialysis. The investigators will calculate the change in cutaneous vascular
        conductance for each compound that is infused, and the investigators will compare the maximum
        change between the three groups (paretic leg, non-paretic leg and control leg). The
        investigators will also examine the relationship between the maximum change in cutaneous
        vascular conductance during acetylcholine infusion (i.e., the maximum vasodilation) and 1)
        the functional sympatholysis magnitude, 2) the time to muscle fatigue, 3) the change in motor
        unit firing rates during a fatiguing muscle contraction, and 4) metabolite buildup in the
        muscle (peak H2PO4- concentration) during fatiguing contractions.
  
        In Aim 3 the investigators will conduct a parallel group, randomized, controlled,
        double-blinded clinical trial that will enroll study participants into either an ischemic
        conditioning (IC) intervention group or an IC-Sham control group. The investigators will
        enroll a total of 40 chronic stroke survivors (20 individuals split between two groups) and
        the investigators will only perform testing on the paretic leg. Study participants will be
        asked to make a total of ten visits to the laboratories at Marquette University and the
        Medical College of Wisconsin over the course of six weeks. Participants in both groups will
        receive a handheld sphygmomanometer and blood pressure cuff and the intervention will be
        performed at home every other day (six total sessions). For the IC group, the cuff be placed
        around the proximal, paretic thigh and inflated to 225 mmHg for 5 minutes with the
        participants in a supine or semi-reclined position, then released for a 5-minute recovery
        period. Five cycles of inflation/recovery will be performed. IC Sham will consist of the same
        physical set-up as above, but the cuff will only be inflated to 10 mmHg. The same compliment
        of tests described in Aim 1 will be performed at baseline, immediately after the two-week
        intervention, and two-weeks after the end of the intervention period. The investigators will
        determine whether the functional sympatholysis response improved in the IC group vs. the
        IC-Sham group and examine relationships between the change in functional sympatholysis and 1)
        the time to muscle fatigue, 2) the change in motor unit firing rates during a fatiguing
        muscle contraction, and 3) metabolite buildup in the muscle (specifically the peak H2PO4-
        concentration) during fatiguing contractions.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: Functional Sympatholysis Magnitude
  time frame: Years 3-5
  description: Functional sympatholysis will be measured as a change in leg vascular conductance (in ml/min/mmHg) from the exercise control condition to the exercise + cold pressor test condition.
  measure: Time to muscle fatigue
  time frame: Years 3-5
  description: The time (in seconds) it takes the knee extensor muscles to fatigue in response to a sustained, isometric muscle contraction will be measured, in seconds.
  measure: Change in motor unit firing rates
  time frame: Years 3-5
  description: The change in motor unit firing rates (in Hz) from the beginning to end of a fatiguing muscle contraction will be measured, in pulses per second, using surface EMG.
  measure: Change in muscle metabolite accumulation will include muscle pH
  time frame: Years 3-5
  description: Changes in muscle metabolite accumulation during fatiguing knee extensor exercise will be measured.
  measure: Change in muscle metabolite accumulation
  time frame: Years 3-5
  description: Changes in muscle metabolite accumulation during fatiguing knee extensor exercise will be measured. These metabolites and markers of muscle fatigue will include inorganic phosphate concentration (in mM), and diprotonated phosphate concentration (in mM).
  arm group label: Ischemic Conditioning
  arm group type: Experimental
  description: Ischemic conditioning is a well-defined, non-invasive procedure which consists of inflating a blood pressure cuff around a limb (in our study, the paretic leg), inflating the cuff to 225 mmHg to occlude blood flow to the limb for 5 minutes, releasing the cuff for 5 minutes, and repeating 5 times. In our study, participants will receive six sessions of ischemic conditioning over the course of two weeks.
  arm group label: Ischemic Conditioning Sham
  arm group type: Sham Comparator
  description: There will also be an IC Sham group which is identical to the IC intervention, except the cuff will only be inflated to 10 mmHg, which is not a high enough pressure to occlude arterial blood flow.
  intervention type: Procedure
  intervention name: Ischemic Conditioning
  description: A cuff will be inflated to a pressure of 225 mmHg.
  arm group label: Ischemic Conditioning
  arm group label: Ischemic Conditioning Sham
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 85 Years
  healthy volunteers: No
  last name: Matthew Durand, Ph.D.
  phone: 4149555619
  email: mdurand@mcw.edu
  last name: Jennifer Nguyen, BS
  email: jnguyen@mcw.edu
  facility: 
  facility: 
  country: United States
  responsible party type: Principal Investigator
  investigator affiliation: Medical College of Wisconsin
  investigator full name: Matthew J. Durand
  investigator title: Associate Professor
  mesh term: Stroke
  sharing ipd: No