<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/NCT02209610</url>
  </required_header>
  <id_info>
    <org_study_id>E1572-P</org_study_id>
    <nct_id>NCT02209610</nct_id>
  </id_info>
  <brief_title>Premature Fatigue in Veterans With Heart Failure: Neuronal Influences</brief_title>
  <official_title>Premature Fatigue in Veterans With Heart Failure: Neuronal Influences</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A hallmark of patients with heart failure (HF) is premature fatigue which impairs their&#xD;
      quality of life and depicts a major source of morbidity. Premature fatigue may be attributed&#xD;
      to a) contraction-induced transient changes within muscles (i.e. peripheral fatigue) and/or&#xD;
      b) failure of the central nervous system to 'drive' / activate locomotor muscles (i.e.&#xD;
      central fatigue). Both determinants of fatigue can lead to a reduction in a muscle's force&#xD;
      and power generating capacity and to a compromised ability to perform whole body activities&#xD;
      (e.g. walking). Recent findings in health have documented that group III/IV afferent fibers&#xD;
      from the working muscle play a critical role in the development of both components of&#xD;
      fatigue. Specifically, group III/IV muscle afferents limit central motor drive (CMD) during&#xD;
      exercise and thereby exaggerate the development of central fatigue. In contrast, muscle&#xD;
      afferents optimize muscle O2 delivery through the precise regulation of circulation and&#xD;
      ventilation during exercise and thereby attenuate the development of peripheral fatigue.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recent findings in HF suggest an altered effect of group III/IV muscle afferents in this&#xD;
      population. Although normal afferent feedback is crucial for adequate O2 delivery during&#xD;
      exercise, excessive neural feedback has substantial negative consequences. HF patients are&#xD;
      characterized by augmented neural feedback arising from overactive muscle afferents. It has&#xD;
      been hypothesized that this abnormality compromises locomotor muscle O2 delivery in these&#xD;
      patients. Therefore, the abnormally elevated muscle afferent feedback in HF might exacerbate,&#xD;
      compared to healthy age- and activity matched individuals (CTRLs), the development of both&#xD;
      peripheral (via limiting O2 delivery) and central (via restricting CMD) fatigue during&#xD;
      exercise. Recent advances in non-invasive stimulation techniques offer a genuine opportunity&#xD;
      to identify the sites and synaptic mechanisms that mediate central and peripheral fatigue&#xD;
      including alterations in the responsiveness of the corticospinal tract (i.e. a determinant of&#xD;
      central fatigue). Taken together, the proposed studies aim to determine the impact of HF on&#xD;
      the precise development of central and peripheral fatigue during both whole body and single&#xD;
      muscle exercise and evaluate the extent to which group III/IV muscle afferents contribute to&#xD;
      this development.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2015</start_date>
  <completion_date type="Actual">January 15, 2017</completion_date>
  <primary_completion_date type="Actual">January 15, 2017</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>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximal Voluntary Quadriceps Force [% Change From Baseline]</measure>
    <time_frame>1 minute after exercise on study day</time_frame>
    <description>Following dynamic single leg knee extension exercise for a given duration (4-8 min), the decline in maximal voluntary contraction force will be measured.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)</measure>
    <time_frame>During (20 second intervals) and 1 minute after exercise on study day</time_frame>
    <description>During a 2-min maximal voluntary quadriceps contraction, central and peripheral fatigue will develop progressively and significantly more in HF vs. CTRLs.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Muscle Afferent Affect</measure>
    <time_frame>1 minute after exercise on study day</time_frame>
    <description>Corticospinal responsiveness will be quantified before and after exercise.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Patients With Heart Failure: Neuromuscular Abnormalities</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients with Heart Failure</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Health Control Subjects and Neuromuscular Function</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Health Control Subjects</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Electrical and Magnetic Nerve Stimulators</intervention_name>
    <description>Stimulation of motor nerve and central nervous system</description>
    <arm_group_label>Health Control Subjects and Neuromuscular Function</arm_group_label>
    <arm_group_label>Patients With Heart Failure: Neuromuscular Abnormalities</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intrathecal Fentanyl</intervention_name>
    <description>Mu-opioid receptor agonist</description>
    <arm_group_label>Health Control Subjects and Neuromuscular Function</arm_group_label>
    <arm_group_label>Patients With Heart Failure: Neuromuscular Abnormalities</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, &gt;1yr&#xD;
             duration, ages 20-75 yr),&#xD;
&#xD;
          -  not pacemaker dependent (no biventricular pacers),&#xD;
&#xD;
          -  NYHA class II and III symptoms,&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF)&lt;35%,&#xD;
&#xD;
          -  no or minimal smoking history (&lt;15 pk yrs) and on stable medications.&#xD;
&#xD;
          -  The investigators will also study subjects with preserved ejection fraction&#xD;
&#xD;
               -  heart failure with a preserved ejection fraction (HFpEF);&#xD;
&#xD;
               -  LVEF &gt;50%,&#xD;
&#xD;
               -  &gt;1yr duration,&#xD;
&#xD;
               -  ages 20-75 yr,&#xD;
&#xD;
          -  not pacemaker dependent,&#xD;
&#xD;
          -  NYHA class II and III symptoms,&#xD;
&#xD;
          -  no or minimal smoking history (&lt;15 pk yrs) and on stable medications. The&#xD;
             investigators will exclude morbidly obese patients (BMI &gt;35), patients with&#xD;
             uncontrolled hypertension (&gt;160/100), anemia (Hgb&lt;9) and severe renal insufficiency&#xD;
             (individuals with creatinine clearance &lt;30 by the Cockcroft-Gault formula).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with significant non-cardiac comorbidities, which if present could alter the&#xD;
             study results, will be excluded.&#xD;
&#xD;
          -  Patients will be sedentary, defined here as no regular physical activity for at least&#xD;
             the prior 6 months and current activity level will be documented by an activity&#xD;
             questionnaire.&#xD;
&#xD;
          -  Candidates must have no orthopedic limitations that would prohibit them from&#xD;
             performing exercise.&#xD;
&#xD;
          -  Due to the typical age of patients with heart failure, all women will be&#xD;
             postmenopausal (either natural or surgical) defined as a cessation of menses for at&#xD;
             least 2 years,&#xD;
&#xD;
               -  and in women without a uterus, follicle stimulating hormone (FSH) &gt;40 IU/L.&#xD;
&#xD;
          -  Women currently taking hormone replacement therapy (HRT) will be excluded from the&#xD;
             proposed studies due to the direct vascular effects of HRT.&#xD;
&#xD;
          -  Patients with a pacemaker and / or defibrillator will be excluded from the study due&#xD;
             to the use of a magnetic/electric stimulators.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Markus Amann, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>VA Salt Lake City Health Care System, Salt Lake City, UT</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VA Salt Lake City Health Care System, Salt Lake City, UT</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84148</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Ives SJ, Amann M, Venturelli M, Witman MA, Groot HJ, Wray DW, Morgan DE, Stehlik J, Richardson RS. The Mechanoreflex and Hemodynamic Response to Passive Leg Movement in Heart Failure. Med Sci Sports Exerc. 2016 Mar;48(3):368-76. doi: 10.1249/MSS.0000000000000782.</citation>
    <PMID>26418560</PMID>
  </results_reference>
  <results_reference>
    <citation>Sidhu SK, Weavil JC, Venturelli M, Rossman MJ, Gmelch BS, Bledsoe AD, Richardson RS, Amann M. Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans. Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1479-89. doi: 10.1152/ajpheart.00433.2015. Epub 2015 Sep 18.</citation>
    <PMID>26386110</PMID>
  </results_reference>
  <results_reference>
    <citation>Weavil JC, Sidhu SK, Mangum TS, Richardson RS, Amann M. Fatigue diminishes motoneuronal excitability during cycling exercise. J Neurophysiol. 2016 Oct 1;116(4):1743-1751. doi: 10.1152/jn.00300.2016. Epub 2016 Jul 20.</citation>
    <PMID>27440242</PMID>
  </results_reference>
  <results_reference>
    <citation>Amann M, Sidhu SK, Weavil JC, Mangum TS, Venturelli M. Autonomic responses to exercise: group III/IV muscle afferents and fatigue. Auton Neurosci. 2015 Mar;188:19-23. doi: 10.1016/j.autneu.2014.10.018. Epub 2014 Oct 23.</citation>
    <PMID>25458423</PMID>
  </results_reference>
  <results_reference>
    <citation>Wray DW, Amann M, Richardson RS. Peripheral vascular function, oxygen delivery and utilization: the impact of oxidative stress in aging and heart failure with reduced ejection fraction. Heart Fail Rev. 2017 Mar;22(2):149-166. doi: 10.1007/s10741-016-9573-4.</citation>
    <PMID>27392715</PMID>
  </results_reference>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>July 10, 2014</study_first_submitted>
  <study_first_submitted_qc>August 4, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 6, 2014</study_first_posted>
  <results_first_submitted>May 10, 2018</results_first_submitted>
  <results_first_submitted_qc>June 4, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 2, 2019</results_first_posted>
  <last_update_submitted>June 4, 2019</last_update_submitted>
  <last_update_submitted_qc>June 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Heart Failure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fentanyl</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Patients With Heart Failure: Neuromuscular Abnormalities</title>
          <description>Patients with Heart Failure are characterized by excessive exercise-induced neuromuscular fatigue Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
        </group>
        <group group_id="P2">
          <title>Health Control Subjects and Neuromuscular Function</title>
          <description>Health Control Subjects&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Patients With Heart Failure: Neuromuscular Abnormalities</title>
          <description>Patients with Heart Failure&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
        </group>
        <group group_id="B2">
          <title>Health Control Subjects and Neuromuscular Function</title>
          <description>Health Control Subjects&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="16"/>
            <count group_id="B2" value="16"/>
            <count group_id="B3" value="32"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="67" spread="3"/>
                    <measurement group_id="B2" value="64" spread="3"/>
                    <measurement group_id="B3" value="66" spread="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>white</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximal Voluntary Quadriceps Force [% Change From Baseline]</title>
        <description>Following dynamic single leg knee extension exercise for a given duration (4-8 min), the decline in maximal voluntary contraction force will be measured.</description>
        <time_frame>1 minute after exercise on study day</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Patients With Heart Failure: Neuromuscular Abnormalities</title>
            <description>Patients with Heart Failure&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
          </group>
          <group group_id="O2">
            <title>Health Control Subjects and Neuromuscular Function</title>
            <description>Health Control Subjects&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
          </group>
        </group_list>
        <measure>
          <title>Maximal Voluntary Quadriceps Force [% Change From Baseline]</title>
          <description>Following dynamic single leg knee extension exercise for a given duration (4-8 min), the decline in maximal voluntary contraction force will be measured.</description>
          <units>percentage change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-30" spread="3"/>
                    <measurement group_id="O2" value="-5" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)</title>
        <description>During a 2-min maximal voluntary quadriceps contraction, central and peripheral fatigue will develop progressively and significantly more in HF vs. CTRLs.</description>
        <time_frame>During (20 second intervals) and 1 minute after exercise on study day</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Patients With Heart Failure: Neuromuscular Abnormalities</title>
            <description>Patients with Heart Failure are characterized by excessive exercise-induced neuromuscular fatigue Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
          </group>
          <group group_id="O2">
            <title>Health Control Subjects and Neuromuscular Function</title>
            <description>Health Control Subjects&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
          </group>
        </group_list>
        <measure>
          <title>Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)</title>
          <description>During a 2-min maximal voluntary quadriceps contraction, central and peripheral fatigue will develop progressively and significantly more in HF vs. CTRLs.</description>
          <units>percentage change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Twitch force</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-60" spread="5"/>
                    <measurement group_id="O2" value="-35" spread="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Voluntary activation [VA]</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-25" spread="6"/>
                    <measurement group_id="O2" value="-20" spread="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Muscle Afferent Affect</title>
        <description>Corticospinal responsiveness will be quantified before and after exercise.</description>
        <time_frame>1 minute after exercise on study day</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Patients With Heart Failure: Neuromuscular Abnormalities</title>
            <description>Patients with Heart Failure are characterized by excessive exercise-induced neuromuscular fatigue Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
          </group>
          <group group_id="O2">
            <title>Health Control Subjects and Neuromuscular Function</title>
            <description>Health Control Subjects&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
          </group>
        </group_list>
        <measure>
          <title>Muscle Afferent Affect</title>
          <description>Corticospinal responsiveness will be quantified before and after exercise.</description>
          <units>percent change</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-30" spread="3"/>
                    <measurement group_id="O2" value="10" spread="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Patients With Heart Failure: Neuromuscular Abnormalities</title>
          <description>Patients with Heart Failure&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
        </group>
        <group group_id="E2">
          <title>Health Control Subjects and Neuromuscular Function</title>
          <description>Health Control Subjects&#xD;
Electrical and Magnetic Nerve Stimulators: Stimulation of motor nerve and central nervous system&#xD;
Intrathecal Fentanyl: Mu-opioid receptor agonist</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="16"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr Markus Amann</name_or_title>
      <organization>VAORD</organization>
      <phone>801-582-1565 ext 4358</phone>
      <email>markus.amann@hsc.utah.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02209610
org study id: E1572-P
nct id: NCT02209610
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
A hallmark of patients with heart failure (HF) is premature fatigue which impairs their
      quality of life and depicts a major source of morbidity. Premature fatigue may be attributed
      to a) contraction-induced transient changes within muscles (i.e. peripheral fatigue) and/or
      b) failure of the central nervous system to 'drive' / activate locomotor muscles (i.e.
      central fatigue). Both determinants of fatigue can lead to a reduction in a muscle's force
      and power generating capacity and to a compromised ability to perform whole body activities
      (e.g. walking). Recent findings in health have documented that group III/IV afferent fibers
      from the working muscle play a critical role in the development of both components of
      fatigue. Specifically, group III/IV muscle afferents limit central motor drive (CMD) during
      exercise and thereby exaggerate the development of central fatigue. In contrast, muscle
      afferents optimize muscle O2 delivery through the precise regulation of circulation and
      ventilation during exercise and thereby attenuate the development of peripheral fatigue.
Recent findings in HF suggest an altered effect of group III/IV muscle afferents in this
      population. Although normal afferent feedback is crucial for adequate O2 delivery during
      exercise, excessive neural feedback has substantial negative consequences. HF patients are
      characterized by augmented neural feedback arising from overactive muscle afferents. It has
      been hypothesized that this abnormality compromises locomotor muscle O2 delivery in these
      patients. Therefore, the abnormally elevated muscle afferent feedback in HF might exacerbate,
      compared to healthy age- and activity matched individuals (CTRLs), the development of both
      peripheral (via limiting O2 delivery) and central (via restricting CMD) fatigue during
      exercise. Recent advances in non-invasive stimulation techniques offer a genuine opportunity
      to identify the sites and synaptic mechanisms that mediate central and peripheral fatigue
      including alterations in the responsiveness of the corticospinal tract (i.e. a determinant of
      central fatigue). Taken together, the proposed studies aim to determine the impact of HF on
      the precise development of central and peripheral fatigue during both whole body and single
      muscle exercise and evaluate the extent to which group III/IV muscle afferents contribute to
      this development.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Single (Participant)
measure: Maximal Voluntary Quadriceps Force [% Change From Baseline]
time frame: 1 minute after exercise on study day
description: Following dynamic single leg knee extension exercise for a given duration (4-8 min), the decline in maximal voluntary contraction force will be measured.
measure: Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)
time frame: During (20 second intervals) and 1 minute after exercise on study day
description: During a 2-min maximal voluntary quadriceps contraction, central and peripheral fatigue will develop progressively and significantly more in HF vs. CTRLs.
measure: Muscle Afferent Affect
time frame: 1 minute after exercise on study day
description: Corticospinal responsiveness will be quantified before and after exercise.
arm group label: Patients With Heart Failure: Neuromuscular Abnormalities
arm group type: Other
description: Patients with Heart Failure
arm group label: Health Control Subjects and Neuromuscular Function
arm group type: Other
description: Health Control Subjects
intervention type: Device
intervention name: Electrical and Magnetic Nerve Stimulators
description: Stimulation of motor nerve and central nervous system
arm group label: Health Control Subjects and Neuromuscular Function
arm group label: Patients With Heart Failure: Neuromuscular Abnormalities
intervention type: Drug
intervention name: Intrathecal Fentanyl
description: Mu-opioid receptor agonist
arm group label: Health Control Subjects and Neuromuscular Function
arm group label: Patients With Heart Failure: Neuromuscular Abnormalities
criteria: 
gender: All
minimum age: 20 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Markus Amann, PhD
role: Principal Investigator
affiliation: VA Salt Lake City Health Care System, Salt Lake City, UT
facility: 
country: United States
citation: Ives SJ, Amann M, Venturelli M, Witman MA, Groot HJ, Wray DW, Morgan DE, Stehlik J, Richardson RS. The Mechanoreflex and Hemodynamic Response to Passive Leg Movement in Heart Failure. Med Sci Sports Exerc. 2016 Mar;48(3):368-76. doi: 10.1249/MSS.0000000000000782.
PMID: 26418560
citation: Sidhu SK, Weavil JC, Venturelli M, Rossman MJ, Gmelch BS, Bledsoe AD, Richardson RS, Amann M. Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans. Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1479-89. doi: 10.1152/ajpheart.00433.2015. Epub 2015 Sep 18.
PMID: 26386110
citation: Weavil JC, Sidhu SK, Mangum TS, Richardson RS, Amann M. Fatigue diminishes motoneuronal excitability during cycling exercise. J Neurophysiol. 2016 Oct 1;116(4):1743-1751. doi: 10.1152/jn.00300.2016. Epub 2016 Jul 20.
PMID: 27440242
citation: Amann M, Sidhu SK, Weavil JC, Mangum TS, Venturelli M. Autonomic responses to exercise: group III/IV muscle afferents and fatigue. Auton Neurosci. 2015 Mar;188:19-23. doi: 10.1016/j.autneu.2014.10.018. Epub 2014 Oct 23.
PMID: 25458423
citation: Wray DW, Amann M, Richardson RS. Peripheral vascular function, oxygen delivery and utilization: the impact of oxidative stress in aging and heart failure with reduced ejection fraction. Heart Fail Rev. 2017 Mar;22(2):149-166. doi: 10.1007/s10741-016-9573-4.
PMID: 27392715
responsible party type: Sponsor
mesh term: Heart Failure
mesh term: Fentanyl
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 