<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/NCT02247245</url>
  </required_header>
  <id_info>
    <org_study_id>LIGHT-TREPPE-1</org_study_id>
    <nct_id>NCT02247245</nct_id>
  </id_info>
  <brief_title>The Influence of Heart Rate Limitation on Exercise Tolerance in Pacemaker Patients.</brief_title>
  <acronym>TREPPE</acronym>
  <official_title>The Influence of Iatrogenic Chronotropic Incompetence on Exercise Tolerance in Pacemaker Patients With Chronic Heart Failure.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Leeds</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Leeds</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To examine the effects of heart rate reduction on exercise capacity in control subjects and&#xD;
      patients with chronic heart failure.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Original proposal: Does iatrogenic chronotropic incompetence lead to impaired exercise&#xD;
      capacity in patients with CHF&#xD;
&#xD;
      Aim The aim of this proposal is to examine the effects of iatrogenic CI on exercise capacity&#xD;
      in control subjects and patients with chronic heart failure.&#xD;
&#xD;
      Hypothesis Iatrogenic chronotropic incompetence does not contribute significantly to&#xD;
      reductions in exercise capacity in patients with heart failure or control subjects with&#xD;
      pacemakers.&#xD;
&#xD;
      Methods REDUCING HEART RATE AT REST AND EXERCISE In patients with sinus rhythm, the present&#xD;
      proposal utilizes a heart failure medication called ivabradine. This agent, an If channel&#xD;
      blocker, specifically targets the sinus node leading to a slower heart rate. The agent is&#xD;
      approved and licensed for use in patients with heart failure at the doses proposed.&#xD;
      Ivabradine slows the sinus rate with none of the peripheral effects of beta-blockers. Heart&#xD;
      rate lowering with ivabradine improves cardiac function, and outcomes related to the degree&#xD;
      of bradycardia achieved.&#xD;
&#xD;
      In patients with atrial fibrillation, the present proposal will recruit patients with CRT and&#xD;
      atrial fibrillation that have undergone atrio-ventricular node (AVN) ablation to improve the&#xD;
      efficacy of CRT. Patients who have undergone AVN ablation are dependent upon their pacemaker,&#xD;
      and we can therefore control their heart rate accurately.&#xD;
&#xD;
      SUBJECT SELECTION Inclusion criteria We will only include patients able to give informed&#xD;
      written consent, which will be obtained in all subjects, and those capable of performing a&#xD;
      peak exercise test. Since we are performing the study on three groups of patients, further&#xD;
      inclusion criteria for each group are outlined below.&#xD;
&#xD;
      Inclusion criteria - CRT-sinus rhythm group We will enrol 25 patients with severe CHF on&#xD;
      otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation&#xD;
      therapy at least 3 months previously. These individuals will be on optimal medical therapy&#xD;
      for their heart failure with no change in medication or exacerbation for the preceding 3&#xD;
      months. They will not currently be taking ivabradine.&#xD;
&#xD;
      Inclusion criteria - CRT-atrial fibrillation group We will enrol 25 patients with severe CHF&#xD;
      on otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation&#xD;
      therapy at least 3 months previously. All patients will be previously pacemaker dependant or&#xD;
      have 'blocked' atrial fibrillation either due to medical therapy or previous&#xD;
      atrio-ventricular nodal ablation.&#xD;
&#xD;
      Inclusion criteria - control group The control subjects (n=25) will be recruited from the&#xD;
      general pacemaker clinic. They will undergo echocardiography to exclude structural heart&#xD;
      disease. They will have no contraindications to exercise testing or ivabradine.&#xD;
&#xD;
      Exclusion criteria We will exclude subjects with musculoskeletal disorders limiting exercise&#xD;
      capacity, patients with peripheral vascular disease, those with inflammatory disorders such&#xD;
      as rheumatoid arthritis, and airways disease. Other exclusions include contraindications to&#xD;
      ivabradine use such as severe hepatic impairment, significant renal impairment (creatinine&#xD;
      clearance &lt;15ml.min-1), and long QT syndrome. We will only include patients able to give&#xD;
      informed written consent, which will be obtained in all subjects.&#xD;
&#xD;
      ECHOCARDIOGRAPHY Each subject will undergo a full echocardiographic examination. The images&#xD;
      will be stored on a commercially available database, (Echopac PC, GE-Vingmed, USA) and&#xD;
      analysed offline. We will assess LV systolic and diastolic function variables, mitral&#xD;
      regurgitation, and pulmonary artery pressure.&#xD;
&#xD;
      EXERCISE TESTING Patients will describe their own NYHA symptom class at the beginning of each&#xD;
      exercise session. Each individual will be invited for a familiarization test once agreeing to&#xD;
      the study. At least one week following the familiarization test, heart failure patients and&#xD;
      controls will return to the exercise laboratory and will be randomised to either ivabradine&#xD;
      (7.5mg) or placebo. The following week they will return for the second arm. The randomization&#xD;
      will be carried out in pharmacy to ensure blinding of the subject, the technician and the&#xD;
      investigator. After ingesting the capsule, the subject will be asked to wait for an hour&#xD;
      before the exercise test commences.&#xD;
&#xD;
      Prior to the start of exercise, patients' devices will be programmed to a base rate of 40&#xD;
      bts/min and they will then be they will be randomised to have their device programmed to&#xD;
      either rate response on or off. A screen will separate the electrocardiographic monitor,&#xD;
      which will be observed by the unblinded technician, from the metabolic cart, which will be&#xD;
      observed by the blinded physician. The following week the other mode will be activated. At&#xD;
      the end of each test the device will be returned to its original setting.&#xD;
&#xD;
      For the treadmill tests we will use the Bruce protocol modified by the addition of a 'stage&#xD;
      0' at onset consisting of 3 minutes of exercise at 1.61km/hr (1mile/hour) with a 5% gradient.&#xD;
      During each test, expired air will be collected continuously and metabolic gas exchange&#xD;
      analysis performed (Vmax 29, Sensormedics, USA). The system will be recalibrated prior to&#xD;
      each test. Subjects will be encouraged to exercise to exhaustion, and a respiratory exchange&#xD;
      ratio (RER), (VCO2/VO2) greater than 1.1 will be taken to suggest a maximal effort. The&#xD;
      anaerobic threshold for each test will be calculated using the VO2/VCO2 slope method. At the&#xD;
      end of each stage and at peak exercise subjects will be asked to indicate their score for&#xD;
      dyspnoea or fatigue on a scale from 0 (no symptoms) to 10 (maximal symptoms) using the&#xD;
      standardised Borg scoring system. The slope relating symptom scores against ventilation&#xD;
      (Borg/VE) for each subject can then be plotted. We will also examine other ventilatory&#xD;
      variables such as tidal volume (VT) and frequency (f) of ventilation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">September 2015</completion_date>
  <primary_completion_date type="Actual">September 2015</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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximal Oxygen Consumption (Peak VO2)</measure>
    <time_frame>Each test lasts up to 20 minutes</time_frame>
    <description>Cardiopulmonary exercise testing performance - measuring peak oxygen uptake during a treadmill CPEX test.&#xD;
Subjects were exercised using the Bruce protocol, modified by the addition of a &quot;stage 0&quot; at onset consisting of 3 min of exercise at 1.61 km·h-1 (1 mile·h-1) with a 5% gradient. Expired air was collected and metabolic gas exchange analysis performed in order to measure the maximal oxygen consumption (peak VO2) (Sensormedics, Yorba Linda, California).&#xD;
The CPX equipment was recalibrated before every exercise test. All test subjects were encouraged to exercise to exhaustion before starting the test, and no further motivation or instructions were given.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Chronic Heart Failure</condition>
  <condition>Atrial Fibrillation</condition>
  <condition>Arrhythmia, Sinus</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects are given a placebo capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ivabradine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects are given an ivabradine capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atrial fibrillation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algortithms switched on.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ivabradine</intervention_name>
    <description>Ivabradine 7.5mg</description>
    <arm_group_label>Ivabradine</arm_group_label>
    <other_name>Precorolan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Atrial fibrillation</intervention_name>
    <description>Pacemaker base rate alteration</description>
    <arm_group_label>Atrial fibrillation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        We will only include patients able to give informed written consent, which will be obtained&#xD;
        in all subjects, and those capable of performing a peak exercise test. Since we are&#xD;
        performing the study on three groups of patients, further inclusion criteria for each group&#xD;
        are outlined below.&#xD;
&#xD;
        Inclusion criteria - CRT-sinus rhythm group We will enrol 25 patients with severe CHF on&#xD;
        otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation&#xD;
        therapy at least 3 months previously. These individuals will be on optimal medical therapy&#xD;
        for their heart failure with no change in medication or exacerbation for the preceding 3&#xD;
        months. They will not currently be taking ivabradine.&#xD;
&#xD;
        Inclusion criteria - CRT-atrial fibrillation group We will enrol 25 patients with severe&#xD;
        CHF on otherwise optimally tolerated medical therapy who have undergone cardiac&#xD;
        resynchronisation therapy at least 3 months previously. All patients will be previously&#xD;
        pacemaker dependant or have 'blocked' atrial fibrillation either due to medical therapy or&#xD;
        previous atrio-ventricular nodal ablation.&#xD;
&#xD;
        Inclusion criteria - control group The control subjects (n=25) will be recruited from the&#xD;
        general pacemaker clinic. They will undergo echocardiography to exclude structural heart&#xD;
        disease. They will have no contraindications to exercise testing or ivabradine.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        We will exclude subjects with musculoskeletal disorders limiting exercise capacity,&#xD;
        patients with peripheral vascular disease, those with inflammatory disorders such as&#xD;
        rheumatoid arthritis, and airways disease. Other exclusions include contraindications to&#xD;
        ivabradine use such as severe hepatic impairment, significant renal impairment (creatinine&#xD;
        clearance &lt;15ml.min-1), and long QT syndrome. We will only include patients able to give&#xD;
        informed written consent, which will be obtained in all subjects.&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Klaus K Witte, FRCP MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Leeds</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Haqeel A Jamil, MbChB MRCP</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Leeds</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Leeds Institute of Cardiovascular and Metabolic Medicine</name>
      <address>
        <city>Leeds</city>
        <state>West Yorkshire</state>
        <zip>LS13ex</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>September 19, 2014</study_first_submitted>
  <study_first_submitted_qc>September 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 23, 2014</study_first_posted>
  <results_first_submitted>May 19, 2019</results_first_submitted>
  <results_first_submitted_qc>December 9, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">January 2, 2020</results_first_posted>
  <last_update_submitted>December 9, 2019</last_update_submitted>
  <last_update_submitted_qc>December 9, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 2, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Leeds</investigator_affiliation>
    <investigator_full_name>Haqeel Jamil</investigator_full_name>
    <investigator_title>Cardiology Registrar and Clinical Research Fellow</investigator_title>
  </responsible_party>
  <keyword>CHF</keyword>
  <keyword>AF</keyword>
  <keyword>SR</keyword>
  <keyword>HFREF</keyword>
  <keyword>CRT</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Atrial Fibrillation</mesh_term>
    <mesh_term>Arrhythmia, Sinus</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>The predicted group size to demonstrate a clinically important change was revised after post hoc analysis of pilot data demonstrating higher pVO2 values for both SR and AF than expected (minimum requirements:12 subjects in AF group, 20 in SR group). To allow for dropouts, recruitment targets were altered 14 with AF and 26 with SR (total 40).</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo First</title>
          <description>Subjects are given a placebo capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Placebo: Placebo&#xD;
n=13 Placebo first, washout 1 week, then Ivabradine 7.5mg</description>
        </group>
        <group group_id="P2">
          <title>Ivabradine First</title>
          <description>Subjects are given an ivabradine capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Ivabradine: Ivabradine 7.5mg&#xD;
Ivabradine 7.5mg first, washout 1 week, then placebo</description>
        </group>
        <group group_id="P3">
          <title>Atrial Fibrillation (Low Rate)</title>
          <description>Atrial fibrillation with pacemaker base rate alteration: Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algortithms switched on.</description>
        </group>
        <group group_id="P4">
          <title>Atrial Fibrillation (Standard Rate)</title>
          <description>Atrial fibrillation with pacemaker base rate alteration: Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algortithms switched on.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="13"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="13"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Placebo First</title>
          <description>Subjects are given a placebo capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Placebo: Placebo</description>
        </group>
        <group group_id="B2">
          <title>Ivabradine First</title>
          <description>Subjects are given an ivabradine capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Ivabradine: Ivabradine 7.5mg</description>
        </group>
        <group group_id="B3">
          <title>Atrial Fibrillation (Low Rate)</title>
          <description>Atrial fibrillation with pacemaker base rate alteration: Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algortithms switched on.&#xD;
This group - low base pacing rate (30)</description>
        </group>
        <group group_id="B4">
          <title>Atrial Fibrilaltion (Standard Rate)</title>
          <description>Atrial fibrillation with pacemaker base rate alteration: Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algortithms switched on.&#xD;
This group - standard base pacing rate (60)</description>
        </group>
        <group group_id="B5">
          <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="13"/>
            <count group_id="B2" value="13"/>
            <count group_id="B3" value="7"/>
            <count group_id="B4" value="7"/>
            <count group_id="B5" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="13"/>
                    <count group_id="B3" value="7"/>
                    <count group_id="B4" value="7"/>
                    <count group_id="B5" value="40"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="74" spread="9"/>
                    <measurement group_id="B2" value="74" spread="9"/>
                    <measurement group_id="B3" value="76" spread="10"/>
                    <measurement group_id="B4" value="76" spread="10"/>
                    <measurement group_id="B5" value="74" spread="9"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="13"/>
                    <count group_id="B3" value="7"/>
                    <count group_id="B4" value="7"/>
                    <count group_id="B5" value="40"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="5"/>
                    <measurement group_id="B5" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                    <count group_id="B4" value="0"/>
                    <count group_id="B5" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="13"/>
                    <count group_id="B3" value="7"/>
                    <count group_id="B4" value="7"/>
                    <count group_id="B5" value="40"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="7"/>
                    <measurement group_id="B5" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>New York Heart Association classification</title>
          <description>NYHA Stages of Heart Failure:&#xD;
Class 1 - No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc.&#xD;
Class 2 - Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity.&#xD;
Class 3 - Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m).Comfortable only at rest.&#xD;
Class 4 - Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.&#xD;
Higher class = worse outcomes</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="13"/>
                    <count group_id="B3" value="7"/>
                    <count group_id="B4" value="7"/>
                    <count group_id="B5" value="40"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2" lower_limit="1" upper_limit="3"/>
                    <measurement group_id="B2" value="2" lower_limit="1" upper_limit="3"/>
                    <measurement group_id="B3" value="2" lower_limit="1" upper_limit="3"/>
                    <measurement group_id="B4" value="2" lower_limit="1" upper_limit="3"/>
                    <measurement group_id="B5" value="2" lower_limit="1" upper_limit="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximal Oxygen Consumption (Peak VO2)</title>
        <description>Cardiopulmonary exercise testing performance - measuring peak oxygen uptake during a treadmill CPEX test.&#xD;
Subjects were exercised using the Bruce protocol, modified by the addition of a &quot;stage 0&quot; at onset consisting of 3 min of exercise at 1.61 km·h-1 (1 mile·h-1) with a 5% gradient. Expired air was collected and metabolic gas exchange analysis performed in order to measure the maximal oxygen consumption (peak VO2) (Sensormedics, Yorba Linda, California).&#xD;
The CPX equipment was recalibrated before every exercise test. All test subjects were encouraged to exercise to exhaustion before starting the test, and no further motivation or instructions were given.</description>
        <time_frame>Each test lasts up to 20 minutes</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Subjects are given a placebo capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Placebo: Placebo</description>
          </group>
          <group group_id="O2">
            <title>Ivabradine</title>
            <description>Subjects are given an ivabradine capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Ivabradine: Ivabradine 7.5mg</description>
          </group>
          <group group_id="O3">
            <title>Atrial Fibrillation: Low Base Rate (+no Rate Adaptive Pacing)</title>
            <description>Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algorithms switched on.&#xD;
Atrial fibrillation: Pacemaker base rate alteration</description>
          </group>
          <group group_id="O4">
            <title>Atrial Fibrn: Standard Base Rate (+Rate Adaptive Pacing)</title>
            <description>Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algortithms switched on.&#xD;
Atrial fibrillation: Pacemaker base rate alteration</description>
          </group>
        </group_list>
        <measure>
          <title>Maximal Oxygen Consumption (Peak VO2)</title>
          <description>Cardiopulmonary exercise testing performance - measuring peak oxygen uptake during a treadmill CPEX test.&#xD;
Subjects were exercised using the Bruce protocol, modified by the addition of a &quot;stage 0&quot; at onset consisting of 3 min of exercise at 1.61 km·h-1 (1 mile·h-1) with a 5% gradient. Expired air was collected and metabolic gas exchange analysis performed in order to measure the maximal oxygen consumption (peak VO2) (Sensormedics, Yorba Linda, California).&#xD;
The CPX equipment was recalibrated before every exercise test. All test subjects were encouraged to exercise to exhaustion before starting the test, and no further motivation or instructions were given.</description>
          <units>ml/kg/min</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
                <count group_id="O3" value="7"/>
                <count group_id="O4" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16" spread="3"/>
                    <measurement group_id="O2" value="17" spread="3"/>
                    <measurement group_id="O3" value="15.3" spread="1.9"/>
                    <measurement group_id="O4" value="14.2" spread="2.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 weeks: immediate/early complications post intervention</time_frame>
      <desc>All-cause mortality, serious adverse events, non-serious/other adverse events</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Subjects are given a placebo capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Placebo: Placebo</description>
        </group>
        <group group_id="E2">
          <title>Ivabradine</title>
          <description>Subjects are given an ivabradine capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.&#xD;
Ivabradine: Ivabradine 7.5mg</description>
        </group>
        <group group_id="E3">
          <title>Atrial Fibrillation (Low Rate)</title>
          <description>Subjects are (double blind) randomised to a low base pacing rate (30) with rate adaptive algortithms switched on.</description>
        </group>
        <group group_id="E4">
          <title>Atrial Fibrilaltion (Standard Rate)</title>
          <description>Subjects are (double blind) randomised to a standard base pacing rate (60) with rate adaptive algortithms switched on.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="7"/>
              </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="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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 Haqeel Jamil</name_or_title>
      <organization>University of Leeds</organization>
      <phone>0113 343 3241</phone>
      <email>haqeel.jamil@nhs.net</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/NCT02247245
org study id: LIGHT-TREPPE-1
nct id: NCT02247245
lead sponsor: 
has dmc: No
To examine the effects of heart rate reduction on exercise capacity in control subjects and
      patients with chronic heart failure.
Original proposal: Does iatrogenic chronotropic incompetence lead to impaired exercise
      capacity in patients with CHF

      Aim The aim of this proposal is to examine the effects of iatrogenic CI on exercise capacity
      in control subjects and patients with chronic heart failure.

      Hypothesis Iatrogenic chronotropic incompetence does not contribute significantly to
      reductions in exercise capacity in patients with heart failure or control subjects with
      pacemakers.

      Methods REDUCING HEART RATE AT REST AND EXERCISE In patients with sinus rhythm, the present
      proposal utilizes a heart failure medication called ivabradine. This agent, an If channel
      blocker, specifically targets the sinus node leading to a slower heart rate. The agent is
      approved and licensed for use in patients with heart failure at the doses proposed.
      Ivabradine slows the sinus rate with none of the peripheral effects of beta-blockers. Heart
      rate lowering with ivabradine improves cardiac function, and outcomes related to the degree
      of bradycardia achieved.

      In patients with atrial fibrillation, the present proposal will recruit patients with CRT and
      atrial fibrillation that have undergone atrio-ventricular node (AVN) ablation to improve the
      efficacy of CRT. Patients who have undergone AVN ablation are dependent upon their pacemaker,
      and we can therefore control their heart rate accurately.

      SUBJECT SELECTION Inclusion criteria We will only include patients able to give informed
      written consent, which will be obtained in all subjects, and those capable of performing a
      peak exercise test. Since we are performing the study on three groups of patients, further
      inclusion criteria for each group are outlined below.

      Inclusion criteria - CRT-sinus rhythm group We will enrol 25 patients with severe CHF on
      otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation
      therapy at least 3 months previously. These individuals will be on optimal medical therapy
      for their heart failure with no change in medication or exacerbation for the preceding 3
      months. They will not currently be taking ivabradine.

      Inclusion criteria - CRT-atrial fibrillation group We will enrol 25 patients with severe CHF
      on otherwise optimally tolerated medical therapy who have undergone cardiac resynchronisation
      therapy at least 3 months previously. All patients will be previously pacemaker dependant or
      have 'blocked' atrial fibrillation either due to medical therapy or previous
      atrio-ventricular nodal ablation.

      Inclusion criteria - control group The control subjects (n=25) will be recruited from the
      general pacemaker clinic. They will undergo echocardiography to exclude structural heart
      disease. They will have no contraindications to exercise testing or ivabradine.

      Exclusion criteria We will exclude subjects with musculoskeletal disorders limiting exercise
      capacity, patients with peripheral vascular disease, those with inflammatory disorders such
      as rheumatoid arthritis, and airways disease. Other exclusions include contraindications to
      ivabradine use such as severe hepatic impairment, significant renal impairment (creatinine
      clearance <15ml.min-1), and long QT syndrome. We will only include patients able to give
      informed written consent, which will be obtained in all subjects.

      ECHOCARDIOGRAPHY Each subject will undergo a full echocardiographic examination. The images
      will be stored on a commercially available database, (Echopac PC, GE-Vingmed, USA) and
      analysed offline. We will assess LV systolic and diastolic function variables, mitral
      regurgitation, and pulmonary artery pressure.

      EXERCISE TESTING Patients will describe their own NYHA symptom class at the beginning of each
      exercise session. Each individual will be invited for a familiarization test once agreeing to
      the study. At least one week following the familiarization test, heart failure patients and
      controls will return to the exercise laboratory and will be randomised to either ivabradine
      (7.5mg) or placebo. The following week they will return for the second arm. The randomization
      will be carried out in pharmacy to ensure blinding of the subject, the technician and the
      investigator. After ingesting the capsule, the subject will be asked to wait for an hour
      before the exercise test commences.

      Prior to the start of exercise, patients' devices will be programmed to a base rate of 40
      bts/min and they will then be they will be randomised to have their device programmed to
      either rate response on or off. A screen will separate the electrocardiographic monitor,
      which will be observed by the unblinded technician, from the metabolic cart, which will be
      observed by the blinded physician. The following week the other mode will be activated. At
      the end of each test the device will be returned to its original setting.

      For the treadmill tests we will use the Bruce protocol modified by the addition of a 'stage
      0' at onset consisting of 3 minutes of exercise at 1.61km/hr (1mile/hour) with a 5% gradient.
      During each test, expired air will be collected continuously and metabolic gas exchange
      analysis performed (Vmax 29, Sensormedics, USA). The system will be recalibrated prior to
      each test. Subjects will be encouraged to exercise to exhaustion, and a respiratory exchange
      ratio (RER), (VCO2/VO2) greater than 1.1 will be taken to suggest a maximal effort. The
      anaerobic threshold for each test will be calculated using the VO2/VCO2 slope method. At the
      end of each stage and at peak exercise subjects will be asked to indicate their score for
      dyspnoea or fatigue on a scale from 0 (no symptoms) to 10 (maximal symptoms) using the
      standardised Borg scoring system. The slope relating symptom scores against ventilation
      (Borg/VE) for each subject can then be plotted. We will also examine other ventilatory
      variables such as tidal volume (VT) and frequency (f) of ventilation.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Maximal Oxygen Consumption (Peak VO2)
time frame: Each test lasts up to 20 minutes
description: Cardiopulmonary exercise testing performance - measuring peak oxygen uptake during a treadmill CPEX test.
Subjects were exercised using the Bruce protocol, modified by the addition of a "stage 0" at onset consisting of 3 min of exercise at 1.61 km·h-1 (1 mile·h-1) with a 5% gradient. Expired air was collected and metabolic gas exchange analysis performed in order to measure the maximal oxygen consumption (peak VO2) (Sensormedics, Yorba Linda, California).
The CPX equipment was recalibrated before every exercise test. All test subjects were encouraged to exercise to exhaustion before starting the test, and no further motivation or instructions were given.
arm group label: Placebo
arm group type: Placebo Comparator
description: Subjects are given a placebo capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.
arm group label: Ivabradine
arm group type: Active Comparator
description: Subjects are given an ivabradine capsule (double-blinded) to take 90 minutes prior to the cardiopulmonary exercise test.
arm group label: Atrial fibrillation
arm group type: Experimental
description: Subjects are (double blind) randomised to either a low base pacing rate (30) or a standard base rate (60), with rate adaptive algortithms switched on.
intervention type: Drug
intervention name: Ivabradine
description: Ivabradine 7.5mg
arm group label: Ivabradine
other name: Precorolan
intervention type: Other
intervention name: Atrial fibrillation
description: Pacemaker base rate alteration
arm group label: Atrial fibrillation
intervention type: Drug
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Klaus K Witte, FRCP MD
role: Principal Investigator
affiliation: University of Leeds
last name: Haqeel A Jamil, MbChB MRCP
role: Principal Investigator
affiliation: University of Leeds
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: University of Leeds
investigator full name: Haqeel Jamil
investigator title: Cardiology Registrar and Clinical Research Fellow
mesh term: Heart Failure
mesh term: Atrial Fibrillation
mesh term: Arrhythmia, Sinus
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 