<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/NCT04426578</url>
  </required_header>
  <id_info>
    <org_study_id>HCM2020-01</org_study_id>
    <nct_id>NCT04426578</nct_id>
  </id_info>
  <brief_title>Role of Perhexiline in Hypertrophic Cardiomyopathy</brief_title>
  <acronym>RESOLVE-HCM</acronym>
  <official_title>Randomised Controlled Trial of pErhexiline on regreSsion Of Left Ventricular hypErtrophy (LVH) in Patients With Symptomatic Hypertrophic CardioMyopathy (RESOLVE-HCM)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Flinders University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Flinders University</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart muscle condition&#xD;
      affecting up to 1 in 200 of the general population. It results from mutations in genes&#xD;
      encoding components of the contractile apparatus in the heart muscle cell (myocyte). These&#xD;
      mutations result in increased energy cost of force production for the myocyte which then&#xD;
      cumulatively causes a myocardial energy deficit. This myocardial energy deficit is then&#xD;
      thought to lead to cardiac hypertrophy ('left ventricular hypertrophy' or LVH) in HCM.&#xD;
&#xD;
      LVH leads to impairments in heart muscle function, heart muscle oxygenation and microvascular&#xD;
      blood flow and is the chief driver of patient symptoms in HCM. These symptoms consist of&#xD;
      chest pain, shortness of breath, dizziness, fainting episodes or palpitations. Occasionally,&#xD;
      the disease may cause sudden cardiac death (SCD). HCM is the most common cause of SCD in&#xD;
      young people including competitive athletes. In addition, HCM has been found to result in&#xD;
      significant global deterioration in health-related quality of life.&#xD;
&#xD;
      Treatment of HCM has focused on relief of symptoms by drugs such as ß-blockers which slow the&#xD;
      heart rate and improve heart function. However, symptom relief is often incomplete and there&#xD;
      is no evidence on the benefit of ß-blockers or related medications to reverse LVH.&#xD;
      Perhexiline, a potent carnitine palmitoyl transferase-1 (CPT-1) inhibitor shifts myocardial&#xD;
      metabolism to more efficient glucose utilisation and rectifies impaired myocardial&#xD;
      energetics. It is currently used to treat angina in patients with coronary artery disease.&#xD;
      There is some preliminary evidence that Perhexiline may aid in the improvement of symptoms in&#xD;
      patients with HCM. However, the effect of any form of therapy on potential regression of LVH&#xD;
      in HCM remains unexplored.&#xD;
&#xD;
      In this randomised double-blind placebo-controlled trial, the investigators will use state of&#xD;
      the art cardiac imaging, principally advanced echocardiography and Cardiovascular Magnetic&#xD;
      Resonance (CMR) to study the effects of perhexiline on LVH, cardiac function, and oxygenation&#xD;
      in symptomatic patients with HCM. The investigators hypothesize that perhexiline will&#xD;
      favourably reduce LVH and improve myocardial oxygenation by improving myocardial energetics,&#xD;
      and that these putative morphological and functional changes can be accurately measured&#xD;
      utilizing echocardiography and CMR. If this pilot study supports the hypothesis, then it will&#xD;
      pave the way for a major randomised controlled trial to definitely determine the role of&#xD;
      Perhexiline in HCM.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 1, 2020</start_date>
  <completion_date type="Anticipated">August 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2022</primary_completion_date>
  <phase>Phase 2</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>Change in Left Ventricular Hypertrophy (LVH)</measure>
    <time_frame>12 months post baseline</time_frame>
    <description>Change in LVH (septal thickness) in symptomatic at 12 months following perhexiline therapy in HCM patients assessed by CMR</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Left Ventricular (LV) mass</measure>
    <time_frame>12 months post baseline</time_frame>
    <description>Change in left ventricular mass in symptomatic at 12 months following perhexiline therapy in HCM patients assessed by CMR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in oxygen-sensitive Cardiac Magnetic Resonance</measure>
    <time_frame>12 months post baseline</time_frame>
    <description>Change in oxygen-sensitive CMR in symptomatic at 12 months following perhexiline therapy in HCM patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular diastolic function</measure>
    <time_frame>12 months post baseline</time_frame>
    <description>Change in left ventricular diastolic function at 12 months following perhexiline therapy in HCM patients assessed by echocardiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New York Heart Association (NYHA) functional classification</measure>
    <time_frame>12 months post baseline</time_frame>
    <description>Change in NYHA classification of Class I, II, III and IV at 12 months following perhexiline therapy in HCM patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Canadian Cardiovascular Society (CCS) functional class</measure>
    <time_frame>12 months post baseline</time_frame>
    <description>Change in CCS functional classification of Grade I, II, III and IV at 12 months following perhexiline therapy in HCM patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life assessment</measure>
    <time_frame>12 months post baseline</time_frame>
    <description>Change in physical activity domain score of Short Form 36 Health Survey Questionnaire (SF36) at 12 months following perhexiline therapy in HCM patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major adverse event on heart failure related hospitalisations</measure>
    <time_frame>Monitored over the 12 months period</time_frame>
    <description>HCM patients admitted with heart failure during the study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major adverse event on arrhythmic events</measure>
    <time_frame>Monitored over the 12 months period</time_frame>
    <description>HCM patients admitted with arrhythmic events during the study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major adverse event on abnormal liver function test</measure>
    <time_frame>Liver function tests at baseline, 1 month, 6 months and 12 months</time_frame>
    <description>HCM patients with abnormal liver function tests during the study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major adverse event on sudden cardiac death</measure>
    <time_frame>Monitored over the 12 months period</time_frame>
    <description>HCM patients with sudden cardiac death during the study period</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Hypertrophic Cardiomyopathy</condition>
  <arm_group>
    <arm_group_label>Perhexiline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Perhexiline</intervention_name>
    <description>All eligible and consented patients will be randomised to initiation of perhexiline 100mg once daily or identical placebo. After 4 days of treatment, a blood sample will be collected to determine plasma perhexiline concentrations: timing of the sample need not be &quot;trough&quot; in view of the long-acting nature of perhexiline. Depending on the blood results, patients might require as little as 50mg/week (slow metabolisers) or as much as 600mg/day (ultra-rapid metabolisers). The initial sample will be utilized primarily to detect presence of hydroxylated metabolite: patients in whom perhexiline is detected in the absence of metabolite will be designated &quot;slow metabolisers&quot; and will have their dosage reduced to 50 mg/week in the first instance. Repeat assay at 30 days will be utilized for individual finer dose titration based on dose adjustment table. Paired dosage adjustment in placebo-treated patients will be performed to avoid unblinding.&#xD;
Compliance will be assessed by capsule count.</description>
    <arm_group_label>Perhexiline</arm_group_label>
    <other_name>Pexsig</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>All eligible and consented patients will be randomised to initiation of perhexiline 100mg once daily or identical placebo. After 4 days of treatment, a blood sample will be collected to determine plasma perhexiline concentrations: timing of the sample need not be &quot;trough&quot; in view of the long-acting nature of perhexiline. Depending on the blood results, patients might require as little as 50mg/week (slow metabolisers) or as much as 600mg/day (ultra-rapid metabolisers). The initial sample will be utilized primarily to detect presence of hydroxylated metabolite: patients in whom perhexiline is detected in the absence of metabolite will be designated &quot;slow metabolisers&quot; and will have their dosage reduced to 50 mg/week in the first instance. Repeat assay at 30 days will be utilized for individual finer dose titration based on dose adjustment table. Paired dosage adjustment in placebo-treated patients will be performed to avoid unblinding.&#xD;
Compliance will be assessed by capsule count.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Left Ventricular Ejection Fraction (LVEF) =/&gt; 55% by echocardiography or CMR during&#xD;
             the screening period or within 6 months prior to study entry&#xD;
&#xD;
          2. Current / prior symptom(s) of HCM (New York Heart Association [NYHA] functional class&#xD;
             II or class III, Canadian Cardiovascular Society [CCS] grade II or grade III) and&#xD;
             requiring treatment with ß-blockers and /or non-dihydropyridine calcium antagonists&#xD;
             and / or disopyramide for at least 30 days prior to study entry&#xD;
&#xD;
          3. Structural heart disease as evidenced by interventricular septal thickness of (= 15&#xD;
             mm) on echocardiography or CMR in the absence of abnormal loading conditions&#xD;
&#xD;
          4. Elevated N terminal pro-brain natriuretic peptide (NT-proBNP), &gt;125 pg/ml&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any prior echocardiographic or CMR measurement of LVEF &lt;55%&#xD;
&#xD;
          2. Current acute decompensated heart failure requiring hospitalisation and / or augmented&#xD;
             medical therapy&#xD;
&#xD;
          3. Cardiac surgery or catheter-based septal reduction therapy planned or having occurred&#xD;
             within the past 1 year&#xD;
&#xD;
          4. Patients with a non-CMR conditional pacemaker / implantable cardioverter-defibrillator&#xD;
             device&#xD;
&#xD;
          5. History of a known chronic liver disease, peripheral neuropathy, recurrent&#xD;
             hypoglycemia&#xD;
&#xD;
          6. Serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline&#xD;
             phosphatase, or lactate dehydrogenase &gt; 2.0 times upper limit of normal&#xD;
&#xD;
          7. Previous adverse reaction to perhexiline at therapeutic plasma levels of the drug&#xD;
&#xD;
          8. Concomitant use of amiodarone, ranolazine or trimetazidine&#xD;
&#xD;
          9. Life-threatening or uncontrolled dysrhythmia&#xD;
&#xD;
         10. Contraindications to CMR, gadolinium, adenosine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joseph Selvanayagam</last_name>
    <role>Study Chair</role>
    <affiliation>Flinders Medical Centre</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Rajiv Ananthakrishna</last_name>
    <role>Principal Investigator</role>
    <affiliation>Flinders Medical Centre</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Joseph Selvanayagam</last_name>
    <phone>+61882045619</phone>
    <email>joseph.selva@sa.gov.au</email>
  </overall_contact>
  <location>
    <facility>
      <name>Flinders Medical Centre</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <zip>5042</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joseph Selvanayagam</last_name>
      <email>joseph.selva@sa.gov.au</email>
    </contact>
    <contact_backup>
      <last_name>Sau Lee</last_name>
      <email>sau.lee@s.gov.au</email>
    </contact_backup>
    <investigator>
      <last_name>Rajiv Ananthakrishna</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>May 14, 2020</study_first_submitted>
  <study_first_submitted_qc>June 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>March 9, 2021</last_update_submitted>
  <last_update_submitted_qc>March 9, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 11, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Flinders University</investigator_affiliation>
    <investigator_full_name>Joseph Selvanayagam</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Heart function and structure</keyword>
  <keyword>Hypertrophy</keyword>
  <keyword>Heart Failure</keyword>
  <keyword>Medication</keyword>
  <keyword>Imaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiomyopathies</mesh_term>
    <mesh_term>Cardiomyopathy, Hypertrophic</mesh_term>
    <mesh_term>Hypertrophy</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Perhexiline</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04426578
org study id: HCM2020-01
nct id: NCT04426578
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart muscle condition
      affecting up to 1 in 200 of the general population. It results from mutations in genes
      encoding components of the contractile apparatus in the heart muscle cell (myocyte). These
      mutations result in increased energy cost of force production for the myocyte which then
      cumulatively causes a myocardial energy deficit. This myocardial energy deficit is then
      thought to lead to cardiac hypertrophy ('left ventricular hypertrophy' or LVH) in HCM.

      LVH leads to impairments in heart muscle function, heart muscle oxygenation and microvascular
      blood flow and is the chief driver of patient symptoms in HCM. These symptoms consist of
      chest pain, shortness of breath, dizziness, fainting episodes or palpitations. Occasionally,
      the disease may cause sudden cardiac death (SCD). HCM is the most common cause of SCD in
      young people including competitive athletes. In addition, HCM has been found to result in
      significant global deterioration in health-related quality of life.

      Treatment of HCM has focused on relief of symptoms by drugs such as ß-blockers which slow the
      heart rate and improve heart function. However, symptom relief is often incomplete and there
      is no evidence on the benefit of ß-blockers or related medications to reverse LVH.
      Perhexiline, a potent carnitine palmitoyl transferase-1 (CPT-1) inhibitor shifts myocardial
      metabolism to more efficient glucose utilisation and rectifies impaired myocardial
      energetics. It is currently used to treat angina in patients with coronary artery disease.
      There is some preliminary evidence that Perhexiline may aid in the improvement of symptoms in
      patients with HCM. However, the effect of any form of therapy on potential regression of LVH
      in HCM remains unexplored.

      In this randomised double-blind placebo-controlled trial, the investigators will use state of
      the art cardiac imaging, principally advanced echocardiography and Cardiovascular Magnetic
      Resonance (CMR) to study the effects of perhexiline on LVH, cardiac function, and oxygenation
      in symptomatic patients with HCM. The investigators hypothesize that perhexiline will
      favourably reduce LVH and improve myocardial oxygenation by improving myocardial energetics,
      and that these putative morphological and functional changes can be accurately measured
      utilizing echocardiography and CMR. If this pilot study supports the hypothesis, then it will
      pave the way for a major randomised controlled trial to definitely determine the role of
      Perhexiline in HCM.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in Left Ventricular Hypertrophy (LVH)
time frame: 12 months post baseline
description: Change in LVH (septal thickness) in symptomatic at 12 months following perhexiline therapy in HCM patients assessed by CMR
measure: Change in Left Ventricular (LV) mass
time frame: 12 months post baseline
description: Change in left ventricular mass in symptomatic at 12 months following perhexiline therapy in HCM patients assessed by CMR
measure: Change in oxygen-sensitive Cardiac Magnetic Resonance
time frame: 12 months post baseline
description: Change in oxygen-sensitive CMR in symptomatic at 12 months following perhexiline therapy in HCM patients
measure: Change in left ventricular diastolic function
time frame: 12 months post baseline
description: Change in left ventricular diastolic function at 12 months following perhexiline therapy in HCM patients assessed by echocardiography
measure: New York Heart Association (NYHA) functional classification
time frame: 12 months post baseline
description: Change in NYHA classification of Class I, II, III and IV at 12 months following perhexiline therapy in HCM patients
measure: Canadian Cardiovascular Society (CCS) functional class
time frame: 12 months post baseline
description: Change in CCS functional classification of Grade I, II, III and IV at 12 months following perhexiline therapy in HCM patients
measure: Quality of life assessment
time frame: 12 months post baseline
description: Change in physical activity domain score of Short Form 36 Health Survey Questionnaire (SF36) at 12 months following perhexiline therapy in HCM patients
measure: Major adverse event on heart failure related hospitalisations
time frame: Monitored over the 12 months period
description: HCM patients admitted with heart failure during the study period
measure: Major adverse event on arrhythmic events
time frame: Monitored over the 12 months period
description: HCM patients admitted with arrhythmic events during the study period
measure: Major adverse event on abnormal liver function test
time frame: Liver function tests at baseline, 1 month, 6 months and 12 months
description: HCM patients with abnormal liver function tests during the study period
measure: Major adverse event on sudden cardiac death
time frame: Monitored over the 12 months period
description: HCM patients with sudden cardiac death during the study period
arm group label: Perhexiline
arm group type: Experimental
arm group label: Placebo
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Perhexiline
description: All eligible and consented patients will be randomised to initiation of perhexiline 100mg once daily or identical placebo. After 4 days of treatment, a blood sample will be collected to determine plasma perhexiline concentrations: timing of the sample need not be "trough" in view of the long-acting nature of perhexiline. Depending on the blood results, patients might require as little as 50mg/week (slow metabolisers) or as much as 600mg/day (ultra-rapid metabolisers). The initial sample will be utilized primarily to detect presence of hydroxylated metabolite: patients in whom perhexiline is detected in the absence of metabolite will be designated "slow metabolisers" and will have their dosage reduced to 50 mg/week in the first instance. Repeat assay at 30 days will be utilized for individual finer dose titration based on dose adjustment table. Paired dosage adjustment in placebo-treated patients will be performed to avoid unblinding.
Compliance will be assessed by capsule count.
arm group label: Perhexiline
other name: Pexsig
intervention type: Other
intervention name: Placebo
description: All eligible and consented patients will be randomised to initiation of perhexiline 100mg once daily or identical placebo. After 4 days of treatment, a blood sample will be collected to determine plasma perhexiline concentrations: timing of the sample need not be "trough" in view of the long-acting nature of perhexiline. Depending on the blood results, patients might require as little as 50mg/week (slow metabolisers) or as much as 600mg/day (ultra-rapid metabolisers). The initial sample will be utilized primarily to detect presence of hydroxylated metabolite: patients in whom perhexiline is detected in the absence of metabolite will be designated "slow metabolisers" and will have their dosage reduced to 50 mg/week in the first instance. Repeat assay at 30 days will be utilized for individual finer dose titration based on dose adjustment table. Paired dosage adjustment in placebo-treated patients will be performed to avoid unblinding.
Compliance will be assessed by capsule count.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joseph Selvanayagam
role: Study Chair
affiliation: Flinders Medical Centre
last name: Rajiv Ananthakrishna
role: Principal Investigator
affiliation: Flinders Medical Centre
last name: Joseph Selvanayagam
phone: +61882045619
email: joseph.selva@sa.gov.au
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Australia
responsible party type: Principal Investigator
investigator affiliation: Flinders University
investigator full name: Joseph Selvanayagam
investigator title: Professor
mesh term: Cardiomyopathies
mesh term: Cardiomyopathy, Hypertrophic
mesh term: Hypertrophy
mesh term: Perhexiline
sharing ipd: No