<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/NCT02226510</url>
  </required_header>
  <id_info>
    <org_study_id>2013CV08</org_study_id>
    <secondary_id>2014-003189-26</secondary_id>
    <secondary_id>14/ES/1061</secondary_id>
    <nct_id>NCT02226510</nct_id>
  </id_info>
  <brief_title>MetfoRmin and Its Effects on Left Ventricular Hypertrophy in Normotensive Patients With Coronary Artery Disease</brief_title>
  <acronym>MET-REMODEL</acronym>
  <official_title>MetfoRmin and Its Effects on Myocardial Dimension and Left Ventricular Hypertrophy in Normotensive Patients With Coronary Artery Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Dundee</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Dundee</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Thickening of the heart muscle (left ventricle) known medically as Left Ventricular&#xD;
      Hypertrophy (LVH) is very common in patients with heart disease. This increases risk of&#xD;
      cerebrovascular/cardiovascular event.&#xD;
&#xD;
      LVH is asymptomatic and managed by the use of medication to control blood pressure, however&#xD;
      LVH may be seen in normotensive patients where factors such as obesity and insulin resistance&#xD;
      are present.&#xD;
&#xD;
      Insulin resistance is a condition where although the body produces insulin it is unable to&#xD;
      utilize it effectively. Metformin, a drug used to treat diabetes, can reduce insulin&#xD;
      resistance and cause weight loss, it may therefore improve LVH. This study will investigate&#xD;
      the ability of metformin to reduce LVH in patients with heart disease, this may be a novel&#xD;
      way forward in the risk reduction of cerebrovascular/cardiovascular events. Participants will&#xD;
      be identified throughout NHS Tayside, those eligible will be randomly allocated to either&#xD;
      metformin or a dummy medication (placebo) and will receive one year of treatment. At the&#xD;
      beginning of the study, the thickness of the heart muscle will be measured by ultrasound scan&#xD;
      and cardiac Magnetic Resonance Imaging (cMRI). We will also perform non-invasive tests to&#xD;
      measure blood vessel function. These tests will be repeated after one year. At the end of the&#xD;
      study, we will investigate the difference between placebo treatment and metformin treatment.&#xD;
&#xD;
      This study is funded by the British Heart Foundation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single centre trial designed to investigate the benefit, if any, of 12 month&#xD;
      metformin XL 2000mg/day treatment on left ventricular hypertrophy (LVH) in 64 nondiabetic&#xD;
      participants with Ischaemic heart disease (IHD) and insulin resistance (IR) and/or&#xD;
      prediabetes.&#xD;
&#xD;
      Participants will be seen on seven occasions: screening, baseline/randomisation, 2 weeks post&#xD;
      randomisation, month 1, month 4, month 8 and final month 12, during which vital signs and&#xD;
      safety bloods will be performed. There will also be three telephone visits at: month 2, month&#xD;
      6 and month 10.&#xD;
&#xD;
      At a screening visit an initial history will be performed following informed consent.&#xD;
      Participants will then undergo an echocardiogram (a painless ultrasound scan of the heart) in&#xD;
      the Department of Clinical Pharmacology, Ninewells Hospital, Dundee. Blood pressure will be&#xD;
      recorded and blood tests to determine fasting insulin resistance index (FIRI), prediabetes&#xD;
      and routine safety, prior to metformin administration, will be performed.&#xD;
&#xD;
      Participants who meet all inclusion criteria will return for the randomisation visit within 4&#xD;
      weeks of screening where a Cardiac Magnetic Resonance Imaging (cMRI) scan will be performed&#xD;
      followed by randomisation to either Metformin XL or placebo in a double blind, randomised&#xD;
      fashion. Also, at this visit endothelial function tests will be performed to assess&#xD;
      peripheral blood vessels in the forearm, central obesity will be quantified using waist&#xD;
      circumference and waist to hip ratio (WHR) and study specific blood sampling performed (with&#xD;
      participant consent).&#xD;
&#xD;
      At the final visit or early withdrawal the following will be performed: vital signs, safety&#xD;
      bloods, study specific bloods (with participant consent), echocardiography, endothelial&#xD;
      function tests and cMRI.&#xD;
&#xD;
      In the active arm, therapy will be metformin XL in an initial dose of 1000mg/day (metformin&#xD;
      XL 500mg x2/day). Participants will continue on Metformin XL 500mg x2/day for two weeks,&#xD;
      following safety blood checks this dose will be increased to 2000 mg/day. If the higher dose&#xD;
      cannot be tolerated it will be reduced to 1000mg/day (or stopped if not tolerated).&#xD;
&#xD;
      The target dose of metformin XL at 2000mg/day was chosen based on a previous study of&#xD;
      metformin in nondiabetic heart failure patients with IR, this study demonstrated a beneficial&#xD;
      effect of metformin on insulin resistance, weight reduction and an improvement in submaximal&#xD;
      exercise. The study used the immediate release form of metformin (target of 1000 mg x2/day)&#xD;
      which was associated with significant gastrointestinal side effects resulting in 13%&#xD;
      withdrawal of study medication. For this reason we have selected metformin XR due to improved&#xD;
      gastrointestinal tolerability.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 2015</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">September 2017</primary_completion_date>
  <phase>Phase 4</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>Left Ventricular Mass Index</measure>
    <time_frame>12 months</time_frame>
    <description>Cardiac magnetic resonance imaging will be performed at baseline and at 12 months, to measure Left Ventricular Mass Index in patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Central and Abdominal obesity</measure>
    <time_frame>12 months</time_frame>
    <description>Abdominal magnetic resonance imaging will be performed at baseline and at 12 months to measure the changes in central and abdominal obesity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricular end systolic volume,</measure>
    <time_frame>12 months</time_frame>
    <description>Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular end systolic volume</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endothelial Function</measure>
    <time_frame>12 months</time_frame>
    <description>Improvement in endothelial function with metformin compared with placebo, measured by FMD and PWA and skin reactive hyperaemia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin Resistance / Prediabetes</measure>
    <time_frame>12 months</time_frame>
    <description>Improvement in insulin resistance (IR)/ prediabetes when treated with metformin compared to placebo in patients with IHD and IR measure using Fasting Insulin Resistance Index (FIRI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory and other cardiovascular blood markers</measure>
    <time_frame>12 months</time_frame>
    <description>Changes in inflammatory and other cardiovascular blood markers such as BNP/F2 Isoprostanes/oxi-LDL/Troponin T, when treated with metformin compared to placebo in patients with IHD and IR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Adverse Event</measure>
    <time_frame>12 months</time_frame>
    <description>Safety and efficacy of Metformin XL will be determined by monitoring changes from randomisation till the end of the study or so long the patient remains in the study, whichever is earlier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricularend diastolic volume</measure>
    <time_frame>12 months</time_frame>
    <description>Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular end diastolic volume</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricular Ejection Fraction</measure>
    <time_frame>12 months</time_frame>
    <description>Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular Ejection Fraction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricular Mass</measure>
    <time_frame>12 months</time_frame>
    <description>Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular Mass</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">68</enrollment>
  <condition>Left Ventricular Hypertrophy</condition>
  <condition>Insulin Resistance</condition>
  <condition>Coronary Artery Disease</condition>
  <condition>PreDiabetes</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo capsules (with an identical appearance to the active drug) and containing only microcrystalline cellulose PhEur</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Metformin XL</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the active arm, the added therapy will be metformin XL in an initial dose of 1000mg/day (metformin XL 500mg x2/day). They will continue on Metformin XL 500mg x2/day for two weeks and after safety blood checks the metformin XL dose will be increased to 2000 mg/day. If the higher dose cannot be tolerated the dose will be reduced to 1000mg/day (and stopped if this cannot be tolerated).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin XL</intervention_name>
    <description>In the active arm, the added therapy will be metformin XL in an initial dose of 1000mg/day . They will continue on Metformin XL 500mg x2/day for 2 weeks and after safety blood checks the metformin XL dose will be increased to 2000 mg/day. If the higher dose cannot be tolerated the dose will be reduced to 1000mg/day.</description>
    <arm_group_label>Metformin XL</arm_group_label>
    <other_name>Diagemet XL</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo capsules (with an identical appearance to the active drug) containing only microcrystalline cellulose PhEur will be administered.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged 18 years or over&#xD;
&#xD;
          -  Participant willing and able to give informed consent.&#xD;
&#xD;
          -  Documented Ischaemic Heart Disease: either angio-graphically documented coronary&#xD;
             artery disease or a previous history of myocardial infarction/angina.&#xD;
&#xD;
          -  Screening echocardiography based diagnosis of LVH (LV mass indexed to height to the&#xD;
             allometric power of 1.7; males &gt; 81g/h1.7, females &gt;60g/h1.7)&#xD;
&#xD;
          -  Fasting insulin resistance index ≥ 2.7 AND/OR HbA1c &gt;5.6 and less than 6.5 at&#xD;
             screening&#xD;
&#xD;
          -  Blood pressure &lt; 140/85 mm Hg or 24hr BP &lt;135/85 daytime average in screening&#xD;
&#xD;
          -  Able (in the Investigators opinion) and willing to comply with all study requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cognitive impairment&#xD;
&#xD;
          -  Type 1 or 2 Diabetes mellitus&#xD;
&#xD;
          -  Chronic Heart Failure as evidenced by echocardiogram or documented diagnosis of CHF&#xD;
&#xD;
          -  Left Ventricular Ejection Fraction &lt;45% on screening echocardiography&#xD;
&#xD;
          -  Contraindications to cardiac MRI (pacemakers, claustrophobia, metal implants, history&#xD;
             of penetrative eye injury or exposure to metal fragments in eye requiring medical&#xD;
             attention)&#xD;
&#xD;
          -  Malignancy (receiving active treatment) or other life threatening disease, renal&#xD;
             disease (CKD class 3B or worse)&#xD;
&#xD;
          -  Pregnancy/lactating females&#xD;
&#xD;
          -  Any other reason considered inappropriate by a study physician&#xD;
&#xD;
          -  Participants who have participated in any other clinical trial within the previous 30&#xD;
             days.&#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>Chim Lang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Dundee</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ninewells Hospital &amp; Medical School</name>
      <address>
        <city>Dundee</city>
        <state>Angus</state>
        <zip>DD1 9SY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>August 18, 2014</study_first_submitted>
  <study_first_submitted_qc>August 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2014</study_first_posted>
  <last_update_submitted>April 8, 2019</last_update_submitted>
  <last_update_submitted_qc>April 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 10, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</mesh_term>
    <mesh_term>Hypertrophy, Left Ventricular</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Hypertrophy</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 20, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT02226510/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 22, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT02226510/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT02226510
org study id: 2013CV08
secondary id: 2014-003189-26
secondary id: 14/ES/1061
nct id: NCT02226510
lead sponsor: 
has dmc: No
Thickening of the heart muscle (left ventricle) known medically as Left Ventricular
      Hypertrophy (LVH) is very common in patients with heart disease. This increases risk of
      cerebrovascular/cardiovascular event.

      LVH is asymptomatic and managed by the use of medication to control blood pressure, however
      LVH may be seen in normotensive patients where factors such as obesity and insulin resistance
      are present.

      Insulin resistance is a condition where although the body produces insulin it is unable to
      utilize it effectively. Metformin, a drug used to treat diabetes, can reduce insulin
      resistance and cause weight loss, it may therefore improve LVH. This study will investigate
      the ability of metformin to reduce LVH in patients with heart disease, this may be a novel
      way forward in the risk reduction of cerebrovascular/cardiovascular events. Participants will
      be identified throughout NHS Tayside, those eligible will be randomly allocated to either
      metformin or a dummy medication (placebo) and will receive one year of treatment. At the
      beginning of the study, the thickness of the heart muscle will be measured by ultrasound scan
      and cardiac Magnetic Resonance Imaging (cMRI). We will also perform non-invasive tests to
      measure blood vessel function. These tests will be repeated after one year. At the end of the
      study, we will investigate the difference between placebo treatment and metformin treatment.

      This study is funded by the British Heart Foundation.
This is a single centre trial designed to investigate the benefit, if any, of 12 month
      metformin XL 2000mg/day treatment on left ventricular hypertrophy (LVH) in 64 nondiabetic
      participants with Ischaemic heart disease (IHD) and insulin resistance (IR) and/or
      prediabetes.

      Participants will be seen on seven occasions: screening, baseline/randomisation, 2 weeks post
      randomisation, month 1, month 4, month 8 and final month 12, during which vital signs and
      safety bloods will be performed. There will also be three telephone visits at: month 2, month
      6 and month 10.

      At a screening visit an initial history will be performed following informed consent.
      Participants will then undergo an echocardiogram (a painless ultrasound scan of the heart) in
      the Department of Clinical Pharmacology, Ninewells Hospital, Dundee. Blood pressure will be
      recorded and blood tests to determine fasting insulin resistance index (FIRI), prediabetes
      and routine safety, prior to metformin administration, will be performed.

      Participants who meet all inclusion criteria will return for the randomisation visit within 4
      weeks of screening where a Cardiac Magnetic Resonance Imaging (cMRI) scan will be performed
      followed by randomisation to either Metformin XL or placebo in a double blind, randomised
      fashion. Also, at this visit endothelial function tests will be performed to assess
      peripheral blood vessels in the forearm, central obesity will be quantified using waist
      circumference and waist to hip ratio (WHR) and study specific blood sampling performed (with
      participant consent).

      At the final visit or early withdrawal the following will be performed: vital signs, safety
      bloods, study specific bloods (with participant consent), echocardiography, endothelial
      function tests and cMRI.

      In the active arm, therapy will be metformin XL in an initial dose of 1000mg/day (metformin
      XL 500mg x2/day). Participants will continue on Metformin XL 500mg x2/day for two weeks,
      following safety blood checks this dose will be increased to 2000 mg/day. If the higher dose
      cannot be tolerated it will be reduced to 1000mg/day (or stopped if not tolerated).

      The target dose of metformin XL at 2000mg/day was chosen based on a previous study of
      metformin in nondiabetic heart failure patients with IR, this study demonstrated a beneficial
      effect of metformin on insulin resistance, weight reduction and an improvement in submaximal
      exercise. The study used the immediate release form of metformin (target of 1000 mg x2/day)
      which was associated with significant gastrointestinal side effects resulting in 13%
      withdrawal of study medication. For this reason we have selected metformin XR due to improved
      gastrointestinal tolerability.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Left Ventricular Mass Index
time frame: 12 months
description: Cardiac magnetic resonance imaging will be performed at baseline and at 12 months, to measure Left Ventricular Mass Index in patients
measure: Central and Abdominal obesity
time frame: 12 months
description: Abdominal magnetic resonance imaging will be performed at baseline and at 12 months to measure the changes in central and abdominal obesity
measure: Left Ventricular end systolic volume,
time frame: 12 months
description: Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular end systolic volume
measure: Endothelial Function
time frame: 12 months
description: Improvement in endothelial function with metformin compared with placebo, measured by FMD and PWA and skin reactive hyperaemia
measure: Insulin Resistance / Prediabetes
time frame: 12 months
description: Improvement in insulin resistance (IR)/ prediabetes when treated with metformin compared to placebo in patients with IHD and IR measure using Fasting Insulin Resistance Index (FIRI)
measure: Inflammatory and other cardiovascular blood markers
time frame: 12 months
description: Changes in inflammatory and other cardiovascular blood markers such as BNP/F2 Isoprostanes/oxi-LDL/Troponin T, when treated with metformin compared to placebo in patients with IHD and IR
measure: Number of participants with Adverse Event
time frame: 12 months
description: Safety and efficacy of Metformin XL will be determined by monitoring changes from randomisation till the end of the study or so long the patient remains in the study, whichever is earlier.
measure: Left Ventricularend diastolic volume
time frame: 12 months
description: Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular end diastolic volume
measure: Left Ventricular Ejection Fraction
time frame: 12 months
description: Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular Ejection Fraction
measure: Left Ventricular Mass
time frame: 12 months
description: Cardiac magnetic resonance imaging will be performed at baseline and at 12 months to measure Left Ventricular Mass
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo capsules (with an identical appearance to the active drug) and containing only microcrystalline cellulose PhEur
arm group label: Metformin XL
arm group type: Active Comparator
description: In the active arm, the added therapy will be metformin XL in an initial dose of 1000mg/day (metformin XL 500mg x2/day). They will continue on Metformin XL 500mg x2/day for two weeks and after safety blood checks the metformin XL dose will be increased to 2000 mg/day. If the higher dose cannot be tolerated the dose will be reduced to 1000mg/day (and stopped if this cannot be tolerated).
intervention type: Drug
intervention name: Metformin XL
description: In the active arm, the added therapy will be metformin XL in an initial dose of 1000mg/day . They will continue on Metformin XL 500mg x2/day for 2 weeks and after safety blood checks the metformin XL dose will be increased to 2000 mg/day. If the higher dose cannot be tolerated the dose will be reduced to 1000mg/day.
arm group label: Metformin XL
other name: Diagemet XL
intervention type: Drug
intervention name: Placebo
description: Placebo capsules (with an identical appearance to the active drug) containing only microcrystalline cellulose PhEur will be administered.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Chim Lang, MD
role: Principal Investigator
affiliation: University of Dundee
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Hypertrophy, Left Ventricular
mesh term: Insulin Resistance
mesh term: Hypertrophy
mesh term: Metformin
provided document: 
provided document: 