<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/NCT03288025</url>
  </required_header>
  <id_info>
    <org_study_id>16-260</org_study_id>
    <nct_id>NCT03288025</nct_id>
  </id_info>
  <brief_title>Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE)</brief_title>
  <official_title>Pulmonary Arterial Hypertension Improvement With Nutrition and Exercise (PHINE) A Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Cleveland Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>The Cleveland Clinic</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>
      The purpose of this study is to investigate the extent to which diet and exercise may improve&#xD;
      PAH through the modulation of insulin sensitivity. The central hypothesis is that&#xD;
      dysregulated glucose metabolism elicits a response in PAH patients that can be modified by&#xD;
      exercise and diet, thereby leading to improvements in pulmonary vascular disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pulmonary arterial hypertension (PAH) leads to premature death as a consequence of increased&#xD;
      pulmonary vascular resistance and right heart failure. PAH-targeted therapies developed over&#xD;
      the past 20 years target excessive vasoconstriction. However, the pathobiology of PAH is more&#xD;
      complicated, and includes dysregulated vascular cell proliferation, cellular metabolic&#xD;
      abnormalities, and inflammation. Even with modern PAH therapies, current outcomes remain&#xD;
      poor, with an estimated 3-year survival rate of only 55%. Thus, there is a clear need for&#xD;
      more effective therapies, based on better understanding of the pathobiology of the disease.&#xD;
&#xD;
      Insulin resistance has emerged as a potential new mechanism in PAH. Animal models of insulin&#xD;
      resistance are associated with PAH, which reverses with the administration of insulin&#xD;
      sensitizing drugs. Over the past decade there has been an epidemiologic shift in PAH, where&#xD;
      the disease is increasingly observed in older, obese, and diabetic subjects. Low levels of&#xD;
      high-density lipoprotein cholesterol in PAH, a feature of insulin resistance, have been&#xD;
      observed and found to be a strong independent predictor of PAH mortality. Elevated&#xD;
      glycosylated hemoglobin (HbA1c) also correlates with PAH diagnosis and severity. As measured&#xD;
      by the OGTT, idiopathic PAH patients have not only insulin resistance, but also an inability&#xD;
      to mount an appropriate insulin response to a glucose challenge. These data point to&#xD;
      dysfunction in the pancreatic beta cells of PAH patients. It is known that an exercise and&#xD;
      low glycemic index diet intervention improves insulin sensitivity in pre-diabetic subjects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 27, 2017</start_date>
  <completion_date type="Anticipated">December 18, 2023</completion_date>
  <primary_completion_date type="Actual">February 18, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Insulin Sensitivity</measure>
    <time_frame>5 years</time_frame>
    <description>Assessed by the frequently-sampled intravenous glucose tolerance test. Units of assessment in min/uU*mL</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Right Ventricular Global Peak Longitudinal Strain</measure>
    <time_frame>5 years</time_frame>
    <description>Assessed by the Doppler Echocardiography 2D longitudinal speckle tracking. Units of assessment in percent.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <condition>Insulin Resistance</condition>
  <arm_group>
    <arm_group_label>Nutrition and Exercise</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 days a week of moderate exercise and biweekly diet counseling on Low Glycemic Index/ Mediterranean Diet for 12 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Counseling at baseline on diet as recommended by USDA and on the benefits of regular aerobic exercise.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Nutrition and Exercise</intervention_name>
    <description>5 times a week exercise training and biweekly diet counseling for 12 weeks.</description>
    <arm_group_label>Nutrition and Exercise</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age range between 18-75 years old&#xD;
&#xD;
          -  Group 1 PAH, including idiopathic, heritable, drugs and toxin induced, and PAH&#xD;
             associated with connective tissue disease, HIV infection and congenital heart disease&#xD;
&#xD;
          -  NYHA Class II or III&#xD;
&#xD;
          -  ≥ 1 PAH-targeted therapy with a stable dose for ≥ 2 months&#xD;
&#xD;
          -  Stable dose of diuretics and rate of supplemental oxygen for the preceding 2 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Decompensated Right Heart Failure&#xD;
&#xD;
          -  NYHA Class IV&#xD;
&#xD;
          -  Syncope within the previous 3 months&#xD;
&#xD;
          -  Cardiac Arrhythmia (except for controlled atrial fibrillation or flutter)&#xD;
&#xD;
          -  Baseline supplemental O2 &gt; 4 LPM&#xD;
&#xD;
          -  Portal Hypertension&#xD;
&#xD;
          -  Pulmonary hypertension due to Lung Disease and Hypoxia&#xD;
&#xD;
          -  Pulmonary Hypertension due to Left Heart Disease&#xD;
&#xD;
          -  Chronic Thromboembolic Pulmonary Hypertension&#xD;
&#xD;
          -  Pulmonary Hypertension associated with systemic diseases such as hematological&#xD;
             disorders and sarcoidosis&#xD;
&#xD;
          -  Type 2 Diabetes&#xD;
&#xD;
          -  Evidence of cardiac ischemia on a graded exercise test&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Raed Dweik, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Cleveland Clinic</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gustavo Heresi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Cleveland Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cleveland Clinic Foundation</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>August 31, 2017</study_first_submitted>
  <study_first_submitted_qc>September 15, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 19, 2017</study_first_posted>
  <last_update_submitted>March 23, 2023</last_update_submitted>
  <last_update_submitted_qc>March 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 24, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Cleveland Clinic</investigator_affiliation>
    <investigator_full_name>Gustavo A Heresi, MD, MS</investigator_full_name>
    <investigator_title>Staff, Pulmonary Medicine</investigator_title>
  </responsible_party>
  <keyword>Insulin Resistance</keyword>
  <keyword>Inflammation</keyword>
  <keyword>Right Ventricular Function</keyword>
  <keyword>Metabolism</keyword>
  <keyword>Glucose</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Arterial Hypertension</mesh_term>
    <mesh_term>Familial Primary Pulmonary Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
  </condition_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/NCT03288025
org study id: 16-260
nct id: NCT03288025
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to investigate the extent to which diet and exercise may improve
      PAH through the modulation of insulin sensitivity. The central hypothesis is that
      dysregulated glucose metabolism elicits a response in PAH patients that can be modified by
      exercise and diet, thereby leading to improvements in pulmonary vascular disease.
Pulmonary arterial hypertension (PAH) leads to premature death as a consequence of increased
      pulmonary vascular resistance and right heart failure. PAH-targeted therapies developed over
      the past 20 years target excessive vasoconstriction. However, the pathobiology of PAH is more
      complicated, and includes dysregulated vascular cell proliferation, cellular metabolic
      abnormalities, and inflammation. Even with modern PAH therapies, current outcomes remain
      poor, with an estimated 3-year survival rate of only 55%. Thus, there is a clear need for
      more effective therapies, based on better understanding of the pathobiology of the disease.

      Insulin resistance has emerged as a potential new mechanism in PAH. Animal models of insulin
      resistance are associated with PAH, which reverses with the administration of insulin
      sensitizing drugs. Over the past decade there has been an epidemiologic shift in PAH, where
      the disease is increasingly observed in older, obese, and diabetic subjects. Low levels of
      high-density lipoprotein cholesterol in PAH, a feature of insulin resistance, have been
      observed and found to be a strong independent predictor of PAH mortality. Elevated
      glycosylated hemoglobin (HbA1c) also correlates with PAH diagnosis and severity. As measured
      by the OGTT, idiopathic PAH patients have not only insulin resistance, but also an inability
      to mount an appropriate insulin response to a glucose challenge. These data point to
      dysfunction in the pancreatic beta cells of PAH patients. It is known that an exercise and
      low glycemic index diet intervention improves insulin sensitivity in pre-diabetic subjects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Insulin Sensitivity
time frame: 5 years
description: Assessed by the frequently-sampled intravenous glucose tolerance test. Units of assessment in min/uU*mL
measure: Right Ventricular Global Peak Longitudinal Strain
time frame: 5 years
description: Assessed by the Doppler Echocardiography 2D longitudinal speckle tracking. Units of assessment in percent.
arm group label: Nutrition and Exercise
arm group type: Experimental
description: 5 days a week of moderate exercise and biweekly diet counseling on Low Glycemic Index/ Mediterranean Diet for 12 weeks.
arm group label: Standard of Care
arm group type: No Intervention
description: Counseling at baseline on diet as recommended by USDA and on the benefits of regular aerobic exercise.
intervention type: Behavioral
intervention name: Nutrition and Exercise
description: 5 times a week exercise training and biweekly diet counseling for 12 weeks.
arm group label: Nutrition and Exercise
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Raed Dweik, MD
role: Principal Investigator
affiliation: The Cleveland Clinic
last name: Gustavo Heresi, MD
role: Principal Investigator
affiliation: The Cleveland Clinic
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: The Cleveland Clinic
investigator full name: Gustavo A Heresi, MD, MS
investigator title: Staff, Pulmonary Medicine
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Insulin Resistance
sharing ipd: No