<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/NCT01712620</url>
  </required_header>
  <id_info>
    <org_study_id>120211</org_study_id>
    <secondary_id>12-CC-0211</secondary_id>
    <nct_id>NCT01712620</nct_id>
  </id_info>
  <brief_title>Spironolactone for Pulmonary Arterial Hypertension</brief_title>
  <official_title>A Pilot Study of the Effect of Spironolactone Therapy on Exercise Capacity and Endothelial Dysfunction in Pulmonary Arterial Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institutes of Health Clinical Center (CC)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Maryland Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medstar Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>New England Medical Center, Tufts University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - High blood pressure in the lungs, known as pulmonary arterial hypertension (PAH), is a rare&#xD;
      disorder. In spite of recent advances in treatment, the death rate remains unacceptably high.&#xD;
      Lung blood vessel function can be harmed by progressive injuries, such as inflammation,&#xD;
      leading to worsening of the disease. A drug called spironolactone has been known to improve&#xD;
      blood vessel function and reduce inflammation. Some people with PAH take spironolactone to&#xD;
      help treat fluid retention. However, its effect on inflammation and blood vessel function in&#xD;
      patients withPAH is not known. Researchers want to see if spironolactone can help these&#xD;
      conditions in people with PAH.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To test the effectiveness of spironolactone in treating pulmonary arterial hypertension.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Individuals at least 18 years of age with pulmonary arterial hypertension.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  This study will last for 24 weeks. Participants will be screened with a physical exam&#xD;
           and medical history. Blood and urine samples will be collected.&#xD;
&#xD;
        -  Participants will take either spironolactone or a placebo. They will take their study&#xD;
           drug or placebo for 7 weeks. Treatment will be monitored with regular blood tests.&#xD;
&#xD;
        -  In Week 8, participants who have had no reaction to the treatment will receive a higher&#xD;
           dose of the drug or placebo.&#xD;
&#xD;
        -  In Week 12, participants will have a study visit with heart and lung function tests.&#xD;
           They will also have a 6-minute walk test, and provide blood and urine samples.&#xD;
&#xD;
        -  After additional study visits for blood samples, participants will have a final visit in&#xD;
           Week 24. The tests from Week 12 will be repeated at this visit.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION:&#xD;
&#xD;
      Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival.&#xD;
      Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering&#xD;
      stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a&#xD;
      central role both in the pathogenesis and progression of PAH. Inflammation appears to drive&#xD;
      this dysfunctional endothelial phenotype, propagating cycles of injury and repair in&#xD;
      genetically susceptible patients with idiopathic PAH (IPAH) and patients with&#xD;
      disease-associated PAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles&#xD;
      of injury and repair and thereby delay or prevent RV failure and death has not been tested.&#xD;
      Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist, has&#xD;
      been shown to improve endothelial function and reduce inflammation. Current management of&#xD;
      patients with severe PAH and NYHA/WHO class IV symptoms includes use of MR antagonists for&#xD;
      their diuretic and natriuretic effects once clinical right heart failure has developed. We&#xD;
      hypothesize that initiating therapy with spironolactone at an earlier stage of disease in&#xD;
      subjects with PAH could provide additional benefits through anti-inflammatory effects and&#xD;
      improvements in pulmonary artery endothelial function.&#xD;
&#xD;
      OBJECTIVES:&#xD;
&#xD;
      Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in a&#xD;
      randomized, double blinded, placebo-controlled study of early treatment with spironolactone&#xD;
      to investigate its effects on exercise capacity, clinical worsening, and vascular&#xD;
      inflammation in vivo.&#xD;
&#xD;
      METHODS:&#xD;
&#xD;
      The total number of PAH subjects enrolled will be up to 70. Subjects will undergo 1) standard&#xD;
      clinical examinations including 6-minute walk distance and echocardiography; 2)&#xD;
      cardiopulmonary exercise testing; 3) plasma profiling of inflammatory and neurohormonal&#xD;
      markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5)&#xD;
      high-resolution MRI-based determination of pulmonary vascular and RV structure and function.&#xD;
      Safety and tolerability of spironolactone in PAH will be assessed with periodic monitoring&#xD;
      for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for&#xD;
      untoward effects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 10, 2014</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in placebo corrected 6-minute walk distance</measure>
    <time_frame>6 months</time_frame>
    <description>Change in placebo corrected 6-minute walk distance.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in placebo corrected VO2 max</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in right ventricular function</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarkers of vascular inflammation</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of study drug discontinuation due to hyperkalemia, renal insufficiency, or other side effects such as breast pain and gynecomastia</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">70</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Spironolactone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Spironolactone</intervention_name>
    <description>Initial dose, 25 mg (pink capsule) orally, daily. If well tolerated at 7-9 wks then increased to 50 mg (brown capsule) daily.</description>
    <arm_group_label>Group A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Initial dose, pink sugar capsule, daily. If well tolerated at 7-9 wks then changed to brown sugar capsule, daily.</description>
    <arm_group_label>Group B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
               1. WHO Group 1 PH patients on either no medical therapy or stable medical therapy&#xD;
                  for at least the past 4 weeks (defined as no new PAH-specific therapy, no change&#xD;
                  in the dose of current PAH-specific therapy and no change in NYHA/WHO functional&#xD;
                  classification within the past 4 weeks) are eligible. The following parameters on&#xD;
                  RHC are required to meet the hemodynamic definition of PAH:&#xD;
&#xD;
               1. mean pulmonary artery pressure of &gt; 25 mmHg at rest,&#xD;
&#xD;
               2. pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a left&#xD;
                  ventricular end-diastolic pressure of less than or equal to 12 mmHg) and&#xD;
&#xD;
               3. pulmonary vascular resistance of &gt; 3 Wood units (240 dyn.s.cm(-5).&#xD;
&#xD;
        If clinically indicated at the time of enrollment, then a RHC will be performed at the NIH&#xD;
        Clinical Center upon study entry under a procedural consent.&#xD;
&#xD;
        2) Females who are able to become pregnant (i.e., are not postmenopausal, have not&#xD;
        undergone surgical sterilization, and are sexually active with men) must agree to use&#xD;
        adequate contraception (hormonal or barrier method of birth control; abstinence) prior to&#xD;
        and for the duration of study participation.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Patients with WHO Group 1 PH and evidence of right heart failure as defined by:&#xD;
&#xD;
               1. NYHA/WHO class IV symptoms and&#xD;
&#xD;
               2. Echocardiographic evidence of severe RV dysfunction and&#xD;
&#xD;
               3. Clinical evidence of right heart failure which may include, but is not limited to&#xD;
                  elevated jugular venous pressure, ascites, and lower extremity edema&#xD;
&#xD;
          2. Patients with WHO Group 1 pulmonary hypertension and a prior diagnosis of cirrhosis&#xD;
             with portal hypertension as evidenced by a history of ascites, hepatic encephalopathy&#xD;
             and/or varices prior to enrollment&#xD;
&#xD;
          3. Patients with WHO Group 1 pulmonary hypertension and evidence of active infection,&#xD;
             (HIV patients with two consecutive viral loads of &lt; 500 on their most recent&#xD;
             determinations within the past 12 months will be considered to have inactive&#xD;
             infection)&#xD;
&#xD;
          4. Patients with WHO Group 1 pulmonary hypertension who have taken spironolactone or&#xD;
             eplerenone within the last 30 days&#xD;
&#xD;
          5. Known or suspected allergy to spironolactone&#xD;
&#xD;
          6. Pregnant or breastfeeding women (all women of childbearing potential will be required&#xD;
             to have a screening urine or blood pregnancy test)&#xD;
&#xD;
          7. Age &lt;18 years&#xD;
&#xD;
          8. Inability to provide informed written consent for participation in the study&#xD;
&#xD;
          9. Chronic kidney disease (an estimated glomerular filtration rate of &lt; 35&#xD;
             mL/min/1.73m(2) of body surface area)&#xD;
&#xD;
         10. Serum potassium at the time of enrollment of &gt; 5 mEq/L&#xD;
&#xD;
         11. Concurrent use of an ACE inhibitor and angiotensin II receptor blocker&#xD;
&#xD;
             OR&#xD;
&#xD;
             Patients currently taking the maximum recommended dose of an ACE inhibitor or an&#xD;
             angiotensin II receptor blocker [For patients taking one of these medicines&#xD;
             (ACE-Inhibitors or ARBs), the investigators agree to do due diligence by consulting a&#xD;
             clinical center pharmacist and/or a standard pharmacy reference (i.e. Micromedex) to&#xD;
             certify whether or not the patient is on a maximum dose of the drug.]&#xD;
&#xD;
         12. Women currently taking drospirenone-containing oral contraceptives&#xD;
&#xD;
        Exclusion Criteria for MRI&#xD;
&#xD;
        These contraindications include but are not limited to the following devices or conditions:&#xD;
&#xD;
          1. Implanted cardiac pacemaker or defibrillator&#xD;
&#xD;
          2. Cochlear Implants&#xD;
&#xD;
          3. Ocular foreign body (e.g. metal shavings)&#xD;
&#xD;
          4. Embedded shrapnel fragments&#xD;
&#xD;
          5. Central nervous system aneurysm clips&#xD;
&#xD;
          6. Implanted neural stimulator&#xD;
&#xD;
          7. Any implanted device that is incompatible with MRI&#xD;
&#xD;
          8. Unsatisfactory performance status as judged by the referring physician such that the&#xD;
             subject could not tolerate an MRI scan. Examples of medical conditions that would not&#xD;
             be accepted would include unstable angina and severe dyspnea at rest&#xD;
&#xD;
          9. Subjects requiring monitored sedation for MRI studies&#xD;
&#xD;
         10. Subjects with a condition precluding entry into the scanner (e.g. morbid obesity,&#xD;
             claustrophobia, etc.)&#xD;
&#xD;
         11. Subjects with severe back-pain or motion disorders who will be unable to tolerate&#xD;
             supine positioning within the MRI scanner and hold still for the duration of the&#xD;
             examination.&#xD;
&#xD;
        EXCLUSION CRITERIA FOR GADOLINIUM BASED MRI STUDIES ONLY:&#xD;
&#xD;
          1. History of severe allergic reaction to gadolinium contrast agents despite pre-&#xD;
             medication with diphenhydramine and prednisone&#xD;
&#xD;
          2. Chronic kidney disease (an estimated glomerular filtration rate of &lt; 60&#xD;
             mL/min/1.73m(2) of body surface area)&#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>Michael A Solomon, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institutes of Health Clinical Center (CC)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Grace M Graninger, R.N.</last_name>
    <phone>(301) 496-9320</phone>
    <email>ggraninger@cc.nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Michael A Solomon, M.D.</last_name>
    <phone>(301) 496-9320</phone>
    <email>msolomon@cc.nih.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)</last_name>
      <phone>800-411-1222</phone>
      <phone_ext>TTY dial 711</phone_ext>
      <email>ccopr@nih.gov</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2012-CC-0211.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>July 6, 2023</verification_date>
  <study_first_submitted>October 20, 2012</study_first_submitted>
  <study_first_submitted_qc>October 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 23, 2012</study_first_posted>
  <last_update_submitted>July 22, 2023</last_update_submitted>
  <last_update_submitted_qc>July 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Magnetic Resonance Imaging</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Spironolactone</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01712620
org study id: 120211
secondary id: 12-CC-0211
nct id: NCT01712620
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - High blood pressure in the lungs, known as pulmonary arterial hypertension (PAH), is a rare
      disorder. In spite of recent advances in treatment, the death rate remains unacceptably high.
      Lung blood vessel function can be harmed by progressive injuries, such as inflammation,
      leading to worsening of the disease. A drug called spironolactone has been known to improve
      blood vessel function and reduce inflammation. Some people with PAH take spironolactone to
      help treat fluid retention. However, its effect on inflammation and blood vessel function in
      patients withPAH is not known. Researchers want to see if spironolactone can help these
      conditions in people with PAH.

      Objectives:

      - To test the effectiveness of spironolactone in treating pulmonary arterial hypertension.

      Eligibility:

      - Individuals at least 18 years of age with pulmonary arterial hypertension.

      Design:

        -  This study will last for 24 weeks. Participants will be screened with a physical exam
           and medical history. Blood and urine samples will be collected.

        -  Participants will take either spironolactone or a placebo. They will take their study
           drug or placebo for 7 weeks. Treatment will be monitored with regular blood tests.

        -  In Week 8, participants who have had no reaction to the treatment will receive a higher
           dose of the drug or placebo.

        -  In Week 12, participants will have a study visit with heart and lung function tests.
           They will also have a 6-minute walk test, and provide blood and urine samples.

        -  After additional study visits for blood samples, participants will have a final visit in
           Week 24. The tests from Week 12 will be repeated at this visit.
INTRODUCTION:

      Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival.
      Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering
      stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a
      central role both in the pathogenesis and progression of PAH. Inflammation appears to drive
      this dysfunctional endothelial phenotype, propagating cycles of injury and repair in
      genetically susceptible patients with idiopathic PAH (IPAH) and patients with
      disease-associated PAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles
      of injury and repair and thereby delay or prevent RV failure and death has not been tested.
      Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist, has
      been shown to improve endothelial function and reduce inflammation. Current management of
      patients with severe PAH and NYHA/WHO class IV symptoms includes use of MR antagonists for
      their diuretic and natriuretic effects once clinical right heart failure has developed. We
      hypothesize that initiating therapy with spironolactone at an earlier stage of disease in
      subjects with PAH could provide additional benefits through anti-inflammatory effects and
      improvements in pulmonary artery endothelial function.

      OBJECTIVES:

      Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in a
      randomized, double blinded, placebo-controlled study of early treatment with spironolactone
      to investigate its effects on exercise capacity, clinical worsening, and vascular
      inflammation in vivo.

      METHODS:

      The total number of PAH subjects enrolled will be up to 70. Subjects will undergo 1) standard
      clinical examinations including 6-minute walk distance and echocardiography; 2)
      cardiopulmonary exercise testing; 3) plasma profiling of inflammatory and neurohormonal
      markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5)
      high-resolution MRI-based determination of pulmonary vascular and RV structure and function.
      Safety and tolerability of spironolactone in PAH will be assessed with periodic monitoring
      for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for
      untoward effects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Change in placebo corrected 6-minute walk distance
time frame: 6 months
description: Change in placebo corrected 6-minute walk distance.
measure: Change in placebo corrected VO2 max
time frame: 6 months
measure: Change in right ventricular function
time frame: 6 months
measure: Biomarkers of vascular inflammation
time frame: 6 months
measure: Rate of study drug discontinuation due to hyperkalemia, renal insufficiency, or other side effects such as breast pain and gynecomastia
time frame: 6 months
arm group label: Group A
arm group type: Experimental
description: Spironolactone
arm group label: Group B
arm group type: Placebo Comparator
description: Placebo
intervention type: Drug
intervention name: Spironolactone
description: Initial dose, 25 mg (pink capsule) orally, daily. If well tolerated at 7-9 wks then increased to 50 mg (brown capsule) daily.
arm group label: Group A
intervention type: Drug
intervention name: Placebo
description: Initial dose, pink sugar capsule, daily. If well tolerated at 7-9 wks then changed to brown sugar capsule, daily.
arm group label: Group B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael A Solomon, M.D.
role: Principal Investigator
affiliation: National Institutes of Health Clinical Center (CC)
last name: Grace M Graninger, R.N.
phone: (301) 496-9320
email: ggraninger@cc.nih.gov
last name: Michael A Solomon, M.D.
phone: (301) 496-9320
email: msolomon@cc.nih.gov
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2012-CC-0211.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Spironolactone