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Spironolactone for Pulmonary Arterial Hypertension

Primary Purpose

Pulmonary Arterial Hypertension

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Spironolactone
Placebo
Sponsored by
National Institutes of Health Clinical Center (CC)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring Magnetic Resonance Imaging

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • INCLUSION CRITERIA:

    1. WHO Group 1 PH patients on either no medical therapy or stable medical therapy for at least the past 4 weeks (defined as no new PAH-specific therapy, no change in the dose of current PAH-specific therapy and no change in NYHA/WHO functional classification within the past 4 weeks) are eligible. The following parameters on RHC are required to meet the hemodynamic definition of PAH:
    1. mean pulmonary artery pressure of > 25 mmHg at rest,
    2. pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a left ventricular end-diastolic pressure of less than or equal to 12 mmHg) and
    3. pulmonary vascular resistance of > 3 Wood units (240 dyn.s.cm(-5).

If clinically indicated at the time of enrollment, then a RHC will be performed at the NIH Clinical Center upon study entry under a procedural consent.

2) Females who are able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to and for the duration of study participation.

EXCLUSION CRITERIA:

  1. Patients with WHO Group 1 PH and evidence of right heart failure as defined by:

    1. NYHA/WHO class IV symptoms and
    2. Echocardiographic evidence of severe RV dysfunction and
    3. Clinical evidence of right heart failure which may include, but is not limited to elevated jugular venous pressure, ascites, and lower extremity edema
  2. Patients with WHO Group 1 pulmonary hypertension and a prior diagnosis of cirrhosis with portal hypertension as evidenced by a history of ascites, hepatic encephalopathy and/or varices prior to enrollment
  3. Patients with WHO Group 1 pulmonary hypertension and evidence of active infection, (HIV patients with two consecutive viral loads of < 500 on their most recent determinations within the past 12 months will be considered to have inactive infection)
  4. Patients with WHO Group 1 pulmonary hypertension who have taken spironolactone or eplerenone within the last 30 days
  5. Known or suspected allergy to spironolactone
  6. Pregnant or breastfeeding women (all women of childbearing potential will be required to have a screening urine or blood pregnancy test)
  7. Age <18 years
  8. Inability to provide informed written consent for participation in the study
  9. Chronic kidney disease (an estimated glomerular filtration rate of < 35 mL/min/1.73m(2) of body surface area)
  10. Serum potassium at the time of enrollment of > 5 mEq/L
  11. Concurrent use of an ACE inhibitor and angiotensin II receptor blocker

    OR

    Patients currently taking the maximum recommended dose of an ACE inhibitor or an angiotensin II receptor blocker [For patients taking one of these medicines (ACE-Inhibitors or ARBs), the investigators agree to do due diligence by consulting a clinical center pharmacist and/or a standard pharmacy reference (i.e. Micromedex) to certify whether or not the patient is on a maximum dose of the drug.]

  12. Women currently taking drospirenone-containing oral contraceptives

Exclusion Criteria for MRI

These contraindications include but are not limited to the following devices or conditions:

  1. Implanted cardiac pacemaker or defibrillator
  2. Cochlear Implants
  3. Ocular foreign body (e.g. metal shavings)
  4. Embedded shrapnel fragments
  5. Central nervous system aneurysm clips
  6. Implanted neural stimulator
  7. Any implanted device that is incompatible with MRI
  8. Unsatisfactory performance status as judged by the referring physician such that the subject could not tolerate an MRI scan. Examples of medical conditions that would not be accepted would include unstable angina and severe dyspnea at rest
  9. Subjects requiring monitored sedation for MRI studies
  10. Subjects with a condition precluding entry into the scanner (e.g. morbid obesity, claustrophobia, etc.)
  11. Subjects with severe back-pain or motion disorders who will be unable to tolerate supine positioning within the MRI scanner and hold still for the duration of the examination.

EXCLUSION CRITERIA FOR GADOLINIUM BASED MRI STUDIES ONLY:

  1. History of severe allergic reaction to gadolinium contrast agents despite pre- medication with diphenhydramine and prednisone
  2. Chronic kidney disease (an estimated glomerular filtration rate of < 60 mL/min/1.73m(2) of body surface area)

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Group A

Group B

Arm Description

Spironolactone

Placebo

Outcomes

Primary Outcome Measures

Change in placebo corrected 6-minute walk distance
Change in placebo corrected 6-minute walk distance.

Secondary Outcome Measures

Change in placebo corrected VO2 max
Change in right ventricular function
Biomarkers of vascular inflammation
Rate of study drug discontinuation due to hyperkalemia, renal insufficiency, or other side effects such as breast pain and gynecomastia

Full Information

First Posted
October 20, 2012
Last Updated
October 20, 2023
Sponsor
National Institutes of Health Clinical Center (CC)
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), University of Pennsylvania, University of Maryland Medical Center, Medstar Health Research Institute, New England Medical Center, Tufts University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT01712620
Brief Title
Spironolactone for Pulmonary Arterial Hypertension
Official Title
A Pilot Study of the Effect of Spironolactone Therapy on Exercise Capacity and Endothelial Dysfunction in Pulmonary Arterial Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
July 6, 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 10, 2014 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institutes of Health Clinical Center (CC)
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), University of Pennsylvania, University of Maryland Medical Center, Medstar Health Research Institute, New England Medical Center, Tufts University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
Keywords
Magnetic Resonance Imaging

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group A
Arm Type
Experimental
Arm Description
Spironolactone
Arm Title
Group B
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Spironolactone
Intervention Description
Initial dose, 25 mg (pink capsule) orally, daily. If well tolerated at 7-9 wks then increased to 50 mg (brown capsule) daily.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Initial dose, pink sugar capsule, daily. If well tolerated at 7-9 wks then changed to brown sugar capsule, daily.
Primary Outcome Measure Information:
Title
Change in placebo corrected 6-minute walk distance
Description
Change in placebo corrected 6-minute walk distance.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Change in placebo corrected VO2 max
Time Frame
6 months
Title
Change in right ventricular function
Time Frame
6 months
Title
Biomarkers of vascular inflammation
Time Frame
6 months
Title
Rate of study drug discontinuation due to hyperkalemia, renal insufficiency, or other side effects such as breast pain and gynecomastia
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: WHO Group 1 PH patients on either no medical therapy or stable medical therapy for at least the past 4 weeks (defined as no new PAH-specific therapy, no change in the dose of current PAH-specific therapy and no change in NYHA/WHO functional classification within the past 4 weeks) are eligible. The following parameters on RHC are required to meet the hemodynamic definition of PAH: mean pulmonary artery pressure of > 25 mmHg at rest, pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a left ventricular end-diastolic pressure of less than or equal to 12 mmHg) and pulmonary vascular resistance of > 3 Wood units (240 dyn.s.cm(-5). If clinically indicated at the time of enrollment, then a RHC will be performed at the NIH Clinical Center upon study entry under a procedural consent. 2) Females who are able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to and for the duration of study participation. EXCLUSION CRITERIA: Patients with WHO Group 1 PH and evidence of right heart failure as defined by: NYHA/WHO class IV symptoms and Echocardiographic evidence of severe RV dysfunction and Clinical evidence of right heart failure which may include, but is not limited to elevated jugular venous pressure, ascites, and lower extremity edema Patients with WHO Group 1 pulmonary hypertension and a prior diagnosis of cirrhosis with portal hypertension as evidenced by a history of ascites, hepatic encephalopathy and/or varices prior to enrollment Patients with WHO Group 1 pulmonary hypertension and evidence of active infection, (HIV patients with two consecutive viral loads of < 500 on their most recent determinations within the past 12 months will be considered to have inactive infection) Patients with WHO Group 1 pulmonary hypertension who have taken spironolactone or eplerenone within the last 30 days Known or suspected allergy to spironolactone Pregnant or breastfeeding women (all women of childbearing potential will be required to have a screening urine or blood pregnancy test) Age <18 years Inability to provide informed written consent for participation in the study Chronic kidney disease (an estimated glomerular filtration rate of < 35 mL/min/1.73m(2) of body surface area) Serum potassium at the time of enrollment of > 5 mEq/L Concurrent use of an ACE inhibitor and angiotensin II receptor blocker OR Patients currently taking the maximum recommended dose of an ACE inhibitor or an angiotensin II receptor blocker [For patients taking one of these medicines (ACE-Inhibitors or ARBs), the investigators agree to do due diligence by consulting a clinical center pharmacist and/or a standard pharmacy reference (i.e. Micromedex) to certify whether or not the patient is on a maximum dose of the drug.] Women currently taking drospirenone-containing oral contraceptives Exclusion Criteria for MRI These contraindications include but are not limited to the following devices or conditions: Implanted cardiac pacemaker or defibrillator Cochlear Implants Ocular foreign body (e.g. metal shavings) Embedded shrapnel fragments Central nervous system aneurysm clips Implanted neural stimulator Any implanted device that is incompatible with MRI Unsatisfactory performance status as judged by the referring physician such that the subject could not tolerate an MRI scan. Examples of medical conditions that would not be accepted would include unstable angina and severe dyspnea at rest Subjects requiring monitored sedation for MRI studies Subjects with a condition precluding entry into the scanner (e.g. morbid obesity, claustrophobia, etc.) Subjects with severe back-pain or motion disorders who will be unable to tolerate supine positioning within the MRI scanner and hold still for the duration of the examination. EXCLUSION CRITERIA FOR GADOLINIUM BASED MRI STUDIES ONLY: History of severe allergic reaction to gadolinium contrast agents despite pre- medication with diphenhydramine and prednisone Chronic kidney disease (an estimated glomerular filtration rate of < 60 mL/min/1.73m(2) of body surface area)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Grace M Graninger, R.N.
Phone
(301) 496-9320
Email
ggraninger@cc.nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Michael A Solomon, M.D.
Phone
(301) 496-9320
Email
msolomon@cc.nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael A Solomon, M.D.
Organizational Affiliation
National Institutes of Health Clinical Center (CC)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY dial 711
Email
ccopr@nih.gov

12. IPD Sharing Statement

Citations:
PubMed Identifier
23547564
Citation
Elinoff JM, Rame JE, Forfia PR, Hall MK, Sun J, Gharib AM, Abd-Elmoniem K, Graninger G, Harper B, Danner RL, Solomon MA. A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial. Trials. 2013 Apr 2;14:91. doi: 10.1186/1745-6215-14-91.
Results Reference
derived
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2012-CC-0211.html
Description
NIH Clinical Center Detailed Web Page

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Spironolactone for Pulmonary Arterial Hypertension

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