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Hormonal, Metabolic, and Signaling Interactions in PAH

This study is currently recruiting participants.
Verified February 2017 by Jim Loyd, Vanderbilt University
Sponsor:
ClinicalTrials.gov Identifier:
NCT01884051
First Posted: June 21, 2013
Last Update Posted: October 31, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Jim Loyd, Vanderbilt University
January 15, 2013
June 21, 2013
October 31, 2017
September 2012
July 2022   (Final data collection date for primary outcome measure)
  • Ratio of sex hormone metabolites [ Time Frame: 5 years ]
    The primary outcome measure is the ratio of 2-hydroxyestrogens to 16-hydroxyestrogens among patients compared to both controls and at risk but well subjects.
  • Evaluation of insulin resistance in pulmonary arterial hypertension patients/Clinical trial of Metformin in Pulmonary Arterial Hypertension [ Time Frame: 5 years ]
    We will assess various measures of insulin resistance among patients, compared to healthy control subjects as well as at risk but well subjects. The primary measure will be assessed using the glucose clamp technique to quantify insulin secretion and resistance.
  • Mechanism, safety, and efficacy of ACE-2 (Angiotensin Converting Enzyme 2) in the treatment of PAH. [ Time Frame: 5 years ]
    We will assess the safety and efficacy of ACE-2 for the treatment of established PAH. The primary objective of the study is to determine safety of rhACE2 when administered as a single dose or multiple doses intravenously to subjects with PAH receiving background PAH-specific therapy.
  • Clinical Trial of Metformin in Pulmonary Arterial Hypertension [ Time Frame: 3 years ]

    Specific Aim 1. To test the hypothesis that metformin will ameliorate oxidant stress in pulmonary arterial hypertension Primary safety endpoint: absence of lactic acidosis, withdrawal from the study if attributed to metformin Primary efficacy endpoint: change in urinary and plasma oxidant stress measures (F2 isoprostanes and metabolites, isofurans, and nitrotyrosine)

    Specific Aim 2. To test the hypothesis that metformin will decrease myocardial lipid content, increase oxidative metabolism and decrease glucose uptake.

    Primary Endpoints: change in myocardial percent triglycerides (%TGs), kmono/RPP of C11 acetate, and uptake of FDG before and after metformin.

  • Ratio of sex hormone metabolites [ Time Frame: 5 years ]
    The primary outcome measure is the ratio of 2-hydroxyestrogens to 16-hydroxyestrogens among patients compared to both controls and at risk but well subjects.
  • Evaluation of insulin resistance in pulmonary arterial hypertension patients. [ Time Frame: 5 ]
    We will assess various measures of insulin resistance among patients, compared to healthy control subjects as well as at risk but well subjects. The primary measure will be assessed using the glucose clamp technique to quantify insulin secretion and resistance.
  • Mechanism, safety, and efficacy of ACE-2 in the treatment of PAH. [ Time Frame: 5 years ]
    We will assess the safety and efficacy of ACE-2 for the treatment of established PAH. Primary outcome measure will be the six-minute walk test to determine subject improvement or clinical worsening.
Complete list of historical versions of study NCT01884051 on ClinicalTrials.gov Archive Site
  • Mechanism, safety, and efficacy of ACE-2 in the treatment of PAH. [ Time Frame: 5-year ]
    The secondary objective of the study is to evaluate changes in biomarkers of disease (BNP, AngII/Ang (1-7, serum soluble IDH, serum NO, cardiac troponin I, SOD2 activity, urine isoprostanes and isofuranes) in subjects with PAH receiving rhACE2. We will also evaluate changes in pulmonary and systemic hemodynamics and echocardiographic markers of right heart function in patients receiving rhACE2.
  • Clinical Trial of Metformin in Pulmonary Arterial Hypertension [ Time Frame: 3 years ]

    Specific Aim 1. To test the hypothesis that metformin will ameliorate oxidant stress in pulmonary arterial hypertension

    Secondary Endpoints: lung cellular proliferation as measured by FDG avidity, change in the markers of insulin resistance and sensitivity, BMPR2 expression in peripheral blood mononuclear cells, and change in glucose and lipid metabolites.

    Specific Aim 2. To test the hypothesis that metformin will decrease myocardial lipid content, increase oxidative metabolism and decrease glucose uptake.

    Secondary Endpoints: change in RVEF, RV mass index, insulin resistance and sensitivity indices, glucose and lipid metabolites, and six-minute walk distance (6MWD)

Mechanism, safety, and efficacy of ACE-2 in the treatment of PAH. [ Time Frame: 5-year ]
Secondary outcomes will be hemodynamics measured by right heart catheterization and PET Scans to measure organ specific changes in metabolites known to be disrupted by PAH.
Not Provided
Not Provided
 
Hormonal, Metabolic, and Signaling Interactions in PAH
Hormonal, Metabolic, and Signaling Interaction in Pulmonary Arterial Hypertension
Our hypothesis is that optimal treatment of the dysfunctional metabolic pathways which underlie PAH will improve pulmonary vascular function and consequences of the disease.

Project 1: This project will work to understand why women are affected by pulmonary arterial hypertension (PAH) so much more often than men. This observation is true in heritable, idiopathic and associated forms of PAH. While males and females have some similar hormone levels, certain hormones exist at higher levels in each gender. For example, estrogen levels are much higher in females, and thus seemed the most sensible place to start looking for differences that may be affecting disease. In a small, early study of our heritable patients, we found differences in how patients break down estrogens as compared to healthy control subjects. Now, we want to confirm that what we found is true in a much larger group of patients that includes idiopathic and associated forms of PAH. We will also look to see if testosterone and other androgenic hormones are somehow protective for males. If the observation holds true in the larger group of patients, then we may try to "fix" the hormone imbalance in a mouse model of PAH with a drug therapy, and see if it helps improve the mouse pulmonary hypertension without bad side effects to the animals. If the animal drug studies work, then we may be able to try this drug in patients to see if it will work as a human treatment.

Project 2: Despite major advances in understanding PAH in recent decades, safe, effective and tolerable therapies remain elusive. The metabolic syndrome (central obesity, insulin resistance, high blood pressure and hyperlipidemia—fats in the blood) has been implicated in PAH. Treating the downstream consequences of insulin resistance in the pulmonary vasculature is a new approach to effective intervention against this highly mortal disease. This project will study the role of insulin resistance in pulmonary arterial hypertension and determine if therapies to treat insulin resistance will improve pulmonary arterial hypertension.

Project 3: In Project 3, we are working on the theory that PAH can be treated by fixing cell-cell junctions in blood vessels with a drug called recombinant ACE2(angiotensin converting enzyme 2). This is the only approach so far that has worked to reverse disease in mouse models of heritable PAH, but we need to better understand how it is working and make sure it has long term safety in animal models before starting human trials, hopefully within a few years. Definition: Cell-cell junctions-all of our organs and body structures are made from cells. Normally, these cells (think of a balloon filled with water) line up right next to each other so that the cell membranes touch each other. Materials can flow from one cell to the next. In PAH patients it is believed that the cells in the linings of the small arteries are not able to line up together as they should.

Observational
Observational Model: Cohort
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:

We plan to collect the following samples on all subjects:

DNA, RNA, white cells, plasma, serum, urine

We plan to collect the following samples on selected subjects:

Skin biopsy

Non-Probability Sample
Cohort 1 subjects will be recruited from our adult and pediatric pulmonary vascular disease clinics. Cohort 2-healthy controls will be recruited form patients families and the general public in middle Tennesssee.
  • Idiopathic Pulmonary Arterial Hypertension
  • Heritable Pulmonary Arterial Hypertension
  • Scleroderma Associated Pulmonary Arterial Hypertension
  • Appetite Suppressant Associate PAH
Not Provided
  • PAH patients
    Patients diagnosed with WHO Group 1 PAH
  • Healthy subjects
    Subjects who have been evaluated for heart and lung disease and found to be healthy

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
2120
July 2022
July 2022   (Final data collection date for primary outcome measure)

Inclusion Criteria:

Project 1

Inclusion:

  1. Diagnosis of IPAH (idiopathic pulmonary arterial hypertension), HPAH (heritable pulmonary arterial hypertension), or APAH (associated pulmonary arterial hypertension), family members of affected persons
  2. Age 0-90, age 12-90 for skin biopsy

Exclusion:

  1. Other diagnosis
  2. Age greater than 90, age less than 12 or greater than 90 for skin biopsy

Project 2

Inclusion:

  1. Diagnosis of IPAH, HPAH, or APAH, family members of affected persons
  2. 0-90
  3. Subjects with reasonably easy access to clinic for blood collection and other testing
  4. Subject able to tolerate fasting state prior to sample collection and EndoPAT (endothelial function assessment) testing

Exclusion:

  1. Other diagnosis
  2. 0-90
  3. Subjects with difficulty reaching clinic for blood collection and other testing
  4. Subjects unable to tolerate fasting state

Project 3

Inclusion:

  1. Diagnosis of IPAH, HPAH, or APAH, family members of affected persons
  2. 7-90

Exclusion:

  1. Other diagnosis
  2. Age less than 7 or greater than 90

    Exclusion Criteria:

Sexes Eligible for Study: All
up to 90 Years   (Child, Adult, Senior)
Yes
Contact: Lisa Wheeler, BSMT 800-288-0378 lisa.wheeler@vanderbilt.edu
Contact: Shannon Cordell, BSN 615-343-8277 shannon.eason@vanderbilt.edu
United States
 
 
NCT01884051
P01HL108800( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
Jim Loyd, Vanderbilt University
Vanderbilt University
Not Provided
Principal Investigator: James E Loyd, MD Vanderbilt University Medical Center
Vanderbilt University Medical Center
February 2017