Clinical Trial: Hormonal, Metabolic, and Signaling Interactions in PAH

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: Hormonal, Metabolic, and Signaling Interaction in Pulmonary Arterial Hypertension

Brief Summary: Our hypothesis is that optimal treatment of the dysfunctional metabolic pathways which underlie PAH will improve pulmonary vascular function and consequences of the disease.

Detailed Summary:

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 a
Sponsor: Vanderbilt University

Current Primary Outcome:

  • 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 nitrotyrosin

    Original Primary Outcome:

    • 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.


    Current Secondary Outcome:

    • 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)



    Original Secondary Outcome: 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.


    Information By: Vanderbilt University Medical Center

    Dates:
    Date Received: January 15, 2013
    Date Started: September 2012
    Date Completion: September 2017
    Last Updated: February 16, 2017
    Last Verified: February 2017