Natural History Study of Biomarkers in Pulmonary Arterial Hypertension

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01730092
First received: November 17, 2012
Last updated: September 3, 2014
Last verified: August 2014
  Purpose

Background:

- High blood pressure in the lungs, known as pulmonary arterial hypertension (PAH), is a rare disorder. Some people have disease-associated PAH and some have PAH from an unknown cause. Researchers want to follow the natural history of all PAH patients to understand how PAH progresses in order to discover targets for future research into new treatments. To further identify treatment targets, they will compare healthy volunteers to patients with PAH.

Objectives:

- To study the natural history of PAH.

Eligibility:

  • Individuals at least 18 years of age who have PAH.
  • Healthy volunteers at least 18 years of age.

Design:

  • Participants with PAH will have periodic visits to the National Institutes of Health Clinical Center. After the first visit, they will return in 6 months and then yearly or every other year for as long as the study continues.
  • The first visit will take up to 3 days. It will involve the following tests:
  • Physical exam and medical history
  • Blood and urine samples
  • Heart and lung function tests and imaging studies
  • Six-minute walk test
  • Questions about exercise and physical activity
  • Healthy volunteers will have only one visit to the Clinical Center, during which they will undergo screening tests, and complete many of the same tests as patients with PAH

Condition
Pulmonary Disease
Pulmonary Hypertension

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: A Natural History Study of Novel Biomarkers in Pulmonary Arterial Hypertension

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Examine whether any novel test (inflammatory markers or high resolution cardiac MRI), accurately classifies PAH subjects according to disease severity as assessed by their baseline 6-minute walk distance.

Estimated Enrollment: 270
Study Start Date: October 2012
Estimated Study Completion Date: August 2022
Estimated Primary Completion Date: August 2022 (Final data collection date for primary outcome measure)
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. However, despite mounting evidence of vascular inflammation in patients with PAH, detailed phenotypic studies are lacking on the temporal evolution of this process and its contribution to right ventricular (RV) and pulmonary vascular remodeling. We hypothesize that a detailed characterization of the temporal evolution of vascular inflammation and neurohormonal activation in PAH and its impact on RV and pulmonary vascular function will add prognostic value to traditional measures of disease severity and suggest novel therapeutic targets for future research.

Objectives:

Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in this natural history study investigating the ability of circulating markers of vascular inflammation as well as high-resolution cardiac magnetic resonance imaging (MRI) to accurately stage severity of disease and/or predict clinically relevant outcomes.

Methods:

The total population for the study will be 150 PAH subjects and approximately 55 age and gender matched controls (i.e. each healthy volunteer is matched to less than or equal to 3 PAH subjects).

PAH subjects will undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) plasma profiling of inflammatory markers 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); 5) high-resolution MRI-based determination of pulmonary vascular and RV structure and function and 6) Cardiac CT scan.

Plasma markers of endothelial inflammation, PBMC expression profiles, and high-resolution cardiac MRI will also be studied in age and gender matched controls to define normal ranges and variability for each of these novel assessments. Comparison of these results to PAH subjects at baseline will be used to determine the degree to which these investigative tests distinguish PAH patients from healthy subjects. Likewise, baseline clinical evaluations of PAH subjects will be used to examine whether any novel test (inflammatory markers, or cardiac MRI), accurately classifies patients according to their disease severity. In addition, these tests will be investigated prospectively for their ability to predict PAH disease progression. Disease progression will be defined prospectively as a decrease in the 6-minute walk distance of greater than or equal to10% from baseline or clinical worsening requiring an escalation in therapy, hospitalization due to right heart failure, transplantation or death.

Additional plasma will be collected from PAH subjects and age/gender matched control subjects. This material will be used to probe for new biomarkers and inflammatory factors using discovery based approaches (i.e. Proteomics and pulmonary artery endothelial cell bioassay).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION AND EXCLUSION CRITERIA FOR PAH SUBJECTS

Inclusion Criteria for PAH Subjects:

The following parameters on RHC are required to meet the hemodynamic definition of PAH (NYHA/WHO Group I PH):

  • mean pulmonary artery pressure of greater than 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 12mmHg) and
  • pulmonary vascular resistance of greater than 3 Wood units (240 dyn s cm(5)).

For patients with suspected PAH (Group I PH) who have not undergone a RHC and/or additional testing to confirm the diagnosis, this testing will be completed as clinically indicated under a procedural consent. If clinically indicated (diagnostic) testing indicates that the subject with suspected PAH does not in fact meet standard criteria for PAH (Group I PH), then the subject will be removed from the study.

Exclusion Criteria for PAH Subjects:

  • Pregnant or breastfeeding women (all women of childbearing potential will be required to have a screening urine or blood pregnancy test)
  • Age less than 18 years
  • Inability to provide informed written consent for participation in the study

INCLUSION AND EXCLUSION CRITERIA FOR HEALTHY CONTROL SUBJECTS

Inclusion Criteria for Control Subjects

Any healthy man or woman who is the appropriate age and gender for matching to a PAH patient

  • Must be eligible for MRI and Gadolinium Based MRI studies
  • Must be eligible for CT and Iodine Based Contrast CT studies

Exclusion Criteria for Healthy Control Subjects

  • Current pregnancy or breastfeeding (All women of childbearing potential will be required to have a screening urine or blood pregnancy test)
  • Electrocardiographic evidence of clinically relevant heart disease
  • Symptoms of coronary or cardiac insufficiency
  • More than one major risk factor for coronary artery disease (excluding age and gender)
  • Obesity (defined as a body mass index > 30 kg/m(2))
  • History of underlying conditions/risk factors associated with pulmonary hypertension such as collagen vascular disease, HIV infection, use of appetite suppressants, chronic liver disease or cirrhosis of the liver, chronic thromboembolic disease, congenital heart defects, hypoxemia and/or significant pulmonary parenchymal disease
  • Systemic hypertension that is not well controlled (i.e. blood pressure at the time of screening greater than or equal to140/90 mmHg) on medications. Subjects taking > 2 anti-hypertensive medications will be excluded irrespective of their current blood pressure at time of screening
  • Anemia, thrombocytopenia or coagulopathy
  • Renal insufficiency (defined as an estimated glomerular filtration rate of < 60 mL/min/1.73m(2) of body surface area)
  • Active tobacco use (> 1 month) in the past ten years, any tobacco use within 30 days prior to the screening evaluation or any tobacco use prior to completion of the study
  • Inability to provide informed written consent for participation in the study
  • History of recreational drug use with the exception of marijuana (as long as marijuana use was > 3 months from the time of study screening).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01730092

Contacts
Contact: Grace M Graninger, R.N. (301) 496-9320 ggraninger@cc.nih.gov
Contact: Michael A Solomon, M.D. (301) 496-9320 msolomon@cc.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Michael A Solomon, M.D. National Institutes of Health Clinical Center (CC)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01730092     History of Changes
Other Study ID Numbers: 130012, 13-CC-0012
Study First Received: November 17, 2012
Last Updated: September 3, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Vascular Inflammation
Microarray
Right Ventricular Function
Endothelial Dysfunction
Magnetic Resonance Imaging

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Lung Diseases
Cardiovascular Diseases
Respiratory Tract Diseases
Vascular Diseases

ClinicalTrials.gov processed this record on October 29, 2014