Pharmacogenomics in Pulmonary Arterial Hypertension

This study is currently recruiting participants.

Verified January 2012 by West Penn Allegheny Health System

First Received on January 3, 2008. Last Updated on January 20, 2012 History of Changes

Sponsor:	West Penn Allegheny Health System
Collaborators:	National Institutes of Health (NIH) Baylor College of Medicine Emory University University of Chicago Johns Hopkins University Tufts Medical Center Sir Mortimer B. Davis - Jewish General Hospital London Health Sciences Centre University of Maryland University of California, San Francisco University of Calgary Chest Medical Associates Columbia University Lung Diagnostics, Ltd. Duke University University of California, Los Angeles Latter Day Saints Hospital Louisiana State University Health Sciences Center in New Orleans Massachusetts General Hospital Mayo Clinic Medical College of Wisconsin Southeastern Lung Care Suncoast Lung Center Children's Hospital Colorad University Hospitals of Cleveland University of Colorado, Denver University of Michigan University of Pittsburgh University of Southern California The University of Texas, Galveston Vanderbilt University Wayne State University Ohio State University University of Alabama at Birmingham Washington University School of Medicine Sentara Norfolk General Hospital University of Texas Southwestern Medical Center Bay Area Chest Physicians
Information provided by (Responsible Party):	Raymond Benza, West Penn Allegheny Health System
ClinicalTrials.gov Identifier:	NCT00593905

Purpose

Our goal is to determine clinically in Pulmonary Arterial Hypertension patients if associations exist between the efficacy and toxicity of sitaxsentan, bosentan, and ambrisentan and several gene polymorphisms in several key disease-specific and therapy specific genes. Also characterized is the relationship between these polymorphisms and the severity of Pulmonary Arterial Hypertension using either baseline hemodynamic or clinical surrogates for disease severity.

Hypothesis: Polymorphisms influence the efficacy and toxicity of specific Pulmonary Arterial Hypertension therapy as well as development/severity of PAH via their effect on PA remodeling, drug response, or metabolism.

This study requires a one time 8.5 ml blood sample and clinical data to be obtained at initiation of therapy, 4 months after initiation of therapy and 12 months after initiation of therapy.

Condition	Intervention
Pulmonary Arterial Hypertension Pulmonary Hypertension PAH WHO Group I	Drug: Sitaxsentan Drug: Bosentan, Ambrisentan

Study Type:	Observational
Study Design:	Observational Model: Cohort
Official Title:	Pharmacogenomics in Pulmonary Arterial Hypertension: A Multi-Center International Study to Determine Whether in PAH Patients Clinical Associations Exist Between the Efficacy and Toxicity of Endothelin Receptor Antagonists and Several Gene Polymorphisms in Several Key Disease-Specific and Therapy Specific Genes

Resource links provided by NLM:

Genetics Home Reference related topics: Help Me Understand Genetics

MedlinePlus related topics: High Blood Pressure Pulmonary Hypertension

Drug Information available for: Bosentan Ambrisentan

U.S. FDA Resources

Further study details as provided by West Penn Allegheny Health System:

Primary Outcome Measures:

6 Minute Walk Test [ Time Frame: 12 months after initiation of drug therapy ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Hemodynamics - Right Heart Catheterization [ Time Frame: 12 months after intitation of drug therapy ] [ Designated as safety issue: No ]
Borg [ Time Frame: 12 months after initiation of drug therapy ] [ Designated as safety issue: No ]
Functional Class - FC [ Time Frame: 12 months after intitation of drug therapy ] [ Designated as safety issue: No ]
Toxicities [ Time Frame: 12 months after initiation of drug therapy ] [ Designated as safety issue: No ]
Time of Clinical Worsening [ Time Frame: 12 months after initiation of drug therapy ] [ Designated as safety issue: No ]
Decline in WHO Functional Class [ Time Frame: 12 months after initiation of drug therapy ] [ Designated as safety issue: No ]

Biospecimen Retention: Samples With DNA

Whole Blood

Estimated Enrollment:	1300
Study Start Date:	July 2005
Estimated Study Completion Date:	July 2013
Estimated Primary Completion Date:	July 2012 (Final data collection date for primary outcome measure)

Groups/Cohorts	Assigned Interventions
Group 1 GROUP 1 Patients have to be currently enrolled or previously enrolled in STRIDE FPH01, FPH01-XC FPH02, FPH02x, FPH03, FPH04 or FPH06. WHO Group 1 Pulmonary arterial Hypertension: Idiopathic, Familial, Associated with (APAH) Collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, Drugs and toxins (e.g., anorexigens, rapeseed oil, L-tryptophan, methamphetamine, and cocaine), other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) Associated with significant venous or capillary involvement, Pulmonary veno-occlusive disease, Pulmonary-capillary hemangiomatosis.	Drug: Sitaxsentan Sitaxsentan sodium 100 mg tablet every morning Other Name: Sitaxsentan-Thelin
Group 2 Group 2 Patients currently receiving bosentan or ambrisentan OR who have previously received bosentan or ambrisentan for greater than 4 (four) months. WHO Group 1 Pulmonary Arterial Hypertension: Idiopathic, Familial, Associated with (APAH), collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, drugs and toxins (e.g., anorexigens, rapeseed oil, L-tryptophan, methamphetamine, and cocaine), other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, or splenectomy), associated with significant venous or capillary involvement, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis.	Drug: Bosentan, Ambrisentan Bosentan 125 mg tablet twice daily Ambrisentan 5-10 mg tablet once daily Other Names: Bosentan-Tracleer Ambrisentan-Letairis

Groups/Cohorts

Assigned Interventions

Group 1

GROUP 1

Patients have to be currently enrolled or previously enrolled in STRIDE FPH01, FPH01-XC FPH02, FPH02x, FPH03, FPH04 or FPH06.
WHO Group 1 Pulmonary arterial Hypertension: Idiopathic, Familial, Associated with (APAH) Collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, Drugs and toxins (e.g., anorexigens, rapeseed oil, L-tryptophan, methamphetamine, and cocaine), other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) Associated with significant venous or capillary involvement, Pulmonary veno-occlusive disease, Pulmonary-capillary hemangiomatosis.

Drug: Sitaxsentan

Sitaxsentan sodium 100 mg tablet every morning

Other Name: Sitaxsentan-Thelin

Group 2

Patients currently receiving bosentan or ambrisentan OR who have previously received bosentan or ambrisentan for greater than 4 (four) months.
WHO Group 1 Pulmonary Arterial Hypertension: Idiopathic, Familial, Associated with (APAH), collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, drugs and toxins (e.g., anorexigens, rapeseed oil, L-tryptophan, methamphetamine, and cocaine), other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, or splenectomy), associated with significant venous or capillary involvement, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis.

Drug: Bosentan, Ambrisentan

Bosentan 125 mg tablet twice daily Ambrisentan 5-10 mg tablet once daily

Other Names:

Bosentan-Tracleer
Ambrisentan-Letairis

Detailed Description:

This study will make use of a large population of well defined patients with Pulmonary Arterial Hypertension who were enrolled in Encysive Pharmaceutical's STRIDE clinical trials or who have received bosentan or ambrisentan for 4 months or longer. This international study constitutes the largest clinical study of this deadly disease and in such has great potential to alter the clinical practice by revealing novel gene-drug interactions. This study tests the hypothesis by executing the following aims:

Aim 1: Determine in Pulmonary Arterial Hypertension (the relationship between known disease-specific polymorphisms (Serotonin transporter gene and PAI HindIII) and variants in BMPR2 and SMAD4 with several well-defined clinical efficacy endpoints of sitaxsentan, bosentan, and ambrisentan therapy.

Aim 2: Determine in Pulmonary Arterial Hypertension the relationship between existing potentially "therapy-specific" polymorphisms in the ET-1, ETAR, ETBR, NPR-C, prostacyclin receptor and prostacyclin synthase with several well-defined clinical efficacy endpoints of sitaxsentan, bosentan, and ambrisentan therapy.

Aim 3: Characterize the relationship between any treatment effect, these polymorphisms and PAH severity, using either clinical data or clinical surrogates for disease activity.

***This study was funded by the NIH from 2005 - 2009. In August 2009 a no-cost extension was granted and this study continued until the end of July 2010. Currently the study is still active and does still have several active sites participating; however, the study is funded by the internal institution and there is no contributing federal funding.***

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Patients must have been diagnosed with WHO Group 1 Pulmonary Arterial Hypertension: Idiopathic, Familial or Associated with (APAH) Collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, Drugs and toxins , other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) Associated with significant venous or capillary involvement, Pulmonary veno-occlusive disease, Pulmonary-capillary hemangiomatosis. Patients currently therapy must include sitaxsentan, bosentan, or ambrisentan OR patients must have previously been treated with sitaxsentan, bosentan or ambrisentan for 4 months or longer.

Criteria

Inclusion Criteria:

GROUP 1

Patients have to be currently enrolled or previously enrolled in STRIDE FPH01, FPH01-XC FPH02, FPH02x, FPH03, FPH04 or FPH06.
WHO Group 1 Pulmonary Arterial Hypertension: Idiopathic, Familial, Associated with (APAH) Collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, Drugs and toxins (e.g., anorexigens, rapeseed oil, L-tryptophan, methamphetamine, and cocaine), other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) Associated with significant venous or capillary involvement, Pulmonary veno-occlusive disease, Pulmonary-capillary hemangiomatosis.

GROUP 2

Patients currently receiving bosentan or ambrisentan OR who have previously received bosentan or ambrisentan for greater than 4 (four) months.
WHO Group 1 Pulmonary Arterial Hypertension: Idiopathic, Familial, Associated with (APAH), collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, drugs and toxins (e.g., anorexigens, rapeseed oil, L-tryptophan, methamphetamine, and cocaine), other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, or splenectomy), associated with significant venous or capillary involvement, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis.

Exclusion Criteria:

GROUP 1

Not enrolled in the Encysive Pharmaceutical's STRIDE study(sitaxsentan).
Known infectious disease (HIV, Hepatitis).

GROUP 2

Never enrolled in the STRIDE study for sitaxsentan patients.
Not currently or previously on bosentan or ambrisentan.
Patients who were previously on bosentan or ambrisentan must have been on bosentan or ambrisentan for greater than 4 months.
Known infectious disease (HIV, Hepatitis).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00593905

Contacts

Contact: Andrea L Nowicki, BA	412.359.3653	phgenotype@wpahs.org
Contact: Raymond L Benza, MD	412.359.3584	rbenza@wpahs.org

Locations

United States, Pennsylvania
Allegheny General Hospital	Recruiting
Pittsburgh, Pennsylvania, United States, 15212
Contact: Andrea L Nowicki, BA 412-359-3653 anowicki@wpahs.org
Contact: Raymond L Benza, MD 412.359.3584 rbenza@wpahs.org
Principal Investigator: Raymond L Benza, MD

Sponsors and Collaborators

West Penn Allegheny Health System

National Institutes of Health (NIH)

Baylor College of Medicine

Emory University

University of Chicago

Johns Hopkins University

Tufts Medical Center

Sir Mortimer B. Davis - Jewish General Hospital

London Health Sciences Centre

University of Maryland

University of California, San Francisco

University of Calgary

Chest Medical Associates

Columbia University

Lung Diagnostics, Ltd.

Duke University

University of California, Los Angeles

Latter Day Saints Hospital

Louisiana State University Health Sciences Center in New Orleans

Massachusetts General Hospital

Mayo Clinic

Medical College of Wisconsin

Southeastern Lung Care

Suncoast Lung Center

Children's Hospital Colorad

University Hospitals of Cleveland

University of Colorado, Denver

University of Michigan

University of Pittsburgh

University of Southern California

The University of Texas, Galveston

Vanderbilt University

Wayne State University

Ohio State University

University of Alabama at Birmingham

Washington University School of Medicine

Sentara Norfolk General Hospital

University of Texas Southwestern Medical Center

Bay Area Chest Physicians

Investigators

Principal Investigator:

Raymond L Benza, MD

Allegheny General Hospital/Allegheny-Singer Research Institute of West Penn Allegheny Health System

More Information

Additional Information:

Pulmonary Hypertension Association website This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Raymond Benza, Professor of Medicine, Drexel University College of Medicine, James Magovern Chair for Cardiovascular Research Director and Section Head Advanced Heart Failure, Transplant, Mechanical Circulatory Support and Pulmonary Hypertension Programs, West Penn Allegheny Health System
ClinicalTrials.gov Identifier:	NCT00593905 History of Changes
Other Study ID Numbers:	RC-4590, RC #4590
Study First Received:	January 3, 2008
Last Updated:	January 20, 2012
Health Authority:	United States: Institutional Review Board United States: Food and Drug Administration Canada: Ethics Review Committee Germany: Ethics Commission Mexico: Ethics Committee Netherlands: Independent Ethics Committee Poland: Ministry of Health Spain: Ethics Committee United Kingdom: Research Ethics Committee Australia: National Health and Medical Research Council Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by West Penn Allegheny Health System:

Pulmonary Arterial Hypertension
Pulmonary Hypertension
Pharmacogenomics
DNA Testing
sitaxsentan
bosentan
ambrisentan

elevated pulmonary artery pressures
Letairis
Tracleer
Thelin
Primary Pulmonary Hypertension
Pulmonary Artery

Additional relevant MeSH terms:

Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases

Bosentan
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 22, 2012