Pharmacogenomics in Pulmonary Arterial Hypertension

Study Description

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

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 or disease	Intervention/treatment
Pulmonary Arterial Hypertension; Pulmonary Hypertension; PAH WHO Group I	Drug: Sitaxsentan; Drug: Bosentan, Ambrisentan

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.***

Study Design

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Study Type :	Observational
Estimated Enrollment :	1300 participants
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
Study Start Date :	July 2005
Estimated Primary Completion Date :	July 2012
Estimated Study Completion Date :	July 2013

Groups and Cohorts

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Group/Cohort	Intervention/treatment
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

Outcome Measures

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. 6 Minute Walk Test [ Time Frame: 12 months after initiation of drug therapy ]

Secondary Outcome Measures :

1. Hemodynamics - Right Heart Catheterization [ Time Frame: 12 months after intitation of drug therapy ]
2. Borg [ Time Frame: 12 months after initiation of drug therapy ]
3. Functional Class - FC [ Time Frame: 12 months after intitation of drug therapy ]
4. Toxicities [ Time Frame: 12 months after initiation of drug therapy ]
5. Time of Clinical Worsening [ Time Frame: 12 months after initiation of drug therapy ]
6. Decline in WHO Functional Class [ Time Frame: 12 months after initiation of drug therapy ]

Biospecimen Retention:   Samples With DNA

Whole Blood

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
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

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

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 Colorado

University Hospitals Cleveland Medical Center

University of Colorado, Denver

University of Michigan

University of Pittsburgh

University of Southern California

The University of Texas Medical Branch, 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

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Pulmonary Hypertension Association website 

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 ( Other Identifier: Allegheny General Hospital )
First Posted:	January 15, 2008
Last Update Posted:	January 24, 2012
Last Verified:	January 2012

Keywords provided by Raymond Benza, 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; Hypertension, Pulmonary; Familial Primary Pulmonary Hypertension; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases	Bosentan; Ambrisentan; Sitaxsentan; Endothelin Receptor Antagonists; Antihypertensive Agents; Molecular Mechanisms of Pharmacological Action