Clinical trial NCT00593905: Pharmacogenomics in Pulmonary Arterial Hypertension
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 type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Pulmonary Arterial Hypertension
Pulmonary Hypertension
PAH WHO Group I
Keywords: Pulmonary Arterial Hypertension
Pulmonary Hypertension
Pharmacogenomics
DNA Testing
sitaxsentan
bosentan
ambrisentan
elevated pulmonary artery pressures
Letairis
Tracleer
Thelin
Primary Pulmonary Hypertension
Pulmonary Artery
Lead sponsor: West Penn Allegheny Health System
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Baylor College of Medicine
name: Emory University
name: University of Chicago
name: Johns Hopkins University
name: Tufts Medical Center
name: Sir Mortimer B. Davis - Jewish General Hospital
name: London Health Sciences Centre
name: University of Maryland, College Park
name: University of California, San Francisco
name: University of Calgary
name: Chest Medical Associates
name: Columbia University
name: Lung Diagnostics, Ltd.
name: Duke University
name: University of California, Los Angeles
name: Latter Day Saints Hospital
name: Louisiana State University Health Sciences Center in New Orleans
name: Massachusetts General Hospital
name: Mayo Clinic
name: Medical College of Wisconsin
name: Southeastern Lung Care
name: Suncoast Lung Center
name: Children's Hospital Colorado
name: University Hospitals Cleveland Medical Center
name: University of Colorado, Denver
name: University of Michigan
name: University of Pittsburgh Medical Center
name: University of Southern California
name: The University of Texas Medical Branch, Galveston
name: Vanderbilt University
name: Wayne State University
name: Ohio State University
name: University of Alabama at Birmingham
name: Washington University School of Medicine
name: Sentara Norfolk General Hospital
name: University of Texas Southwestern Medical Center
name: Bay Area Chest Physicians
First posted: 2008-01-15
Enrollment: 0
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
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.

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.

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 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).

Primary outcomes:
measure: 6 Minute Walk Test
timeFrame: 12 months after initiation of drug therapy
Secondary outcomes:
measure: Hemodynamics - Right Heart Catheterization
timeFrame: 12 months after intitation of drug therapy
measure: Borg
timeFrame: 12 months after initiation of drug therapy
measure: Functional Class - FC
timeFrame: 12 months after intitation of drug therapy
measure: Toxicities
timeFrame: 12 months after initiation of drug therapy
measure: Time of Clinical Worsening
timeFrame: 12 months after initiation of drug therapy
measure: Decline in WHO Functional Class
timeFrame: 12 months after initiation of drug therapy
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
Study officials:
affiliation: Allegheny General Hospital/Allegheny-Singer Research Institute of West Penn Allegheny Health System
name: Raymond L Benza, MD
role: PRINCIPAL_INVESTIGATOR
References: