PAH WHO Group I, Pulmonary Arterial Hypertension, Pulmonary Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension, Pulmonary Hypertension, Pharmacogenomics, DNA Testing, sitaxsentan, bosentan, ambrisentan, elevated pulmonary artery pressures, Letairis, Tracleer, Thelin, Primary Pulmonary Hypertension, Pulmonary Artery
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.\*\*\*
Interventions
DRUGSitaxsentan
Sitaxsentan sodium 100 mg tablet every morning
DRUGBosentan, Ambrisentan
Bosentan 125 mg tablet twice daily Ambrisentan 5-10 mg tablet once daily
Sponsors
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, College Park
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 Medical Center
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
West Penn Allegheny Health System
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 6 Minute Walk Test | 12 months after initiation of drug therapy |
Secondary
| Measure | Time frame |
|---|---|
| Borg | 12 months after initiation of drug therapy |
| Functional Class - FC | 12 months after intitation of drug therapy |
| Hemodynamics - Right Heart Catheterization | 12 months after intitation of drug therapy |
| Time of Clinical Worsening | 12 months after initiation of drug therapy |
| Decline in WHO Functional Class | 12 months after initiation of drug therapy |
| Toxicities | 12 months after initiation of drug therapy |
Countries
United States
Outcome results
None listed