Pharmacogenomics in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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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
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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.***

Official Title
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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

Conditions
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Pulmonary Arterial Hypertension, Pulmonary Hypertension, PAH WHO Group I

Intervention / Treatment
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* Drug: Sitaxsentan
* Drug: Bosentan, Ambrisentan


Participation Criteria
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Eligibility Criteria
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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).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>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<br>* Sitaxsentan sodium 100 mg tablet every morning<br>* Other names: Sitaxsentan-Thelin;|
| Group 2<br>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<br>* Bosentan 125 mg tablet twice daily Ambrisentan 5-10 mg tablet once daily<br>* Other names: Ambrisentan-Letairis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Minute Walk Test |  | 12 months after initiation of drug therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics - Right Heart Catheterization |  | 12 months after intitation of drug therapy | 
| Borg |  | 12 months after initiation of drug therapy | 
| Functional Class - FC |  | 12 months after intitation of drug therapy | 
| Toxicities |  | 12 months after initiation 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Letairis, Pulmonary Arterial Hypertension, Pulmonary Hypertension, Pharmacogenomics, DNA Testing, sitaxsentan, bosentan, ambrisentan, elevated pulmonary artery pressures, Tracleer, Thelin, Primary Pulmonary Hypertension, Pulmonary Artery