Pharmacogenomics in Pulmonary Arterial Hypertension

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Pulmonary Arterial Hypertension; Pulmonary Hypertension; PAH WHO Group I
• Intervention / Treatment: 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 Type: Observational

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

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 Names: 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Pulmonary Hypertension Association website

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: January 3, 2008
• First Submitted That Met QC Criteria: January 3, 2008
• First Posted (Estimate): January 15, 2008

Study Record Updates

• Last Update Posted (Actual): December 9, 2021
• Last Update Submitted That Met QC Criteria: November 29, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Pulmonary Arterial Hypertension; Pharmacogenomics; ambrisentan; DNA Testing; bosentan; sitaxsentan; elevated pulmonary artery pressures; Letairis; Tracleer; Thelin; Primary Pulmonary Hypertension; Pulmonary Artery
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan; Sitaxsentan; Ambrisentan
• Other Study ID Numbers: RC-4590; RC #4590 (Other Identifier: Allegheny General Hospital)