Pharmacogenomics in Pulmonary Arterial Hypertension

Pulmonary Hypertension Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00593905
• Other study ID #: RC-4590
• Secondary ID: RC #4590
• Status: Withdrawn
• Start date: July 2005
• Est. completion date: July 2012

Study information

• Verified date: November 2021
• Source: West Penn Allegheny Health System
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.***

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: July 2012
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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).

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary
• PAH WHO Group I
• Pulmonary Arterial Hypertension
• Pulmonary Hypertension

Intervention

Drug:
• Sitaxsentan
Sitaxsentan sodium 100 mg tablet every morning
• Bosentan, Ambrisentan
Bosentan 125 mg tablet twice daily Ambrisentan 5-10 mg tablet once daily

Locations

Country	Name	City	State
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania

Sponsors (39)

Lead Sponsor

Collaborator

West Penn Allegheny Health System

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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	6 Minute Walk Test		12 months after initiation of drug therapy
Secondary	Hemodynamics - Right Heart Catheterization		12 months after intitation of drug therapy
Secondary	Borg		12 months after initiation of drug therapy
Secondary	Functional Class - FC		12 months after intitation of drug therapy
Secondary	Toxicities		12 months after initiation of drug therapy
Secondary	Time of Clinical Worsening		12 months after initiation of drug therapy
Secondary	Decline in WHO Functional Class		12 months after initiation of drug therapy

External Links

•   Pulmonary Hypertension Association website