Pharmacogenomics in Pulmonary Arterial Hypertension
| Status: | Completed |
|---|---|
| Conditions: | High Blood Pressure (Hypertension) |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 4/2/2016 |
| Start Date: | July 2005 |
| End Date: | July 2013 |
| Contact: | Andrea L Nowicki, BA |
| Email: | phgenotype@wpahs.org |
| Phone: | 412.359.3653 |
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.
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.
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.***
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.***
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).
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