Official Title: “A Randomized, Multicenter Study of Ambrisentan and Sildenafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension Who Have Demonstrated a Sub-Optimal Response to Sildenafil”

Compare the change in pulmonary vascular resistance following the addition of ambrisentan or placebo to sildenafil therapy in subjects with pulmonary arterial hypertension who have demonstrated a sub-optimal response to sildenafil monotherapy.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: October 2009

Intervention(s) in this Clinical Trial

• Drug: ambrisentan and sildenafil
  • ambrisentan 5mg, 10mg, oral, one daily sildenafil 20mg through 100mg, oral
• Drug: placebo and sildenafil
  • placebo, oral, one daily sildenafil 20mg through 100mg, oral

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • ambrisentan plus sildenafil
• Placebo Comparator: 2
  • placebo plus sildenafil

Primary Measures

• The primary efficacy endpoint is the change from baseline in the PVR evaluated after 24 weeks. Efficacy endpoints supportive of the primary endpoint include change from baseline in other hemodynamic measures (mPAP, mean RAP and cardiac output).
  • Time Frame: 24 weeks
    Safety Issue?: Yes

Secondary Measures

• The secondary efficacy endpoints include: A change from baseline measured at week 24 in: - 6WMD - BDI immediately following exercise - CAMPHOR Quality of Life (QoL) - WHO functional class - NT-proBNP
  • Time Frame: 24 weeks
    Safety Issue?: Yes

Inclusion Criteria:

• Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
• 1. Subject must be between 16 and 75 years of age, inclusive, at the Screening Visit
• 2. Subject must weigh greater than 40 kg at the Screening Visit
• 3. Subject must have a current diagnosis of IPAH, FPAH, or PAH associated with:
• 1. Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed
• CTD, systemic lupus erythematosus, or overlap syndrome)
• 2. Congenital heart defects, including
• i. Congenital systemic-to-pulmonary shunts repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus) ii. Unrepaired secundum atrial septal defects iii. Eisenmenger Syndrome c. Anorexigen use d. HIV infection
• 4. Subject must have WHO functional class III symptoms at the Screening Visit, as assessed by the Investigator
• 5. Subject must be receiving sildenafil (Revatio or Viagra) monotherapy for the treatment of PAH at a stable dose of greater than 20 mg and less than 100 mg tid for at least 12 weeks prior to the Screening Visit
• 6. Subject must meet all of the following hemodynamic criteria by means of a RHC completed during the 3 weeks between the Screening and Randomization Visits:
• 1. mPAP of greater than 25 mmHg
• 2. PVR greater than 400 dyne-sec/cm5
• 3. PCWP or LVEDP of ≤15 mmHg
• 7. Subject must meet all of the following pulmonary function tests completed no more than 12 weeks before the Screening visit:
• 1. Total lung capacity (TLC) greater than 60% of predicted normal and 2. Forced expiratory volume in one second (FEV1) greater than 65% of predicted normal
• 8. Subject must walk a distance of at least 150 m but no more than 425 m during the screening 6-minute walk test
• 9. Subject must meet all of the following hematology criteria:
• 1. A hemoglobin concentration greater than 10 g/dL at the Screening Visit
• 2. A hematocrit greater than 30% at the Screening Visit
• 10. Subject (except for subjects with Eisenmenger Syndrome), with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) greater than 90% as measured by pulse oximetry at the Screening Visit. Subject that has PAH associated with Eisenmenger Syndrome must have SaO2 greater than 80% as measured by pulse oximetry at the Screening Visit.
• 11. Subject receiving CCBs or HMG-CoA reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks prior to the Screening Visit
• 12. Subject with a diagnosis of HIV must have stable disease status. For this study, stable HIV status is defined as:
• 1. No addition of medications for treatment of HIV for at least 8 weeks prior to screening
• 2. No active opportunistic infection during the Screening Period
• 3. No hospitalizations due to HIV for at least 4 weeks prior to screening
• 13. Female subject of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit. A female subject of childbearing potential is defined in Section 8.7.
• 14. Female subject of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of study drug (reliable methods of contraception are described in Section 8.7)
• 15. Male subject must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking this study drug and queried regarding his understanding of the potential risks as described in the Informed Consent Form (ICF)
• 16. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study
• 17. Subject must be competent to understand the information given in the Institutional
• Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF and must sign the form prior to the initiation of any study procedures

Exclusion Criteria:

• Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
• 1. Subject with a current PH diagnosis other than IPAH, FPAH, or PAH associated with:
• 1. Connective tissue disease (e.g., limited scleroderma, diffuse scleroderma, mixed
• CTD, systemic lupus erythematosus, or overlap syndrome)
• 2. Congenital heart defects, including
• i. Congenital systemic-to-pulmonary shunts repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus) ii. Unrepaired secundum atrial septal defects iii. Eisenmenger Syndrome c. Anorexigen use d. HIV infection
• 2. Subject previously treated with ambrisentan in another clinical study or treated with commercial product (Letairis)
• 3. Subject has received chronic prostanoid or ERA therapy within the 12 weeks prior to the Screening Visit. Chronic prostanoid use is considered >7 days of treatment.
• 4. Subject received ERA treatment (e.g., bosentan or sitaxsentan) at any time and discontinued for reasons other than those associated with liver function abnormalities
• 5. Subject receiving iv inotropes within 2 weeks prior to the Screening Visit
• 6. Subject has a serum ALT or AST lab value that is greater than 2.0xULN at the Screening Visit
• 7. Subject has a history of malignancies within the past 5 years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix
• 8. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject
• 9. Female subject who is pregnant or breastfeeding
• 10. Subject has demonstrated noncompliance with previous medical regimens
• 11. Subject has a recent history of abusing alcohol or illicit drugs
• 12. Subject has participated in a clinical study involving another investigational drug or device within 12 weeks before the Screening Visit
• 13. Subject has a known hypersensitivity to the study drugs, the metabolites, or formulation excipients

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 16 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Gilead Sciences

Overall Clinical Trial Officials and Contacts

Overall Contact: Sarah Gilroy 720-887-8582 sarah.gilroy@gilead.com

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00617305

Study ID Number: GS-US-300-0117

ClinicalTrials.gov Identifier: NCT00617305

Health Authority: United States: Food and Drug Administration