Study of Ambrisentan and Phosphodiesterase Type-5 Inhibitor (PDE-5i) to Treat Pulmonary Arterial Hypertension

Official Title: “An Open-label, Multicenter Study of Ambrisentan and a Phosphodiesterase Type-5 Inhibitor Combination Therapy in Subjects With Pulmonary Arterial Hypertension Who Have Demonstrated a Sub-Optimal Response to a Phosphodiesterase Type-5 Inhibitor”

To evaluate the change from baseline in pulmonary vascular resistance (PVR), and other hemodynamic parameters, following the addition of ambrisentan to background phosphodiesterase type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial hypertension (PAH) who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The primary objective of this study is to evaluate the change from baseline in pulmonary vascular resistance (PVR), and other hemodynamic parameters, following the addition of ambrisentan to background phosphodiesterase type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial hypertension (PAH) who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The secondary objectives of this study are to evaluate the change from baseline in other clinical measures of PAH following the addition of ambrisentan to background PDE-5i therapy in subjects with PAH who have demonstrated a sub-optimal response to PDE-5i monotherapy.

The safety and tolerability of ambrisentan/PDE-5i combination therapy will be evaluated throughout the study. In addition, long-term efficacy will be examined.

Intervention(s) in this Clinical Trial

• Drug: ambrisentan plus sildenafil or tadalafil
  • ambrisentan: 5mg to 10mg, oral, once daily sildenafil: 20mg to 100mg, oral, three times daily tadalafil: not to exceed 40mg, oral, once daily

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor for the treatment of PAH (sildenafil or tadalafil)

Primary Measures

• The primary efficacy endpoint is the change from baseline in PVR evaluated after 24 weeks. Efficacy endpoints supportive of the primary endpoint include other hemodynamic measures (mPAP, mean right atrial pressure [mRAP], and cardiac output).
  • Time Frame: 24 weeks
    Safety Issue?: No

Secondary Measures

• A change from baseline measured at week 24 in: 6WMD, BDI immediately following exercise, CAMPHOR Quality of Life (QoL), WHO functional class, and NT-proBNP.
  • Time Frame: 24 weeks
    Safety Issue?: No
• Time to clinical worsening of PAH evaluated for the 24-week primary endpoint period.
  • Time Frame: 24 weeks
    Safety Issue?: No
• Survival through the 24-week primary endpoint period.
  • Time Frame: 24 weeks
    Safety Issue?: No

• Select

Inclusion Criteria

• Must be between 16 and 75 years of age;
• Must weigh at least 40 kg;
• Have a current diagnosis of IPAH, FPAH, or PAH that is primarily due to connective tissue disease, congenital heart defects, drug or toxin use or HIV;
• Have WHO functional class III symptoms;
• Be receiving sildenafil or tadalafil monotherapy for the treatment of PAH for at least the past 12 weeks;
• Meet all of the following hemodynamic criteria by means of a right heart;
• catheterization: mPAP of at least 25 mmHg; PVR of at least 400 dyne*sec/cm5; LCWP or LVEDP of not more than 15 mmHg;
• Meet all of the following pulmonary function test criteria: total lung capacity at least 60% of predicted normal and forced expiratory volume in 1 second of at least 65% of predicted normal;
• Able to walk at least 150 meters during a 6-minute walk test (6MWT);
• If receiving CCBs or HMG-CoA reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks;
• If diagnosed with HIV, must have stable disease status.

Selected Exclusion Criteria:

• Have a current PH diagnosis other than IPAH, FPAH, or PAH;
• Have left ventricular ejection fraction (LVEF) ≤40% or clinically significant ischemic, valvular, or constrictive heart disease;
• Have received chronic prostanoid or ERA therapy within the past 12 weeks;
• Have discontinued ERA treatment for any adverse reaction other than those associated with liver function test abnormalities;
• Have received IV inotropes within 2 weeks;
• Have serum ALT or AST lab value that is greater than 2.0x the upper limit of normal.

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 Investigator: Gilead Sciences Industry

Information obtained from ClinicalTrials.gov on February 12, 2012

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