ARTEMIS-PH - Study of Ambrisentan in Subjects With Pulmonary Hypertension Associated With Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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Ambrisentan is an endothelin receptor antagonist used for the treatment of pulmonary hypertension (PH). Based on research suggesting a role for endothelin-1 in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the poor prognosis for patients with IPF who are also diagnosed with PH, this study was designed to evaluate the effectiveness and safety of ambrisentan in that patient population.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Parallel-Group Study to Evaluate the Efficacy and Safety of Ambrisentan in Subjects With Idiopathic Pulmonary Fibrosis and Pulmonary Hypertension

Conditions
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Idiopathic Pulmonary Fibrosis, Pulmonary Hypertension

Intervention / Treatment
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* Drug: Ambrisentan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Selected Inclusion Criteria: Weight ≥ 40 kg at screening Diagnosis of IPF based on modified American Thoracic Society-European Respiratory Society guidelines Diagnosis of PH based on the following hemodynamic requirements: mean pulmonary artery pressure (mPAP ≥ 25 mm Hg; pulmonary vascular resistance > 240 dyne.sec/cm^5; pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤ 15 mm Hg Forced vital capacity (FVC) ≥ 40% Able to walk at least 50 meters during two 6-minute walk tests If receiving calcium channel blockers, low-dose oral corticosteroids, immunosuppressive, cytoxic, or antifibrotic drugs dose must have been stable. Selected Exclusion Criteria: Diagnosis of PH primarily due to an etiology other than IPF Surgical lung biopsy diagnosis other than Usual Interstitial Pneumonia Other known cause of interstitial lung disease Evidence of significant obstructive lung disease Recent hospitalization for an acute exacerbation of IPF Recent active pulmonary or upper respiratory tract infection Left ventricular ejection fraction < 40% Serum creatinine ≥ 2.5 mg/dL Required hemodialysis, peritoneal dialysis, or hemofiltration Female subject who was pregnant or breastfeeding Recent treatment for PH with an endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor, or prostacyclin derivative Recent treatment with high dose oral corticosteroids Recent treatment (within 4 weeks prior to screening) with imatinib mesylate (Gleevec) Alanine aminotransferase or aspartate aminotransferase lab value that was greater than 1.5 x the upper limit of the normal range Discontinued other ERA treatment for any adverse reaction other than those associated with liver function test abnormalities

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ambrisentan<br>Participants were randomized to receive ambrisentan treatment at an initial dose of 5 mg for 4 weeks, followed by ambrisentan at the target dose of 10 mg for an additional 52 weeks | Drug: Ambrisentan<br>* Ambrisentan (5 mg or 10 mg tablet) administered orally once daily.<br>* Other names: Letairis;|
| Placebo Comparator: Placebo<br>Participants were randomized to receive placebo to match ambrisentan for 48 weeks, then transition to ambrisentan treatment at the initial dose of 5 mg for 4 weeks, followed by ambrisentan at the target dose of 10 mg for an additional 4 weeks. | Drug: Ambrisentan<br>* Ambrisentan (5 mg or 10 mg tablet) administered orally once daily.<br>* Other names: Letairis;Drug: Placebo<br>* Placebo to match ambrisentan administered orally once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Six-minute Walk Distance (6MWD). | The change from baseline in 6MWD at Week 16 (end of blinded treatment) was evaluated. | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term Survival | Long-term survival was assessed as a Kaplan-Meier (KM) estimate of the percent probability of survival, with censoring at Week 48. | Week 48 | 
| Transition Dyspnea Index (TDI) | The change in TDI at Week 16 (end of blinded treatment) was evaluated. TDI measures the change from the baseline characteristic Baseline Dyspnea Index. The TDI range is -9 to +9 (worst to best; 0 = no change). | Baseline to Week 16 | 
| Change From Baseline in WHO Functional Class | WHO functional class rates severity of pulmonary hypertension, with 4 categories on a scale of 1 to 4 with the worst category being 4. Change is represented as an increase (+1: Improved), decrease (-1: Deteriorated), or no change (0: No change) on the scale. | Baseline to Week 16 | 
| Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted | FVC is a pulmonary function test, and is defined as the volume of air that can forcibly be blown out after taking a full breath. FVC% predicted is defined as FVC% of the patient divided by the average FVC% in the population for any person of similar age, sex and body composition. | Baseline to Week 16 | 
| Change From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) | Assessment of the the level of the amino acid fragment NT-proBNP is used to establish prognosis in cardiovascular disease. | Baseline to Week 16 | 
| Change From Baseline in the Borg Dyspnea Index (BORG) Immediately Following Exercise | Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). | Baseline to Week 16 | 
| Hemoglobin-corrected Diffusing Capacity for Carbon Monoxide (DLCO) Percent Predicted | DLCO is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide. DLCO% predicted is defined as DLCO% of the patient divided by the average DLCO% in the population for any person of similar age, sex and body composition. | Baseline to Week 16 | 
| Change in Quality of Life (QOL) Score as Assessed by the Short-Form 36® (SF-36) | Each SF-36 score is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. An increase in score indicates an improvement in health state. | Baseline to Week 16 | 
| Change in QOL Score as Assessed by the St. George's Respiratory Questionnaire (SRGQ) | The SRGQ is designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency & severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations. | Baseline to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic Pulmonary Fibrosis, Pulmonary Hypertension, PH, IPF, Ambrisentan, ERA, Endothelin Receptor Antagonist, Cardiovascular