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

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

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.

Study Overview

• Status: Terminated
• Conditions: Idiopathic Pulmonary Fibrosis; Pulmonary Hypertension
• Intervention / Treatment: Drug: Ambrisentan; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • St. Vincents Hospital
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • The Prince Charles Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Austria
  • Graz, Austria, 8036
    • Medizinische Universität Graz
  • Innsbruck, Austria
    • Universitätsklinikum Innsbruck
  • Vienna, Austria, 1090
    • Medizinische Universität Wien
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Peter Loughheed Center- Calgary General Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • University of British Columbia
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
    • Toronto, Ontario, Canada
      • Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Centre Hospitalier de l'Université de Montréal
    • Montreal, Quebec, Canada
      • Sir Mortimer B. Davis Jewish General Center
    • Sainte foy, Quebec, Canada, G1V 4G5
      • Centre de Pneumologie de L'Hospital Laval
• Germany
  • Berlin, Germany, 13125
    • Evangelische Lungenklinik Berlin
  • Berlin, Germany
    • Charite-Universitatsmedizin Berlin
  • Donaustauf, Germany, 93093
    • Krankenhaus Donaustauf der LVA
  • Freiburg, Germany, 79095
    • Universitätsklinikum Freiburg
  • Greifswald, Germany, 17475
    • Universitat Greifswald
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Heidelberg, Germany, 66126
    • Thorax Klinik
  • Munchen, Germany
    • LMU Klinikum der Universität
• Italy
  • Catania, Italy
    • Azienda Ospedaliero Universitaria
  • Forli, Italy
    • Presidio Ospedaliero G.B. Morgagni
  • Milan, Italy
    • Ospedale S.Giuseppe Fatebenefratelli
  • Milano, Italy, 20132
    • Unita Funzionale di Pneumologia e Fisiopatologia Respiratoria
  • Padova, Italy
    • Azienda Ospedaliera Di Padova
  • Palermo, Italy
    • Instituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione
  • Rome, Italy
    • Policlinico Universitario Tor Vergata
  • Siena, Italy, 53100
    • Azienda Ospedaliera Universitaria Senese
  • Torino, Italy, 10043
    • Centro delle Interstiziopatie Polmonari e Malattie Rare del Polmone
• United Kingdom
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital NHS Foundation Trust
  • Liverpool, United Kingdom
    • University Hospital Aintree
  • London, United Kingdom
    • University College Hosptial
  • Sheffield, United Kingdom
    • Royal Hallamshire Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Arizona
  • California
    • Davis, California, United States, 95817
      • University of California Davis
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine UCLA
    • San Diego, California, United States, 92103
      • University of California San Diego Medical Center
    • San Francisco, California, United States, 94143
      • University of California at San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Heatlh Sciences Center
  • Florida
    • Clearwater, Florida, United States, 33756
      • Bay Area Chest Physicians
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami Medical Center
    • Sarasota, Florida, United States, 34239
      • Sarasota Memorial Hospital
    • Sarasota, Florida, United States, 34233
      • Suncoast Lung Center
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Decatur, Georgia, United States, 30030
      • Atlanta Institute for Medical Research
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Kentucky
    • Louisville, Kentucky, United States
      • Kentuckiana Pulmonary Association
  • Maine
    • Portland, Maine, United States
      • Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deacones Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health Systems
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University
  • Nebraska
    • Omaha, Nebraska, United States, 68131
      • Creighton University Center for Allergy & Asthma
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Medical School
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
      • North Shore Health System
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina At Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Center for Research & Education at The Christ Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland Case Western
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University School of Medicine
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Cancer Institute
    • Pittsburgh, Pennsylvania, United States, 12512
      • Alleghany General Hospital
  • South Carolina
    • Charleston, South Carolina, United States
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Heart Institiute and Vascular Institute
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Health System
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Everett Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ambrisentan; 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; Ambrisentan (5 mg or 10 mg tablet) administered orally once daily.; Other Names: Letairis
PLACEBO_COMPARATOR: Placebo; 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; Ambrisentan (5 mg or 10 mg tablet) administered orally once daily.; Other Names: Letairis; Drug: Placebo; Placebo to match ambrisentan administered orally once daily.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Hunter Gillies, M.D., Gilead Sciences

Publications and helpful links

General Publications

• Ruocco G, Cekorja B, Rottoli P, Refini RM, Pellegrini M, Di Tommaso C, Del Castillo G, Franci B, Nuti R, Palazzuoli A. Role of BNP and echo measurement for pulmonary hypertension recognition in patients with interstitial lung disease: An algorithm application model. Respir Med. 2015 Mar;109(3):406-15. doi: 10.1016/j.rmed.2014.12.011. Epub 2015 Jan 3.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (ACTUAL): February 1, 2011
• Study Completion (ACTUAL): February 1, 2011

Study Registration Dates

• First Submitted: April 8, 2009
• First Submitted That Met QC Criteria: April 8, 2009
• First Posted (ESTIMATE): April 9, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): May 15, 2014
• Last Update Submitted That Met QC Criteria: May 5, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Cardiovascular; PH; Idiopathic Pulmonary Fibrosis; IPF; ERA; Endothelin Receptor Antagonist; Ambrisentan
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Hypertension; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Hypertension, Pulmonary; Antihypertensive Agents; Ambrisentan
• Other Study ID Numbers: GS-US-300-0128