(ARTEMIS-IPF) Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF (ARTEMIS-IPF)

ARTEMIS-IPF: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Parallel-Group, Event Driven Study to Evaluate the Efficacy and Safety of Ambrisentan in Subjects With Early Idiopathic Pulmonary Fibrosis (IPF)

The ARTEMIS-IPF study was conducted to determine if ambrisentan was effective in delaying disease progression and death in participants with idiopathic pulmonary fibrosis (IPF), to evaluate its safety, and to evaluate its effect on development of pulmonary hypertension, quality of life, and dyspnea (shortness of breath) symptoms in this participant population. Participants were randomized in a 2:1 ratio to receive ambrisentan or placebo, respectively. Participation in the study was to be up to 4 years, depending on how long it would take to enroll participants and observe study events. After randomization, visits to the clinic took place every 3 months, and laboratory procedures were performed every month.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 494
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425DES
  • Ciudad Autonoma de Buenos Aires, Argentina, C1280AEB
  • Ciudad Autonoma de Buenos Aires, Argentina, C1181ACH
  • Mar del Plata, Buenos Aires, Argentina, B7602DCK
  • San Miguel de Tucuman, Argentina, T4000HXU
  • Provincia de Buenos Aires
    • Mar del Plata, Provincia de Buenos Aires, Argentina, B7602DCK
• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
    • Darlinghurst, New South Wales, Australia, 2010
  • Queensland
    • Chermside, Queensland, Australia, 4032
  • South Australia
    • Woodville, South Australia, Australia, 5011
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
  • Victoria
    • Parkville, Victoria, Australia, 3050
    • Prahran, Victoria, Australia, 3181
  • Western Australia
    • Perth, Western Australia, Australia, 6000
• Austria
  • Graz, Austria, 8036
  • Innsbruck, Austria, 6020
  • Linz, Austria, 4020
  • Wien, Austria, 1090
• Belgium
  • Anderlecht, Belgium, 1070
  • Bruxelles, Belgium, 1200
  • Leuven, Belgium, 3000
  • Yvoir, Belgium, 5530
• Brazil
  • Belo Horizonte, Brazil, 30430-1
  • Florianopolis, Brazil, 88040-970
  • Goiania, Brazil, 74605-050
  • Porto Alegre, Brazil, 90610-000
  • Porto Alegre, Brazil, 91350-200
  • Porto Alegre, Brazil, 90035-074
  • Rio de Janeiro, Brazil, 21949-900
  • Santo Andre, Brazil, 09060-650
  • Sao Paolo, Brazil, 04023-062
• Canada
  • Toronto, Canada, M4X1104
  • Alberta
    • Calgary, Alberta, Canada, T1Y6J4
    • Edmondton, Alberta, Canada, T6G 2C8
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
    • Vancouver, British Columbia, Canada, V6Z 1YP
  • Newfoundland and Labrador
    • St. Johns, Newfoundland and Labrador, Canada, A1B 3V6
  • Quebec
    • Montreal, Quebec, Canada, H2W1T8
    • Sainte Foy, Quebec, Canada, G1V 4G5
• Chile
  • Santiago, Chile, 7500691
  • Talcahuano, Chile, 4270918
  • Valparaiso, Chile, 2352499
• Colombia
  • Bogota, Colombia
  • Floridablanca, Colombia
• Czech Republic
  • Brno, Czech Republic, 625-00
  • Hradec Kralove, Czech Republic, 500 05
  • Jihlava, Czech Republic, 586 33
  • Liberec, Czech Republic, 460 63
  • Olomouc, Czech Republic, 775-20
  • Plzen, Czech Republic, 305 99
• France
  • Lille, France, 59037
  • Marseille, France, 13009
  • Montpellier, France, 34295
  • Nice, France, 06002
  • Paris, France, 75018
  • Paris, France, 75015
  • Pessac, France, 33604
  • Rennes, France, 35033
  • Tours, France, 37044
• Germany
  • Berlin, Germany, 10117
  • Berlin, Germany, D-13125
  • Coswig, Germany, 01640
  • Donaustauf, Germany, 93093
  • Essen, Germany, D-45239
  • Freiburg, Germany, 79106
  • Greifswald, Germany, D-17475
  • Heidelberg, Germany, 69126
  • Lowenstein, Germany, D-74245
  • Munchen, Germany, 81377
• Ireland
  • Dublin, Ireland, 7
• Israel
  • Ashkelon, Israel, 78306
  • Beer-Sheva, Israel, 84101
  • Haifa, Israel, 34362
  • Haifa, Israel, 31096
  • Jerusalem, Israel, 91120
  • Jerusalem, Israel, 91031
  • Petach Tikva, Israel, 49100
  • Rehovot, Israel, 76100
  • Tel Aviv, Israel, 64239
  • Tel-Hashomer, Israel, 52621
• Italy
  • Catania, Italy, 95123
  • Forlì, Italy, 47100
  • Milano, Italy, 20132
  • Milano, Italy, 20123
  • Modena, Italy, 41100
  • Napoli, Italy, 80131
  • Padova, Italy, 35128
  • Palermo, Italy, 90127
  • Roma, Italy, 00133
  • Siena, Italy, 53100
  • Torino, Italy, 10043
• Mexico
  • Huixquilucan Edo. de Mexico, Mexico, 52763
  • Mexico City, DF, Mexico, 14080
  • Monterrey, Mexico, 64460
  • Zapopan, Jalisco, Mexico, 45200
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44670
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64718
• Netherlands
  • Almelo, Netherlands, 7609 PP
• Peru
  • Callao, Peru, Callao 02
  • Lima, Peru, Lima 27
  • Lima, Peru, Lima 41
  • Lima, Peru, Lima 01
  • Lima, Peru, L31
  • Lima, Peru, L33
• Poland
  • Bydgoszcz, Poland, 85-681
  • Lodz, Poland, 90-153
• Spain
  • Badalona, Spain, 08916
  • Barcelona, Spain, 08036
  • Madrid, Spain, 28007
  • Andalucia
    • Cadiz, Andalucia, Spain, 11009
    • Sevilla, Andalucia, Spain, 41011
      • Hospital Virgen del Rocio
  • Asturias
    • Oviedo, Asturias, Spain, 33006
  • Castilla
    • Leon, Castilla, Spain, 24080
      • Complejo Asistencial Universitario de León
  • Galicia
    • Pontevedra, Galicia, Spain, 36071
  • Madrid, Communidad de
    • Pozuelo de Alarcon, Madrid, Communidad de, Spain, 28223
• Switzerland
  • Basel, Switzerland, 4031
  • Bern, Switzerland, 3010
  • Lausanne, Switzerland, 1011
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QQ
  • Chelmsford, United Kingdom, CM1 7ET
  • Edinburgh, United Kingdom, EH16 4SA
  • Glasgow, United Kingdom, G4 0SF
  • Liverpool, United Kingdom, L9 7AL
  • London, United Kingdom, NW1 2PG
  • London, United Kingdom, SW3 6NP
  • Mancesheter, United Kingdom, M23 9LT
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
  • Surrey
    • Chertsey, Surrey, United Kingdom, KT16 0PZ
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama At Birmingham Hospital
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Pulmonary Associates
    • Scottsdale, Arizona, United States, 85258
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA(Harbor-UCLA Medical Center)
    • Sacramento, California, United States, 95817
      • University of California, Davis
    • San Diego, California, United States, 92103-8373
    • San Francisco, California, United States, 94143
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Medical and Research Center
  • Delaware
    • Newark, Delaware, United States, 19713
  • Florida
    • Clearwater, Florida, United States, 33756
      • Bay Area Chest Physicians
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Tampa, Florida, United States, 33606
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Iowa
    • Council Bluffs, Iowa, United States, 51503
  • Kentucky
    • Louisville, Kentucky, United States, 40202
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Association
  • Maryland
    • Baltimore, Maryland, United States, 21201
    • Baltimore, Maryland, United States, 21205
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
    • Boston, Massachusetts, United States, 02115
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Saint Lukes Foundation
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Medical School
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
    • Piscataway, New Jersey, United States, 08854
    • Summit, New Jersey, United States, 07091
      • Pulmonary & Allergy Associates
  • New York
    • Albany, New York, United States, 12205
      • Pulmonary And Critical Care Services, P.C.
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10029
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
    • Cleveland, Ohio, United States, 44795
      • The Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43215
  • Oregon
    • Portland, Oregon, United States, 97220
      • The Oregon Clinic, P.C.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health Systems
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15212
    • Reading, Pennsylvania, United States, 19611
      • The Reading Hospital and Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Lexington, South Carolina, United States, 29072
    • Spartanburg, South Carolina, United States, 29303
  • Tennessee
    • Nashville, Tennessee, United States, 37232
  • Texas
    • Houston, Texas, United States, 77030
    • McKinney, Texas, United States, 75069
  • Utah
    • Provo, Utah, United States, 84604
    • Salt Lake City, Utah, United States, 84108
  • Virginia
    • Charlottesville, Virginia, United States, 22908
    • Falls Church, Virginia, United States, 22042
    • Lynchburg, Virginia, United States, 24501
  • Washington
    • Everett, Washington, United States, 98201
    • Seattle, Washington, United States, 98195

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or females from 40 to 80 years of age
• Diagnosis of IPF
• Honeycombing (fibrosis in the lung) on high-resolution computerised tomography (HRCT) scan of less than or equal to 5%
• Willing and able to have 2 right heart catheterizations performed
• Willing to have monthly lab tests to monitor liver function
• Able to perform the 6 minute walk test (indicated adequate physical function)
• Must have meet lung function requirements
• Normal liver function tests
• Negative serum pregnancy test
• Willing to use at least 2 reliable methods of contraception
• Able to understand and willing to sign informed consent form

Exclusion Criteria:

• No restrictive lung disease (other than usual interstitial pneumonia or IPF)
• No obstructive lung disease
• No recent or active respiratory exacerbations
• No recent hospitalization for an IPF exacerbation
• No recent history of alcohol abuse
• Chronic sildenafil (or same drug class) use for pulmonary hypertension
• Chronic treatment with certain medications for IPF within 30 days of randomization
• No other serious medical conditions

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Death or Disease (IPF) Progression.	The median time to death or disease progression was based on Kaplan-Meier (KM) estimates of pooling over strata, and was defined as the first occurrence of any of the following: Either 1) a decrease of ≥ 10% in FVC (L) and a decrease of ≥ 5% in diffuse lung capacity for carbon monoxide (DLCO) (ml/min/mmHg), or 2) a decrease of ≥ 5% in FVC (L) and a decrease of ≥ 15% in DLCO (ml/min/mmHg); deterioration in FVC and DLCO must be confirmed at the subsequent visit within 28 (± 14) days; Respiratory hospitalization (hospitalization involving worsening of, or deterioration in respiratory symptoms, gas exchange/hypoxemia, or radiographic findings on chest x-ray or high-resolution computerised tomography (HRCT) scan; All-cause mortality	Up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With No Disease Progression or Death at 48 Weeks	The proportion of participants with no disease progression or death is presented as a percentage using a Kaplan-Meier (KM) estimate of survival or not experiencing disease progression.	Baseline and Week 48
Change in FVC % Predicted at Week 48	FVC is defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted is defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition.	Baseline and Week 48
Change in DLCO % Predicted at Week 48	DLCO is the extent to which oxygen passes from the air sacs of the lungs into the blood. DLCO % predicted is defined as DLCO % of the participant divided by the average DLCO % in the population for any person of similar age, sex and body composition.	Baseline and Week 48
Change in 6MWT at Week 48	The 6MWT is a measure of exercise tolerance, and measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface.	Baseline and Week 48
Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36)	The range of each health domain score is 0-100, with 0 indicating a poorer health state and 100 indicating a better health state. An increase in score indicates an improvement in health state.	Baseline and Week 48
Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ)	The SGRQ is designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airways disease. The range of each score is 0-100, with 0 indicating fewer limitations and 100 indicating more limitations; an increase in score indicates an increase in limitations.	Baseline and Week 48
Change in Dyspnea Score at Week 48 as Assessed by the Transitional Dyspnea Index (TDI)	The transitional focal score (-9 to 9) is the sum of relative change from baseline for the Functional Impairment, Magnitude of Task, and Magnitude of Effort scores (each -3 to 3 scale). A TDI score of -9 represents a maximum degradation of all three tests; a score of 9 represents a maximum improvement of all three tests.	Baseline and Week 48
Percentage of Participants Who Developed PH on Study	The percentage of participants known to have developed pulmonary hypertension on study documented by right heart catheterization (RHC) was analyzed. RHC was done at baseline and 48 weeks, or at the early termination visit.	Up to 48 weeks

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Chair: Ganesh Raghu, MD, University of Washington, Div. of Pulmonary and Critical Care Medicine Chair

Publications and helpful links

General Publications

• Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, Martinez FJ, Nathan SD, Wells AU, Collard HR, Costabel U, Richeldi L, de Andrade J, Khalil N, Morrison LD, Lederer DJ, Shao L, Li X, Pedersen PS, Montgomery AB, Chien JW, O'Riordan TG; ARTEMIS-IPF Investigators*. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013 May 7;158(9):641-9. doi: 10.7326/0003-4819-158-9-201305070-00003. Erratum In: Ann Intern Med. 2014 May 6;160(9):658.
• Raghu G, Lynch D, Godwin JD, Webb R, Colby TV, Leslie KO, Behr J, Brown KK, Egan JJ, Flaherty KR, Martinez FJ, Wells AU, Shao L, Zhou H, Pedersen PS, Sood R, Montgomery AB, O'Riordan TG. Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial. Lancet Respir Med. 2014 Apr;2(4):277-84. doi: 10.1016/S2213-2600(14)70011-6. Epub 2014 Feb 18.
• Chien JW, Richards TJ, Gibson KF, Zhang Y, Lindell KO, Shao L, Lyman SK, Adamkewicz JI, Smith V, Kaminski N, O'Riordan T. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. Eur Respir J. 2014 May;43(5):1430-8. doi: 10.1183/09031936.00141013. Epub 2013 Oct 31.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (ACTUAL): February 1, 2011
• Study Completion (ACTUAL): February 1, 2011

Study Registration Dates

• First Submitted: October 7, 2008
• First Submitted That Met QC Criteria: October 7, 2008
• First Posted (ESTIMATE): October 8, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): April 8, 2014
• Last Update Submitted That Met QC Criteria: February 27, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: interstitial lung disease; idiopathic pulmonary fibrosis; ambrisentan
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Fibrosis; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Antihypertensive Agents; Ambrisentan
• Other Study ID Numbers: GS-US-231-0101