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) - ARTEMIS-IPF

• Register: EUCTR
• Last refreshed on: 18 April 2012
• Main ID: EUCTR2008-004405-34-CZ
• Date of registration: 07/01/2009
• Prospective Registration: Yes
• Primary sponsor: Gilead Sciences Incorporated
• Public title: 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) - ARTEMIS-IPF
• Scientific title: 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) - ARTEMIS-IPF
• Date of first enrolment: 13/09/2010
• Target sample size: 660
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-004405-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Event-Driven If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Belgium, Czech Republic, France, Germany, Ireland, Italy, Netherlands, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or females from 40 to 80 years of age
2. Diagnosis of Idiopathic Pulmonary Fibrosis (IPF) based on the following criteria in
accordance with ATS-ERS guidelines for diagnosing IPF:
— Definite or probable UIP confirmed on SLB by core pathologist
or
— In absence of SLB, HRCT scan showing definite findings for IPF (bibasilar
reticular abnormalities with minimal ground glass opacities) as determined by core
review
and three of the following “minor criteria”:
— Age > 50 years
— Insidious onset of otherwise unexplained dyspnea on exertion
— Duration of illness = 3 months
— Bibasilar, inspiratory crackles
Within 90 days of study enrollment, diagnosis must be confirmed by HRCT
3. Honeycombing = 5% as assessed on HRCT; HRCT results will undergo a core review
process (please see Section 7.4 of the protocol) to confirm diagnosis.
4. Willingness to undergo RHC at baseline and at Visit 7 or end of study (EOS)
5. Willingness and ability to comply with required monitoring of liver function every
28 days. LFTs include serum ALT, AST, alkaline phosphatase, gamma glutamyl
transferase (GGT), and total bilirubin concentrations
6. Forced vital capacity (FVC) > 50 to = 95% of predicted with a ratio of
FEV1 (L) / FVC (L) = 0.7. Pulmonary function tests must be completed no more than
90 days before enrollment
7. Ability to perform and complete 6MWT at screening
8. Negative serum pregnancy test at screening and negative urine pregnancy test at
randomization for female subjects of childbearing potential (defined in Section 6.3 of the protocol).
9. Female subjects of childbearing potential must be willing to use at least two reliable
methods of contraception throughout their participation in the study and 30 days after
discontinuation of IMP unless the subject has had a tubal sterilization, is
postmenopausal, or has a Copper T 380A intrauterine device (IUD) or LNg 20 IUD
inserted, in which case no other contraception is needed. Subjects of childbearing
potential must also be willing to undergo pregnancy tests every 28 days.
10. Male subjects must be capable of understanding and acknowledging potential risks of
testicular tubular atrophy and infertility associated with taking this IMP as described
in the Informed Consent Form (ICF)
11. Competency to understand the information given in the Institutional Review Board
(IRB) or Independent Ethics Committee (IEC) approved ICF. Subjects must sign the
form prior to the initiation of any study procedures, unless the assessment is
performed in the routine care for this disease
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Diagnosis of an ILD or restrictive lung disease other than UIP or IPF
2. Obstructive lung disease as determined by evidence of airflow obstruction on HRCT
or physiologic criteria including:
• FEV1/FVC ratio < 0.7
• RV > 120% by plethysmography or significant (verified by radiologist) emphysema on HRCT if plethysmography not available
• Evidence of reactive airway disease by change in FEV1 of > 12% following bronchodilator challenge

3. Evidence of sustained improvement of IPF condition defined as improvement from
pre-therapy PFTs observed with two or more successive post-therapy PFTs over the
year prior to randomization
4. Condition(s) that is or are a contraindication for RHC including:
• Tricuspid or pulmonary valve stenosis
• Prosthetic tricuspid or pulmonary valve
• Right atrial or right ventricular masses
• Cyanotic heart disease
• Allergy to latex or catheter material
• Previous pneumonectomy.
5. Active or recent (= 60 days prior to enrollment) pulmonary or upper respiratory tract
infection
6. Hospitalization within 60 days of screening for an acute exacerbation of IPF
(AE-IPF)
7. Chronic heart failure (NYHA class III/IV) or known left ventricular ejection
fraction < 25%
8. Chronic treatment with the following drugs prescribed for IPF (within 4 weeks of
randomization):oral corticosteroids (> 20 mg/day of prednisone or equivalent),
immunosuppressive or cytotoxic drugs, antifibrotic drugs, chronic use of Nacetylcysteine
(prescribed for IPF)
9. Acute or chronic impairment (other than dyspnea) which limits the ability to comply
with study requirements and procedures including the 6MWT
10. Treatment with ambrisentan in a clinical study or with commercial product
11. Treatment with an approved or experimental ERA within 30 days prior to
randomization
12. Chronic use of sildenafil or other phosphodiesterase type 5 (PDE-5) inhibitor for
pulmonary hypertension
13. Chronic treatment with immunosuppressive, cytotoxic, or antifibrotic drugs including
pirfenidone, D-penicillamine, colchicine, TNF-a antagonists, imatinib,
interferon-gamma, cyclophosphamide, cyclosporine A, or azathioprine within 30 days
of randomization (Section 5.4 of the protocol)
14. Prior ERA treatment discontinued for any toxicity
15. ALT or AST > 1.5 × ULN at screening
16. Hemoglobin concentration < 75% of LLN at screening
17. Serum creatinine = 2.5 mg/dL (221 µmol/L) or subject requires hemodialysis,
peritoneal dialysis or hemofiltration
18. Systolic blood pressure < 85 mmHg
19. History of malignancies within the past 5 years, with the exception of basal cell
carcinoma of the skin or successfully treated in situ carcinoma of the cervix
20. Female who is pregnant or nursing
21. Known history of alcohol abuse within 1 year of enrollment
22. Participation in a clinical study involving another investigational drug or device (not placebo) within 28 days of screening
23. Comorbid condition or illness limiting life expectancy to < 1 year at time of screening
24. Serious or active medical or psychiatric condition which, in the opinion of the Investigator, would interfere with subject treatment, assessment or compliance with
the protocol


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Idiopathic pulmonary fibrosis (IPF)
MedDRA version: 9.1 Level: LLT Classification code 10021240 Term: Idiopathic pulmonary fibrosis

Intervention(s)

Trade Name: Letairis 5 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Ambrisentan
CAS Number: 177036-94-1
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Letairis 10 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Ambrisentan
CAS Number: 177036-94-1
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): A composite endpoint of Progression Free Survival (PFS) will be used in this study. The primary endpoint, time to death or disease progression, will be defined as the first incidence of any of the following:
• Either a decrease of =10% in FVC (L) and a decrease of = 5% in diffuse lung capacity for carbon monoxide (DLCO) (ml/min/mmHg) or 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 (as defined in Section 7.10 of the protocol).Events will be adjudicated by a blinded Endpoint Committee
• All-cause mortality.

Main Objective: The primary objective of the study is to determine if ambrisentan is effective in delaying disease progression and death in subjects with IPF.

Secondary Objective: Secondary objectives include evaluation of the safety and effect of ambrisentan on
development of pulmonary hypertension, quality of life and dyspnea symptoms in this patient population.

Exploratory evaluations will include changes in other disease-related assessments including the UNOS LAS, changes in microRNA expression and biomarkers related to IPF pathogenesis. Blood will be collected and stored for later analysis to determine relationships between serum and plasma marker levels and relation to treatment effect and outcomes measures.

Secondary ID(s)

GS-US-231-0101