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

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00768300
• Collaborator: (none)
• Enrollment: 494
• Locations: 185
• Arms: 2
• Duration (Months): 26
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: Ambrisentan; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 494 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Feb 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Time to Death or Disease (IPF) Progression. [Up to 48 months]

   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

Secondary Outcome Measures

1. Proportion of Participants With No Disease Progression or Death at 48 Weeks [Baseline and Week 48]

   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.

2. Change in FVC % Predicted at Week 48 [Baseline and 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.

3. Change in DLCO % Predicted at Week 48 [Baseline and 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.

4. Change in 6MWT at Week 48 [Baseline and 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.

5. Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36) [Baseline and Week 48]

   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.

6. Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ) [Baseline and Week 48]

   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.

7. Change in Dyspnea Score at Week 48 as Assessed by the Transitional Dyspnea Index (TDI) [Baseline and Week 48]

   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.

8. Percentage of Participants Who Developed PH on Study [Up to 48 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Hospital	Birmingham	Alabama	United States	35294
2	Pulmonary Associates	Phoenix	Arizona	United States	85006
3		Scottsdale	Arizona	United States	85258
4	David Geffen School of Medicine at UCLA(Harbor-UCLA Medical Center)	Los Angeles	California	United States	90095
5	University of California, Davis	Sacramento	California	United States	95817
6		San Diego	California	United States	92103-8373
7		San Francisco	California	United States	94143
8	Stanford University	Stanford	California	United States	94305
9	National Jewish Medical And Research Center	Denver	Colorado	United States	80206
10		Newark	Delaware	United States	19713
11	Bay Area Chest Physicians	Clearwater	Florida	United States	33756
12	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
13		Tampa	Florida	United States	33606
14	Emory University	Atlanta	Georgia	United States	30322
15	University of Chicago	Chicago	Illinois	United States	60637
16		Council Bluffs	Iowa	United States	51503
17	Kentuckiana Pulmonary Association	Louisville	Kentucky	United States	40202
18		Louisville	Kentucky	United States	40202
19		Baltimore	Maryland	United States	21201
20		Baltimore	Maryland	United States	21205
21		Boston	Massachusetts	United States	02115
22		Boston	Massachusetts	United States	02215
23		Ann Arbor	Michigan	United States	48109
24	Mayo Clinic	Rochester	Minnesota	United States	55905
25	Saint Lukes Foundation	Chesterfield	Missouri	United States	63017
26	Dartmouth Medical School	Lebanon	New Hampshire	United States	03756
27		New Brunswick	New Jersey	United States	08903
28		Piscataway	New Jersey	United States	08854
29	Pulmonary & Allergy Associates	Summit	New Jersey	United States	07091
30	Pulmonary And Critical Care Services, P.C.	Albany	New York	United States	12205
31	Winthrop University Hospital	Mineola	New York	United States	11501
32		New Hyde Park	New York	United States	11040
33		New York	New York	United States	10029
34	Columbia University Medical Center	New York	New York	United States	10032
35	Duke University Medical Center	Durham	North Carolina	United States	27710
36		Cincinnati	Ohio	United States	45267
37	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44795
38		Columbus	Ohio	United States	43215
39	The Oregon Clinic, P.C.	Portland	Oregon	United States	97220
40	University of Pennsylvania Health Systems	Philadelphia	Pennsylvania	United States	19104
41		Philadelphia	Pennsylvania	United States	19140
42		Pittsburgh	Pennsylvania	United States	15212
43	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
44	The Reading Hospital and Medical Center	Reading	Pennsylvania	United States	19611
45	Medical University of South Carolina	Charleston	South Carolina	United States	29425
46		Lexington	South Carolina	United States	29072
47		Spartanburg	South Carolina	United States	29303
48		Nashville	Tennessee	United States	37232
49		Houston	Texas	United States	77030
50		McKinney	Texas	United States	75069
51		Provo	Utah	United States	84604
52		Salt Lake City	Utah	United States	84108
53		Charlottesville	Virginia	United States	22908
54		Falls Church	Virginia	United States	22042
55		Lynchburg	Virginia	United States	24501
56		Everett	Washington	United States	98201
57		Seattle	Washington	United States	98195
58		Mar del Plata	Provincia de Buenos Aires	Argentina	B7602DCK
59		Buenos Aires		Argentina	C1425DES
60		Ciudad Autonoma de Buenos Aires		Argentina	C1181ACH
61		Ciudad Autonoma de Buenos Aires		Argentina	C1280AEB
62		Mar del Plata, Buenos Aires		Argentina	B7602DCK
63		San Miguel de Tucuman		Argentina	T4000HXU
64		Concord	New South Wales	Australia	2139
65		Darlinghurst	New South Wales	Australia	2010
66		Chermside	Queensland	Australia	4032
67		Woodville	South Australia	Australia	5011
68		Hobart	Tasmania	Australia	7000
69		Parkville	Victoria	Australia	3050
70		Prahran	Victoria	Australia	3181
71		Perth	Western Australia	Australia	6000
72		Graz		Austria	8036
73		Innsbruck		Austria	6020
74		Linz		Austria	4020
75		Wien		Austria	1090
76		Anderlecht		Belgium	1070
77		Bruxelles		Belgium	1200
78		Leuven		Belgium	3000
79		Yvoir		Belgium	5530
80		Belo Horizonte		Brazil	30430-1
81		Florianopolis		Brazil	88040-970
82		Goiania		Brazil	74605-050
83		Porto Alegre		Brazil	90035-074
84		Porto Alegre		Brazil	90610-000
85		Porto Alegre		Brazil	91350-200
86		Rio de Janeiro		Brazil	21949-900
87		Santo Andre		Brazil	09060-650
88		Sao Paolo		Brazil	04023-062
89		Calgary	Alberta	Canada	T1Y6J4
90		Edmondton	Alberta	Canada	T6G 2C8
91		Vancouver	British Columbia	Canada	V5Z 1M9
92		Vancouver	British Columbia	Canada	V6Z 1YP
93		St. Johns	Newfoundland and Labrador	Canada	A1B 3V6
94		Montreal	Quebec	Canada	H2W1T8
95		Sainte Foy	Quebec	Canada	G1V 4G5
96		Toronto		Canada	M4X1104
97		Santiago		Chile	7500691
98		Talcahuano		Chile	4270918
99		Valparaiso		Chile	2352499
100		Bogota		Colombia
101		Floridablanca		Colombia
102		Brno		Czech Republic	625-00
103		Hradec Kralove		Czech Republic	500 05
104		Jihlava		Czech Republic	586 33
105		Liberec		Czech Republic	460 63
106		Olomouc		Czech Republic	775-20
107		Plzen		Czech Republic	305 99
108		Lille		France	59037
109		Marseille		France	13009
110		Montpellier		France	34295
111		Nice		France	06002
112		Paris		France	75015
113		Paris		France	75018
114		Pessac		France	33604
115		Rennes		France	35033
116		Tours		France	37044
117		Berlin		Germany	10117
118		Berlin		Germany	D-13125
119		Coswig		Germany	01640
120		Donaustauf		Germany	93093
121		Essen		Germany	D-45239
122		Freiburg		Germany	79106
123		Greifswald		Germany	D-17475
124		Heidelberg		Germany	69126
125		Lowenstein		Germany	D-74245
126		Munchen		Germany	81377
127		Dublin		Ireland	7
128		Ashkelon		Israel	78306
129		Beer-Sheva		Israel	84101
130		Haifa		Israel	31096
131		Haifa		Israel	34362
132		Jerusalem		Israel	91031
133		Jerusalem		Israel	91120
134		Petach Tikva		Israel	49100
135		Rehovot		Israel	76100
136		Tel Aviv		Israel	64239
137		Tel-Hashomer		Israel	52621
138		Catania		Italy	95123
139		Forlì		Italy	47100
140		Milano		Italy	20123
141		Milano		Italy	20132
142		Modena		Italy	41100
143		Napoli		Italy	80131
144		Padova		Italy	35128
145		Palermo		Italy	90127
146		Roma		Italy	00133
147		Siena		Italy	53100
148		Torino		Italy	10043
149		Guadalajara	Jalisco	Mexico	44670
150		Monterrey	Nuevo Leon	Mexico	64718
151		Huixquilucan Edo. de Mexico		Mexico	52763
152		Mexico City, DF		Mexico	14080
153		Monterrey		Mexico	64460
154		Zapopan, Jalisco		Mexico	45200
155		Almelo		Netherlands	7609 PP
156		Callao		Peru	Callao 02
157		Lima		Peru	L31
158		Lima		Peru	L33
159		Lima		Peru	Lima 01
160		Lima		Peru	Lima 27
161		Lima		Peru	Lima 41
162		Bydgoszcz		Poland	85-681
163		Lodz		Poland	90-153
164		Cadiz	Andalucia	Spain	11009
165	Hospital Virgen del Rocio	Sevilla	Andalucia	Spain	41011
166		Oviedo	Asturias	Spain	33006
167	Complejo Asistencial Universitario de León	Leon	Castilla	Spain	24080
168		Pontevedra	Galicia	Spain	36071
169		Pozuelo de Alarcon	Madrid, Communidad de	Spain	28223
170		Badalona		Spain	08916
171		Barcelona		Spain	08036
172		Madrid		Spain	28007
173		Basel		Switzerland	4031
174		Bern		Switzerland	3010
175		Lausanne		Switzerland	1011
176		Sheffield	South Yorkshire	United Kingdom	S10 2JF
177		Chertsey	Surrey	United Kingdom	KT16 0PZ
178		Cambridge		United Kingdom	CB2 2QQ
179		Chelmsford		United Kingdom	CM1 7ET
180		Edinburgh		United Kingdom	EH16 4SA
181		Glasgow		United Kingdom	G4 0SF
182		Liverpool		United Kingdom	L9 7AL
183		London		United Kingdom	NW1 2PG
184		London		United Kingdom	SW3 6NP
185		Mancesheter		United Kingdom	M23 9LT

Sponsors and Collaborators

• Gilead Sciences

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00768300
• Other Study ID Numbers: GS-US-231-0101
• First Posted: Oct 8, 2008
• Last Update Posted: Apr 8, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Gilead Sciences: idiopathic pulmonary fibrosis; interstitial lung disease; ambrisentan
• Additional relevant MeSH terms: Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Ambrisentan

Study Results

Participant Flow

Recruitment Details	Participants were enrolled in a total of 136 study sites in North and South America, Europe, and Australia. The first participant was screened on 10 December 2008. The last participant observation was on 28 February 2011.
Pre-assignment Detail	494 participants were randomized; 492 participants were treated, and comprise the Safety Analysis Set and the Full Analysis Set.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Period Title: Overall Study
STARTED	330	164
Randomized and Treated	329	163
COMPLETED	1	1
NOT COMPLETED	329	163

Baseline Characteristics

Arm/Group Title	Ambrisentan	Placebo	Total
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily	Total of all reporting groups
Overall Participants	329	163	492
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.8 (7.4)	66.1 (7.1)	65.9 (7.3)
Sex: Female, Male (Count of Participants)
Female	85 25.8%	52 31.9%	137 27.8%
Male	244 74.2%	111 68.1%	355 72.2%
Race/Ethnicity, Customized (participants) [Number]
Black or African Heritage	1 0.3%	0 0%	1 0.2%
White	293 89.1%	145 89%	438 89%
Asian	4 1.2%	1 0.6%	5 1%
American Indian or Alaskan Native	1 0.3%	1 0.6%	2 0.4%
Other	27 8.2%	16 9.8%	43 8.7%
Not Permitted	3 0.9%	0 0%	3 0.6%
Region of Enrollment (participants) [Number]
United States	141 42.9%	62 38%	203 41.3%
Canada	25 7.6%	14 8.6%	39 7.9%
Australia	22 6.7%	12 7.4%	34 6.9%
France	21 6.4%	10 6.1%	31 6.3%
Germany	17 5.2%	9 5.5%	26 5.3%
Brazil	18 5.5%	6 3.7%	24 4.9%
Peru	12 3.6%	6 3.7%	18 3.7%
Czech Republic	10 3%	6 3.7%	16 3.3%
Israel	8 2.4%	7 4.3%	15 3%
Italy	11 3.3%	3 1.8%	14 2.8%
Belgium	7 2.1%	6 3.7%	13 2.6%
Colombia	8 2.4%	3 1.8%	11 2.2%
Mexico	5 1.5%	4 2.5%	9 1.8%
United Kingdom	3 0.9%	6 3.7%	9 1.8%
Spain	7 2.1%	1 0.6%	8 1.6%
Poland	3 0.9%	3 1.8%	6 1.2%
Switzerland	5 1.5%	1 0.6%	6 1.2%
Austria	2 0.6%	2 1.2%	4 0.8%
Chile	3 0.9%	1 0.6%	4 0.8%
Argentina	1 0.3%	2 1.2%	3 0.6%
Ireland	1 0.3%	0 0%	1 0.2%
Baseline Pulmonary Hypertension (PH) per interactive voice response system (IVRS) (participants) [Number]
No	293 89.1%	145 89%	438 89%
Yes	36 10.9%	18 11%	54 11%
Smoking status (participants) [Number]
Never	105 31.9%	53 32.5%	158 32.1%
Current	7 2.1%	5 3.1%	12 2.4%
Former	217 66%	104 63.8%	321 65.2%
Surgical lung biopsy (SLB) to Confirm Diagnosis of IPF (per IVRS) (participants) [Number]
No	175 53.2%	87 53.4%	262 53.3%
Yes	154 46.8%	76 46.6%	230 46.7%
Disease duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.13 (1.39)	0.91 (1.19)	1.06 (1.33)
Forced vital capacity (FVC) percent predicted (percentage of FVC % predicted) [Least Squares Mean (Standard Deviation) ]
Least Squares Mean (Standard Deviation) [percentage of FVC % predicted]	68.74 (13.12)	69.86 (13.75)	69.11 (13.33)
Six mile walk test (6MWT) (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	410.4 (118.7)	420.5 (121.4)	413.7 (119.6)
Hemoglobin Adjusted Diffusing lung capacity for carbon monoxide (DLCO) percent predicted (percentage of DLCO % predicted) [Least Squares Mean (Standard Deviation) ]
Least Squares Mean (Standard Deviation) [percentage of DLCO % predicted]	42.04 (13.77)	45.57 (13.25)	43.20 (13.69)
Prior IPF Medications (participants) [Number]
No	205 62.3%	97 59.5%	302 61.4%
Yes	124 37.7%	65 39.9%	189 38.4%
N-acetylcysteine (NAC) Use (participants) [Number]
No	310 94.2%	153 93.9%	463 94.1%
Yes	19 5.8%	8 4.9%	27 5.5%

Outcome Measures

1. Primary Outcome

Title	Time to Death or Disease (IPF) Progression.
Description	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
Time Frame	Up to 48 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set: participants who were randomized and treated

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	329	163
Median (Inter-Quartile Range) [weeks]	84.14	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	P-value was based on a stratified log-rank test with strata of baseline presence of pulmonary hypertension and whether a surgical lung biopsy was performed with definite or probable usual interstitial pneumonia (UIP) based on core pathology review.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; 1.14 to 2.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was based on a stratified Cox proportional hazards model with strata of baseline presence of pulmonary hypertension and whether a surgical lung biopsy was performed with definite or probable UIP based on core pathology review.

2. Secondary Outcome

Title	Proportion of Participants With No Disease Progression or Death at 48 Weeks
Description	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.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	329	163
Number [percentage of participants]	65 19.8%	80 49.1%

3. Secondary Outcome

Title	Change in FVC % Predicted at Week 48
Description	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.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with evaluable change data were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	163	80
Mean (Standard Deviation) [percent change in FVC % predicted]	-10.24 (25.95)	-5.28 (15.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments	P-value was calculated using the Van Elteren test with strata of baseline presence of PH and whether a SLB was performed with definite or probable UIP based on core pathology review.
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Point estimate
	Estimated Value	4.29
	Confidence Interval	(2-Sided) 95%; -0.805 to 9.376
	Parameter Dispersion	Type: Value:
	Estimation Comments	The point estimate and 95% confidence interval (CI) were based on the Hodges-Lehmann Estimate of treatment effect for percent change from baseline.

4. Secondary Outcome

Title	Change in DLCO % Predicted at Week 48
Description	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.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with evaluable change data were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	163	80
Mean (Standard Deviation) [percent change in DLCO % predicted]	-2.68 (27.60)	-11.28 (32.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.250
	Comments	P-value was calculated using the Van Elteren test with strata of baseline presence of PH and whether a SLB was performed with definite or probable UIP based on core pathology review.
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Point estimate
	Estimated Value	2.85
	Confidence Interval	(2-Sided) 95%; -2.20 to 7.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	The point estimate and its 95% CI were based on the Hodges-Lehmann Estimate of treatment effect for percent change from baseline.

5. Secondary Outcome

Title	Change in 6MWT at Week 48
Description	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.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with evaluable change data were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	162	80
Mean (Standard Deviation) [meters]	-52.5 (148.7)	-10.6 (89.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.150
	Comments	P-value was calculated using the Van Elteren test with strata of baseline presence of PH and whether a SLB was performed with definite or probable UIP based on core pathology review.
	Method	Van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Point estimate
	Estimated Value	16.00
	Confidence Interval	(2-Sided) 95%; -5.00 to 37.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	The point estimate and 95% CI were based on the Hodges-Lehmann Estimate of treatment effect for percent change from baseline.

6. Secondary Outcome

Title	Change in Quality of Life (QOL) Score at Week 48 as Assessed by the Short-Form 36® (SF-36)
Description	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.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with evaluable change data were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	158	78
Physical function	-1.65 (10.86)	-2.60 (7.25)
General Health	-2.81 (9.77)	-1.95 (8.63)
Vitality	-1.67 (12.67)	-0.12 (7.69)

7. Secondary Outcome

Title	Change in Quality of Life (QOL) Score at Week 48 as Assessed by the St. George's Respiratory Questionnaire (SGRQ)
Description	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.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with evaluable change data were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	159	78
Symptoms Score	3.30 (22.11)	2.84 (20.43)
Activity Score	5.54 (19.38)	2.05 (16.47)
Impacts Score	4.68 (24.07)	3.09 (15.80)
Total Score	4.70 (19.92)	3.04 (13.80)

8. Secondary Outcome

Title	Change in Dyspnea Score at Week 48 as Assessed by the Transitional Dyspnea Index (TDI)
Description	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.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with evaluable change data were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	163	80
Mean (Standard Deviation) [units on a scale]	-1.23 (3.74)	-0.84 (2.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.793
	Comments	The p-value was based on a Wilcoxon rank sum test stratified by baseline pulmonary hypertension (Yes/No) and surgical lung biopsy was performed with definite or probable UIP based on core pathology review (Yes/No).
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Point estimate
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.00 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	The point estimate and 95% confidence interval were based on the Hodges-Lehmann Estimate of treatment effect

9. Secondary Outcome

Title	Percentage of Participants Who Developed PH on Study
Description	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.
Time Frame	Up to 48 weeks

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set without PH at baseline were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily	Placebo to match ambrisentan administered orally once daily
Measure Participants	293	145
Number [percentage of participants]	0.7 0.2%	2.1 1.3%

Adverse Events

Time Frame	Up to 48 months
Arm/Group Title	Ambrisentan		Placebo
Arm/Group Description	Ambrisentan (5 mg or 10 mg tablet) administered orally once daily		Placebo to match ambrisentan administered orally once daily
All Cause Mortality
	Ambrisentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ambrisentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/329 (22.2%)		25/163 (15.3%)
Blood and lymphatic system disorders
Anaemia	1/329 (0.3%)		0/163 (0%)
Cardiac disorders
Acute myocardial infarction	3/329 (0.9%)		0/163 (0%)
Angina pectoris	1/329 (0.3%)		0/163 (0%)
Angina unstable	1/329 (0.3%)		0/163 (0%)
Atrial fibrillation	2/329 (0.6%)		0/163 (0%)
Sinus tachycardia	1/329 (0.3%)		0/163 (0%)
Cardiac failure congestive	4/329 (1.2%)		0/163 (0%)
Cardiomegaly	1/329 (0.3%)		0/163 (0%)
Dilatation atrial	1/329 (0.3%)		0/163 (0%)
Tricuspid valve incompetence	1/329 (0.3%)		0/163 (0%)
Palpitations	1/329 (0.3%)		0/163 (0%)
Extrasystoles	1/329 (0.3%)		0/163 (0%)
Electromechanical dissociation	1/329 (0.3%)		0/163 (0%)
Cardiac ventricular disorder	1/329 (0.3%)		0/163 (0%)
Ear and labyrinth disorders
Acute vestibular syndrome	1/329 (0.3%)		0/163 (0%)
Eye disorders
Cataract	0/329 (0%)		1/163 (0.6%)
Choroidal haemorrage	0/329 (0%)		1/163 (0.6%)
Visual impairment	1/329 (0.3%)		0/163 (0%)
Gastrointestinal disorders
Constipation	4/329 (1.2%)		0/163 (0%)
Gastrooesophageal reflux disease	2/329 (0.6%)		2/163 (1.2%)
Diarrhoea	1/329 (0.3%)		1/163 (0.6%)
Colitis	1/329 (0.3%)		1/163 (0.6%)
Nausea	2/329 (0.6%)		0/163 (0%)
Colonic polyp	1/329 (0.3%)		0/163 (0%)
Small intestinal obstruction	1/329 (0.3%)		0/163 (0%)
Abdominal pain upper	0/329 (0%)		1/163 (0.6%)
Upper gastrointestinal haemorrhage	1/329 (0.3%)		0/163 (0%)
Aptyalism	0/329 (0%)		1/163 (0.6%)
General disorders
Oedema peripheral	4/329 (1.2%)		1/163 (0.6%)
Oedema	1/329 (0.3%)		0/163 (0%)
Chest pain	2/329 (0.6%)		1/163 (0.6%)
Pain	2/329 (0.6%)		0/163 (0%)
Pyrexia	2/329 (0.6%)		0/163 (0%)
Fatigue	2/329 (0.6%)		0/163 (0%)
Catheter site haemorrhage	1/329 (0.3%)		0/163 (0%)
Influenza like illness	1/329 (0.3%)		0/163 (0%)
Hyperthermia	1/329 (0.3%)		0/163 (0%)
Infections and infestations
Nasopharyngitis	2/329 (0.6%)		2/163 (1.2%)
Upper respiratory tract infection	1/329 (0.3%)		1/163 (0.6%)
Pharyngitis	1/329 (0.3%)		0/163 (0%)
Sinusitis	1/329 (0.3%)		0/163 (0%)
Pneumonia	9/329 (2.7%)		2/163 (1.2%)
Bronchitis	3/329 (0.9%)		0/163 (0%)
Lobar pneumonia	1/329 (0.3%)		1/163 (0.6%)
Bronchopneumonia	1/329 (0.3%)		0/163 (0%)
Lower respiratory tract infection	0/329 (0%)		1/163 (0.6%)
Respiratory tract infection	2/329 (0.6%)		1/163 (0.6%)
Infection	1/329 (0.3%)		0/163 (0%)
Cellulitis	2/329 (0.6%)		0/163 (0%)
Endocarditis bacterial	1/329 (0.3%)		1/163 (0.6%)
Sepsis	2/329 (0.6%)		0/163 (0%)
Bacteraemia	0/329 (0%)		1/163 (0.6%)
Appendicitis	0/329 (0%)		1/163 (0.6%)
Influenza	2/329 (0.6%)		0/163 (0%)
Urinary tract infection	1/329 (0.3%)		0/163 (0%)
Oral candidiasis	1/329 (0.3%)		0/163 (0%)
Conjunctivitis viral	1/329 (0.3%)		0/163 (0%)
Injury, poisoning and procedural complications
Road traffic accident	1/329 (0.3%)		0/163 (0%)
Rib fracture	1/329 (0.3%)		0/163 (0%)
Investigations
Alanine aminotransferase increased	0/329 (0%)		2/163 (1.2%)
Aspartate aminotransferase increased	0/329 (0%)		1/163 (0.6%)
Hepatic enzyme increased	0/329 (0%)		1/163 (0.6%)
Electrocardiogram ST-T segment abnormal	1/329 (0.3%)		0/163 (0%)
Electrocardiogram T wave inversion	1/329 (0.3%)		0/163 (0%)
Computerised tomogram thorax abnormal	1/329 (0.3%)		0/163 (0%)
Metabolism and nutrition disorders
Hyperkalaemia	4/329 (1.2%)		0/163 (0%)
Hypokalaemia	2/329 (0.6%)		0/163 (0%)
Hyperglycaemia	2/329 (0.6%)		0/163 (0%)
Anorexia	1/329 (0.3%)		0/163 (0%)
Diabetic ketoacidosis	1/329 (0.3%)		0/163 (0%)
Hypophosphataemia	1/329 (0.3%)		0/163 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/329 (0.3%)		0/163 (0%)
Musculoskeletal pain	1/329 (0.3%)		0/163 (0%)
Osteoarthritis	2/329 (0.6%)		1/163 (0.6%)
Clubbing	1/329 (0.3%)		0/163 (0%)
Joint swelling	0/329 (0%)		1/163 (0.6%)
Pain in jaw	1/329 (0.3%)		0/163 (0%)
Myalgia	1/329 (0.3%)		0/163 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/329 (0%)		1/163 (0.6%)
Squamous cell carcinoma	1/329 (0.3%)		0/163 (0%)
Prostate cancer	1/329 (0.3%)		0/163 (0%)
Prostate cancer metastatic	1/329 (0.3%)		0/163 (0%)
Lung neoplasm malignant	1/329 (0.3%)		0/163 (0%)
Malignant melanoma	0/329 (0%)		1/163 (0.6%)
Nervous system disorders
Headache	5/329 (1.5%)		1/163 (0.6%)
Cerebrovascular accident	1/329 (0.3%)		0/163 (0%)
Ischaemic stroke	1/329 (0.3%)		0/163 (0%)
Syncope	1/329 (0.3%)		1/163 (0.6%)
Somnolence	1/329 (0.3%)		0/163 (0%)
Carotid artery stenosis	1/329 (0.3%)		0/163 (0%)
Coma	1/329 (0.3%)		0/163 (0%)
Grand mal convulsion	1/329 (0.3%)		0/163 (0%)
Nerve compression	1/329 (0.3%)		0/163 (0%)
Hypoaesthesia	1/329 (0.3%)		0/163 (0%)
Psychiatric disorders
Anxiety	3/329 (0.9%)		0/163 (0%)
Delirium	1/329 (0.3%)		0/163 (0%)
Insomnia	1/329 (0.3%)		0/163 (0%)
Renal and urinary disorders
Renal failure acute	2/329 (0.6%)		0/163 (0%)
Renal failure	1/329 (0.3%)		0/163 (0%)
Reproductive system and breast disorders
Prostatomegaly	0/329 (0%)		1/163 (0.6%)
Benign prostatic hyperplasia	1/329 (0.3%)		0/163 (0%)
Respiratory, thoracic and mediastinal disorders
Idiopathic pulmonary fibrosis	20/329 (6.1%)		4/163 (2.5%)
Emphysema	2/329 (0.6%)		0/163 (0%)
Pulmonary fibrosis	2/329 (0.6%)		0/163 (0%)
Pulmonary alveolar haemorrhage	1/329 (0.3%)		0/163 (0%)
Dyspnoea	17/329 (5.2%)		2/163 (1.2%)
Respiratory arrest	1/329 (0.3%)		0/163 (0%)
Cough	4/329 (1.2%)		1/163 (0.6%)
Haemoptysis	4/329 (1.2%)		0/163 (0%)
Productive cough	1/329 (0.3%)		0/163 (0%)
Acute respiratory failure	5/329 (1.5%)		1/163 (0.6%)
Respiratory failure	4/329 (1.2%)		0/163 (0%)
Nasal congestion	4/329 (1.2%)		0/163 (0%)
Rhinitis allergic	1/329 (0.3%)		0/163 (0%)
Choking	1/329 (0.3%)		0/163 (0%)
Rhinorrhoea	1/329 (0.3%)		0/163 (0%)
Hypoxia	1/329 (0.3%)		0/163 (0%)
Pneumothorax	1/329 (0.3%)		0/163 (0%)
Pneumonitis	1/329 (0.3%)		0/163 (0%)
Hiccups	1/329 (0.3%)		0/163 (0%)
Epistaxis	0/329 (0%)		1/163 (0.6%)
Pleurisy	1/329 (0.3%)		0/163 (0%)
Pulmonary embolism	0/329 (0%)		1/163 (0.6%)
Skin and subcutaneous tissue disorders
Rash	0/329 (0%)		1/163 (0.6%)
Vascular disorders
Hypotension	4/329 (1.2%)		1/163 (0.6%)
Hypertension	3/329 (0.9%)		0/163 (0%)
Subclavian vein thrombosis	1/329 (0.3%)		0/163 (0%)
Flushing	1/329 (0.3%)		0/163 (0%)
Hot flush	1/329 (0.3%)		0/163 (0%)
Peripheral ischaemia	1/329 (0.3%)		0/163 (0%)
Other (Not Including Serious) Adverse Events
	Ambrisentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	227/329 (69%)		104/163 (63.8%)
Gastrointestinal disorders
Constipation	19/329 (5.8%)		10/163 (6.1%)
Diarrhoea	20/329 (6.1%)		8/163 (4.9%)
Nausea	15/329 (4.6%)		9/163 (5.5%)
General disorders
Oedema peripheral	73/329 (22.2%)		14/163 (8.6%)
Fatigue	22/329 (6.7%)		14/163 (8.6%)
Infections and infestations
Nasopharyngitis	37/329 (11.2%)		18/163 (11%)
Bronchitis	23/329 (7%)		15/163 (9.2%)
Sinusitis	20/329 (6.1%)		6/163 (3.7%)
Respiratory tract infection	9/329 (2.7%)		12/163 (7.4%)
Musculoskeletal and connective tissue disorders
Back pain	18/329 (5.5%)		5/163 (3.1%)
Nervous system disorders
Headache	47/329 (14.3%)		17/163 (10.4%)
Dizziness	20/329 (6.1%)		2/163 (1.2%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	47/329 (14.3%)		18/163 (11%)
Dyspnoea	40/329 (12.2%)		11/163 (6.7%)
Cough	34/329 (10.3%)		20/163 (12.3%)
Idiopathic pulmonary fibrosis	19/329 (5.8%)		2/163 (1.2%)
Nasal congestion	27/329 (8.2%)		6/163 (3.7%)
Productive cough	8/329 (2.4%)		9/163 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years