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

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00879229
• Collaborator: (none)
• Enrollment: 40
• Locations: 85
• Arms: 2
• Duration (Months): 19.1
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Feb 1, 2011

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Six-minute Walk Distance (6MWD). [Baseline to Week 16]

   The change from baseline in 6MWD at Week 16 (end of blinded treatment) was evaluated.

Secondary Outcome Measures

1. Long-term Survival [Week 48]

   Long-term survival was assessed as a Kaplan-Meier (KM) estimate of the percent probability of survival, with censoring at Week 48.

2. Transition Dyspnea Index (TDI) [Baseline to Week 16]

   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).

3. Change From Baseline in WHO Functional Class [Baseline to Week 16]

   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.

4. Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted [Baseline to Week 16]

   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.

5. Change From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) [Baseline to Week 16]

   Assessment of the the level of the amino acid fragment NT-proBNP is used to establish prognosis in cardiovascular disease.

6. Change From Baseline in the Borg Dyspnea Index (BORG) Immediately Following Exercise [Baseline to Week 16]

   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).

7. Hemoglobin-corrected Diffusing Capacity for Carbon Monoxide (DLCO) Percent Predicted [Baseline to Week 16]

   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.

8. Change in Quality of Life (QOL) Score as Assessed by the Short-Form 36® (SF-36) [Baseline to Week 16]

   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.

9. Change in QOL Score as Assessed by the St. George's Respiratory Questionnaire (SRGQ) [Baseline to Week 16]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85259
3	University of California Davis	Davis	California	United States	95817
4	David Geffen School of Medicine UCLA	Los Angeles	California	United States	90095
5	University of California San Diego Medical Center	San Diego	California	United States	92103
6	University of California at San Francisco	San Francisco	California	United States	94143
7	Stanford University	Stanford	California	United States	94305
8	University of Colorado Heatlh Sciences Center	Aurora	Colorado	United States	80045
9	Bay Area Chest Physicians	Clearwater	Florida	United States	33756
10	University of Florida	Gainesville	Florida	United States	32610
11	University of Miami Medical Center	Miami	Florida	United States	33136
12	Suncoast Lung Center	Sarasota	Florida	United States	34233
13	Sarasota Memorial Hospital	Sarasota	Florida	United States	34239
14	Cleveland Clinic Florida	Weston	Florida	United States	33331
15	Atlanta Institute for Medical Research	Decatur	Georgia	United States	30030
16	University of Chicago	Chicago	Illinois	United States	60637
17	Kentuckiana Pulmonary Association	Louisville	Kentucky	United States
18	Maine Medical Center	Portland	Maine	United States
19	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21205
20	Tufts Medical Center	Boston	Massachusetts	United States	02111
21	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
22	Boston University Medical Center	Boston	Massachusetts	United States	02118
23	Beth Israel Deacones Medical Center	Boston	Massachusetts	United States	02215
24	University of Michigan Health Systems	Ann Arbor	Michigan	United States	48109
25	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
26	Washington University	St Louis	Missouri	United States	63110
27	Creighton University Center for Allergy & Asthma	Omaha	Nebraska	United States	68131
28	Dartmouth Medical School	Lebanon	New Hampshire	United States	03756
29	Albany Medical Center	Albany	New York	United States	12208
30	Winthrop University Hospital	Mineola	New York	United States	11501
31	North Shore Health System	New Hyde Park	New York	United States	11040
32	Mount Sinai School of Medicine	New York	New York	United States	10029
33	Columbia University	New York	New York	United States	10032
34	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
35	Duke University Medical Center	Durham	North Carolina	United States	27710
36	The Lindner Center for Research & Education at The Christ Hospital	Cincinnati	Ohio	United States	45219
37	University Hospitals of Cleveland Case Western	Cleveland	Ohio	United States	44106
38	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
39	Ohio State University	Columbus	Ohio	United States	43210
40	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
41	Temple University School of Medicine	Philadelphia	Pennsylvania	United States	19140
42	Alleghany General Hospital	Pittsburgh	Pennsylvania	United States	12512
43	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15213
44	Medical University of South Carolina	Charleston	South Carolina	United States
45	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
46	University of Texas Southwestern	Dallas	Texas	United States	75390
47	Baylor College of Medicine	Houston	Texas	United States	77030
48	University of Utah	Salt Lake City	Utah	United States	84108
49	Inova Heart Institiute and Vascular Institute	Falls Church	Virginia	United States	22042
50	Virginia Commonwealth University Health System	Richmond	Virginia	United States	23298
51	Providence Everett Medical Center	Everett	Washington	United States	98201
52	St. Vincents Hospital	Sydney	New South Wales	Australia	2010
53	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
54	Royal Perth Hospital	Perth	Western Australia	Australia	6000
55	Medizinische Universität Graz	Graz		Austria	8036
56	Universitatsklinikum Innsbruck	Innsbruck		Austria
57	Medizinische Universität Wien	Vienna		Austria	1090
58	Peter Loughheed Center- Calgary General Hospital	Calgary	Alberta	Canada	T1Y 6J4
59	University of British Columbia	Vancouver	British Columbia	Canada	V5Z 1M9
60	London Health Sciences Centre	London	Ontario	Canada	N6A 5W9
61	Toronto General Hospital	Toronto	Ontario	Canada
62	Centre Hospitalier De L'Universite de Montreal	Montreal	Quebec	Canada	H2W 1T8
63	Sir Mortimer B. Davis Jewish General Center	Montreal	Quebec	Canada
64	Centre de Pneumologie de L'Hospital Laval	Sainte foy	Quebec	Canada	G1V 4G5
65	Evangelische Lungenklinik Berlin	Berlin		Germany	13125
66	Charite-Universitatsmedizin Berlin	Berlin		Germany
67	Krankenhaus Donaustauf der LVA	Donaustauf		Germany	93093
68	Universitatsklinikum Freiburg	Freiburg		Germany	79095
69	Universitat Greifswald	Greifswald		Germany	17475
70	Medizinische Hochschule Hannover	Hannover		Germany	30625
71	Thorax Klinik	Heidelberg		Germany	66126
72	LMU Klinikum der Universitat	Munchen		Germany
73	Azienda Ospedaliero Universitaria	Catania		Italy
74	Presidio Ospedaliero G.B. Morgagni	Forli		Italy
75	Unita Funzionale di Pneumologia e Fisiopatologia Respiratoria	Milano		Italy	20132
76	Ospedale S.Giuseppe Fatebenefratelli	Milan		Italy
77	Azienda Ospedaliera di Padova	Padova		Italy
78	Instituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione	Palermo		Italy
79	Policlinico Universitario Tor Vergata	Rome		Italy
80	Azienda Ospedaliera Universitaria Senese	Siena		Italy	53100
81	Centro delle Interstiziopatie Polmonari e Malattie Rare del Polmone	Torino		Italy	10043
82	Papworth Hospital NHS Foundation Trust	Cambridge		United Kingdom	CB23 3RE
83	University Hospital Aintree	Liverpool		United Kingdom
84	University College Hosptial	London		United Kingdom
85	Royal Hallamshire Hospital	Sheffield		United Kingdom

Sponsors and Collaborators

• Gilead Sciences

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00879229
• Other Study ID Numbers: GS-US-300-0128
• First Posted: Apr 9, 2009
• Last Update Posted: May 15, 2014
• Last Verified: May 1, 2014

• Keywords provided by Gilead Sciences: Idiopathic Pulmonary Fibrosis; Pulmonary Hypertension; PH; IPF; Ambrisentan; ERA; Endothelin Receptor Antagonist; Cardiovascular
• Additional relevant MeSH terms: Hypertension, Pulmonary; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Hypertension; Fibrosis; Ambrisentan

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled in a total of 29 study sites in Australia, Europe, and North America. The first participant was screened on 21 October 2009. The last participant observation was on 22 February 2011.
Pre-assignment Detail	96 participants were screened; 40 participants were randomized and treated, and comprise the Safety Analysis Set and the Full Analysis Set.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Period Title: Overall Study
STARTED	25	15
COMPLETED	3	1
NOT COMPLETED	22	14

Baseline Characteristics

Arm/Group Title	Ambrisentan	Placebo	Total
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.	Total of all reporting groups
Overall Participants	25	15	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68 (7.7)	68 (5.2)	68 (6.8)
Sex: Female, Male (Count of Participants)
Female	5 20%	5 33.3%	10 25%
Male	20 80%	10 66.7%	30 75%
Race/Ethnicity, Customized (participants) [Number]
White	25 100%	14 93.3%	39 97.5%
Asian	0 0%	1 6.7%	1 2.5%
Region of Enrollment (participants) [Number]
United States	14 56%	9 60%	23 57.5%
Australia	3 12%	2 13.3%	5 12.5%
Italy	4 16%	1 6.7%	5 12.5%
Canada	3 12%	1 6.7%	4 10%
Germany	1 4%	2 13.3%	3 7.5%
Baseline Dyspnea Index (BDI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.0 (2.15)	4.4 (2.10)	4.8 (2.13)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set (randomized and received at least one dose of study medication) with evaluable data were analyzed.

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	21	9
Mean (Standard Error) [meters]	-96 (38)	-67 (51)

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	0.696
	Comments	This is an exact Wilcoxon rank sum test p-value for testing equality of ambrisentan and placebo distributions.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-29
	Confidence Interval	(2-Sided) 95%; -54 to 17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 67
	Estimation Comments

2. Secondary Outcome

Title	Long-term Survival
Description	Long-term survival was assessed as a Kaplan-Meier (KM) estimate of the percent probability of survival, with censoring at Week 48.
Time Frame	Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	25	15
Number (95% Confidence Interval) [percent probability (KM% estimate)]	22	23

3. Secondary Outcome

Title	Transition Dyspnea Index (TDI)
Description	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).
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	14	8
Mean (Standard Deviation) [units on a scale]	-1.5 (3.08)	-1.4 (3.78)

4. Secondary Outcome

Title	Change From Baseline in WHO Functional Class
Description	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.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	14	8
-1: Deteriorated	0	1
0: No change	11	5
+1: Improved	3	2

5. Secondary Outcome

Title	Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted
Description	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.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Insufficient data due to study termination

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	0	0

6. Secondary Outcome

Title	Change From Baseline in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)
Description	Assessment of the the level of the amino acid fragment NT-proBNP is used to establish prognosis in cardiovascular disease.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Insufficient data due to study termination

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	0	0

7. Secondary Outcome

Title	Change From Baseline in the Borg Dyspnea Index (BORG) Immediately Following Exercise
Description	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).
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Insufficient data due to study termination

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	0	0

8. Secondary Outcome

Title	Hemoglobin-corrected Diffusing Capacity for Carbon Monoxide (DLCO) Percent Predicted
Description	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.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Insufficient data due to study termination

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	0	0

9. Secondary Outcome

Title	Change in Quality of Life (QOL) Score as Assessed by the Short-Form 36® (SF-36)
Description	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.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Insufficient data due to study termination

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	0	0

10. Secondary Outcome

Title	Change in QOL Score as Assessed by the St. George's Respiratory Questionnaire (SRGQ)
Description	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.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Insufficient data due to study termination

Arm/Group Title	Ambrisentan	Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks	Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
Measure Participants	0	0

Adverse Events

Time Frame	Baseline to end of treatment
Adverse Event Reporting Description	Adverse events were collected based on the randomization group and not with regards to the specific treatment received.
Arm/Group Title	Ambrisentan		Placebo
Arm/Group Description	Participants were randomized to receive ambrisentan treatment for 56 weeks		Participants were randomized to receive placebo for 48 weeks, followed by ambrisentan treatment for 8 weeks.
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	12/25 (48%)		3/15 (20%)
Blood and lymphatic system disorders
Anaemia	1/25 (4%)		0/15 (0%)
Cardiac disorders
Atrioventricular block complete	1/25 (4%)		0/15 (0%)
Bradycardia	1/25 (4%)		0/15 (0%)
Gastrointestinal disorders
Abdominal pain lower	1/25 (4%)		0/15 (0%)
Infections and infestations
Pneumonia	2/25 (8%)		0/15 (0%)
Respiratory tract infection	0/25 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Procedural complication	0/25 (0%)		1/15 (6.7%)
Investigations
Electrocardiogram T wave inversion	1/25 (4%)		0/15 (0%)
Metabolism and nutrition disorders
Hyperkalaemia	1/25 (4%)		0/15 (0%)
Musculoskeletal and connective tissue disorders
Groin pain	1/25 (4%)		0/15 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/25 (4%)		0/15 (0%)
Renal and urinary disorders
Renal failure	1/25 (4%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Idiopathic pulmonary fibrosis	3/25 (12%)		1/15 (6.7%)
Dyspnoea	2/25 (8%)		0/15 (0%)
Hypoxia	2/25 (8%)		0/15 (0%)
Acute respiratory failure	1/25 (4%)		0/15 (0%)
Haemoptysis	1/25 (4%)		0/15 (0%)
Interstitial lung disease	1/25 (4%)		0/15 (0%)
Pulmonary fibrosis	1/25 (4%)		0/15 (0%)
Respiratory failure	1/25 (4%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Ambrisentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/25 (72%)		12/15 (80%)
Blood and lymphatic system disorders
Anaemia	1/25 (4%)		1/15 (6.7%)
Cardiac disorders
Myocardial infarction	0/25 (0%)		1/15 (6.7%)
Palpitations	0/25 (0%)		1/15 (6.7%)
Endocrine disorders
Hyperparathyroidism secondary	0/25 (0%)		1/15 (6.7%)
Gastrointestinal disorders
Constipation	4/25 (16%)		1/15 (6.7%)
Abdominal distension	2/25 (8%)		0/15 (0%)
Abdominal pain upper	1/25 (4%)		1/15 (6.7%)
Abdominal discomfort	0/25 (0%)		1/15 (6.7%)
Abdominal pain	0/25 (0%)		1/15 (6.7%)
Diarrhoea	0/25 (0%)		2/15 (13.3%)
Dry mouth	0/25 (0%)		1/15 (6.7%)
Dyspepsia	0/25 (0%)		1/15 (6.7%)
Nausea	0/25 (0%)		2/15 (13.3%)
Vomiting	0/25 (0%)		1/15 (6.7%)
General disorders
Oedema peripheral	5/25 (20%)		3/15 (20%)
Pyrexia	2/25 (8%)		0/15 (0%)
Fatigue	1/25 (4%)		4/15 (26.7%)
Chest discomfort	0/25 (0%)		1/15 (6.7%)
Chest pain	0/25 (0%)		1/15 (6.7%)
Malaise	0/25 (0%)		1/15 (6.7%)
Infections and infestations
Upper respiratory tract infection	4/25 (16%)		1/15 (6.7%)
Pneumonia	1/25 (4%)		1/15 (6.7%)
Respiratory tract infection	1/25 (4%)		1/15 (6.7%)
Sinusitis	1/25 (4%)		1/15 (6.7%)
Bronchitis	0/25 (0%)		1/15 (6.7%)
Diverticulitis	0/25 (0%)		2/15 (13.3%)
Influenza	0/25 (0%)		1/15 (6.7%)
Lower respiratory tract infection	0/25 (0%)		2/15 (13.3%)
Nasopharyngitis	0/25 (0%)		1/15 (6.7%)
Rhinitis	0/25 (0%)		1/15 (6.7%)
Urinary tract infection	0/25 (0%)		3/15 (20%)
Viral infection	0/25 (0%)		1/15 (6.7%)
Injury, poisoning and procedural complications
Joint sprain	0/25 (0%)		1/15 (6.7%)
Investigations
Cardiac murmur	2/25 (8%)		0/15 (0%)
Eosinophil count increased	0/25 (0%)		1/15 (6.7%)
Metabolism and nutrition disorders
Decreased appetite	0/25 (0%)		1/15 (6.7%)
Hypercalcaemia	0/25 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Back pain	2/25 (8%)		3/15 (20%)
Muscle spasms	1/25 (4%)		1/15 (6.7%)
Musculoskeletal chest pain	0/25 (0%)		1/15 (6.7%)
Neck pain	0/25 (0%)		1/15 (6.7%)
Pain in extremity	0/25 (0%)		1/15 (6.7%)
Nervous system disorders
Headache	5/25 (20%)		3/15 (20%)
Dizziness	0/25 (0%)		2/15 (13.3%)
Neuropathy peripheral	0/25 (0%)		1/15 (6.7%)
Syncope	0/25 (0%)		1/15 (6.7%)
Psychiatric disorders
Anxiety	0/25 (0%)		1/15 (6.7%)
Renal and urinary disorders
Proteinuria	0/25 (0%)		1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	6/25 (24%)		5/15 (33.3%)
Nasal congestion	6/25 (24%)		1/15 (6.7%)
Cough	3/25 (12%)		2/15 (13.3%)
Hypoxia	2/25 (8%)		1/15 (6.7%)
Orthopnoea	0/25 (0%)		1/15 (6.7%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	2/25 (8%)		0/15 (0%)
Alopecia	0/25 (0%)		1/15 (6.7%)
Ecchymosis	0/25 (0%)		1/15 (6.7%)
Vascular disorders
Flushing	1/25 (4%)		2/15 (13.3%)

Limitations/Caveats

Study GS-US-300-0128 was terminated early with enrollment of 40 of 225 planned subjects.

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