Phase 2 Extension Study of Ambrisentan in Pulmonary Arterial Hypertension

Sponsor

Gilead Sciences (Industry)

Overall Status

Completed

CT.gov ID

NCT00424021

Collaborator

(none)

Enrollment

Duration (Months)

Study Details

Study Description

Brief Summary

AMB-220-E is an international, multicenter, open-label study examining the long-term safety of ambrisentan (BSF 208075) in subjects who have previously completed Myogen study NCT00046319, "A Phase II, Randomized, Double-Blind, Dose-Controlled, Dose-Ranging, Multicenter Study of BSF 208075 Evaluating Exercise Capacity in Subjects with Moderate to Severe Pulmonary Arterial Hypertension".

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension	Drug: ambrisentan	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

54 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-Label, Long-Term Study of Ambrisentan in Pulmonary Hypertension Subjects Having Completed Myogen Study AMB-220

Study Start Date :

Apr 1, 2003

Actual Primary Completion Date :

Dec 1, 2009

Actual Study Completion Date :

Dec 1, 2009

Outcome Measures

Primary Outcome Measures

Number of Participants With Pulmonary Arterial Hypertension (PAH) Who Completed the Phase II NCT00046319 Study and Who Experienced Severe Adverse Events (AEs) During Long-term Ambrisentan Exposure [Week 24 (AMB-220-E baseline) to Week 334]
The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of severe severity (ie, made it impossible to perform routine activities and the subject may have experienced intolerable discomfort or pain) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study.
Number of Participants With PAH Who Completed the Phase II NCT00046319 Study and Who Experienced AEs of Moderate Severity During Long-term Ambrisentan Exposure [Week 24 (AMB-220-E baseline) to Week 329.3]
The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of moderate severity (ie, interfered with routine activities and subject may have experienced significant discomfort) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study.
Number of Participants With PAH Who Completed the Phase II NCT00046319 Study and Who Experienced AEs of Mild Severity During Long-term Ambrisentan Exposure [Week 24 (AMB-220-E baseline) to Week 329.3]
The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of mild severity (ie, did not interfere with routine activities and the subject may have experienced slight discomfort) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study.

Secondary Outcome Measures

Baseline Measurement in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (Baseline [Week 24]) [Week 24 (AMB-220-E baseline)]
The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (Last Observation Carried Forward [LOCF]) (Week 48) [24 weeks (Week 24 to Week 48)]
The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 108) [84 weeks (Week 24 to Week 108)]
The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 156) [132 weeks (Week 24 to Week 156)]
The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 204) [180 weeks (Week 24 to Week 204)]
The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Baseline Measurement in Exercise Capacity as Measured by the Borg Dyspnea Index (BDI) (Baseline [Week 24]) [Week 24 (AMB-220-E baseline)]
Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 48) [24 weeks (Week 24 to Week 48)]
Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 108) [84 weeks (Week 24 to Week 108)]
Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 156) [132 weeks (Week 24 to Week 156)]
Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 204) [180 weeks (Week 24 to Week 204)]
Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Baseline Measurement in Exercise Capacity as Measured by the World Health Organization (WHO) Functional Classification (Baseline [Week 24]) [Week 24 (AMB-220-E baseline)]
Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 24 Weeks of Treatment in AMB-220-E [24 weeks (Week 24 [baseline of AMB-220-E] to Week 48)]
Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 84 Weeks of Treatment in AMB-220-E [84 weeks (Week 24 of NCT00046319 to Week 108)]
Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 132 Weeks of Treatment in AMB-220-E [132 weeks (Week 24 of NCT00046319 to Week 156)]
Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 180 Weeks of Treatment in AMB-220-E [180 weeks (Week 24 of NCT00046319 to Week 204)]
Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Baseline Measurement in Exercise Capacity as Measured by the Subject Global Assessment (SGA) (Baseline [Week 24]) [Week 24 (AMB-220-E baseline)]
The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 48) [24 weeks (Week 24 to Week 48)]
The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 108) [84 weeks (Week 24 to Week 108)]
The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 156) [132 weeks (Week 24 to Week 156)]
The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 204) [180 weeks (Week 24 to Week 204)]
The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Time to Clinical Worsening of PAH [Week 0 (NCT00046319 baseline) to Week 360]
Clinical worsening of PAH was defined as death, lung transplantation, hospitalization for PAH, atrial septostomy, the addition of approved prostanoid therapy, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents. Sildenafil, a type 5 phosphodiesterase (PDE-5) inhibitor, had not received regulatory approval for the treatment of PAH until late in the conduct of AMB 220 and AMB 220-E, and did not count toward clinical worsening. Results are presented as the Kaplan-Meier estimate (% probability) of not having clinical worsening after a given time.
Failure-free Treatment Status [Week 0 (NCT00046319 baseline) to Week 360]
Failure-free treatment status was defined as the time from initiation of active treatment to the first occurrence of death, lung transplantation, the addition of approved prostanoid therapy, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents. Results are presented as the Kaplan-Meier estimate (% probability) of not having treatment failure after a given time.
Long-term Survival [Week 24 (AMB-220-E baseline) to Week 329.3]
Long-term survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of survival after a given time.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must have completed Visit 14/Week 24 of the NCT00046319 study.
Women of childbearing potential must have a negative urine pregnancy test at the Screening/Enrollment Visit and agree to use a reliable double barrier method of contraception until study completion and for >=4 weeks following their final study visit.
Must have completed the Down-titration Period of NCT00046319 prior to enrollment in

AMB-220-E and will meet the following additional criteria:

Subjects with a diagnosis of HIV must have stable disease status at the time of Screening/Enrollment.
Must be stable on conventional therapy for PAH for >=4 weeks prior to the Screening Visit.

Exclusion Criteria:

Chronic prostanoid therapy, or other investigational prostacyclin derivative within 4 weeks prior to the Screening Visit.
Intravenous inotrope use within 2 weeks prior to the Screening Visit.
Females who are pregnant or breastfeeding.
Contraindication to treatment with an endothelin receptor antagonist (ERA).

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Gilead Sciences

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Pulmonary Hypertension Association

Publications

None provided.

Responsible Party:

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT00424021

Other Study ID Numbers:

AMB-220-E

First Posted:

Jan 18, 2007

Last Update Posted:

Jan 27, 2012

Last Verified:

Dec 1, 2011

Additional relevant MeSH terms:

Hypertension, Pulmonary

Hypertension

Ambrisentan

Study Results

Participant Flow

Recruitment Details	Participants who completed Week 24 of NCT00046319 and responded to ambrisentan were eligible for enrollment. Response to ambrisentan treatment was determined by the investigator at Week 24 of NCT00046319 based on improvement in efficacy, acceptable safety profile, and >= 4 weeks of stable, conventional pulmonary arterial hypertension (PAH) therapy.
Pre-assignment Detail	No subjects failed screening. Subjects who completed an optional down-titration period at the end of NCT00046319 were re-titrated if their final dose was 5 mg or 10 mg.

Arm/Group Title	1 mg	2.5 mg	5 mg	10 mg
Arm/Group Description	The optimized final dose from the open-label period of AMB 220 (given once daily [QD] by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of AMB 220 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of AMB 220 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.	The optimized final dose from the open-label period of AMB 220 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.
Period Title: NCT00046319 Study Period
STARTED	16	19	16	13
COMPLETED	15	16	15	12
NOT COMPLETED	1	3	1	1
Period Title: NCT00046319 Study Period
STARTED	2	7	19	26
COMPLETED	1	5	14	16
NOT COMPLETED	1	2	5	10

Baseline Characteristics

Arm/Group Title	1 mg	2.5 mg	5 mg	10 mg	Total
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.	Total of all reporting groups
Overall Participants	2	7	19	26	54
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.0 (12.73)	43.0 (17.18)	56.7 (13.48)	49.0 (15.59)	51.1 (15.33)
Sex: Female, Male (Count of Participants)
Female	1 50%	6 85.7%	17 89.5%	22 84.6%	46 85.2%
Male	1 50%	1 14.3%	2 10.5%	4 15.4%	8 14.8%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	1 50%	5 71.4%	13 68.4%	20 76.9%	39 72.2%
Black	1 50%	1 14.3%	1 5.3%	1 3.8%	4 7.4%
Asian	0 0%	1 14.3%	2 10.5%	0 0%	3 5.6%
Hispanic	0 0%	0 0%	3 15.8%	5 19.2%	8 14.8%
Years Pulmonary Arterial Hypertension (PAH) Present (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	2.0 (0.00)	4.4 (3.87)	2.7 (2.91)	4.8 (4.81)	3.9 (4.07)
6-minute Walk Distance (Meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Meters]	462.0 (132.94)	400.4 (85.13)	398.8 (111.56)	410.7 (93.79)	406.9 (98.56)
Borg Dyspnea Index (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	2.5 (0.71)	1.6 (1.65)	2.8 (1.77)	2.9 (1.81)	2.7 (1.76)
World Health Organization Class (Number) [Number]
I	1 50%	3 42.9%	0 0%	4 15.4%	8 14.8%
II	0 0%	3 42.9%	11 57.9%	13 50%	27 50%
III	1 50%	1 14.3%	8 42.1%	9 34.6%	19 35.2%
Primary Diagnosis (Number) [Number]
Idiopathic Pulmonary Arterial Hypertension	0 0%	5 71.4%	12 63.2%	15 57.7%	32 59.3%
Mixed Connective Tissue Disease	0 0%	1 14.3%	1 5.3%	5 19.2%	7 13%
Systemic Lupus Erythematosus	0 0%	0 0%	0 0%	2 7.7%	2 3.7%
Systemic Sclerosis	1 50%	0 0%	2 10.5%	0 0%	3 5.6%
Overlap Syndrome	0 0%	0 0%	0 0%	1 3.8%	1 1.9%
Anorexigen Use	0 0%	0 0%	2 10.5%	2 7.7%	4 7.4%
Human immunodeficiency virus (HIV) Infection	1 50%	1 14.3%	0 0%	0 0%	2 3.7%
Other	0 0%	0 0%	2 10.5%	1 3.8%	3 5.6%
Height (Centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Centimeters]	169.8 (3.11)	160.6 (11.84)	163.1 (8.07)	164.5 (10.03)	163.7 (9.42)
Weight (Kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms]	66.0 (8.49)	68.1 (14.97)	74.6 (21.32)	76.1 (17.96)	74.2 (18.51)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Pulmonary Arterial Hypertension (PAH) Who Completed the Phase II NCT00046319 Study and Who Experienced Severe Adverse Events (AEs) During Long-term Ambrisentan Exposure
Description	The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of severe severity (ie, made it impossible to perform routine activities and the subject may have experienced intolerable discomfort or pain) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study.
Time Frame	Week 24 (AMB-220-E baseline) to Week 334

Outcome Measure Data

Analysis Population Description
The AMB-220-E population consisted of all subjects who received at least 1 dose of study drug during the AMB-220-E study.

Arm/Group Title	1 mg	2.5 mg	5 mg	10 mg
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.
Measure Participants	2	7	19	26
Abdominal Pain NOS	0 0%	1 14.3%	1 5.3%	0 0%
Alanine Aminotransferase Increased	0 0%	0 0%	0 0%	2 7.7%
Anaemia NOS	0 0%	1 14.3%	1 5.3%	0 0%
Angina Pectoris	0 0%	0 0%	1 5.3%	1 3.8%
Aspartate Aminotransferase Increased	0 0%	0 0%	0 0%	2 7.7%
Gastrointestinal Arteriovenous Malformation	0 0%	0 0%	0 0%	2 7.7%
Gastrointestinal Hemorrhage NOS	0 0%	0 0%	0 0%	2 7.7%
Infection NOS	0 0%	0 0%	1 5.3%	1 3.8%
Oedema Peripheral	0 0%	0 0%	1 5.3%	2 7.7%
Ovarian Cyst	0 0%	1 14.3%	0 0%	1 3.8%
Pulmonary Hypertension NOS Aggravated	0 0%	0 0%	0 0%	4 15.4%
Right Ventricular Failure	0 0%	0 0%	1 5.3%	6 23.1%
Syncope	0 0%	0 0%	0 0%	4 15.4%

2. Secondary Outcome

Title	Baseline Measurement in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (Baseline [Week 24])
Description	The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Time Frame	Week 24 (AMB-220-E baseline)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg once daily by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group. Results are presented using the LOCF imputation.
Measure Participants	54
Mean (Standard Deviation) [Meters]	406.1 (97.78)

3. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (Last Observation Carried Forward [LOCF]) (Week 48)
Description	The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Time Frame	24 weeks (Week 24 to Week 48)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Meters]	4.5 (46.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.5
	Confidence Interval	(2-Sided) 95% -8.3 to 17.3
	Parameter Dispersion	Type: Standard Deviation Value: 46.93
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 108)
Description	The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Time Frame	84 weeks (Week 24 to Week 108)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Meters]	-10.3 (73.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.3
	Confidence Interval	(2-Sided) 95% -30.3 to 9.7
	Parameter Dispersion	Type: Standard Deviation Value: 73.16
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 156)
Description	The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Time Frame	132 weeks (Week 24 to Week 156)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Meters]	-4.7 (83.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.7
	Confidence Interval	(2-Sided) 95% -27.4 to 18.0
	Parameter Dispersion	Type: Standard Deviation Value: 83.08
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the 6-minute Walk Test (6MWT) Distance (LOCF) (Week 204)
Description	The 6MWT was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.) Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).
Time Frame	180 weeks (Week 24 to Week 204)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Meters]	-13.9 (77.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-13.9
	Confidence Interval	(2-Sided) 95% -34.9 to 7.1
	Parameter Dispersion	Type: Standard Deviation Value: 77.04
	Estimation Comments

7. Secondary Outcome

Title	Baseline Measurement in Exercise Capacity as Measured by the Borg Dyspnea Index (BDI) (Baseline [Week 24])
Description	Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time Frame	Week 24 (AMB-220-E baseline)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg once daily by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group. Results are presented using the LOCF imputation.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	2.69 (1.728)

8. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 48)
Description	Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time Frame	24 weeks (Week 24 to Week 48)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	0.21 (1.323)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95% -0.15 to 0.57
	Parameter Dispersion	Type: Standard Deviation Value: 1.323
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 108)
Description	Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time Frame	84 weeks (Week 24 to Week 108)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	0.46 (1.659)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95% 0.01 to 0.92
	Parameter Dispersion	Type: Standard Deviation Value: 1.659
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 156)
Description	Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time Frame	132 weeks (Week 24 to Week 156)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	0.50 (1.888)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95% -0.02 to 1.02
	Parameter Dispersion	Type: Standard Deviation Value: 1.888
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the BDI (LOCF) (Week 204)
Description	Change from baseline evaluated after 24 (baseline), 48, 108, 156, and 204 weeks of ambrisentan therapy in BDI (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time Frame	180 weeks (Week 24 to Week 204)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	0.46 (1.721)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95% -0.01 to 0.93
	Parameter Dispersion	Type: Standard Deviation Value: 1.721
	Estimation Comments

12. Secondary Outcome

Title	Baseline Measurement in Exercise Capacity as Measured by the World Health Organization (WHO) Functional Classification (Baseline [Week 24])
Description	Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Time Frame	Week 24 (AMB-220-E baseline)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg once daily by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group. Results are presented using the LOCF imputation.
Measure Participants	54
WHO Classification I	8 400%
WHO Classification II	27 1350%
WHO Classification III	19 950%
WHO Classification IV	0 0%

13. Secondary Outcome

Title	Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 24 Weeks of Treatment in AMB-220-E
Description	Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Time Frame	24 weeks (Week 24 [baseline of AMB-220-E] to Week 48)

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
WHO Classification I	7 350%
WHO Classification II	29 1450%
WHO Classification III	18 900%
WHO Classification IV	0 0%

14. Secondary Outcome

Title	Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 84 Weeks of Treatment in AMB-220-E
Description	Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Time Frame	84 weeks (Week 24 of NCT00046319 to Week 108)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
WHO Classification I	5 250%
WHO Classification II	25 1250%
WHO Classification III	21 1050%
WHO Classification IV	3 150%

15. Secondary Outcome

Title	Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 132 Weeks of Treatment in AMB-220-E
Description	Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Time Frame	132 weeks (Week 24 of NCT00046319 to Week 156)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
WHO Classification I	10 500%
WHO Classification II	18 900%
WHO Classification III	24 1200%
WHO Classification IV	2 100%

16. Secondary Outcome

Title	Exercise Capacity as Measured by the WHO Functional Classification (LOCF) After 180 Weeks of Treatment in AMB-220-E
Description	Classes: I) PH; ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possibly at rest.
Time Frame	180 weeks (Week 24 of NCT00046319 to Week 204)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
WHO Classification I	10 500%
WHO Classification II	19 950%
WHO Classification III	23 1150%
WHO Classification IV	2 100%

17. Secondary Outcome

Title	Baseline Measurement in Exercise Capacity as Measured by the Subject Global Assessment (SGA) (Baseline [Week 24])
Description	The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Time Frame	Week 24 (AMB-220-E baseline)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study).

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg once daily by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group. Results are presented using the LOCF imputation.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	69.5 (20.49)

18. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 48)
Description	The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Time Frame	24 weeks (Week 24 to Week 48)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	-0.6 (19.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95% -5.9 to 4.7
	Parameter Dispersion	Type: Standard Deviation Value: 19.41
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 108)
Description	The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Time Frame	84 weeks (Week 24 to Week 108)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	-7.4 (25.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.4
	Confidence Interval	(2-Sided) 95% -14.4 to -0.3
	Parameter Dispersion	Type: Standard Deviation Value: 25.79
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 156)
Description	The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Time Frame	132 weeks (Week 24 to Week 156)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	-5.1 (25.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.1
	Confidence Interval	(2-Sided) 95% -12.0 to 1.8
	Parameter Dispersion	Type: Standard Deviation Value: 25.31
	Estimation Comments

21. Secondary Outcome

Title	Change From Baseline (Week 24 of NCT00046319) in Exercise Capacity as Measured by the SGA (LOCF) (Week 204)
Description	The SGA was determined using a visual-analog scale. Subjects were asked the question, "How are you feeling today?" and were asked to draw a vertical mark on a 100-mm horizontal line in which zero represented "very poor" and 100 represented "excellent."
Time Frame	180 weeks (Week 24 to Week 204)

Outcome Measure Data

Analysis Population Description
Primary efficacy analyses were performed for the AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study). Results are presented using the last-observation-carried-forward (LOCF) imputation.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	54
Mean (Standard Deviation) [Units on a Scale]	-1.9 (23.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 mg
	Comments	The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95% -8.4 to 4.6
	Parameter Dispersion	Type: Standard Deviation Value: 23.69
	Estimation Comments

22. Secondary Outcome

Title	Time to Clinical Worsening of PAH
Description	Clinical worsening of PAH was defined as death, lung transplantation, hospitalization for PAH, atrial septostomy, the addition of approved prostanoid therapy, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents. Sildenafil, a type 5 phosphodiesterase (PDE-5) inhibitor, had not received regulatory approval for the treatment of PAH until late in the conduct of AMB 220 and AMB 220-E, and did not count toward clinical worsening. Results are presented as the Kaplan-Meier estimate (% probability) of not having clinical worsening after a given time.
Time Frame	Week 0 (NCT00046319 baseline) to Week 360

Outcome Measure Data

Analysis Population Description
The NCT00046319 analysis set (all subjects who received at least 1 dose of study drug during the AMB-220 study) was evaluated during the NCT00046319 and AMB-220-E study periods.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg once daily by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	64
No clinical worsening after 1 year of treatment	78 (116.662)
No clinical worsening after 2 years of treatment	69
No clinical worsening after 3 years of treatment	60
No clinical worsening after 4 years of treatment	55

23. Secondary Outcome

Title	Failure-free Treatment Status
Description	Failure-free treatment status was defined as the time from initiation of active treatment to the first occurrence of death, lung transplantation, the addition of approved prostanoid therapy, or study withdrawal due to the addition of other clinically approved PAH therapeutic agents. Results are presented as the Kaplan-Meier estimate (% probability) of not having treatment failure after a given time.
Time Frame	Week 0 (NCT00046319 baseline) to Week 360

Outcome Measure Data

Analysis Population Description
The NCT00046319 analysis set (all subjects who received at least 1 dose of study drug during the NCT00046319 study) was evaluated during the NCT00046319 and AMB-220-E study periods.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg once daily by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	64
No treatment failure after 1 year of treatment	89 (110.672)
No treatment failure after 2 years of treatment	77
No treatment failure after 3 years of treatment	74
No treatment failure after 4 years of treatment	70

24. Secondary Outcome

Title	Long-term Survival
Description	Long-term survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of survival after a given time.
Time Frame	Week 24 (AMB-220-E baseline) to Week 329.3

Outcome Measure Data

Analysis Population Description
The AMB-220-E analysis set (all subjects who received at least 1 dose of study drug during the AMB-220-E study) was evaluated during the AMB-220-E study period.

Arm/Group Title	Combined Ambrisentan Treatment
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg once daily by oral administration) was used in this study, with further dose refinement at the investigator's discretion. The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.
Measure Participants	64
Survival after 1 year of treatment	94 (111.873)
Survival after 2 years of treatment	87
Survival after 3 years of treatment	87
Survival after 4 years of treatment	87

25. Primary Outcome

Title	Number of Participants With PAH Who Completed the Phase II NCT00046319 Study and Who Experienced AEs of Moderate Severity During Long-term Ambrisentan Exposure
Description	The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of moderate severity (ie, interfered with routine activities and subject may have experienced significant discomfort) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study.
Time Frame	Week 24 (AMB-220-E baseline) to Week 329.3

Outcome Measure Data

Analysis Population Description
The AMB-220-E population consisted of all subjects who received at least 1 dose of study drug during the AMB-220-E study.

Arm/Group Title	1 mg	2.5 mg	5 mg	10 mg
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of AMB 220 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of AMB 220 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.	The optimized final dose from the open-label period of AMB 220 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.
Measure Participants	2	7	19	26
Abdominal Distension	0 0%	1 14.3%	0 0%	1 3.8%
Activated Partial Thromboplastin Time Prolonged	0 0%	0 0%	2 10.5%	0 0%
Alanine Aminotransferase Increased	2 100%	0 0%	0 0%	0 0%
Anaemia NOS	0 0%	0 0%	0 0%	2 7.7%
Angina Pectoris	1 50%	0 0%	0 0%	1 3.8%
Anxiety	0 0%	0 0%	1 5.3%	2 7.7%
Arthralgia	1 50%	0 0%	3 15.8%	5 19.2%
Arrhythmia NOS	0 0%	0 0%	1 5.3%	1 3.8%
Aspartate Aminotransferase Increased	2 100%	0 0%	0 0%	0 0%
Atrial Fibrillation	0 0%	0 0%	0 0%	2 7.7%
Back Pain	0 0%	0 0%	2 10.5%	2 7.7%
Basal Cell Carcinoma	0 0%	0 0%	0 0%	2 7.7%
Bronchitis NOS	1 50%	3 42.9%	1 5.3%	4 15.4%
Bronchospasm NOS	1 50%	0 0%	0 0%	1 3.8%
Bursitis	0 0%	0 0%	0 0%	2 7.7%
Calcinosis	0 0%	1 14.3%	1 5.3%	0 0%
Cataract	1 50%	0 0%	0 0%	2 7.7%
Cellulitis	0 0%	0 0%	2 10.5%	0 0%
Chest Pain	0 0%	3 42.9%	2 10.5%	0 0%
Constipation	0 0%	0 0%	3 15.8%	3 11.5%
Contusion	0 0%	0 0%	1 5.3%	1 3.8%
Cough	1 50%	1 14.3%	2 10.5%	2 7.7%
Cyanosis NOS	0 0%	1 14.3%	0 0%	1 3.8%
Depression	0 0%	0 0%	2 10.5%	5 19.2%
Diarrhoea NOS	0 0%	0 0%	3 15.8%	2 7.7%
Dizziness	0 0%	1 14.3%	2 10.5%	2 7.7%
Dyspepsia	0 0%	0 0%	1 5.3%	1 3.8%
Dyspnoea Exacerbated	0 0%	2 28.6%	5 26.3%	1 3.8%
Dyspnoea NOS	0 0%	1 14.3%	0 0%	2 7.7%
Ear Infection NOS	0 0%	0 0%	1 5.3%	1 3.8%
Epistaxis	0 0%	0 0%	0 0%	2 7.7%
Erythema	0 0%	0 0%	1 5.3%	1 3.8%
Fatigue	0 0%	0 0%	2 10.5%	1 3.8%
Fatigue Aggravated	0 0%	0 0%	1 5.3%	1 3.8%
Flushing	0 0%	1 14.3%	1 5.3%	0 0%
Foot Fracture	0 0%	0 0%	2 10.5%	0 0%
Gamma-glutamyltransferase Increased	1 50%	0 0%	0 0%	1 3.8%
Gastroenteritis NOS	0 0%	0 0%	0 0%	2 7.7%
Gastroenteritis Viral NOS	0 0%	0 0%	1 5.3%	2 7.7%
Gastrooesophageal Reflux Disease	0 0%	1 14.3%	1 5.3%	2 7.7%
Gingival Infection	0 0%	0 0%	1 5.3%	1 3.8%
Gout	0 0%	0 0%	2 10.5%	0 0%
Headache	0 0%	0 0%	0 0%	2 7.7%
Hepatobiliary Disorders	0 0%	0 0%	1 5.3%	4 15.4%
Herpes Zoster	0 0%	0 0%	0 0%	2 7.7%
Hypertension NOS	0 0%	0 0%	2 10.5%	0 0%
Hypokalaemia	0 0%	0 0%	1 5.3%	2 7.7%
Hypotension NOS	1 50%	0 0%	1 5.3%	1 3.8%
Hypoxia	0 0%	1 14.3%	1 5.3%	2 7.7%
Influenza	0 0%	1 14.3%	1 5.3%	1 3.8%
Insomnia	0 0%	0 0%	2 10.5%	4 15.4%
International Normalised Ratio Increased	0 0%	1 14.3%	2 10.5%	2 7.7%
Intervertebral Disc Herniation	0 0%	0 0%	1 5.3%	1 3.8%
Iron Deficiency Anaemia	0 0%	1 14.3%	1 5.3%	0 0%
Limb Injury NOS	0 0%	0 0%	1 5.3%	1 3.8%
Localised Infection	0 0%	0 0%	1 5.3%	1 3.8%
Localised Osteoarthritis	0 0%	0 0%	1 5.3%	1 3.8%
Lower Respiratory Tract Infection NOS	0 0%	0 0%	0 0%	2 7.7%
Menorrhagia	0 0%	0 0%	0 0%	3 11.5%
Migraine NOS	0 0%	0 0%	0 0%	2 7.7%
Nasal Congestion	0 0%	0 0%	2 10.5%	1 3.8%
Nasopharyngitis	0 0%	0 0%	1 5.3%	1 3.8%
Nausea	0 0%	0 0%	1 5.3%	5 19.2%
Nausea Postoperative	0 0%	0 0%	1 5.3%	2 7.7%
Neck Pain	0 0%	0 0%	2 10.5%	0 0%
Oedema Peripheral	0 0%	0 0%	1 5.3%	4 15.4%
Oesophageal Candidiasis	0 0%	1 14.3%	0 0%	1 3.8%
Osteoporosis NOS	0 0%	0 0%	2 10.5%	0 0%
Otitis Media NOS	0 0%	0 0%	1 5.3%	1 3.8%
Pain in Limb	0 0%	0 0%	1 5.3%	3 11.5%
Palpitations	0 0%	0 0%	0 0%	2 7.7%
Pneumonia NOS	0 0%	0 0%	1 5.3%	1 3.8%
Post Procedural Pain	0 0%	0 0%	0 0%	2 7.7%
Prothrombin Time Prolonged	0 0%	0 0%	2 10.5%	0 0%
Pruritus	0 0%	0 0%	3 15.8%	1 3.8%
Pulmonary Hypertension NOS Aggravated	0 0%	1 14.3%	3 15.8%	3 11.5%
Pyrexia	0 0%	1 14.3%	0 0%	1 3.8%
Right Ventricular Failure	0 0%	1 14.3%	1 5.3%	3 11.5%
Sinusitis Chronic NOS	0 0%	0 0%	0 0%	2 7.7%
Sinusitis NOS	0 0%	0 0%	0 0%	5 19.2%
Skin Infection	0 0%	0 0%	1 5.3%	1 3.8%
Syncope	0 0%	1 14.3%	3 15.8%	1 3.8%
Tooth Infection	0 0%	1 14.3%	0 0%	1 3.8%
Tooth Injury	0 0%	1 14.3%	0 0%	1 3.8%
Upper Respiratory Tract Infection NOS	1 50%	1 14.3%	3 15.8%	8 30.8%
Upper Respiratory Tract Infection Viral NOS	0 0%	0 0%	0 0%	2 7.7%
Urinary Tract Infection NOS	0 0%	0 0%	4 21.1%	3 11.5%
Visual Disturbance NOS	0 0%	1 14.3%	0 0%	1 3.8%
Vomiting NOS	0 0%	1 14.3%	0 0%	1 3.8%

26. Primary Outcome

Title	Number of Participants With PAH Who Completed the Phase II NCT00046319 Study and Who Experienced AEs of Mild Severity During Long-term Ambrisentan Exposure
Description	The number of participants in the AMB-220-E analysis set who experienced AEs (including serious AEs) of mild severity (ie, did not interfere with routine activities and the subject may have experienced slight discomfort) that began after entering AMB-220-E (treatment-emergent AEs) and that occurred in more than 1 participant are summarized by dose group. The AMB-220-E analysis set consisted of all participants who received at least 1 dose of study drug during the AMB-220-E study.
Time Frame	Week 24 (AMB-220-E baseline) to Week 329.3

Outcome Measure Data

Analysis Population Description
The AMB-220-E population consisted of all subjects who received at least 1 dose of study drug during the AMB-220-E study.

Arm/Group Title	1 mg	2.5 mg	5 mg	10 mg
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of AMB 220 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.	The optimized final dose from the open-label period of AMB 220 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.	The optimized final dose from the open-label period of AMB 220 (1, 2.5, 5, or 10 mg QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.
Measure Participants	2	7	19	26
Abdominal Distension	0 0%	0 0%	1 5.3%	3 11.5%
Abdominal Pain Upper	0 0%	0 0%	2 10.5%	0 0%
Acquired Hypothyroidism	0 0%	0 0%	1 5.3%	1 3.8%
Anaemia NOS	0 0%	1 14.3%	1 5.3%	2 7.7%
Anorexia	0 0%	0 0%	2 10.5%	1 3.8%
Anxiety	0 0%	2 28.6%	2 10.5%	1 3.8%
Arrhythmia NOS	0 0%	0 0%	1 5.3%	1 3.8%
Arthralgia	0 0%	2 28.6%	0 0%	4 15.4%
Asthenia	0 0%	0 0%	1 5.3%	1 3.8%
Blood Alkaline Phosphatase NOS Increased	0 0%	0 0%	1 5.3%	1 3.8%
Blood Potassium Decreased	1 50%	1 14.3%	0 0%	1 3.8%
Bradycardia NOS	1 50%	1 14.3%	0 0%	0 0%
Bronchitis NOS	0 0%	1 14.3%	1 5.3%	1 3.8%
Bundle Branch Block Right	0 0%	0 0%	2 10.5%	0 0%
Cardiac Murmur NOS	0 0%	0 0%	3 15.8%	2 7.7%
Chest Pain	0 0%	1 14.3%	1 5.3%	4 15.4%
Clubbing	0 0%	0 0%	0 0%	2 7.7%
Colonic Polyp	0 0%	0 0%	1 5.3%	1 3.8%
Constipation	0 0%	1 14.3%	1 5.3%	2 7.7%
Cough	0 0%	2 28.6%	6 31.6%	6 23.1%
Crackles Lung	0 0%	0 0%	1 5.3%	3 11.5%
Cyanosis NOS	0 0%	0 0%	0 0%	3 11.5%
Depression	0 0%	0 0%	1 5.3%	1 3.8%
Diarrhoea NOS	0 0%	1 14.3%	4 21.1%	4 15.4%
Diverticulum NOS	0 0%	1 14.3%	0 0%	1 3.8%
Dizziness	1 50%	0 0%	3 15.8%	3 11.5%
Dizziness Postural	0 0%	1 14.3%	0 0%	1 3.8%
Dry Mouth	0 0%	0 0%	1 5.3%	1 3.8%
Dry Skin	0 0%	0 0%	2 10.5%	1 3.8%
Dyspnoea Exacerbated	0 0%	1 14.3%	3 15.8%	1 3.8%
Enanthema	0 0%	0 0%	0 0%	2 7.7%
Epistaxis	1 50%	0 0%	4 21.1%	1 3.8%
Erythema	0 0%	0 0%	3 15.8%	0 0%
Eye redness	0 0%	0 0%	1 5.3%	2 7.7%
Fatigue	0 0%	1 14.3%	1 5.3%	1 3.8%
Fatigue Aggravated	0 0%	0 0%	0 0%	4 15.4%
Flatulence	0 0%	0 0%	1 5.3%	1 3.8%
Feeling Cold	0 0%	1 14.3%	1 5.3%	1 3.8%
Flushing	0 0%	0 0%	2 10.5%	2 7.7%
Gastroenteritis NOS	0 0%	0 0%	1 5.3%	1 3.8%
Gastrointestinal Upset	0 0%	1 14.3%	0 0%	1 3.8%
Gastrooesophageal Reflux Disease	1 50%	1 14.3%	0 0%	0 0%
Haemorrhoids	0 0%	1 14.3%	0 0%	1 3.8%
Headache	1 50%	0 0%	3 15.8%	6 23.1%
Heart Sounds Abnormal	0 0%	1 14.3%	2 10.5%	2 7.7%
Hepatomegaly	0 0%	2 28.6%	0 0%	2 7.7%
Herpes Simplex	0 0%	0 0%	0 0%	2 7.7%
Hypercholesterolaemia	1 50%	0 0%	1 5.3%	0 0%
Hypertension NOS	0 0%	0 0%	1 5.3%	2 7.7%
Hyperuricaemia	0 0%	1 14.3%	1 5.3%	0 0%
Hypokalaemia	1 50%	0 0%	1 5.3%	1 3.8%
Hypotension NOS	0 0%	0 0%	3 15.8%	0 0%
Influenza	0 0%	1 14.3%	0 0%	1 3.8%
Influenza Like Illness	0 0%	0 0%	2 10.5%	0 0%
Insomnia	0 0%	1 14.3%	1 5.3%	4 15.4%
International Normalised Ratio Increased	0 0%	0 0%	2 10.5%	0 0%
Lymphadenopathy	0 0%	0 0%	2 10.5%	1 3.8%
Muscle Cramp	0 0%	0 0%	1 5.3%	1 3.8%
Nail Fungal Infection NOS	0 0%	0 0%	1 5.3%	1 3.8%
Nasal Congestion	1 50%	0 0%	4 21.1%	5 19.2%
Nasopharyngitis	0 0%	1 14.3%	2 10.5%	5 19.2%
Nausea	0 0%	0 0%	2 10.5%	5 19.2%
Neck Pain	0 0%	0 0%	1 5.3%	1 3.8%
Nocturia	0 0%	0 0%	2 10.5%	0 0%
Oedema Peripheral	1 50%	3 42.9%	10 52.6%	9 34.6%
Oxygen Saturation Decreased	0 0%	0 0%	1 5.3%	1 3.8%
Pain in Jaw	0 0%	0 0%	0 0%	2 7.7%
Palpitations	0 0%	1 14.3%	3 15.8%	4 15.4%
Pericardial Effusion	0 0%	0 0%	0 0%	2 7.7%
Pharyngitis	1 50%	0 0%	1 5.3%	3 11.5%
Pneumonia NOS	0 0%	0 0%	1 5.3%	1 3.8%
Productive Cough	0 0%	2 28.6%	0 0%	0 0%
Pruritus	0 0%	0 0%	2 10.5%	2 7.7%
Pyrexia	0 0%	1 14.3%	3 15.8%	1 3.8%
Rash NOS	0 0%	0 0%	1 5.3%	3 11.5%
Renal Cyst NOS	0 0%	0 0%	0 0%	2 7.7%
Respiratory Tract Infection NOS	0 0%	0 0%	1 5.3%	2 7.7%
Scleroderma	0 0%	1 14.3%	0 0%	1 3.8%
Seasonal Allergy	1 50%	0 0%	1 5.3%	1 3.8%
Sinusitis NOS	0 0%	0 0%	1 5.3%	3 11.5%
Skin Ulcer	0 0%	0 0%	2 10.5%	0 0%
Sleep Apnoea Syndrome	0 0%	0 0%	0 0%	2 7.7%
Somnolence	0 0%	0 0%	1 5.3%	1 3.8%
Squamous Cell Carcinoma	0 0%	1 14.3%	0 0%	1 3.8%
Syncope	0 0%	1 14.3%	2 10.5%	0 0%
Tachycardia NOS	0 0%	0 0%	1 5.3%	2 7.7%
Thyroid Disorder	0 0%	0 0%	0 0%	2 7.7%
Transient Ischaemic Attack	0 0%	0 0%	0 0%	2 7.7%
Upper Respiratory Tract Infection NOS	0 0%	3 42.9%	2 10.5%	6 23.1%
Vein Distended	0 0%	0 0%	1 5.3%	3 11.5%
Venous Stasis	0 0%	0 0%	0 0%	2 7.7%
Vertigo	0 0%	0 0%	1 5.3%	1 3.8%
Viral Infection NOS	0 0%	0 0%	1 5.3%	1 3.8%
Vision Blurred	0 0%	0 0%	1 5.3%	1 3.8%
Vomiting NOS	0 0%	1 14.3%	0 0%	1 3.8%
Weight Decreased	1 50%	0 0%	0 0%	1 3.8%
White Blood Cell Count Increased	1 50%	1 14.3%	0 0%	0 0%

Adverse Events

	1 mg		2.5 mg		5 mg		10 mg
Time Frame
Adverse Event Reporting Description

Arm/Group Title	1 mg		2.5 mg		5 mg		10 mg
Arm/Group Description	The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.		The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion.		The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.		The optimized final dose from the open-label period of NCT00046319 (given QD by oral administration) was used in this study, with further dose refinement at the investigator's discretion. Subjects who completed an optional down-titration period at the end of AMB 220 were re-titrated if their final dose was 5 or 10 mg.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	1 mg		2.5 mg		5 mg		10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		2/7 (28.6%)		12/19 (63.2%)		18/26 (69.2%)
Blood and lymphatic system disorders
Anaemia NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Coagulopathy	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Neutropenia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Secondary anaemia	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Cardiac disorders
Angina pectoris	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Atrial fibrillation	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Atrial flutter	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Atrial tachycardia	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Bradycardia NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Cardiac arrest	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Right ventricular failure	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	3	8/26 (30.8%)	11
Congenital, familial and genetic disorders
Gastrointestinal arteriovenous malformation	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Gastrointestinal disorders
Abdominal pain NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Abdominal symptom NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Constipation	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Gastrointestinal haemorrhage NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Inguinal hernia NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Intestinal ischemia	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Intestinal obstruction NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Pancreatitis NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
General disorders
Calcinosis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Chest pain	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Drug withdrawal syndrome	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Hepatobiliary disorders
Cholecystitis acute NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Infections and infestations
Abdominal wall infection	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Bronchopneumonia NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Infection NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Lobar pneumonia NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Lower respiratory tract infection NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Pneumonia NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Pneumonia chlamydial	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Pneumonia viral NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Septic shock	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Urinary tract infection NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Viral infection NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Investigations
Alanine aminotransferase increased	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Aspartate aminotransferase increased	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
C-reactive protein increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Liver function tests NOS abnormal	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Metabolism and nutrition disorders
Dehydration	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Fluid retention	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Haemarthrosis	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Localised osteoarthritis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	0/26 (0%)	0
Musculoskeletal pain	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Neck pain	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Multiple myeloma	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Nervous system disorders
Cerebral arterial aneurysm	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Lumbar radiculopathy	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Lumbar spinal stenosis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Syncope	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	3/26 (11.5%)	4
Transient ischaemic attack	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Vasovagal attack	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Renal and urinary disorders
Hydronephrosis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Nephrolithiasis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Renal failure acute	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Urinary tract obstruction NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Reproductive system and breast disorders
Menometrorrhagia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Ovarian cyst	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Pelvic haematoma	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Vaginal haemorrhage	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Brain hypoxia	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Bronchitis NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Dyspnoea exacerbated	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Hypoxia	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Pneumonitis NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Pulmonary hypertension NOS aggravated	0/2 (0%)	0	1/7 (14.3%)	1	2/19 (10.5%)	2	4/26 (15.4%)	4
Vascular disorders
Haemodynamic instability	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Peripheral occlusion	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Venous ulcer NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	1 mg		2.5 mg		5 mg		10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		7/7 (100%)		19/19 (100%)		26/26 (100%)
Blood and lymphatic system disorders
Anaemia NOS	0/2 (0%)	0	2/7 (28.6%)	5	2/19 (10.5%)	5	4/26 (15.4%)	5
Iron deficiency anaemia	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	0/26 (0%)	0
Leukopenia NOS	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	0/26 (0%)	0
Lymphadenopathy	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	2/26 (7.7%)	3
Splenomegaly	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Cardiac disorders
Angina pectoris	1/2 (50%)	2	0/7 (0%)	0	1/19 (5.3%)	2	1/26 (3.8%)	1
Arrhythmia NOS	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	2/26 (7.7%)	2
Bradycardia NOS	1/2 (50%)	2	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Bundle branch block right	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	0/26 (0%)	0
Clubbing	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Cyanosis NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	4/26 (15.4%)	5
Palpitations	0/2 (0%)	0	1/7 (14.3%)	2	3/19 (15.8%)	7	6/26 (23.1%)	8
Palpitations aggravated	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Pericardial effusion	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Right ventricular failure	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	5/26 (19.2%)	6
Tachycardia NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Congenital, familial and genetic disorders
Pigmented naevus	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Ear and labyrinth disorders
Ear congestion	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Hypoacusis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Sensation of block in ear	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Tinnitus	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Vertigo	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	1/26 (3.8%)	1
Endocrine disorders
Acquired hypothyroidism	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Thyroid disorder NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Eye disorders
Blepharitis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Cataract	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Cataract bilateral NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Eye irritation	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Eye pruritis	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Eye redness	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	3
Lacrimation increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Vision blurred	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Visual acuity reduced	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Visual disturbance NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	2/26 (7.7%)	2
Gastrointestinal disorders
Abdominal distension	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	4/26 (15.4%)	5
Abdominal pain NOS	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	1/26 (3.8%)	1
Abdominal pain upper	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	1
Ascites	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Colonic polyp	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Constipation	0/2 (0%)	0	1/7 (14.3%)	1	4/19 (21.1%)	5	5/26 (19.2%)	8
Dental discomfort	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Diarrhoea NOS	0/2 (0%)	0	1/7 (14.3%)	1	7/19 (36.8%)	13	6/26 (23.1%)	6
Diverticulum NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Dry mouth	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Duodenal ulcer	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Dyspepsia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	3/26 (11.5%)	4
Dysphagia	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	0/26 (0%)	0
Faecal incontinence	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Flatulence	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Gastroenteritis NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	3/26 (11.5%)	3
Gastrointestinal upset	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Gastrooesophageal reflux disease	1/2 (50%)	1	2/7 (28.6%)	2	1/19 (5.3%)	3	2/26 (7.7%)	5
Gingival bleeding	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Gingival pain	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Gingival swelling	1/2 (50%)	1	0/7 (0%)	0	1/19 (5.3%)	2	0/26 (0%)	0
Haemorrhoids	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	2/26 (7.7%)	2
Hiatus hernia	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Ileus paralytic	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	2
Intestinal polyp	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	0/26 (0%)	0
Melanosis coli	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	0/26 (0%)	0
Nausea	0/2 (0%)	0	1/7 (14.3%)	1	3/19 (15.8%)	4	10/26 (38.5%)	12
Rectal haemorrhage	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Stomatitis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Vomiting NOS	0/2 (0%)	0	2/7 (28.6%)	3	0/19 (0%)	0	3/26 (11.5%)	3
General disorders
Asthenia	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	1
Calcinosis	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	2	0/26 (0%)	0
Chest discomfort	1/2 (50%)	1	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Chest pain	0/2 (0%)	0	4/7 (57.1%)	8	2/19 (10.5%)	3	4/26 (15.4%)	5
Chest pressure sensation	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	0/26 (0%)	0
Enanthema	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	3
Fall	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Fatigue	0/2 (0%)	0	1/7 (14.3%)	2	3/19 (15.8%)	5	2/26 (7.7%)	2
Fatigue aggravated	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	6/26 (23.1%)	6
Feeling cold	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	1/26 (3.8%)	1
Feeling hot	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Influenza like illness	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	1
Lethargy	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Malaise	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Mucosal oedema NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Oedema peripheral	1/2 (50%)	1	3/7 (42.9%)	8	12/19 (63.2%)	20	15/26 (57.7%)	26
Pain NOS	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Pyrexia	0/2 (0%)	0	2/7 (28.6%)	3	3/19 (15.8%)	4	2/26 (7.7%)	2
Rigors	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Chest tightness	0/2 (0%)	0	1/7 (14.3%)	2	0/19 (0%)	0	0/26 (0%)	0
Hepatobiliary disorders
Hepatic pain	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Hepatomegaly	0/2 (0%)	0	2/7 (28.6%)	2	0/19 (0%)	0	3/26 (11.5%)	3
Immune system disorders
Seasonal allergy	1/2 (50%)	1	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Infections and infestations
Abscess limb	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Cellulitis	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	0/26 (0%)	0
Erysipelas	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Gastroenteritis viral NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Gingival infection	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Herpes simplex	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	3
Herpes zoster	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	3/26 (11.5%)	4
Influenza	0/2 (0%)	0	2/7 (28.6%)	4	1/19 (5.3%)	1	2/26 (7.7%)	3
Localised infection	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	5	1/26 (3.8%)	1
Nail fungal infection NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Oesphageal candidiasis	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Oral candidiasis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Otitis media NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Pneumonia NOS	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	2
Respiratory tract infection NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	3/26 (11.5%)	3
Respiratory tract infection viral NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Sinusitis NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	8/26 (30.8%)	9
Sinusitis chronic NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Skin fungal infection NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Skin infection	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	1
Tinea pedis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Tooth abscess	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	0/26 (0%)	0
Tooth infection	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	2/26 (7.7%)	2
Upper respiratory tract infection NOS	1/2 (50%)	2	4/7 (57.1%)	9	5/19 (26.3%)	7	14/26 (53.8%)	23
Upper respiratory tract infection viral NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Urinary tract infection NOS	0/2 (0%)	0	1/7 (14.3%)	2	4/19 (21.1%)	10	4/26 (15.4%)	6
Viral diarrhoea	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Viral infection NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	2
Injury, poisoning and procedural complications
Abrasion NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Anaemia postoperative	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Ankle fracture	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Blister	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Foot fracture	0/2 (0%)	0	0/7 (0%)	0	3/19 (15.8%)	3	0/26 (0%)	0
Joint sprain	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Limb injury NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	3	2/26 (7.7%)	2
Nausea postoperative	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Open wound	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Post procedural discomfort	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Post procedural pain	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	3
Spinal compression fracture	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Tooth injury	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Investigations
Activated partial thromboplastin time	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	0/26 (0%)	0
Alanine aminotransferase increased	2/2 (100%)	2	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	2
Aspartate aminotransferase increased	2/2 (100%)	2	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	2
Blood alkaline phosphatase NOS increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Blood amylase increased	1/2 (50%)	4	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Blood chloride decreased	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Blood glucose increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Blood potassium decreased	1/2 (50%)	1	1/7 (14.3%)	1	1/19 (5.3%)	1	1/26 (3.8%)	1
Blood potassium increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Blood sodium decreased	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
C-reactive protein increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	3	0/26 (0%)	0
Cardiac murmur NOS	0/2 (0%)	0	0/7 (0%)	0	3/19 (15.8%)	3	2/26 (7.7%)	2
Carotid bruit	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Gamma-glutamyltransferase increased	1/2 (50%)	1	0/7 (0%)	0	1/19 (5.3%)	1	2/26 (7.7%)	2
Heart rate irregular	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Heart sounds abnormal	0/2 (0%)	0	1/7 (14.3%)	4	2/19 (10.5%)	2	2/26 (7.7%)	2
International normalised ratio increased	0/2 (0%)	0	1/7 (14.3%)	1	4/19 (21.1%)	7	2/26 (7.7%)	2
Lipase increased	1/2 (50%)	4	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Mean cell haemoglobin increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	0/26 (0%)	0
Mean cell volume increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	0/26 (0%)	0
Oxygen saturation decreased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Platelet count decreased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Prothrombin time prolonged	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	0/26 (0%)	0
Pulmonary arterial wedge pressure increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
QRS axis abnormal	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Venous pressure jugular increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Weight decreased	1/2 (50%)	1	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
White blood cell count increased	1/2 (50%)	1	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	1
Appetite decreased NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Diabetes mellitus NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Gout	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	0/26 (0%)	0
Hypercholesterolaemia	1/2 (50%)	1	0/7 (0%)	0	2/19 (10.5%)	3	0/26 (0%)	0
Hyperuricaemia	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	0/26 (0%)	0
Hypokalaemia	1/2 (50%)	3	0/7 (0%)	0	2/19 (10.5%)	2	3/26 (11.5%)	4
Hyponatraemia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Obesity	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	0/26 (0%)	0
Muscle cramp	1/2 (50%)	1	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Myalgia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Neck pain	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/2 (50%)	1	2/7 (28.6%)	2	4/19 (21.1%)	5	9/26 (34.6%)	13
Back pain	0/2 (0%)	0	0/7 (0%)	0	3/19 (15.8%)	3	3/26 (11.5%)	4
Bursitis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Haemarthrosis	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Intervertebral disc herniation	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Knee deformity NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Localised osteoarthritis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	3	1/26 (3.8%)	1
Monoarthritis	0/2 (0%)	0	1/7 (14.3%)	2	0/19 (0%)	0	1/26 (3.8%)	1
Musculoskeletal discomfort	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Musculoskeletal stiffness	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Osteoarthritis NOS	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	3	0/26 (0%)	0
Osteopenia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Osteoporosis NOS	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	1
Pain in jaw	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	3/26 (11.5%)	3
Pain in limb	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	4/26 (15.4%)	4
Polymyalgia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Scleroderma	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	2/26 (7.7%)	2
Tendonitis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Breast cancer NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Squamous cell carcinoma	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Uterine fibroids	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Nervous system disorders
Balance impaired NOS	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	0/26 (0%)	0
Burning sensation NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Dizziness	1/2 (50%)	1	1/7 (14.3%)	4	5/19 (26.3%)	9	5/26 (19.2%)	6
Dizziness postural	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Headache	1/2 (50%)	1	1/7 (14.3%)	3	3/19 (15.8%)	3	8/26 (30.8%)	9
Hypoaesthesia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Memory impairment	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Migraine NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Sinus headache	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Sleep apnoea syndrome	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Syncope	0/2 (0%)	0	2/7 (28.6%)	2	4/19 (21.1%)	5	3/26 (11.5%)	5
Vasovagal attack	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Somnolence	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Psychiatric disorders
Acute psychosis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Anxiety	0/2 (0%)	0	2/7 (28.6%)	2	3/19 (15.8%)	4	3/26 (11.5%)	3
Confusional state	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Delirium	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Depression	0/2 (0%)	0	0/7 (0%)	0	3/19 (15.8%)	3	7/26 (26.9%)	7
Depression aggravated	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	0/26 (0%)	0
Insomnia	0/2 (0%)	0	1/7 (14.3%)	1	3/19 (15.8%)	3	8/26 (30.8%)	11
Insomnia exacerbated	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Renal and urinary disorders
Cystitis NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Nephrolithiasis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Nocturia	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	0/26 (0%)	0
Renal cyst NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Urine odour abnormal	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Reproductive system and breast disorders
Amenorrhoea NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Breast mass NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Menometrorrhagia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Menorrhagia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	3/26 (11.5%)	4
Ovarian cyst	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Pelvic pain NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Prostatic hypertrophy	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Vaginal haemorrage	0/2 (0%)	0	1/7 (14.3%)	2	0/19 (0%)	0	0/26 (0%)	0
Productive cough	0/2 (0%)	0	2/7 (28.6%)	2	1/19 (5.3%)	1	0/26 (0%)	0
Pulmonary congestion	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Pulmonary hypertension NOS aggravated	0/2 (0%)	0	0/7 (0%)	0	3/19 (15.8%)	5	7/26 (26.9%)	8
Rhinitis allergic NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Ronchi	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Wheezing	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Bronchitis NOS	1/2 (50%)	1	4/7 (57.1%)	7	2/19 (10.5%)	2	5/26 (19.2%)	5
Bronchospasm NOS	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	1/26 (3.8%)	1
Cough	1/2 (50%)	3	3/7 (42.9%)	5	9/19 (47.4%)	10	8/26 (30.8%)	11
Crackles lung	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	3/26 (11.5%)	3
Dyspnoea NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	2/26 (7.7%)	2
Dyspnoea exacerbated	0/2 (0%)	0	3/7 (42.9%)	6	9/19 (47.4%)	12	2/26 (7.7%)	2
Dyspnoea exertional	0/2 (0%)	0	1/7 (14.3%)	1	1/19 (5.3%)	1	0/26 (0%)	0
Epistaxis	1/2 (50%)	1	0/7 (0%)	0	4/19 (21.1%)	4	3/26 (11.5%)	4
Haemoptysis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	4
Hoarseness	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	1/26 (3.8%)	1
Hypoxia	0/2 (0%)	0	1/7 (14.3%)	2	1/19 (5.3%)	1	3/26 (11.5%)	3
Lung infiltration NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Nasal congestion	1/2 (50%)	2	0/7 (0%)	0	6/19 (31.6%)	8	6/26 (23.1%)	7
Nasal mucosal disorder NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Nasopharyngitis	0/2 (0%)	0	1/7 (14.3%)	5	3/19 (15.8%)	4	6/26 (23.1%)	13
Pharyngitis	1/2 (50%)	2	1/7 (14.3%)	1	1/19 (5.3%)	3	3/26 (11.5%)	5
Pulmonary vascular disorder NOS	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Respiratory fremitus	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Sneezing	1/2 (50%)	1	0/7 (0%)	0	0/19 (0%)	0	0/26 (0%)	0
Wheezing aggravated	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Skin and subcutaneous tissue disorders
Acne NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Alopecia	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Contusion	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Dermatitis NOS	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	0/26 (0%)	0
Dry skin	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	1/26 (3.8%)	1
Eczema	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	4
Eczema weeping	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Erythema	0/2 (0%)	0	0/7 (0%)	0	4/19 (21.1%)	4	1/26 (3.8%)	2
Hair disorder NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Hyperkeratosis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	2
Nail disorder NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Panniculitis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Pruritis	0/2 (0%)	0	0/7 (0%)	0	5/19 (26.3%)	6	3/26 (11.5%)	3
Rash NOS	0/2 (0%)	0	0/7 (0%)	0	2/19 (10.5%)	2	3/26 (11.5%)	4
Skin lesion NOS	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	3/26 (11.5%)	6
Skin ulcer	0/2 (0%)	0	0/7 (0%)	0	3/19 (15.8%)	3	0/26 (0%)	0
Solar keratosis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	4
Sweating increased	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Swelling face	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Telangiectasia	0/2 (0%)	0	1/7 (14.3%)	1	2/19 (10.5%)	2	0/26 (0%)	0
Urticaria NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Vascular disorders
Aortic stenosis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Flushing	0/2 (0%)	0	1/7 (14.3%)	2	3/19 (15.8%)	3	2/26 (7.7%)	2
Haematoma NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	1/26 (3.8%)	1
Hot flushes NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Hypertension NOS	0/2 (0%)	0	0/7 (0%)	0	3/19 (15.8%)	3	2/26 (7.7%)	2
Hypertensive crisis	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	2	0/26 (0%)	0
Hypotension NOS	1/2 (50%)	1	0/7 (0%)	0	4/19 (21.1%)	4	1/26 (3.8%)	3
Orthostatic hypotension	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	1/26 (3.8%)	1
Peripheral coldness	0/2 (0%)	0	1/7 (14.3%)	1	0/19 (0%)	0	0/26 (0%)	0
Peripheral occlusion	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0
Vein distended	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	4/26 (15.4%)	8
Venous stasis	0/2 (0%)	0	0/7 (0%)	0	0/19 (0%)	0	2/26 (7.7%)	2
Venous ulcer NOS	0/2 (0%)	0	0/7 (0%)	0	1/19 (5.3%)	1	0/26 (0%)	0

Limitations/Caveats

The small sample size, nonrandomized dose group assignments, and the potential for dose adjustments precluded meaningful comparisons between the dose groups. Therefore, efficacy results are only presented for the combined ambrisentan group.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title	Karen L Miller, PhD
Organization	Gilead Sciences, Inc.
Phone	650-524-3892
Email	KarenL.Miller@gilead.com

Responsible Party:

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT00424021

Other Study ID Numbers:

AMB-220-E

First Posted:

Jan 18, 2007

Last Update Posted:

Jan 27, 2012

Last Verified:

Dec 1, 2011

Phase 2 Extension Study of Ambrisentan in Pulmonary Arterial Hypertension

Study Details

Study Description

Brief Summary

Study Design

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

AMB-220-E and will meet the following additional criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact