Trial Outcomes & Findings for A Open Label Study to Assess the Long-term Safety, Tolerability and Efficacy of Ambrisentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (NCT NCT01894022)

Last Updated: 2017-09-11

Results Overview

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect. Refer to the general AE/SAE module for a list of AEs and SAEs. Participant's final visit in Study AMB115811 was used as the entry visit of this open-label extension study. Safety (Extension) Population: all participants who enrolled and took at least one dose of study treatment during the extension study.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

19 participants

Primary outcome timeframe

From entry visit of the extension study up to approximately 16 months

Results posted on

2017-09-11

Participant Flow

This was an open label, long-term extension study to the double-blind, placebo-controlled study AMB115811 (NCT01884675). Only those participants (par.) in study AMB115811 were eligible for enrollment in this study. The planned duration was a minimum of 18 months, but the study was terminated due to futility of enrollment in study AMB115811.

Out of the 33 participants randomized (16 participants in the Placebo arm and 17 in the Ambrisentan arm) in study AMB115811, a total of 19 participants were enrolled in this extension study.

Participant milestones

Participant milestones
Measure	Previous Placebo Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Overall Study STARTED	9	10
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	9	10

Reasons for withdrawal

Reasons for withdrawal
Measure	Previous Placebo Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Overall Study Death	1	0
Overall Study Adverse Event, non-fatal	1	0
Overall Study Study Closed/terminated	7	10

Baseline Characteristics

A Open Label Study to Assess the Long-term Safety, Tolerability and Efficacy of Ambrisentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Total n=19 Participants Total of all reporting groups
Age, Continuous	63.0 Years INTER_QUARTILE_RANGE 7.99 • n=5 Participants	61.0 Years INTER_QUARTILE_RANGE 11.71 • n=7 Participants	63.0 Years INTER_QUARTILE_RANGE 10.06 • n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	5 Participants n=5 Participants	8 Participants n=7 Participants	13 Participants n=5 Participants

PRIMARY outcome

Timeframe: From entry visit of the extension study up to approximately 16 months

Population: Safety (Extension) Population

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Any AE	8 Participants	6 Participants
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Any SAE	3 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in basophils, eosinophils, lymphocytes, monocytes, total neutrophils (ANC), platelet count, and WBC count are summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in Study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, Month 9, n=2, 5	-1.135 Giga per Liter (GI/L) Interval -1.72 to -0.55	-0.590 Giga per Liter (GI/L) Interval -0.81 to 0.61
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, Month 12, n=1, 3	1.730 Giga per Liter (GI/L) Interval 1.73 to 1.73	-0.290 Giga per Liter (GI/L) Interval -0.78 to -0.23
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, Month 9, n=2, 5	-0.025 Giga per Liter (GI/L) Interval -0.04 to -0.01	-0.010 Giga per Liter (GI/L) Interval -0.02 to -0.01
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, Entry visit, n=9, 10	-0.010 Giga per Liter (GI/L) Interval -0.02 to 0.0	0.000 Giga per Liter (GI/L) Interval -0.01 to 0.01
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, Month 1, n=7, 10	-0.010 Giga per Liter (GI/L) Interval -0.01 to 0.0	0.000 Giga per Liter (GI/L) Interval -0.02 to 0.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, Month 3, n=7, 8	-0.010 Giga per Liter (GI/L) Interval -0.02 to 0.01	0.000 Giga per Liter (GI/L) Interval -0.01 to 0.02
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, Month 6, n=5, 6	0.000 Giga per Liter (GI/L) Interval -0.02 to 0.0	0.000 Giga per Liter (GI/L) Interval -0.01 to 0.03
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, Month 12, n=1, 3	-0.020 Giga per Liter (GI/L) Interval -0.02 to -0.02	0.000 Giga per Liter (GI/L) Interval -0.02 to 0.01
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, Month 15, n=0, 1	NA Giga per Liter (GI/L) No participants were analyzed at this time point.	-0.010 Giga per Liter (GI/L) Interval -0.01 to -0.01
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Basophils, End of study, n=8, 9	-0.005 Giga per Liter (GI/L) Interval -0.025 to 0.015	0.000 Giga per Liter (GI/L) Interval 0.0 to 0.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, Entry visit , n=9,10	-0.010 Giga per Liter (GI/L) Interval -0.09 to 0.04	0.005 Giga per Liter (GI/L) Interval -0.09 to 0.03
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, Month 1, n=7, 10	-0.020 Giga per Liter (GI/L) Interval -0.03 to 0.01	-0.025 Giga per Liter (GI/L) Interval -0.06 to 0.03
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, Month 3, n=7, 8	-0.030 Giga per Liter (GI/L) Interval -0.05 to 0.02	-0.005 Giga per Liter (GI/L) Interval -0.055 to 0.075
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, Month 6, n=5, 6	0.020 Giga per Liter (GI/L) Interval -0.03 to 0.11	-0.035 Giga per Liter (GI/L) Interval -0.07 to 0.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, Month 9, n=2, 5	0.155 Giga per Liter (GI/L) Interval -0.04 to 0.35	-0.020 Giga per Liter (GI/L) Interval -0.02 to 0.15
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, Month 12, n=1, 3	-0.120 Giga per Liter (GI/L) Interval -0.12 to -0.12	0.150 Giga per Liter (GI/L) Interval -0.06 to 0.27
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, Month 15, n=0, 1	NA Giga per Liter (GI/L) No participants were analyzed at this time point.	0.190 Giga per Liter (GI/L) Interval 0.19 to 0.19
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Eosinophils, End of study, n=8,9	-0.020 Giga per Liter (GI/L) Interval -0.055 to 0.035	0.010 Giga per Liter (GI/L) Interval -0.03 to 0.03
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, Entry visit , n=9,10	-0.050 Giga per Liter (GI/L) Interval -0.16 to 0.19	-0.090 Giga per Liter (GI/L) Interval -0.47 to 0.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, Month 1, n=7, 10	-0.190 Giga per Liter (GI/L) Interval -0.46 to 0.14	-0.225 Giga per Liter (GI/L) Interval -0.27 to 0.08
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, Month 3, n=7, 8	-0.040 Giga per Liter (GI/L) Interval -0.18 to 0.24	-0.215 Giga per Liter (GI/L) Interval -0.795 to 0.185
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, Month 6, n=5, 6	-0.250 Giga per Liter (GI/L) Interval -0.34 to -0.17	-0.110 Giga per Liter (GI/L) Interval -1.03 to -0.01
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, Month 9, n=2, 5	-0.075 Giga per Liter (GI/L) Interval -0.38 to 0.23	-0.360 Giga per Liter (GI/L) Interval -0.49 to -0.09
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, Month 12, n=1, 3	-0.090 Giga per Liter (GI/L) Interval -0.09 to -0.09	-0.260 Giga per Liter (GI/L) Interval -0.28 to 0.48
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, Month 15, n=0, 1	NA Giga per Liter (GI/L) No participants were analyzed at this time point.	-0.730 Giga per Liter (GI/L) Interval -0.73 to -0.73
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Lymphocytes, End of study, n=8,9	-0.090 Giga per Liter (GI/L) Interval -0.28 to 0.005	-0.230 Giga per Liter (GI/L) Interval -0.39 to 0.08
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, Entry visit, n=9, 10	-0.060 Giga per Liter (GI/L) Interval -0.09 to 0.05	-0.055 Giga per Liter (GI/L) Interval -0.15 to 0.01
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, Month 1, n=7, 10	0.000 Giga per Liter (GI/L) Interval -0.05 to 0.06	0.000 Giga per Liter (GI/L) Interval -0.17 to 0.13
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, Month 3, n=7, 8	0.010 Giga per Liter (GI/L) Interval -0.08 to 0.22	-0.035 Giga per Liter (GI/L) Interval -0.175 to 0.025
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, Month 6, n=5, 6	0.080 Giga per Liter (GI/L) Interval 0.03 to 0.1	-0.035 Giga per Liter (GI/L) Interval -0.2 to 0.05
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, Month 9, n=2, 5	0.075 Giga per Liter (GI/L) Interval -0.13 to 0.28	0.060 Giga per Liter (GI/L) Interval -0.1 to 0.2
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, Month 12, n=1, 3	0.010 Giga per Liter (GI/L) Interval 0.01 to 0.01	-0.100 Giga per Liter (GI/L) Interval -0.14 to 0.06
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, Month 15, n=0, 1	NA Giga per Liter (GI/L) No participants were analyzed at this time point.	0.130 Giga per Liter (GI/L) Interval 0.13 to 0.13
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Monocytes, End of study, n=8, 9	-0.005 Giga per Liter (GI/L) Interval -0.11 to 0.105	0.030 Giga per Liter (GI/L) Interval -0.09 to 0.1
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, Entry visit, n=9, 10	-0.390 Giga per Liter (GI/L) Interval -0.55 to 0.84	-0.595 Giga per Liter (GI/L) Interval -1.06 to 0.83
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, Month 1, n=7,10	0.220 Giga per Liter (GI/L) Interval -1.45 to 0.53	-0.550 Giga per Liter (GI/L) Interval -1.0 to 0.32
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, Month 3, n=7, 8	0.190 Giga per Liter (GI/L) Interval -0.12 to 0.45	-0.675 Giga per Liter (GI/L) Interval -0.965 to -0.085
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, Month 6, n=5, 6	0.150 Giga per Liter (GI/L) Interval 0.04 to 0.29	-0.285 Giga per Liter (GI/L) Interval -0.45 to -0.25
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, Month 15, n=0, 1	NA Giga per Liter (GI/L) No participants were analyzed at this time point.	-0.940 Giga per Liter (GI/L) Interval -0.94 to -0.94
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Total Neutrophils, End of study, n=8, 9	-0.025 Giga per Liter (GI/L) Interval -0.435 to 0.52	-0.740 Giga per Liter (GI/L) Interval -1.39 to -0.25
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, Entry visit , n=9, 9	-7.0 Giga per Liter (GI/L) Interval -10.0 to 5.0	-7.0 Giga per Liter (GI/L) Interval -40.0 to 19.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, Month 1, n=7, 10	-16.0 Giga per Liter (GI/L) Interval -31.0 to 5.0	-1.5 Giga per Liter (GI/L) Interval -29.0 to 26.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, Month 3, n=7, 8	-9.0 Giga per Liter (GI/L) Interval -34.0 to 7.0	17.0 Giga per Liter (GI/L) Interval -8.0 to 28.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, Month 6, n=5, 6	-17.0 Giga per Liter (GI/L) Interval -18.0 to -8.0	-2.0 Giga per Liter (GI/L) Interval -27.0 to 7.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, Month 9, n=2, 5	-11.0 Giga per Liter (GI/L) Interval -20.0 to -2.0	-6.0 Giga per Liter (GI/L) Interval -21.0 to 8.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, Month 12, n=1, 3	-78.0 Giga per Liter (GI/L) Interval -78.0 to -78.0	-9.0 Giga per Liter (GI/L) Interval -34.0 to 11.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, Month 15, n=0, 1	NA Giga per Liter (GI/L) No participants were analyzed at this time point.	-49.0 Giga per Liter (GI/L) Interval -49.0 to -49.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points Platelet count, End of study, n=8, 9	-5.0 Giga per Liter (GI/L) Interval -53.0 to 9.5	12.0 Giga per Liter (GI/L) Interval -4.0 to 14.0
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, Entry visit, n=9, 10	-0.20 Giga per Liter (GI/L) Interval -1.4 to 0.9	-0.65 Giga per Liter (GI/L) Interval -1.6 to 0.6
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, Month 1, n=7, 10	-0.10 Giga per Liter (GI/L) Interval -1.5 to 0.5	-0.50 Giga per Liter (GI/L) Interval -1.1 to -0.2
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, Month 3, n=7, 8	0.20 Giga per Liter (GI/L) Interval -0.4 to 0.8	-1.10 Giga per Liter (GI/L) Interval -1.65 to -0.15
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, Month 6, n=5, 6	0.10 Giga per Liter (GI/L) Interval 0.0 to 0.2	-0.55 Giga per Liter (GI/L) Interval -1.5 to -0.3
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, Month 9, n=2, 5	-1.00 Giga per Liter (GI/L) Interval -1.1 to -0.9	-0.60 Giga per Liter (GI/L) Interval -1.1 to 0.3
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, Month 12, n=1, 3	1.50 Giga per Liter (GI/L) Interval 1.5 to 1.5	-0.70 Giga per Liter (GI/L) Interval -0.8 to 0.3
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, Month 15, n=0, 1	NA Giga per Liter (GI/L) No participants were analyzed at this time point.	-1.40 Giga per Liter (GI/L) Interval -1.4 to -1.4
Change From Study AMB115811 Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Absolute Neutrophil Count [ANC]), Platelet Count, and White Blood Cell (WBC) Count at the Indicated Time Points WBC count, End of study, n=8, 9	-0.25 Giga per Liter (GI/L) Interval -0.6 to 0.6	-1.00 Giga per Liter (GI/L) Interval -1.4 to -0.5

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in hemoglobin and MCHC is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in Study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, Entry visit, n=9, 10	-5.0 Grams per Liter (g/L) Interval -10.0 to 2.0	-5.5 Grams per Liter (g/L) Interval -9.0 to -3.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, Month 1, n=7, 10	-3.0 Grams per Liter (g/L) Interval -7.0 to 1.0	-6.5 Grams per Liter (g/L) Interval -9.0 to -4.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, Month 3, n=7, 8	-7.0 Grams per Liter (g/L) Interval -25.0 to 8.0	-10.5 Grams per Liter (g/L) Interval -14.5 to -1.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, Month 6, n=5, 6	-10.0 Grams per Liter (g/L) Interval -18.0 to 0.0	-6.5 Grams per Liter (g/L) Interval -12.0 to -3.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, Month 9, n=2, 5	-25.0 Grams per Liter (g/L) Interval -31.0 to -19.0	-6.0 Grams per Liter (g/L) Interval -6.0 to -4.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, Month 12, n=1, 3	21.0 Grams per Liter (g/L) Interval 21.0 to 21.0	-6.0 Grams per Liter (g/L) Interval -9.0 to -2.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, Month 15, n=0, 1	NA Grams per Liter (g/L) No participants were analyzed at this time point.	-11.0 Grams per Liter (g/L) Interval -11.0 to -11.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points Hemoglobin, End of study, n=8, 9	-10.0 Grams per Liter (g/L) Interval -15.5 to -2.0	-8.0 Grams per Liter (g/L) Interval -11.0 to -2.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, Entry visit, n=9, 10	6.0 Grams per Liter (g/L) Interval -1.0 to 9.0	4.0 Grams per Liter (g/L) Interval -4.0 to 9.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, Month 1, n=7, 10	5 Grams per Liter (g/L) Interval -9.0 to 10.0	1 Grams per Liter (g/L) Interval -4.0 to 6.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, Month 3, n=7, 8	1 Grams per Liter (g/L) Interval -2.0 to 4.0	4.5 Grams per Liter (g/L) Interval -2.5 to 6.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, Month 6, n=5, 6	3 Grams per Liter (g/L) Interval 1.0 to 5.0	-1.5 Grams per Liter (g/L) Interval -2.0 to 0.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, Month 9, n=2, 5	0.5 Grams per Liter (g/L) Interval -2.0 to 3.0	-1 Grams per Liter (g/L) Interval -8.0 to 0.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, Month 12, n=1, 3	6.0 Grams per Liter (g/L) Interval 6.0 to 6.0	-4 Grams per Liter (g/L) Interval -9.0 to 5.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, Month 15, n=0, 1	NA Grams per Liter (g/L) No participants were analyzed at this time point.	1 Grams per Liter (g/L) Interval 1.0 to 1.0
Change From Study AMB115811 Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points MCHC, End of study, n=8, 9	-2.0 Grams per Liter (g/L) Interval -6.0 to 2.5	-6.0 Grams per Liter (g/L) Interval -9.0 to -1.0

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in hematocrit is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, Entry visit, n=9, 10	-0.007 Ratio Interval -0.031 to 0.004	-0.018 Ratio Interval -0.043 to -0.005
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, Month 1, n=7, 10	-0.018 Ratio Interval -0.028 to 0.011	-0.024 Ratio Interval -0.035 to -0.005
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, Month 3, n=7, 8	-0.027 Ratio Interval -0.084 to 0.023	-0.034 Ratio Interval -0.052 to -0.006
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, Month 6, n=5, 6	-0.033 Ratio Interval -0.057 to 0.005	-0.019 Ratio Interval -0.03 to -0.012
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, Month 9, n=2, 5	-0.083 Ratio Interval -0.107 to -0.058	-0.016 Ratio Interval -0.021 to -0.011
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, Month 12, n=1, 3	0.058 Ratio Interval 0.058 to 0.058	-0.009 Ratio Interval -0.036 to 0.001
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, Month 15, n=0, 1	NA Ratio No participants were analyzed at this time point.	-0.034 Ratio Interval -0.034 to -0.034
Change From Study AMB115811 Baseline in Hematocrit at the Indicated Time Points Hematocrit, End of study, n=8, 9	-0.033 Ratio Interval -0.049 to 0.004	-0.015 Ratio Interval -0.024 to -0.001

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in mean corpuscle volume is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, Entry visit, n=9, 10	-2.0 Femtoliter (fL) Interval -4.0 to -1.0	-0.5 Femtoliter (fL) Interval -2.0 to 0.0
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, Month 1, n=7, 10	-2.0 Femtoliter (fL) Interval -4.0 to 1.0	-0.5 Femtoliter (fL) Interval -3.0 to 1.0
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, Month 3, n=7, 8	-2.0 Femtoliter (fL) Interval -6.0 to 1.0	-1.0 Femtoliter (fL) Interval -4.0 to -0.5
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, Month 6, n=5, 6	-3.0 Femtoliter (fL) Interval -3.0 to 0.0	-0.5 Femtoliter (fL) Interval -2.0 to 0.0
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, Month 9, n=2, 5	-7.0 Femtoliter (fL) Interval -11.0 to -3.0	0.0 Femtoliter (fL) Interval 0.0 to 1.0
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, Month 12, n=1, 3	-2.0 Femtoliter (fL) Interval -2.0 to -2.0	2.0 Femtoliter (fL) Interval -1.0 to 2.0
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, Month 15, n=0, 1	NA Femtoliter (fL) No participants were analyzed at this time point.	1.0 Femtoliter (fL) Interval 1.0 to 1.0
Change From Study AMB115811 Baseline in Mean Corpuscle Volume at the Indicated Time Points Mean corpuscle volume, End of study, n=8, 9	-2.5 Femtoliter (fL) Interval -3.5 to 0.5	0.0 Femtoliter (fL) Interval 0.0 to 2.0

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Hematology parameters were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in red blood cell count and reticulocytes is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, Entry visit , n=9, 10	-0.20 Tera per Liter (TI/L) Interval -0.3 to 0.2	-0.15 Tera per Liter (TI/L) Interval -0.4 to -0.1
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, Month 1, n=7, 10	0.00 Tera per Liter (TI/L) Interval -0.5 to 0.2	-0.25 Tera per Liter (TI/L) Interval -0.3 to -0.1
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, Month 3, n=7, 8	0.00 Tera per Liter (TI/L) Interval -0.7 to 0.4	-0.25 Tera per Liter (TI/L) Interval -0.45 to -0.05
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, Month 6, n=5, 6	-0.30 Tera per Liter (TI/L) Interval -0.7 to 0.1	-0.15 Tera per Liter (TI/L) Interval -0.3 to 0.0
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, Month 9, n=2, 5	-0.55 Tera per Liter (TI/L) Interval -0.6 to -0.5	-0.20 Tera per Liter (TI/L) Interval -0.2 to -0.1
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, Month 12, n=1, 3	0.70 Tera per Liter (TI/L) Interval 0.7 to 0.7	-0.20 Tera per Liter (TI/L) Interval -0.3 to -0.1
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, Month 15, n=0, 1	NA Tera per Liter (TI/L) No participants were analyzed at this time point.	-0.40 Tera per Liter (TI/L) Interval -0.4 to -0.4
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Red blood cell count, End of study, n=8, 9	-0.15 Tera per Liter (TI/L) Interval -0.4 to 0.0	-0.20 Tera per Liter (TI/L) Interval -0.4 to 0.1
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, Entry visit, n=9, 10	0.001 Tera per Liter (TI/L) Interval -0.004 to 0.012	0.000 Tera per Liter (TI/L) Interval -0.026 to 0.004
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, Month 1, n=7, 10	-0.007 Tera per Liter (TI/L) Interval -0.016 to 0.024	-0.001 Tera per Liter (TI/L) Interval -0.02 to 0.011
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, Month 3, n=7, 8	0.001 Tera per Liter (TI/L) Interval -0.016 to 0.011	-0.001 Tera per Liter (TI/L) Interval -0.022 to 0.011
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, Month 6, n=5, 6	0.005 Tera per Liter (TI/L) Interval -0.023 to 0.018	-0.019 Tera per Liter (TI/L) Interval -0.032 to -0.005
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, Month 9, n=2, 5	-0.013 Tera per Liter (TI/L) Interval -0.019 to -0.006	0.005 Tera per Liter (TI/L) Interval -0.04 to 0.014
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, Month 12, n=1, 3	-0.032 Tera per Liter (TI/L) Interval -0.032 to -0.032	0.017 Tera per Liter (TI/L) Interval -0.003 to 0.027
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, Month 15, n=0, 1	NA Tera per Liter (TI/L) No participants were analyzed at this time point.	-0.011 Tera per Liter (TI/L) Interval -0.011 to -0.011
Change From Study AMB115811 Baseline in Red Blood Cell Count and Reticulocytes at the Indicated Time Points Reticulocytes, End of study, n=8, 9	-0.007 Tera per Liter (TI/L) Interval -0.022 to 0.018	-0.002 Tera per Liter (TI/L) Interval -0.049 to 0.001

PRIMARY outcome

Timeframe: Post entry visit of the extension study and up to End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Blood samples were collected post Entry visit of the extension study and up to end of study for evaluation of the clinical chemistry parameters of alanine amino transferase (ALT), aspartate amino transferase (AST), gamma glutamyl transferase (GGT), and total bilirubin. The clinical chemistry parameters of potential clinical concern high were defined as follows: ALT, AST, GGT \>=3 times upper limit of normal (ULN); total bilirubin \>=2 times ULN. Participants with both normal and high values were counted once under their worst case (high). Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern at Any Time Post Entry Visit ALT, >clinical concern high	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern at Any Time Post Entry Visit AST, >clinical concern high	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern at Any Time Post Entry Visit GGT, >clinical concern high	1 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern at Any Time Post Entry Visit Total bilirubin, >clinical concern high	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study plus any unscheduled lab tests (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Blood samples were collected at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study plus any unscheduled lab tests for creatinine. A creatinine value of potential clinical concern high was defined as \>=176.8 micromoles per Liter. Participants with both normal and high values were counted once under their worst case (high). Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Number of Participants With Creatinine Values of Potential Clinical Concern at Any Time Post Entry Visit	1 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Vital signs including SBP and DBP were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in SBP and DBP is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, Entry visit, n=9, 10	-6.0 millimeter of mercury (mmHg) Interval -11.0 to 3.0	-3.0 millimeter of mercury (mmHg) Interval -8.0 to 11.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, Month 1, n=8, 10	-0.5 millimeter of mercury (mmHg) Interval -21.0 to 4.5	-5.5 millimeter of mercury (mmHg) Interval -7.0 to 3.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, Month 3, n=8, 8	-4.0 millimeter of mercury (mmHg) Interval -13.5 to 14.5	-4.0 millimeter of mercury (mmHg) Interval -8.0 to 0.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, Month 6, n=5, 6	-10.0 millimeter of mercury (mmHg) Interval -30.0 to -9.0	-5.0 millimeter of mercury (mmHg) Interval -14.0 to 0.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, Month 9, n=3, 5	-1.0 millimeter of mercury (mmHg) Interval -14.0 to 14.0	-2.0 millimeter of mercury (mmHg) Interval -6.0 to 4.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, Month 12, n=1, 4	15.0 millimeter of mercury (mmHg) Interval 15.0 to 15.0	-8.5 millimeter of mercury (mmHg) Interval -15.5 to 6.5
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, Month 15, n=0, 1	NA millimeter of mercury (mmHg) No participants were analyzed at this time point.	-2.0 millimeter of mercury (mmHg) Interval -2.0 to -2.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Systolic blood pressure, End of study, n=8, 10	2.5 millimeter of mercury (mmHg) Interval -14.0 to 12.5	1.0 millimeter of mercury (mmHg) Interval -5.0 to 5.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, Entry visit, n=9, 10	-5.0 millimeter of mercury (mmHg) Interval -11.0 to 5.0	-9.0 millimeter of mercury (mmHg) Interval -12.0 to 4.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, Month 1, n=8, 10	-9.0 millimeter of mercury (mmHg) Interval -17.5 to -3.0	-7.0 millimeter of mercury (mmHg) Interval -10.0 to 4.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, Month 3, n=8, 8	-1.0 millimeter of mercury (mmHg) Interval -10.5 to 10.0	-11.0 millimeter of mercury (mmHg) Interval -15.5 to -4.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, Month 6, n=5, 6	-13.0 millimeter of mercury (mmHg) Interval -18.0 to -10.0	-11.0 millimeter of mercury (mmHg) Interval -12.0 to -7.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, Month 9, n=3, 5	-5.0 millimeter of mercury (mmHg) Interval -7.0 to -4.0	-7.0 millimeter of mercury (mmHg) Interval -12.0 to -5.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, Month 12, n=1, 4	0.0 millimeter of mercury (mmHg) Interval 0.0 to 0.0	-9.0 millimeter of mercury (mmHg) Interval -16.0 to -5.5
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, Month 15, n=0, 1	NA millimeter of mercury (mmHg) No participants were analyzed at this time point.	-4.0 millimeter of mercury (mmHg) Interval -4.0 to -4.0
Change From Study AMB115811 Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at the Indicated Time Points Diastolic blood pressure, End of study, n=8, 10	-4.0 millimeter of mercury (mmHg) Interval -12.0 to 12.0	-9.5 millimeter of mercury (mmHg) Interval -18.0 to -2.0

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Vital signs including heart rate were assessed at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and end of study. Change from study AMB115811 Baseline in heart rate is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, Entry visit, n=9, 10	-2.0 beats per minute Interval -17.0 to 5.0	-7.0 beats per minute Interval -17.0 to 1.0
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, Month 1, n=8, 10	-12.0 beats per minute Interval -19.5 to 4.0	-2.0 beats per minute Interval -7.0 to 3.0
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, Month 3, n=8, 8	-8.5 beats per minute Interval -19.0 to 1.5	-1.0 beats per minute Interval -11.0 to 4.5
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, Month 6, n=5, 6	-19.0 beats per minute Interval -24.0 to -14.0	-3.5 beats per minute Interval -6.0 to -1.0
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, Month 9, n=3, 5	-12.0 beats per minute Interval -12.0 to -11.0	-6.0 beats per minute Interval -7.0 to -2.0
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, Month 12, n=1, 4	-12.0 beats per minute Interval -12.0 to -12.0	-12.5 beats per minute Interval -16.5 to -4.5
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, Month 15, n=0, 1	NA beats per minute No participants were analyzed at this time point.	-11.0 beats per minute Interval -11.0 to -11.0
Change From Study AMB115811 Baseline in Heart Rate at the Indicated Time Points Heart rate, End of study, n=8, 10	-10.5 beats per minute Interval -15.0 to 1.0	0.5 beats per minute Interval -5.0 to 4.0

PRIMARY outcome

Timeframe: Baseline from study AMB115811; Entry visit of the extension study; Months 1, 3, 6, 9, 12, 15; and End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

Weight was measured at Entry visit of the extension study, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, and at end of study. Change from study AMB115811 Baseline in weight is summarized. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, Entry visit, n=9, 10	-1.00 kilogram (kg) Interval -1.5 to 1.4	-1.00 kilogram (kg) Interval -2.8 to 0.5
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, Month 1, n=8, 10	0.00 kilogram (kg) Interval -1.5 to 0.6	-0.50 kilogram (kg) Interval -2.2 to 0.5
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, Month 3, n=8, 8	-0.50 kilogram (kg) Interval -2.0 to 0.55	-2.00 kilogram (kg) Interval -4.45 to 0.5
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, Month 6, n=5, 6	0.00 kilogram (kg) Interval -10.0 to 1.1	-3.10 kilogram (kg) Interval -5.0 to -0.5
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, Month 9, n=3, 5	0.00 kilogram (kg) Interval -19.7 to 1.6	-3.50 kilogram (kg) Interval -5.5 to 1.0
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, Month 12, n=1, 4	0.00 kilogram (kg) Interval 0.0 to 0.0	-1.15 kilogram (kg) Interval -3.25 to 1.0
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, Month 15, n=0, 1	NA kilogram (kg) No participants were analyzed at this time point.	-2.50 kilogram (kg) Interval -2.5 to -2.5
Change From Study AMB115811 Baseline in Weight at the Indicated Time Points Weight, End of study, n=8, 10	0.00 kilogram (kg) Interval -1.0 to 0.85	-0.05 kilogram (kg) Interval -2.0 to 1.8

PRIMARY outcome

Timeframe: From the Entry visit of the extension study up to approximately 16 months

Population: Safety (Extension) Population

The time to change in dose of ambrisentan or other targeted PAH (pulmonary arterial hypertension) therapeutic agents (prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events). Dosing data were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including time to first change in dose of open-label ambrisentan. This decision was documented in the reporting and analysis plan prior to database lock.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: During Study AMB115811: Months 0 (Baseline), 1, 2, 3, 4, Early Withdrawal (EW); During Extension Study: Months 1, 3, 6, 9, 12, 15 and at End of Study (assessed up to approximately 20 months)

Population: ITT Population

The 6-minute walk test was conducted according to the American Thoracic Society guidelines in accordance with local standard operating procedures. 6MWD was measured by a 6-minute walk test. This test measures the distance that a par. can walk in a period of 6 minutes. AMB115811 Baseline was the Week 0 value in that study. Change from study AMB115811 Baseline was calculated as the value at the indicated visit minus the Baseline value. Par.'s final visit in study AMB115811 was used as the entry visit of this extension study. For the Extension study, the visit schedule (Months 1, 3, 6, 9, 12 and 15) was mapped to the visit schedule (Months 5, 7, 10, 13, 16 and 19) for continuity with study AMB115811. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Intent-to-treat (ITT) Population: all par. who were randomized and took at least one dose of study medication in the double-blind phase (placebo or ambrisentan).

Outcome measures

Outcome measures
Measure	Previous Placebo n=16 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points (AMB115811) Month 1, n=15, 17	5.00 Meters Interval -1.5 to 16.5	14.00 Meters Interval 1.0 to 42.5
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 2, n=14, 16	7.50 Meters Interval -14.5 to 22.5	26.25 Meters Interval 3.25 to 61.25
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 3, n=13, 15	5.50 Meters Interval -23.0 to 39.5	20.50 Meters Interval 4.0 to 68.0
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 4, n=13, 15	-10.00 Meters Interval -32.5 to 20.0	25.00 Meters Interval 12.0 to 49.0
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points EW (AMB115811) visit, n=3, 2	7.50 Meters Interval -46.5 to 43.5	41.25 Meters Interval 0.0 to 82.5
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points (Extension study) Month 5, n=7, 9	0.00 Meters Interval -15.5 to 40.0	51.50 Meters Interval 19.0 to 80.5
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 7, n=7, 8	-8.00 Meters Interval -22.5 to 55.0	57.50 Meters Interval 23.5 to 88.75
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 10, n=5, 6	55.00 Meters Interval -10.5 to 65.0	52.25 Meters Interval 21.0 to 100.0
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 13, n=2, 4	8.50 Meters Interval -5.5 to 22.5	33.25 Meters Interval 19.0 to 46.25
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 16, n=1, 4	65.00 Meters Interval 65.0 to 65.0	47.25 Meters Interval 23.5 to 61.25
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points Month 19, n=0, 1	NA Meters No participants were analyzed at this time point.	69.00 Meters Interval 69.0 to 69.0
Change From Study AMB115811 Baseline in the 6 Minutes Walking Distance (6MWD) at the Indicated Time Points End of study, n=7, 8	30.00 Meters Interval 4.5 to 43.0	29.50 Meters Interval 4.0 to 80.25

SECONDARY outcome

Timeframe: During Study AMB115811: Months (M) 0 (Baseline), 1, 2, 3, 4, Early Withdrawal (EW); During Extension (ext) Study: Months 1, 3, 6, 9, 12, 15 and at End of Study (assessed up to approximately 20 months)

Population: ITT Population

WHO FC indicates severity of pulmonary arterial hypertension (PAH) and is an adaptation of the New York Heart Association classification, assessed by the investigator. There are 4 grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). Grades mapped to numeric scale 1-4 (i.e. Class IV = 4). WHO FC system links symptoms with activity limitations, allowing clinicians to predict disease progression and prognosis. AMB115811 BL is the last value recorded on or prior to start of study treatment in that study. Change from AMB115811 BL was calculated as the value at the indicated visit minus the BL value (positive change = worsening). Par.'s final visit in AMB115811 was used as entry visit of this ext study. For Ext study, the visit schedule (M1,3,6,9,12 and 15) was mapped to the visit schedule (M5,7,10,13,16 and 19) for continuity with study AMB115811. Only par. available at the specified TP were analyzed (represented by n=X,X in the category title).

Outcome measures

Outcome measures
Measure	Previous Placebo n=16 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points (AMB115811) Month 1, n=15, 17	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 2, n=14, 16	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 3, n=13, 15	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 4, n=13, 15	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points EW (AMB115811) visit, n=3, 2	0.0 Scores on a scale Interval -1.0 to 0.0	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points (Extension study) Month 5, n=8, 10	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 7, n=8, 8	0.0 Scores on a scale Interval 0.0 to 0.5	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 10, n=5, 6	0.0 Scores on a scale Interval 0.0 to 0.0	-0.5 Scores on a scale Interval -1.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 13, n=3, 5	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 16, n=1, 4	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval -0.5 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 19, n=0, 1	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Study AMB115811 Baseline (BL) in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points End of study, n=8, 10	0.0 Scores on a scale Interval -0.5 to 0.0	0.0 Scores on a scale Interval -1.0 to 0.0

SECONDARY outcome

Timeframe: During Study AMB115811: Months (M) 0 (Baseline), 1, 2, 3, 4, Early Withdrawal (EW); During Extension (Ext) Study: Months 1, 3, 6, 9, 12, 15 and at End of Study (assessed up to approximately 20 months)

Population: ITT Population

BCR10S score, a rating of perceived exertion, was collected immediately following completion of the 6-minute walk test. Scores range from 0 to 10 (0=nothing at all, 10=extremely strong). If par.'s perception or feeling was stronger than "10", that is "extremely strong", "Maximal" -a larger number could be used, for example 12 or still higher, that is "Absolute maximum"). AMB115811 BL data was calculated as average of 2 BCR10S values obtained following the 2 6MWD tests used in determining the BL 6MWD in that study. If only 1 measurement was available, it was used. Change from AMB115811 BL was calculated as the value at the indicated visit minus the BL value. Par.'s final visit in AMB115811 was used as the entry visit of ext study. For the Ext study, the visit schedule (M1,3,6,9,12 and 15) mapped to the visit schedule (M5,7,10,13,16 and 19) for continuity with AMB115811. Only those par. available at the specified time points were analyzed (represented by n=X,X in the category titles).

Outcome measures

Outcome measures
Measure	Previous Placebo n=16 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points (AMB115811) Month 1, n=15, 17	0.00 Scores on a scale Interval -1.0 to 0.75	-0.40 Scores on a scale Interval -0.5 to 0.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 2, n=14, 16	0.25 Scores on a scale Interval -0.5 to 1.0	-0.20 Scores on a scale Interval -1.13 to 1.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 3, n=13, 15	0.00 Scores on a scale Interval -0.5 to 2.25	-0.40 Scores on a scale Interval -1.0 to 1.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 4, n=13, 15	1.00 Scores on a scale Interval -0.5 to 2.5	-0.50 Scores on a scale Interval -1.5 to 1.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points EW (AMB115811) visit, n=3, 2	2.00 Scores on a scale Interval -1.5 to 4.0	-0.25 Scores on a scale Interval -0.5 to 0.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points (Extension study) Month 5, n=7, 9	0.00 Scores on a scale Interval -0.5 to 1.5	1.50 Scores on a scale Interval -0.5 to 2.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 7, n=7, 8	0.50 Scores on a scale Interval -0.5 to 2.5	0.00 Scores on a scale Interval -1.38 to 1.75
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 10, n=5, 6	0.50 Scores on a scale Interval 0.5 to 1.5	0.50 Scores on a scale Interval -1.5 to 1.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 13, n=2, 4	0.50 Scores on a scale Interval 0.5 to 0.5	1.00 Scores on a scale Interval -0.75 to 2.75
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 16, n=1, 4	0.50 Scores on a scale Interval 0.5 to 0.5	0.50 Scores on a scale Interval -0.75 to 1.75
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 19, n=0, 1	NA Scores on a scale No participants were analyzed at this time point.	1.00 Scores on a scale Interval 1.0 to 1.0
Change From Study AMB115811 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points End of study, n=7, 8	1.25 Scores on a scale Interval 0.0 to 1.5	0.88 Scores on a scale Interval -0.25 to 1.5

SECONDARY outcome

Timeframe: From randomization up to End of Study for the extension study (assessed up to approximately 20 months)

Population: ITT Population

Time to clinical worsening of CTEPH was defined as the time from randomization in study AMB115811 to the first occurrence of any of the following events: death (all cause), lung transplantation, hospitalization for CTEPH deterioration, atrial septostomy, addition of parenteral prostanoids, appearance of two or more CTEPH worsening events. Worsening events included: \>=20% of decrease in 6MWD; \>=1 increase of WHO Functional Classes; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; refractory systolic hypotension (SBP \<85 mmHg).

Outcome measures

Outcome measures
Measure	Previous Placebo n=16 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Number of Participants With Clinical Worsening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline from study AMB115811 up to End of Study for the extension study (assessed up to approximately 20 months)

Population: ITT Population

The SF-36 version 2 is a self-administered, health-related quality of life (QoL) metric. It is a 36-item questionnaire designed to measure 8 domains of functional health status and well-being: physical functioning, role-physical, bodily pain, general health perceptions, vitality, social functioning, role-emotional, and mental health as well as 2 summary measures (Physical Health and Mental Health). Each domain is scored from 0 (poorer health) to 100 (better health). Baseline of study AMB115811 was to be used. Change from study AMB115811 Baseline was to be calculated as the value at the indicated visit minus the Baseline value. The SF-36 data were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including the SF-36. This decision was documented in the reporting and analysis plan prior to database lock.

Outcome measures

Outcome data not reported

SECONDARY outcome

Population: ITT Population

The ratio to Baseline in NT-proBNP was calculated as the ratio of the value at the specified time-point to the AMB115811 Baseline value and was expressed as a percent change from AMB115811 Baseline. This was done by taking the mean change on the log scale, exponentiating, subtracting 1 and multiplying by 100. Standard deviation (SD) of the logged values (log\[SD\]) have been presented. AMB115811 Baseline is the last value recorded on or prior to start of study treatment in that study. Participant's final visit in study AMB115811 was used as the entry visit of this open-label extension study. For the Extension study, the visit schedule (Months 1, 3, 6, 9, 12 and 15) was mapped to the visit schedule (Months 5, 7, 10, 13, 16 and 19) for continuity with study AMB115811. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). NA indicates that data were not available.

Outcome measures

Outcome measures
Measure	Previous Placebo n=16 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) (AMB115811) Month 1, n=13, 15	43.6 Percent change Standard Deviation 0.41	-15.8 Percent change Standard Deviation 0.36
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 2, n=13, 15	12.4 Percent change Standard Deviation 0.49	-23.3 Percent change Standard Deviation 0.59
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 3, n=12, 14	12.4 Percent change Standard Deviation 0.59	-21.9 Percent change Standard Deviation 0.61
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 4, n=12, 14	14.1 Percent change Standard Deviation 0.55	-29.4 Percent change Standard Deviation 0.50
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) EW (AMB115811) visit, n=3, 2	35.7 Percent change Standard Deviation 0.69	-14.9 Percent change Standard Deviation 0.31
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) (Extension study) Month 5, n=8, 10	-34.7 Percent change Standard Deviation 1.22	-24.5 Percent change Standard Deviation 0.69
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 7, n=8, 8	3.3 Percent change Standard Deviation 0.64	-32.5 Percent change Standard Deviation 0.73
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 10, n=5, 6	-36.5 Percent change Standard Deviation 0.86	-20.1 Percent change Standard Deviation 0.78
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 13, n=3, 5	-8.6 Percent change Standard Deviation 0.60	7.7 Percent change Standard Deviation 0.79
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 16, n=1, 4	-62.4 Percent change Standard Deviation NA The standard deviation could not be calculated as the number of participants analyzed was 1.	-2.8 Percent change Standard Deviation 1.15
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 19, n=0, 1	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	43.1 Percent change Standard Deviation NA The standard deviation could not be calculated as the number of participants analyzed was 1
Percent Change From Study AMB115811 Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) End of study, n=8, 9	-13.2 Percent change Standard Deviation 0.72	-41.7 Percent change Standard Deviation 0.86

SECONDARY outcome

Timeframe: Previous Placebo: Months 0 (Entry visit of the extension), 1, 3, 6, 9, 12; Previous Ambrisentan: Month 0 (Baseline of study AMB115811), 1, 2, 3, 4, Early Withdrawal (EW) (AMB115811), 5, 7, 10, 13, 16, 19; and at End of Study

Population: ITT Population. Placebo arm: includes par. who received ambrisentan treatment during extension study

The 6 minute walk distance data in a previous outcome measure were also analyzed as change from start of ambrisentan treatment. As participants started to receive ambrisentan treatment in two studies, two different time points for start of ambrisentan treatment were used for this analysis. For participants who received ambrisentan treatment in Study AMB115811, the Baseline for that study was used. For participants who received placebo in Study AMB115811, entry visit of the Extension study was defined as Baseline. Change from start of ambrisentan was calculated as the value at the indicated visit minus the start of ambrisentan value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category title).

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 10, n=0, 6	NA Meters No participants were analyzed at this time point.	52.25 Meters Interval 21.0 to 100.0
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 1, n=7, 17	20.00 Meters Interval 15.0 to 30.0	14.00 Meters Interval 1.0 to 42.5
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 2, n=0, 16	NA Meters No participants were analyzed at this time point.	26.25 Meters Interval 3.25 to 61.25
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 3, n=7, 15	20.00 Meters Interval 15.0 to 35.0	20.50 Meters Interval 4.0 to 68.0
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 4, n= 0, 15	NA Meters No participants were analyzed at this time point.	25.00 Meters Interval 12.0 to 49.0
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points EW (AMB115811), n=0, 2	NA Meters No participants were analyzed at this time point.	41.25 Meters Interval 0.0 to 82.5
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 5, n=0, 9	NA Meters No participants were analyzed at this time point.	51.50 Meters Interval 19.0 to 80.5
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 6, n=5, 0	45.00 Meters Interval 27.0 to 60.0	NA Meters No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 7, n=0, 8	NA Meters No participants were analyzed at this time point.	57.50 Meters Interval 23.5 to 88.75
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 9, n=2, 0	32.50 Meters Interval 5.0 to 60.0	NA Meters No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 12, n=1, 0	45.00 Meters Interval 45.0 to 45.0	NA Meters No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 13, n=0, 4	NA Meters No participants were analyzed at this time point.	33.25 Meters Interval 19.0 to 46.25
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 16, n=0, 4	NA Meters No participants were analyzed at this time point.	47.25 Meters Interval 23.5 to 61.25
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points Month 19, n=0, 1	NA Meters No participants were analyzed at this time point.	69.00 Meters Interval 69.0 to 69.0
Change From Start of Ambrisentan Treatment in 6 Minutes Walking Distance at the Indicated Time Points End of study, n=7, 8	37.00 Meters Interval 0.0 to 60.0	29.50 Meters Interval 4.0 to 80.25

SECONDARY outcome

Population: ITT Population. Placebo arm: includes par. who received ambrisentan treatment during extension study

The WHO functional class data in a previous outcome measure were also analyzed as change from start of ambrisentan treatment. There are 4 grades for WHO FC based on severity of symptoms of pulmonary arterial hypertension (Class I = none, Class IV = most severe). Grades mapped to numeric scale 1-4 (i.e. Class IV = 4). As participants started to receive ambrisentan treatment in two studies, two different time points for start of ambrisentan treatment were used for this analysis. For participants who received ambrisentan treatment in Study AMB115811, the Baseline for that study was used. For participants who received placebo in Study AMB115811, entry visit of the Extension study was defined as Baseline. Change from start of ambrisentan was calculated as the value at the indicated visit minus the start of ambrisentan value (positive change = worsening). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 1, n=8, 17	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 2, n=0, 16	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 3, n=8, 15	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 4, n= 0, 15	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points EW (AMB115811), n=0, 2	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 5, n=0, 10	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 6, n=5, 0	0.0 Scores on a scale Interval 0.0 to 0.0	NA Scores on a scale No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 7, n=0, 8	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval -1.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 9, n=3, 0	0.0 Scores on a scale Interval 0.0 to 0.0	NA Scores on a scale No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 10, n=0, 6	NA Scores on a scale No participants were analyzed at this time point.	-0.5 Scores on a scale Interval -1.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 12, n=1, 0	0.0 Scores on a scale Interval 0.0 to 0.0	NA Scores on a scale No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 13, n=0, 5	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 16, n=0, 4	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval -0.5 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points Month 19, n=0, 1	NA Scores on a scale No participants were analyzed at this time point.	0.0 Scores on a scale Interval 0.0 to 0.0
Change From Start of Ambrisentan Treatment in World Health Organization (WHO) Functional Class (FC) at the Indicated Time Points End of study, n=8, 10	0.0 Scores on a scale Interval 0.0 to 0.0	0.0 Scores on a scale Interval -1.0 to 0.0

SECONDARY outcome

Population: ITT Population. Placebo arm: includes par. who received ambrisentan treatment during extension study

The BCR10S data in a previous outcome measure were also analyzed as change from start of ambrisentan treatment. BCR10S score, a rating of perceived exertion, ranges from 0 to 10 (0=nothing at all, 10 extremely strong). If par.'s perception or feeling was stronger than "10", a larger number could be used. As participants started to receive ambrisentan treatment in two studies, two different time points for start of ambrisentan treatment were used for this analysis. For participants who received ambrisentan treatment in Study AMB115811, the Baseline for that study was used. For participants who received placebo in Study AMB115811, entry visit of the Extension study was defined as Baseline. Change from start of ambrisentan was calculated as the value at the indicated visit minus the start of ambrisentan value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category title).

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 13, n=0, 4	NA Scores on a scale No participants were analyzed at this time point.	1.00 Scores on a scale Interval -0.75 to 2.75
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 1, n=7, 17	0.00 Scores on a scale Interval -1.0 to 1.0	-0.40 Scores on a scale Interval -0.5 to 0.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 2, n=0, 16	NA Scores on a scale No participants were analyzed at this time point.	-0.20 Scores on a scale Interval -1.13 to 1.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 3, n=7, 15	0.00 Scores on a scale Interval 0.0 to 1.0	-0.40 Scores on a scale Interval -1.0 to 1.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 4, n= 0, 15	NA Scores on a scale No participants were analyzed at this time point.	-0.50 Scores on a scale Interval -1.5 to 1.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points EW (AMB115811), n=0, 2	NA Scores on a scale No participants were analyzed at this time point.	-0.25 Scores on a scale Interval -0.5 to 0.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 5, n=0, 9	NA Scores on a scale No participants were analyzed at this time point.	1.50 Scores on a scale Interval -0.5 to 2.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 6, n=5, 0	1.00 Scores on a scale Interval 1.0 to 2.0	NA Scores on a scale No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 7, n=0, 8	NA Scores on a scale No participants were analyzed at this time point.	0.00 Scores on a scale Interval -1.38 to 1.75
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 9, n=2, 0	0.50 Scores on a scale Interval -1.0 to 2.0	NA Scores on a scale No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 10, n=0, 6	NA Scores on a scale No participants were analyzed at this time point.	0.50 Scores on a scale Interval -1.5 to 1.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 12, n=1,0	1.00 Scores on a scale Interval 1.0 to 1.0	NA Scores on a scale No participants were analyzed at this time point.
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 16, n=0, 4	NA Scores on a scale No participants were analyzed at this time point.	0.50 Scores on a scale Interval -0.75 to 1.75
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points Month 19, n=0, 1	NA Scores on a scale No participants were analyzed at this time point.	1.00 Scores on a scale Interval 1.0 to 1.0
Change From Start of Ambrisentan Treatment in Borg CR10 Scale (BCR10S) Immediately Following Exercise at the Indicated Time Points End of study, n=7, 8	0.00 Scores on a scale Interval -1.0 to 1.0	0.88 Scores on a scale Interval -0.25 to 1.5

SECONDARY outcome

Population: ITT Population. Placebo arm: includes par. who received ambrisentan treatment during extension study

The NT-proBNP data in a previous outcome measure were also analyzed as change from start of ambrisentan treatment. The ratio to start of ambrisentan in NT-proBNP was calculated as the ratio of the value at the specified time-point to the start of ambrisentan value and was expressed as a percent change from start of ambrisentan. This was done by taking the mean change on the log scale, exponentiating, subtracting 1 and multiplying by 100. Standard deviation (SD) of the logged values (log\[SD\]) have been presented. As par. started to receive ambrisentan treatment in 2 studies, 2 different time points for start of ambrisentan treatment were used for this analysis. For par. who received ambrisentan treatment in study AMB115811, the Baseline for that study was used. For par. who received placebo in Study AMB115811, entry visit of the Extension study was defined as Baseline. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category title).

Outcome measures

Outcome measures
Measure	Previous Placebo n=9 Participants Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=17 Participants Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 1, n=8, 15	-49.5 Percent change Standard Deviation 1.40	-15.8 Percent change Standard Deviation 0.36
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 2, n=0, 15	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	-23.3 Percent change Standard Deviation 0.59
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 3, n=8, 14	-20.1 Percent change Standard Deviation 0.86	-21.9 Percent change Standard Deviation 0.61
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 4, n= 0, 14	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	-29.4 Percent change Standard Deviation 0.50
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) EW (AMB115811), n=0, 2	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	-14.9 Percent change Standard Deviation 0.31
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 5, n=1, 10	NA Percent change Standard Deviation NA Month 5 for the Previous Placebo arm was an unscheduled lab assessment; therefore, the value was entered as NA for the 1 participant at this time point.	-24.5 Percent change Standard Deviation 0.69
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 6, n=5, 0	-53.5 Percent change Standard Deviation 1.22	NA Percent change Standard Deviation NA No participants were analyzed at this time point.
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 7, n=0, 8	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	-32.5 Percent change Standard Deviation 0.73
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 9, n=3, 1	-11.2 Percent change Standard Deviation 0.71	NA Percent change Standard Deviation NA Month 9 for the Previous ambrisentan arm was an unscheduled lab assessment; therefore, the value was entered as NA for the 1 participant at this time point.
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 10, n=0, 6	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	-20.1 Percent change Standard Deviation 0.78
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 12, n=1, 0	-67.9 Percent change Standard Deviation NA The standard deviation could not be calculated as the number of participants analyzed was 1.	NA Percent change Standard Deviation NA No participants were analyzed at this time point.
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 13, n=0, 5	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	7.7 Percent change Standard Deviation 0.79
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 16, n=0, 4	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	-2.8 Percent change Standard Deviation 1.15
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Month 19, n=0, 1	NA Percent change Standard Deviation NA No participants were analyzed at this time point.	43.1 Percent change Standard Deviation NA The standard deviation could not be calculated as the number of participants analyzed was 1.
Percent Change From Start of Ambrisentan Treatment in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) End of study, n=8, 9	-30.5 Percent change Standard Deviation 0.85	-41.7 Percent change Standard Deviation 0.86

SECONDARY outcome

Timeframe: From Entry visit of the extension study up to End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population

The time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition. Dosing data were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including time to first change in dose of open-label ambrisentan. This decision was documented in the reporting and analysis plan prior to database lock.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From Entry visit of the extension study up to End of Study (assessed up to approximately 16 months)

Population: Safety (Extension) Population.

The time to addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to the following reasons: Deterioration of clinical condition; Lack of beneficial effect with previous therapy (not reaching set treatment goals). PAH therapies were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including time to first addition of another targeted PAH therapeutic agent. This decision was documented in the reporting and analysis plan prior to database lock.

Outcome measures

Outcome data not reported

Adverse Events

Previous Placebo

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

Previous Ambrisentan

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Previous Placebo n=9 participants at risk Participants received placebo tablet once daily (OD) for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants received ambrisentan 5 milligrams (mg) tablet OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.	Previous Ambrisentan n=10 participants at risk Participants received ambrisentan 5 mg tablet OD for 16 weeks in study AMB115811. Upon enrollment in the extension study AMB116457, participants continued to receive ambrisentan 5 mg OD. The dose could be up-titrated to ambrisentan 10 mg OD or adjusted back to ambrisentan 5 mg OD.
Cardiac disorders Atrial fibrillation	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Cardiac disorders Bradyarrhythmia	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Cardiac disorders Cardiac failure	22.2% 2/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Cardiac disorders Right ventricular failure	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Cardiac disorders Ventricular tachycardia	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Gastrointestinal disorders Vomiting	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
General disorders Implant site extravasation	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
General disorders Oedema peripheral	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Infections and infestations Gastroenteritis	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Investigations Electrocardiogram repolarisation abnormality	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Investigations Oxygen saturation decreased	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.
Vascular disorders Aortic stenosis	11.1% 1/9 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.	0.00% 0/10 • Treatment-emergent adverse events (TEAEs) will include AEs up to 30 days after their last dose, assessed up to approximately 16 months. TEAEs are reported for the Safety (Extension) Population. TEAEs are: a) new events that started during the extension study. For par. withdrawn from the study, TEAEs included AEs up to 30 days after last dose b) ongoing AEs that started before the extension study but were either not reported in study AMB115811 or worsened during the extension study.

Other adverse events

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