Trial Outcomes & Findings for Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension. (NCT NCT01884675)

Last Updated: 2017-03-06

Results Overview

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 participant can walk in a period of 6 minutes. Change from baseline was calculated at Weeks 4, 8, 12 and 16. Change from Baseline was calculated as value at the specified visit minus the Baseline value. Data at Baseline is based on average of two consecutive test results during Screening/Baseline period that differ by \<10%. If only one measurement was available, that measurement was used. In any cases where the protocol-defined criteria for Baseline 6MWD was not met, the Baseline value was based on the last two consecutive measurements for a participant.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

33 participants

Primary outcome timeframe

Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

Results posted on

2017-03-06

Participant Flow

A total of 160 participants were planned to be enrolled, however only 33 participants were randomized in the study.

This was a double-blind study which included clinic visits at Screening, Baseline visit, Weeks 4, 8, 12 and 16. A Follow-up visit was scheduled approximately 30 days after the Week 16 visit for those participants not continuing into study AMB116457 (Open-label extension study).

Participant milestones

Participant milestones
Measure	Placebo Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Overall Study STARTED	16	17
Overall Study COMPLETED	13	15
Overall Study NOT COMPLETED	3	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Overall Study Study closed/terminated	3	2

Baseline Characteristics

Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.	Total n=33 Participants Total of all reporting groups
Age, Continuous	59.0 Years INTER_QUARTILE_RANGE 8.99 • n=5 Participants	63.0 Years INTER_QUARTILE_RANGE 13.38 • n=7 Participants	62.0 Years INTER_QUARTILE_RANGE 11.31 • n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	8 Participants n=7 Participants	18 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	9 Participants n=7 Participants	15 Participants n=5 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	6 Participants n=5 Participants	11 Participants n=7 Participants	17 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

Population: Intent-to-Treat (ITT) Population: comprised of all randomized participants who received at least 1 dose of study drug. Only those participants with available data at Baseline and the specified timepoint (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16 Week 4, n=15, 17	5.00 Meters Interval -1.5 to 16.5	14.00 Meters Interval 1.0 to 42.5
Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16 Week 8, n=14, 16	7.50 Meters Interval -14.5 to 22.5	26.25 Meters Interval 3.25 to 61.25
Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16 Week 12, n=13, 15	5.50 Meters Interval -23.0 to 39.5	20.50 Meters Interval 4.0 to 68.0
Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16 Week 16, n=13, 15	-10.00 Meters Interval -32.5 to 20.0	25.00 Meters Interval 12.0 to 49.0
Change From Baseline in Six Minutes Walking Distance (6MWD) at Week 16 Early Withdrawal, n=3, 2	7.50 Meters Interval -46.5 to 43.5	41.25 Meters Interval 0.0 to 82.5

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 16

Population: ITT Population. Only those participants with available data at Baseline and the specified timepoint were analysed.

PVR is a measure of cardiopulmonary haemodynamics. Change from Baseline was calculated as value at specified visit minus Baseline value. Baseline is the last value recorded on or prior to start of study treatment.

Outcome measures

Outcome measures
Measure	Placebo n=11 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=13 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16	-103.0 Dynes*second/centimeter^5 Interval -122.0 to -88.0	-130.0 Dynes*second/centimeter^5 Interval -502.0 to -78.0

SECONDARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

The WHO FC indicates the severity of PAH and is an adaptation of the New York Heart Association classification. It was assessed by the investigator. There are four grades for WHO FC based on severity of symptoms (Class I = none, Class IV = most severe). This functional classification system links symptoms with activity limitations, and allows clinicians to quickly predict disease progression and prognosis, as well as the need for specific treatment regimens, irrespective of the underlying etiology of PAH. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value. For analyse purposes, the WHO FC Class categories of I-IV were mapped to a numeric scale of 1-4.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal Week 4, 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 Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal Week 8, 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 Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal Week 12, 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 Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal Week 16, 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 Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal Early Withdrawal, 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

SECONDARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

The BCR10S score was collected immediately following completion of the 6-minute walk test. Baseline data was calculated as the average of the two BCR10S values obtained following the two 6MWD tests used in determining the Baseline 6MWD. If only one measurement was available, that measurement has been used. BCR10S scores ranges from 0 to 10 (0=nothing at all, 10=extremely strong). If participant's perception or feeling was stronger than "10", i.e "extremely strong", "Maximal" - a larger number could be used, e.g. 12 or still higher i.e "Absolute maximum"). Change from Baseline was calculated as the value at specified visit minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal Week 4, 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 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal Week 8, 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 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal Week 12, 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 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal Week 16, 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 Baseline in Borg CR10 Scale (BCR10S) Immediately Following Exercise at Weeks 4, 8, 12 and 16/Early Withdrawal Early Withdrawal, 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

SECONDARY outcome

Timeframe: From randomization to Week 16/Follow up visit (21 weeks)

Population: ITT Population

Clinical worsening of CTEPH is defined by the time from randomization to the first occurrence of death, lung transplantation, hospitalization for CTEPH, atrial septostomy, addition of parenteral prostanoids, or study withdrawal due to two or more early escape criteria included: a decrease from Baseline of at least 20 percent in the distance walked during the six-minute walk test; an increase of one or more WHO functional class; worsening right ventricular failure (e.g., as indicated by increased jugular venous pressure; new/worsening hepatomegaly, ascites, or peripheral edema; worsening echocardiographic parameters such as tricuspid annulus plane systolic excursion (TAPSE) and Tissue Doppler Imaging of the tricuspid annulus); rapidly progressing cardiogenic, hepatic, or renal failure; refractory systolic hypotension (systolic blood pressure less than 85 millimeter of mercury \[mmHg\]).

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Number of Participants With Clinical Worsening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 16

mPAP and mRAP are measures of cardiopulmonary hemodynamics. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Mean Right Atrial Pressure (mRAP) and Mean Pulmonary Artery Pressure (mPAP) at Week 16 mRAP, Week 16, n=11, 13	-2.0 Millimeter of mercury (mmHg) Interval -5.0 to 4.0	-1.0 Millimeter of mercury (mmHg) Interval -4.0 to 3.0
Change From Baseline in Mean Right Atrial Pressure (mRAP) and Mean Pulmonary Artery Pressure (mPAP) at Week 16 mPAP, Week 16, n=11, 12	-6.0 Millimeter of mercury (mmHg) Interval -10.0 to -1.0	-3.0 Millimeter of mercury (mmHg) Interval -11.6 to 2.0

SECONDARY outcome

Timeframe: Baseline (Week 0) and Week 16

Cardiac index is measure of cardiopulmonary hemodynamics. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the value at specified visit minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=11 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=12 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Cardiac Index at Week 16	0.100 Litre per minute per meter squared Interval -0.04 to 0.37	0.440 Litre per minute per meter squared Interval 0.03 to 1.015

SECONDARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12 and 16/Early Withdrawal

The ratio to baseline \[BL\] in NT-proBNP was calculated as the ratio of the value at the specified time-point to the BL value and was expressed as a percent change from BL. For each treatment group, the mean change from BL at the specified time-point was determined on the log scale. This mean was then back transformed to give a geometric mean (GM) of the ratio of the value at the specified time-point to BL on the original scale. The GM was expressed as a percentage (100\*\[GM - 1\]). Standard Deviation(SD) is the SD of the mean change from baseline values on the log scale.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Week 4, n=13, 15	43.6 Percent change 95% Confidence Interval 0.41 • Interval 12.0 to 84.1	-15.8 Percent change 95% Confidence Interval 0.36 • Interval -30.9 to 2.5
Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Week 8, n=13, 15	12.4 Percent change 95% Confidence Interval 0.49 • Interval -16.2 to 50.8	-23.3 Percent change 95% Confidence Interval 0.59 • Interval -44.7 to 6.5
Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Week 12, n=12, 14	12.4 Percent change 95% Confidence Interval 0.59 • Interval -22.9 to 63.9	-21.9 Percent change 95% Confidence Interval 0.61 • Interval -45.2 to 11.1
Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Week 16, n=12, 14	14.1 Percent change 95% Confidence Interval 0.55 • Interval -19.5 to 61.6	-29.4 Percent change 95% Confidence Interval 0.50 • Interval -47.2 to -5.5
Percent Change From Baseline in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Early withdrawal, n=3, 2	35.7 Percent change 95% Confidence Interval 0.69 • Interval -75.8 to 659.8	-14.9 Percent change 95% Confidence Interval 0.31 • Interval -95.0 to 1337.1

SECONDARY outcome

Timeframe: Baseline and up to Week 16/Early Withdrawal

Population: ITT Population

The SF-36 v2 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). Change from Baseline was calculated as the post-Baseline score minus the Baseline score. 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

Timeframe: From the start of study treatment and until follow up (Week 16/Follow up)

Population: ITT Population

AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. A 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 or is a congenital anomaly/birth defect or important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Any AE	15 Participants	11 Participants
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) Any SAE	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Haemoglobin levels were assessed at Screening, Baseline, Weeks 4, 8, 12, and 16/Early Withdrawal. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 4, n=15, 15	-2.0 Grams per liter Interval -5.0 to 6.0	-5.0 Grams per liter Interval -10.0 to 2.0
Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Early withdrawal, n=3, 2	-2.0 Grams per liter Interval -2.0 to 26.0	-14.5 Grams per liter Interval -16.0 to -13.0
Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 8, n=13, 16	0.0 Grams per liter Interval -8.0 to 3.0	-7.5 Grams per liter Interval -10.5 to 1.5
Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 12, n=13, 14	2.0 Grams per liter Interval -6.0 to 8.0	-5.0 Grams per liter Interval -9.0 to -1.0
Change From Baseline in Haemoglobin Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 16, n=13, 15	-3.0 Grams per liter Interval -10.0 to 2.0	-6.0 Grams per liter Interval -9.0 to -3.0

SECONDARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Haematocrit levels were assessed at Screening, Baseline, Weeks 4, 8, 12, and 16/Early Withdrawal. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 4, n=15, 15	0.000 Proportion of 1 Interval -0.016 to 0.015	-0.015 Proportion of 1 Interval -0.033 to 0.012
Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 8, n=13, 16	-0.003 Proportion of 1 Interval -0.026 to 0.014	-0.021 Proportion of 1 Interval -0.035 to 0.003
Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 12, n=13, 14	0.007 Proportion of 1 Interval -0.017 to 0.022	-0.023 Proportion of 1 Interval -0.029 to -0.004
Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Week 16, n=13, 15	-0.007 Proportion of 1 Interval -0.031 to 0.004	-0.019 Proportion of 1 Interval -0.033 to -0.003
Change From Baseline in Haematocrit Levels at Weeks 4, 8, 12, and 16/Early Withdrawal Early withdrawal, n=3, 2	-0.008 Proportion of 1 Interval -0.01 to 0.083	-0.030 Proportion of 1 Interval -0.032 to -0.028

SECONDARY outcome

Timeframe: Weeks 4, 8, 12, and 16/Early Withdrawal

Population: ITT Population

A significant liver chemistry result is defined as any result which met the stopping criteria defined in the study protocol. Liver events were assessed at Screening, Baseline, Weeks 4, 8, 12, and 16/Early Withdrawal. Number of participants who reported a significant liver chemistry result are presented.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Number of Participants With Significant Liver Events at Weeks 4, 8, 12, and 16/Early Withdrawal	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Vital sign measurements including supine systolic and diastolic blood pressure at Weeks 4, 8, 12, and 16/Early Withdrawal weeks. Supine blood pressure measurement was taken in a supine position having rested in this position for at least 10 minutes before each reading. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal DBP, Week 4, n=15, 17	0.0 millimeter of mercury (mmHg) Interval -5.0 to 9.0	-1.0 millimeter of mercury (mmHg) Interval -12.0 to 1.0
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal DBP, Week 8, n=14, 16	1.5 millimeter of mercury (mmHg) Interval -7.0 to 13.0	-9.0 millimeter of mercury (mmHg) Interval -16.0 to -5.5
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal DBP, Week 12, n=13, 15	1.0 millimeter of mercury (mmHg) Interval 0.0 to 7.0	-8.0 millimeter of mercury (mmHg) Interval -14.0 to 5.0
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal DBP, Week 16, n=13, 15	-2.0 millimeter of mercury (mmHg) Interval -10.0 to 8.0	-10.0 millimeter of mercury (mmHg) Interval -16.0 to 3.0
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal DBP, Early Withdrawal, n=3, 2	16.0 millimeter of mercury (mmHg) Interval 8.0 to 26.0	-17.0 millimeter of mercury (mmHg) Interval -19.0 to -15.0
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal SBP, Week 4, n=15, 17	0.0 millimeter of mercury (mmHg) Interval -10.0 to 4.0	-4.0 millimeter of mercury (mmHg) Interval -9.0 to 19.0
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal SBP, Week 8, n=14, 16	5.5 millimeter of mercury (mmHg) Interval -8.0 to 14.0	-10.0 millimeter of mercury (mmHg) Interval -18.5 to -2.5
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal SBP, Week 12, n=13, 15	-2.0 millimeter of mercury (mmHg) Interval -12.0 to 11.0	-5.0 millimeter of mercury (mmHg) Interval -10.0 to 0.0
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal SBP, Week 16, n=13, 15	-4.0 millimeter of mercury (mmHg) Interval -11.0 to 15.0	-6.0 millimeter of mercury (mmHg) Interval -8.0 to 10.0
Change From Baseline in Supine Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal SBP, Early Withdrawal, n=3, 2	15.0 millimeter of mercury (mmHg) Interval 10.0 to 18.0	-8.0 millimeter of mercury (mmHg) Interval -16.0 to 0.0

SECONDARY outcome

Timeframe: Baseline (Week 0); Weeks 4, 8, 12, and 16/Early Withdrawal

Vital sign measurements including heart rate at Weeks 4, 8, 12, and 16/Early Withdrawal weeks. Baseline is the last value recorded on or prior to start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal Early withdrawal, n=3, 2	-6.0 beats per minute Interval -24.0 to -3.0	-18.0 beats per minute Interval -32.0 to -4.0
Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal Week 4, n=15, 17	0.0 beats per minute Interval -14.0 to 3.0	4.0 beats per minute Interval -3.0 to 10.0
Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal Week 8, n=14, 16	-8.0 beats per minute Interval -17.0 to 3.0	1.0 beats per minute Interval -12.5 to 8.5
Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal Week 12, n=13, 15	-2.0 beats per minute Interval -15.0 to 3.0	0.0 beats per minute Interval -6.0 to 5.0
Change From Baseline in Heart Rate Assessed at Weeks 4, 8, 12, and 16/Early Withdrawal Week 16, n=13, 15	0.0 beats per minute Interval -17.0 to 8.0	-1.0 beats per minute Interval -14.0 to 2.0

SECONDARY outcome

Timeframe: Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal,

Population: ITT Population

Clinical chemistry parameters including alanine amino transferase (ALT), aspartate amino transferase (AST), creatinine, gamma glutamyl transferase (GGT) and total bilirubin (TB) assessed any time post Baseline. ALT: lower concern value and high concern value was considered as none and \>=3xupper limit of normal (ULN) respectively. AST: lower concern value and high concern value was considered as none or \>=3xULN respectively. creatinine: lower concern value and high concern value was considered as none and \>=176.8 micromoles per liter (umol/L) respectively. GGT: lower concern value and high concern value was considered as none and \>=3xULN respectively. For TB: lower concern value was none and high concern value was \>=2xULN. Participants with both normal and low values were counted once under their worst case (Low). Participants with both normal and high values were counted once under their worst case (High). Participants with both high and low values are counted under both categories.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline ALT, >clinical concern high	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline ALT, <clinical concern low	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline AST, >clinical concern high	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline AST, <clinical concern low	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline Creatinine, >clinical concern high	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline Creatinine, <clinical concern low	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline GGT, >clinical concern high	1 Participants	1 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline GGT, <clinical concern low	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline TB, >clinical concern high	0 Participants	0 Participants
Number of Participants With Clinical Chemistry Parameters of Potential Clinical Concern Any Time Post Baseline TB, <clinical concern low	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (Week 0), Weeks 4, 8, 12 and 16/early withdrawal

Hematology parameters including hemoglobin, international normalized ratio (INR), and platelet count assessed any time post Baseline. Baseline is the last value recorded on or prior to start of study treatment. For hemoglobin: lower concern value and high concern value was considered as \<100 gram per liter (G/L) and none respectively. For INR: lower concern value and high concern value was considered as none or \>5 prothrombin time respectively. For platelet count: lower concern value and high concern value was considered as \<50 giga cells per liter (GI/L) and \>500 GI/L respectively. Participants with both normal and low values were counted once under their worst case (Low). Participants with both normal and high values were counted once under their worst case (High). Participants with both high and low values are counted under both categories.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 Participants Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline Hemoglobin, >clinical concern high, n=16, 17	0 Participants	0 Participants
Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline Hemoglobin, <clinical concern low, n=16, 17	0 Participants	0 Participants
Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline INR, >clinical concern high, n=2, 0	0 Participants	0 Participants
Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline INR, <clinical concern low, n=2, 0	0 Participants	0 Participants
Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline Platelet count, >clinical concern high, n=16, 17	0 Participants	0 Participants
Number of Participants With Hematology Parameters of Potential Clinical Concern Any Time Post Baseline Platelet count, <clinical concern low, n=16, 17	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, Weeks 4 and 16/early withdrawal

Population: ITT Population

For male participants testicular function (total testosterone, sex hormone binding globulin \[SHBG-calculated free testosterone), follicle stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B were assessed at Weeks 4 and 16/early withdrawal. The testicular function data were collected, but after the study was terminated, not all endpoints listed in the protocol were analyzed, including Testicular Function. This decision was documented in the reporting and analysis plan prior to database lock.

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Ambrisentan 5mg

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=16 participants at risk Participants received a matching placebo tablet once daily for a period of 16 weeks.	Ambrisentan 5mg n=17 participants at risk Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.
Respiratory, thoracic and mediastinal disorders Asthma	6.2% 1/16 • Adverse events (AEs) and serious adverse events (SAEs) were collected from the start of study treatment and until the follow up contact (Week 21) AEs and SAEs were collected from the members of ITT population which comprised of all randomized participants who received at least 1 dose of study drug.	0.00% 0/17 • Adverse events (AEs) and serious adverse events (SAEs) were collected from the start of study treatment and until the follow up contact (Week 21) AEs and SAEs were collected from the members of ITT population which comprised of all randomized participants who received at least 1 dose of study drug.

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER