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Clinical Trial Results:
A Randomised, Multicentre, Double-Blind, Placebo-Controlled Study Of Ambrisentan In Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Summary
EudraCT number	2012-001646-18
Trial protocol	ES AT DE GB IT CZ NL
Global end of trial date	30 Mar 2015

Results information
Results version number	v1
This version publication date	01 Apr 2016
First version publication date	01 Apr 2016
Other versions	v2 , v3

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

115811

ISRCTN number

US NCT number

NCT01884675

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Middlesex, Brentford, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, +1 8664357343,

Scientific contact

GSK Response Center, GlaxoSmithKline, +1 8664357343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

26 Aug 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Mar 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

It is hypothesised that ambrisentan may provide benefit to subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). This Phase III, randomized, double-blind placebo controlled parallel group, 16 week study will compare the safety and efficacy of ambrisentan 5 milligrams (mg) versus placebo in subjects with inoperable CTEPH. The study will enroll 160 subjects, to assure at least 72 evaluable subjects per treatment arm, based on 10% drop-out rate.

Protection of trial subjects

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Sep 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 11

Country: Number of subjects enrolled

Czech Republic: 2

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Japan: 5

Country: Number of subjects enrolled

Mexico: 2

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

United Kingdom: 1

Country: Number of subjects enrolled

Netherlands: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

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

Screening details

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).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received a matching placebo tablet once daily for a period of 16 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5mg round, white, film-coated, immediate-release tablets, once daily

Ambrisentan 5mg

Arm description

Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.

Arm type

Experimental

Investigational medicinal product name

Ambrisentan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5mg round, white, film-coated, immediate-release tablets, once daily

Number of subjects in period 1	Placebo	Ambrisentan 5mg
Started	16	17
Completed	13	15
Not completed	3	2
Study terminated	3	2

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received a matching placebo tablet once daily for a period of 16 weeks.

Reporting group title

Ambrisentan 5mg

Reporting group description

Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.

Reporting group values	Placebo	Ambrisentan 5mg	Total
Number of subjects	16	17	33
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	59.8 ( 8.99 )	61.2 ( 13.38 )	-
Gender categorical
Units: Subjects
Female	10	8	18
Male	6	9	15
RaceEthnicityOther
Units: Subjects
Asian - East Asian Heritage	6	5	11
Asian - Japanese Heritage	4	1	5
White - White/Caucasian/European Heritage	6	11	17

End points

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Reporting group title

Placebo

Reporting group description

Participants received a matching placebo tablet once daily for a period of 16 weeks.

Reporting group title

Ambrisentan 5mg

Reporting group description

Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.

Primary: Change from Baseline in Six Minutes Walking Distance (6MWD) at Week 16

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End point title

Change from Baseline in Six Minutes Walking Distance (6MWD) at Week 16 ^[1]

End point description

The 6-minute walk test(6MWT) was conducted according to the American Thoracic Society guidelines in accordance with local standard operating procedures. 6MWD was measured by a 6MWT. This test measures the distance that a participant can walk in a period of 6 minutes. Change from BL was calculated at Weeks 4, 8, 12 and 16 as the value at the specified visit minus the BL value. Data at BL was based on average of two consecutive test results during Screening/BL period that differ by <10%. If only one measurement was available, that measurement was used. In any cases where the protocol-defined criteria for BL 6MWD was not met, the BL value was based on the last two consecutive measurements for a participant. Intent-to-Treat (ITT) Population: comprised of all randomized participants who received at least 1 dose of study drug. Only participants with available data at BL and the specified timepoint (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Primary

End point timeframe

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

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As this study was terminated for futility of enrollment, the achieved sample size was approximately 1/5th of the intended sample size. As a result, the approach to characterizing the data was descriptive in nature with no formal hypotheses tested.

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Meters
median (inter-quartile range (Q1-Q3))
Week 4, n=15, 17	5 (-1.5 to 16.5)	14 (1 to 42.5)
Week 8, n=14, 16	7.5 (-14.5 to 22.5)	26.25 (3.25 to 61.25)
Week 12, n=13, 15	5.5 (-23 to 39.5)	20.5 (4 to 68)
Week 16, n=13, 15	-10 (-32.5 to 20)	25 (12 to 49)
Early Withdrawal, n=3, 2	7.5 (-46.5 to 43.5)	41.25 (0 to 82.5)

No statistical analyses for this end point

Secondary: Change from Baseline in pulmonary vascular resistance (PVR) at Week 16

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End point title

Change from Baseline in pulmonary vascular resistance (PVR) at Week 16

End point description

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. ITT Population. Only those participants with available data at Baseline and the specified time point were analyzed.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 16

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	11	13
Units: Dynes*second per centimeter^5
median (inter-quartile range (Q1-Q3))	-103 (-122 to -88)	-130 (-502 to -78)

No statistical analyses for this end point

Secondary: Change from Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal

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End point title

Change from Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal

End point description

The WHO FC indicates the severity of PAH and is an adaptation of the New York Heart Association classification as 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 predict disease progression and prognosis, and the need for specific treatment regimens irrespective of the underlying etiology of PAH. BL is the last value recorded on or prior to start of study treatment. Change from BL was calculated as the value at specified visit minus the BL value. For analysis purposes, the WHO FC Class categories of I-IV were mapped to a numeric scale of 1-4. Intent-to-Treat (ITT) Population: comprised of all randomized participants who received at least 1 dose of study drug. Only participants with available data at BL and the specified timepoint (represented as n=X,X in the category titles) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Scores on a scale
median (inter-quartile range (Q1-Q3))
Week 4, n=15, 17	0 (0 to 0)	0 (0 to 0)
Week 8, n=14, 16	0 (0 to 0)	0 (0 to 0)
Week 12, n=13, 15	0 (0 to 0)	0 (-1 to 0)
Week 16, n=13, 15	0 (0 to 0)	0 (-1 to 0)
Early Withdrawal, n=3, 2	0 (-1 to 0)	0 (0 to 0)

No statistical analyses for this end point

Secondary: Change from Baseline in Borg CR10 Scale (BCR10S) immediately following exercise at Weeks 4, 8, 12 and 16/Early Withdrawal

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End point title

Change from Baseline in Borg CR10 Scale (BCR10S) immediately following exercise at Weeks 4, 8, 12 and 16/Early Withdrawal

End point description

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. 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 time point (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Scores on a scale
median (inter-quartile range (Q1-Q3))
Week 4, n=15, 17	0 (-1 to 0.75)	-0.4 (-0.5 to 0)
Week 8, n=14, 16	0.25 (-0.5 to 1)	-0.2 (-1.13 to 1)
Week 12, n=13, 15	0 (-0.5 to 2.25)	-0.4 (-1 to 1)
Week 16, n=13, 15	1 (-0.5 to 2.5)	-0.5 (-1.5 to 1)
Early Withdrawal, n=3, 2	2 (-1.5 to 4)	-0.25 (-0.5 to 0)

No statistical analyses for this end point

Secondary: Number of participants with clinical worsening of chronic thromboembolic pulmonary hypertension (CTEPH)

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End point title

Number of participants with clinical worsening of chronic thromboembolic pulmonary hypertension (CTEPH)

End point description

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 BL of at least 20% 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 (TDI) (of the tricuspid annulus; rapidly progressing cardiogenic, hepatic, or renal failure; refractory systolic hypotension(systolic blood pressure less than 85 millimeter of mercury[mmHg]). No participants experienced a clinically worsening event therefore there are no data to present. ITT Population

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Participants
number (not applicable)	0	0

No statistical analyses for this end point

Secondary: Change from Baseline in mean right atrial pressure (mRAP) and mean pulmonary artery pressure (mPAP) at Week 16

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End point title

Change from Baseline in mean right atrial pressure (mRAP) and mean pulmonary artery pressure (mPAP) at Week 16

End point description

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. 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 time point (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 16

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Millimeter of mercury (mmHg)
median (inter-quartile range (Q1-Q3))
mRAP, Week 16, n=11, 13	-2 (-5 to 4)	-1 (-4 to 3)
mPAP, Week 16, n=11, 12	-6 (-10 to -1)	-3 (-11.6 to 2)

No statistical analyses for this end point

Secondary: Change from Baseline in cardiac index at Week 16

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End point title

Change from Baseline in cardiac index at Week 16

End point description

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. 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 time point were summarized.

End point type

Secondary

End point timeframe

Baseline (Week 0) and Week 16

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	11	12
Units: Litre per minute per meter per square
median (inter-quartile range (Q1-Q3))	0.1 (-0.04 to 0.37)	0.44 (0.03 to 1.015)

No statistical analyses for this end point

Secondary: Percent change from Baseline in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP)

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End point title

Percent change from Baseline in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP)

End point description

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. 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 time point (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Percent change
geometric mean (standard deviation)
Week 4, n=13, 15	43.6 ( 0.41 )	-15.8 ( 0.36 )
Week 8, n=13, 15	12.4 ( 0.49 )	-23.3 ( 0.59 )
Week 12, n=12, 14	12.4 ( 0.59 )	-21.9 ( 0.61 )
Week 16, n=12, 14	14.1 ( 0.55 )	-29.4 ( 0.5 )
Early withdrawal, n=3, 2	35.7 ( 0.69 )	-14.9 ( 0.31 )

No statistical analyses for this end point

Secondary: Change from Baseline in Quality of Life as measured by Short form 36 Health Survey (SF-36)

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End point title

Change from Baseline in Quality of Life as measured by Short form 36 Health Survey (SF-36)

End point description

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. ITT population: Data for this outcome measure was not summarized therefore there are no data to present.

End point type

Secondary

End point timeframe

Baseline and up to Week 16/Early Withdrawal

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	0 ^[2]	0 ^[3]
Units: Scores on a scale
number (not applicable)

Notes
[2] - This endpoint was not summarized therefore there is no data to present.
[3] - This endpoint was not summarized therefore there is no data to present.

No statistical analyses for this end point

Secondary: Number of participants with any adverse events (AEs) and serious adverse events (SAEs)

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End point title

Number of participants with any adverse events (AEs) and serious adverse events (SAEs)

End point description

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. ITT Population

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Participants
number (not applicable)
Any AE	15	11
Any SAE	1	0

No statistical analyses for this end point

Secondary: Change from Baseline in haemoglobin levels at Weeks 4, 8, 12, and 16/Early Withdrawal

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End point title

Change from Baseline in haemoglobin levels at Weeks 4, 8, 12, and 16/Early Withdrawal

End point description

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. 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 time point (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Grams per liter
median (inter-quartile range (Q1-Q3))
Week 4, n=15, 15	-2 (-5 to 6)	-5 (-10 to 2)
Week 8, n=13, 16	0 (-8 to 3)	-7.5 (-10.5 to 1.5)
Week 12, n=13, 14	2 (-6 to 8)	-5 (-9 to -1)
Week 16, n=13, 15	-3 (-10 to 2)	-6 (-9 to -3)
Early withdrawal, n=3, 2	-2 (-2 to 26)	-14.5 (-16 to -13)

No statistical analyses for this end point

Secondary: Change from Baseline in haematocrit levels at Weeks 4, 8, 12, and 16/Early Withdrawal

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End point title

Change from Baseline in haematocrit levels at Weeks 4, 8, 12, and 16/Early Withdrawal

End point description

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. 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 time point (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Proportion of 1
median (inter-quartile range (Q1-Q3))
Week 4, n=15, 15	0 (-0.016 to 0.015)	-0.015 (-0.033 to 0.012)
Week 8, n=13, 16	-0.003 (-0.026 to 0.014)	-0.021 (-0.035 to 0.003)
Week 12, n=13, 14	0.007 (-0.017 to 0.022)	-0.023 (-0.029 to -0.004)
Week 16, n=13, 15	-0.007 (-0.031 to 0.004)	-0.019 (-0.033 to -0.003)
Early withdrawal, n=3, 2	-0.008 (-0.01 to 0.083)	-0.03 (-0.032 to -0.028)

No statistical analyses for this end point

Secondary: Number of participants with significant liver events at Weeks 4, 8, 12, and 16/Early Withdrawal

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End point title

Number of participants with significant liver events at Weeks 4, 8, 12, and 16/Early Withdrawal

End point description

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. ITT population.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Participants
number (not applicable)	0	0

No statistical analyses for this end point

Secondary: Change from Baseline in supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

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End point title

Change from Baseline in supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

End point description

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. 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 time point (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: millimeter of mercury (mmHg)
median (inter-quartile range (Q1-Q3))
DBP, Week 4, n=15, 17	0 (-5 to 9)	-1 (-12 to 1)
DBP, Week 8, n=14, 16	1.5 (-7 to 13)	-9 (-16 to -5.5)
DBP, Week 12, n=13, 15	1 (0 to 7)	-8 (-14 to 5)
DBP, Week 16, n=13, 15	-2 (-10 to 8)	-10 (-16 to 3)
DBP, Early Withdrawal, n=3, 2	16 (8 to 26)	-17 (-19 to -15)
SBP, Week 4, n=15, 17	0 (-10 to 4)	-4 (-9 to 19)
SBP, Week 8, n=14, 16	5.5 (-8 to 14)	-10 (-18.5 to -2.5)
SBP, Week 12, n=13, 15	-2 (-12 to 11)	-5 (-10 to 0)
SBP, Week 16, n=13, 15	-4 (-11 to 15)	-6 (-8 to 10)
SBP, Early Withdrawal, n=3, 2	15 (10 to 18)	-8 (-16 to 0)

No statistical analyses for this end point

Secondary: Change from Baseline in heart rate assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

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End point title

Change from Baseline in heart rate assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

End point description

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. 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 time point (represented as n=X, X for placebo and ambrisentan respectively) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: beats per minute
median (inter-quartile range (Q1-Q3))
Week 4, n=15, 17	0 (-14 to 3)	4 (-3 to 10)
Week 8, n=14, 16	-8 (-17 to 3)	1 (-12.5 to 8.5)
Week 12, n=13, 15	-2 (-15 to 3)	0 (-6 to 5)
Week 16, n=13, 15	0 (-17 to 8)	-1 (-14 to 2)
Early withdrawal, n=3, 2	-6 (-24 to -3)	-18 (-32 to -4)

No statistical analyses for this end point

Secondary: Number of participants (par) with clinical chemistry parameters of potential clinical concern any time post Baseline

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End point title

Number of participants (par) with clinical chemistry parameters of potential clinical concern any time post Baseline

End point description

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 BL. 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. Par with both normal and low values were counted once under their worst case (Low). Par with both normal and high values were counted once under their worst case (High). Par with both high and low values are counted under both categories. ITT Population.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Participants
number (not applicable)
ALT, >clinical concern high	0	0
ALT, <clinical concern low	0	0
AST, >clinical concern high	0	0
AST, <clinical concern low	0	0
Creatinine, >clinical concern high	0	0
Creatinine, <clinical concern low	0	0
GGT, >clinical concern high	1	1
GGT, <clinical concern low	0	0
TB, >clinical concern high	0	0
TB, <clinical concern low	0	0

No statistical analyses for this end point

Secondary: Number of participants (par) with hematology parameters of potential clinical concern any time post Baseline

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End point title

Number of participants (par) with hematology parameters of potential clinical concern any time post Baseline

End point description

Hematology parameters including hemoglobin(Hb), international normalized ratio(INR), and platelet count assessed any time post BL. BL is the last value recorded on or prior to start of study treatment. For Hb: 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. Par with both normal and low values were counted once under their worst case(Low). Par with both normal and high values were counted once under their worst case(High). Par with both high and low values are counted under both categories. ITT Population: all randomized par who received at least 1 dose of study drug. Only par with available data at BL and the specified timepoint(n=X,X in the category titles) were summarized.

End point type

Secondary

End point timeframe

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

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	16	17
Units: Participants
number (not applicable)
Hemoglobin, >clinical concern high, n=16, 17	0	0
Hemoglobin, <clinical concern low, n=16, 17	0	0
INR, >clinical concern high, n=2, 0	0	0
INR, <clinical concern low, n=2, 0	0	0
Platelet count, >clinical concern high, n=16, 17	0	0
Platelet count, <clinical concern low, n=16, 17	0	0

No statistical analyses for this end point

Secondary: Number of participants with testicular function (males only) of potential clinical concern any time post Baseline

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End point title

Number of participants with testicular function (males only) of potential clinical concern any time post Baseline

End point description

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. ITT population: Data for this outcome measure was not summarized therefore there are no data to present.

End point type

Secondary

End point timeframe

Baseline, Weeks 4 and 16/early withdrawal

End point values	Placebo	Ambrisentan 5mg
Number of subjects analysed	0 ^[4]	0 ^[5]
Units: Participants
number (not applicable)

Notes
[4] - This endpoint was not summarized therefore there are no data to present.
[5] - This endpoint was not summarized therefore there are no data to present.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Serious and non-serious treatment emergent adverse events (AEs) were collected from the start of study treatment and until the follow up contact (Week 21)

Adverse event reporting additional description

AEs and serious AEs (SAEs) were collected from the members of ITT population which comprised of all randomized participants who received at least 1 dose of study drug. Treatment-emergent AEs (TEAEs) were defined as post-first dose AEs. Includes AEs up to 30 days after stopping study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Ambrisentan 5mg

Reporting group description

Participants received an ambrisentan 5milligram (mg) tablet, once daily for a period of 16 weeks.

Reporting group title

Placebo

Reporting group description

Participants received a matching placebo tablet once daily for a period of 16 weeks.

Serious adverse events	Ambrisentan 5mg	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Ambrisentan 5mg	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 17 (64.71%)	15 / 16 (93.75%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fibroma
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Peripheral venous disease
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	3 / 17 (17.65%)	2 / 16 (12.50%)
occurrences all number	4	2
Feeling abnormal
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Non-cardiac chest pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Chest discomfort
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Reproductive system and breast disorders
Nipple pain
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Haemoptysis
subjects affected / exposed	0 / 17 (0.00%)	3 / 16 (18.75%)
occurrences all number	0	3
Pleurisy
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Productive cough
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Investigations
Weight increased
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Joint dislocation
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Thermal burn
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Atrial fibrillation
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Headache
subjects affected / exposed	2 / 17 (11.76%)	3 / 16 (18.75%)
occurrences all number	2	3
Hypoaesthesia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Movement disorder
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Eye disorders
Eyelid oedema
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Dyspepsia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Cheilitis
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Constipation
subjects affected / exposed	1 / 17 (5.88%)	1 / 16 (6.25%)
occurrences all number	1	1
Hypoaesthesia oral
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Infections and infestations
Erysipelas
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Nasopharyngitis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Onychomycosis
subjects affected / exposed	1 / 17 (5.88%)	0 / 16 (0.00%)
occurrences all number	1	0
Bronchitis
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Influenza
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 17 (0.00%)	2 / 16 (12.50%)
occurrences all number	0	2
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 16 (6.25%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

04 Apr 2013

Revision to anticipated treatment effect size and therefore study sample size. Clarification that exclusion criteria for renal impairment is based on the estimated Creatinine Clearance method. Clarification of subjects who should be sent to the operability adjudication committee. Clarification that on withdrawal from the study and entry into the open-label extension, the prior blind will be maintained (except in medical emergency) and Investigators should consider carefully treatment of the subject. Revision to reporting timelines and withdrawal of IP in event of pregnancy. Deletion of contradictory text in Section 6.3.5.1: Definition of an AE

16 Jul 2013

Clarification on the study design: subject’s study participation in the open label extension. Clarification on the treatment after the end of the study

18 Jul 2013

Clarification on the amendment 03 about the date of study end

16 Aug 2013

Addition of an exclusion criterion excluding subjects who have previously undergone a balloon pulmonary angioplasty

02 Jan 2014

Clarification on the population included in the open label extension study

23 Apr 2014

Addition of information on the registration of riociguat in CTEPH Revision of the timelines for CTEPH diagnosis and RHC to be done prior to screening Increase of the upper limit of inclusion age from 75 to 80 years Addition of balloon pulmonary angioplasty as an exclusion criteria Description of country specific amendments (China, Russia, and United Kingdom)

11 Jul 2014

To clarify that riociguat is a prohibited medication in the study

11 Aug 2014

To integrate the previous amendment No.05 (specific to Italy) and new global amendment No.07 in the same protocol

16 Feb 2015

To provide clarity following GSK decision to stop the study early.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

This study was terminated early therefore all analyses were not necessarily run as planned.

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Clinical trials

Clinical Trial Results: A Randomised, Multicentre, Double-Blind, Placebo-Controlled Study Of Ambrisentan In Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in Six Minutes Walking Distance (6MWD) at Week 16

Primary: Change from Baseline in Six Minutes Walking Distance (6MWD) at Week 16

Secondary: Change from Baseline in pulmonary vascular resistance (PVR) at Week 16

Secondary: Change from Baseline in pulmonary vascular resistance (PVR) at Week 16

Secondary: Change from Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal

Secondary: Change from Baseline in WHO Functional Class (FC) at Weeks 4, 8, 12 and 16/Early Withdrawal

Secondary: Change from Baseline in Borg CR10 Scale (BCR10S) immediately following exercise at Weeks 4, 8, 12 and 16/Early Withdrawal

Secondary: Change from Baseline in Borg CR10 Scale (BCR10S) immediately following exercise at Weeks 4, 8, 12 and 16/Early Withdrawal

Secondary: Number of participants with clinical worsening of chronic thromboembolic pulmonary hypertension (CTEPH)

Secondary: Number of participants with clinical worsening of chronic thromboembolic pulmonary hypertension (CTEPH)

Secondary: Change from Baseline in mean right atrial pressure (mRAP) and mean pulmonary artery pressure (mPAP) at Week 16

Secondary: Change from Baseline in mean right atrial pressure (mRAP) and mean pulmonary artery pressure (mPAP) at Week 16

Secondary: Change from Baseline in cardiac index at Week 16

Secondary: Change from Baseline in cardiac index at Week 16

Secondary: Percent change from Baseline in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP)

Secondary: Percent change from Baseline in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP)

Secondary: Change from Baseline in Quality of Life as measured by Short form 36 Health Survey (SF-36)

Secondary: Change from Baseline in Quality of Life as measured by Short form 36 Health Survey (SF-36)

Secondary: Number of participants with any adverse events (AEs) and serious adverse events (SAEs)

Secondary: Number of participants with any adverse events (AEs) and serious adverse events (SAEs)

Secondary: Change from Baseline in haemoglobin levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Change from Baseline in haemoglobin levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Change from Baseline in haematocrit levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Change from Baseline in haematocrit levels at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Number of participants with significant liver events at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Number of participants with significant liver events at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Change from Baseline in supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Change from Baseline in supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Change from Baseline in heart rate assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Change from Baseline in heart rate assessed at Weeks 4, 8, 12, and 16/Early Withdrawal

Secondary: Number of participants (par) with clinical chemistry parameters of potential clinical concern any time post Baseline

Secondary: Number of participants (par) with clinical chemistry parameters of potential clinical concern any time post Baseline

Secondary: Number of participants (par) with hematology parameters of potential clinical concern any time post Baseline

Secondary: Number of participants (par) with hematology parameters of potential clinical concern any time post Baseline

Secondary: Number of participants with testicular function (males only) of potential clinical concern any time post Baseline

Secondary: Number of participants with testicular function (males only) of potential clinical concern any time post Baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomised, Multicentre, Double-Blind, Placebo-Controlled Study Of Ambrisentan In Subjects With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH).