Trial Outcomes & Findings for Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH) (NCT NCT02290613)

NCT ID: NCT02290613

Last Updated: 2020-04-30

Results Overview

Determine whether mean pulmonary arterial pressure of SSc patients with borderline - PAH (mPAP 21 24 mmHg, TPG \>11 mmHg) can be reduced by 3 mm Hg (absolute change baseline vs. 6 months; equals 15%) following treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 6 months (primary endpoint) compared to baseline and placebo.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 38 participants
• Primary outcome timeframe: baseline, 6 months
• Results posted on: 2020-04-30

Participant Flow

Participant milestones

Measure	Ambrisentan Verum Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Overall Study STARTED	19	19
Overall Study COMPLETED	17	15
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Ambrisentan Verum n=19 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=19 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)	Total n=38 Participants Total of all reporting groups
Age, Continuous	58.8 years STANDARD_DEVIATION 10.8 • n=19 Participants	54.9 years STANDARD_DEVIATION 11.2 • n=19 Participants	56.8 years STANDARD_DEVIATION 11.0 • n=38 Participants
Sex: Female, Male Female	16 Participants n=19 Participants	14 Participants n=19 Participants	30 Participants n=38 Participants
Sex: Female, Male Male	3 Participants n=19 Participants	5 Participants n=19 Participants	8 Participants n=38 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Type of SSc dcSSc	4 Participants n=19 Participants	11 Participants n=19 Participants	15 Participants n=38 Participants
Type of SSc lcSSc	15 Participants n=19 Participants	8 Participants n=19 Participants	23 Participants n=38 Participants

PRIMARY outcome

Timeframe: baseline, 6 months

Determine whether mean pulmonary arterial pressure of SSc patients with borderline - PAH (mPAP 21 24 mmHg, TPG >11 mmHg) can be reduced by 3 mm Hg (absolute change baseline vs. 6 months; equals 15%) following treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 6 months (primary endpoint) compared to baseline and placebo.

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Mean Pulmonary Arterial Pressure Change From Baseline	-1.0 mmHg Standard Deviation 6.4	-0.73 mmHg Standard Deviation 3.6

SECONDARY outcome

Timeframe: baseline, 6 months

Determine whether exercise induced elevated mean pulmonary arterial pressure-values (>30 mmHg without left heart or severe lung disease or systemic arterial hypertension) can be reduced by ambrisentan 10 mg/die over 6 months.

Outcome measures

Measure	Ambrisentan Verum n=15 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=13 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Mean Pulmonary Arterial Pressure During Exercise Change From Baseline	-0.73 mmHg Standard Deviation 6.23	1.08 mmHg Standard Deviation 7.39

SECONDARY outcome

Timeframe: baseline, 6 months

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
6-Minute-walking Test	21.53 meters Standard Deviation 34.6	-16.53 meters Standard Deviation 77.32

SECONDARY outcome

Timeframe: baseline, 6 months

measured directly after 6 minute walking distance; The Borg dyspnea index is an standardized scale which reports the subjective feeling of exertion from 0 (no dyspnea) to 10 (maximal feeling of dyspnea).

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Borg Dyspnea Index	0.62 units on a scale Standard Deviation 1.7	0.08 units on a scale Standard Deviation 1.54

SECONDARY outcome

Timeframe: baseline, 6 months

SF-36 Questionnaire; physical Summation score; All scores and subscores of the SF-36 questionnaire range from 0 (low quality of life) to 100 (high quality of life). The physical Summation score is a compound score including the physical dimensions of the SF-36.

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Quality of Life (SF-36) Questionnaire	-6.71 units on a scale Standard Deviation 12.17	0.87 units on a scale Standard Deviation 16.01

SECONDARY outcome

Timeframe: baseline,6 months

DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO))

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=13 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Lung Function	1.19 % of target value Standard Deviation 1.81	-0.44 % of target value Standard Deviation 1.84

SECONDARY outcome

Timeframe: baseline, 6 months

DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO))

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Lung Function	-0.32 mmol/min/kPa Standard Deviation 1.44	-0.45 mmol/min/kPa Standard Deviation 1.70

SECONDARY outcome

Timeframe: baseline, 6 months

FVC (forced vital capacity)

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Lung Function	-3.31 % of target Standard Deviation 5.56	-1.04 % of target Standard Deviation 5.60

SECONDARY outcome

Timeframe: baseline, 6 months

FEV1 (forced expiratory volume in one second)

Outcome measures

Measure	Ambrisentan Verum n=16 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Lung Function	-0.11 Litres Standard Deviation 0.21	-0.06 Litres Standard Deviation 0.20

SECONDARY outcome

Timeframe: baseline, 6 months

TLC (total lung capacity)

Outcome measures

Measure	Ambrisentan Verum n=16 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Lung Function	-0.06 Litres Standard Deviation 0.37	-0.03 Litres Standard Deviation 0.36

SECONDARY outcome

Timeframe: baseline, 6 months

residual volume

Outcome measures

Measure	Ambrisentan Verum n=16 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Lung Function	-0.03 Litres Standard Deviation 0.33	0.05 Litres Standard Deviation 0.37

SECONDARY outcome

Timeframe: baseline, 6 months

RA-area (right atrial area)

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Echocardiography	1.65 cm^2 Standard Deviation 2.67	-0.47 cm^2 Standard Deviation 4.07

SECONDARY outcome

Timeframe: baseline, 6 months

RV-area (right ventricular area)

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Echocardiography	-0.15 cm^2 Standard Deviation 3.46	-0.8 cm^2 Standard Deviation 3.05

SECONDARY outcome

Timeframe: baseline, 6 months

TAPSE (tricuspid annular plane systolic excursion)

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Echocardiography	0.12 cm Standard Deviation 0.41	-0.19 cm Standard Deviation 0.54

SECONDARY outcome

Timeframe: baseline, 6 months

sPAP (systolic pulmonary arterial pressure)

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Echocardiography	-0.82 mmHg Standard Deviation 4.46	-0.93 mmHg Standard Deviation 6.08

SECONDARY outcome

Timeframe: baseline

The World Health Organization functional class includes four categories with

1. Patients with Pulmonary Hypertension but without any resulting limitation of physical activity.

2. Patients with Pulmonary Hypertension resulting in slight limitation of physical activity.

3. Patients with Pulmonary Hypertension resulting in marked limitation of physical activity.

4. Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms.

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
WHO-functional Class FC III	0 Participants	2 Participants
WHO-functional Class FC II	17 Participants	13 Participants

SECONDARY outcome

Timeframe: change from baseline to 6 months

right atrial pressure

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Hemodynamics	0.82 mmHg Standard Deviation 4.11	-0.2 mmHg Standard Deviation 2.76

SECONDARY outcome

Timeframe: baseline, 6 months

pulmonary vascular resistance

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Hemodynamics	-0.59 Wood Units Standard Deviation 0.79	0.02 Wood Units Standard Deviation 0.76

SECONDARY outcome

Timeframe: baseline, 6 months

cardiac output (CO)

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Hemodynamics	0.58 L/min Standard Deviation 1.17	-0.26 L/min Standard Deviation 1.11

SECONDARY outcome

Timeframe: baseline, 6 months

cardiac index (CI)

Outcome measures

Measure	Ambrisentan Verum n=16 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Hemodynamics	0.36 L/min/m^2 Standard Deviation 0.66	-0.31 L/min/m^2 Standard Deviation 0.71

SECONDARY outcome

Timeframe: baseline , 6 months

PAWP (pulmonary arterial wedge pressure)

Outcome measures

Measure	Ambrisentan Verum n=17 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=15 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Hemodynamics	1.24 mmHg Standard Deviation 5.31	0.13 mmHg Standard Deviation 3.20

SECONDARY outcome

Timeframe: baseline, 6 months

venous oxygen saturation (SvO2)

Outcome measures

Measure	Ambrisentan Verum n=12 Participants Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=13 Participants Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Hemodynamics	-2.79 % saturation Standard Deviation 7.56	-3.48 % saturation Standard Deviation 12.26

Adverse Events

Ambrisentan Verum

Serious events: 1 serious events

Other events: 17 other events

Deaths: 0 deaths

Placebo

Serious events: 5 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ambrisentan Verum n=19 participants at risk Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=19 participants at risk Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Musculoskeletal and connective tissue disorders Lower jaw fracture	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Cardiac disorders Angina Pectoris	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Cardiac disorders Coronary artery disease	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Gastrointestinal disorders Gastrointestinal infection	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Blood and lymphatic system disorders Lymphangitis	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Musculoskeletal and connective tissue disorders Raynaud	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.

Other adverse events

Measure	Ambrisentan Verum n=19 participants at risk Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/die). Ambrisentan: Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake.	Placebo n=19 participants at risk Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Nervous system disorders Headache	31.6% 6/19 • Number of events 6 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	31.6% 6/19 • Number of events 6 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Cardiac disorders Edema	42.1% 8/19 • Number of events 8 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	21.1% 4/19 • Number of events 4 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Nervous system disorders Dizziness	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	31.6% 6/19 • Number of events 6 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Gastrointestinal disorders Diarrhea	21.1% 4/19 • Number of events 4 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	10.5% 2/19 • Number of events 2 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Nervous system disorders Paraesthesia	21.1% 4/19 • Number of events 4 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	0.00% 0/19 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Cardiac disorders Coronary artery disease	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	15.8% 3/19 • Number of events 3 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Cardiac disorders arterial hypotension	10.5% 2/19 • Number of events 2 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	10.5% 2/19 • Number of events 2 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Vascular disorders Epistaxis	15.8% 3/19 • Number of events 3 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	5.3% 1/19 • Number of events 1 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Gastrointestinal disorders Nausea	10.5% 2/19 • Number of events 2 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.	15.8% 3/19 • Number of events 3 • adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.

Additional Information

Prof. Dr. med. E. Grünig

Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital

Phone: +49 6221 396

Email: ekkehard.gruenig@med.uni-heidelberg.de

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place