Intervention: Ambrisentan
Trial phase: Phase 2
ATC code: C02KX02 | C02KX52
SMILES: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(C)n1)C(=O)O
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 19
Group description: 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.
Eligibility criteria:
Inclusion Criteria:

mPAP 21-24 mmHg, TPG > 11mmHg, PAWP <15 mmHg and/or
Exercise induced elevated mPAP-values >30 mmHg, PAWP <18 mmHg; TPG >15 mmHg, as defined in Saggar et al. (2012) without left heart or severe lung disease or systemic arterial hypertension
Adult patients having completed his/her 18th birthday
Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria of the American Rheumatism Association
SSc-disease duration >3 years
Able to understand and willing to sign the Informed Consent Form
Negative pregnancy test at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.

Exclusion Criteria:

Any connective tissue diseases (CTD) other than SSc
Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment, i.e. mPAP ≥25 mmHg at rest
Patients presenting normal mPAP values, that is mPAP<21 mmHg at rest, ≤30 mmHg during exercise, PAWP >=15 mmHg at rest or <=18 mmHg during exercise
Ongoing or a history of >2 weeks of continued use of therapies that are considered definitive PH treatment: endothelin receptor antagonists (ERA; e.g. bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, vardenafil), prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost) and soluble guanylate cyclase stimulator (e.g. Riociguat). Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted.
Except for diuretics and corticosteroids medical treatment should not be expected to change 4 weeks prior inclusion into the study and during the entire 12-week study period.
Known intolerance to ambrisentan or one of its excipients
Clinically significant anemia (hemoglobin concentration of less than 75% of the lower limit of normal, LLN)
Forced vital capacity (FVC) <60%, forced expiratory volume in first second (FEV1) <65%
Severe interstitial lung disease, idiopathic pulmonary fibrosis
Renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73m2 for at least 3 months)
Baseline values of hepatic aminotransferases (ALT and/or AST) >3 x upper limit of normal (ULN)
Systolic blood pressure <85 mmHg;
evidence of inadequately treated blood pressure >160/90 mmHg and/or blood pressure during exercise >220/120 mmHg
Patients referred with clinically significant overt heart failure
Clinically significant fluid retention
Previous evidence or diagnosis of clinically relevant left heart disease, i.e. at least one of the following: Previous echocardiography with estimated left ventricular (LV) ejection fraction <50%, previous history of cardiogenic pulmonary edema, increased size of left atrium (>50 mm)
Known significant diastolic dysfunction associated with clinical heart failure
Known coronary disease or significant valvular heart disease
Known congenital heart defects such as single ventricle, transposition, Eisenmenger
Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular septum thickness (IVS) or posterior wall thickness (PWD) >1.2 cm)
Participation in any clinical drug trial within 4 weeks prior to screening of this study and/or who is scheduled to receive another investigational medicinal product (IMP) during the course of this study
Pregnancy or lactation