Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH)
Condition: Systemic Sclerosis; Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Intervention: Ambrisentan; Placebo
Intervention description: 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/day.
Administration:
Ambrisentan and placebo will be administered orally with or without food intake.; Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Intervention MeSH terms: Ambrisentan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 38.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: pulmonary hypertension; systemic sclerosis

Summary:

      Trial Design Patients with borderline PAH indicated by borderline mPAP values will be
      included in this single centre study. This clinical investigation is performed as a
      Proof-of-Concept (PoC) investigator initiated trial (IIT) using a prospective, randomized,
      double-blind, parallel group, placebo-controlled, phase IIA clinical study design. On their
      first visit their medical history will be obtained and physical examination will be
      conducted. Moreover, an electrocardiogram (ECG), laboratory testing (NT-proBNP, uric acid and
      other laboratory tests), echocardiography at rest and right heart catheterization will be
      carried out. If patients have been identified within the last 6 months before screening
      investigations by right heart catheterization, the measurements are considered valid as
      baseline investigations and will not be repeated. If patients fulfill the inclusion criteria
      and still suffer from borderline mPAP values they will be invited to join the study. The
      clinical investigations will begin within 28 days. The prospective study will comprise a 6
      months study period (180 ±2 weeks) plus the screening phase up to 28 days and a follow-up
      phase of 30 ±7 days.
    

Eligibility criteria:

        Inclusion Criteria:

          1. mPAP 21-24 mmHg, TPG > 11mmHg, PAWP <15 mmHg and/or

          2. 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

          3. Adult patients having completed his/her 18th birthday

          4. Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria
             of the American Rheumatism Association

          5. SSc-disease duration >3 years

          6. Able to understand and willing to sign the Informed Consent Form

          7. Negative pregnancy test at the start of the trial and appropriate contraception
             throughout the study for women with child-bearing potential.

        Exclusion Criteria:

          1. Any connective tissue diseases (CTD) other than SSc

          2. Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment,
             i.e. mPAP ≥25 mmHg at rest

          3. 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

          4. 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.

          5. 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.

          6. Known intolerance to ambrisentan or one of its excipients

          7. Clinically significant anemia (hemoglobin concentration of less than 75% of the lower
             limit of normal, LLN)

          8. Forced vital capacity (FVC) <60%, forced expiratory volume in first second (FEV1) <65%

          9. Severe interstitial lung disease, idiopathic pulmonary fibrosis

         10. Renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73m2 for at least 3
             months)

         11. Baseline values of hepatic aminotransferases (ALT and/or AST) >3 x upper limit of
             normal (ULN)

         12. Systolic blood pressure <85 mmHg;

         13. evidence of inadequately treated blood pressure >160/90 mmHg and/or blood pressure
             during exercise >220/120 mmHg

         14. Patients referred with clinically significant overt heart failure

         15. Clinically significant fluid retention

         16. 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)

         17. Known significant diastolic dysfunction associated with clinical heart failure

         18. Known coronary disease or significant valvular heart disease

         19. Known congenital heart defects such as single ventricle, transposition, Eisenmenger

         20. Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular
             septum thickness (IVS) or posterior wall thickness (PWD) >1.2 cm)

         21. 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

         22. Pregnancy or lactation