Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH)

• Status: Completed
• Trial end date: 2017-12-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Heidelberg University
• Collaborator: GlaxoSmithKline
• Treatments: Ambrisentan

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