Drug treatment of patients with systemic sclerosis to prevent deterioration of pulmonary hypertension

• Register: EUCTR
• Last refreshed on: 8 January 2018
• Main ID: EUCTR2014-001882-28-DE
• Date of registration: 07/08/2014
• Prospective Registration: Yes
• Primary sponsor: Thoraxklinik-Heidelberg gGmbH
• Public title: Drug treatment of patients with systemic sclerosis to prevent deterioration of pulmonary hypertension
• Scientific title: Early Treatment of Borderline Pulmonary Arterial Hypertension Associated with Systemic Sclerosis (SSc-APAH) - EDITA
• Date of first enrolment: 13/10/2014
• Target sample size: 38
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-001882-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany

Contacts

• Name: Director of the clinic
• Affiliation: Thoraxklinik am Universitätsklinikum Heidelberg

• Name: Director of the clinic
• Affiliation: Thoraxklinik am Universitätsklinikum Heidelberg

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female SSc patients with borderline - PAH and:
2. mPAP 21-24 mmHg, transpulmonary gradient >11 mmHg, as defined by the current ESC Guidelines, PAWP <15 mmHg and/or
3. 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
4. Adult patients having completed his/her 18th birthday
5. Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria of the American Rheumatism Association
6. SSc - disease duration >3 years
7. Able to understand and willing to sign the Informed Consent Form
8. Negative pregnancy test at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 18

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, i.e. mPAP<21 mmHg at rest, and mPAP =30 mmHg during exercise, and/or 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), and 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 at least for the last 3 months before inclusion)
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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Systemic sclerosis-patients (SSc) with borderline pulmonary arterial hypertension

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Trade Name: Volibris
Product Name: Ambrisentan
Pharmaceutical Form: Tablet
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: Determine whether mPAP of SSc patients with borderline - PAH (mPAP 21 24 mmHg, TPG >11 mmHg) can be reduced by 15% following treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 6 months compared to baseline and placebo.

Primary end point(s): 1) Determine whether mPAP 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%) by 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

Secondary Objective: 2) Determine whether exercise induced elevated mPAP-values (>30 mmHg without left heart or severe lung disease or systemic arterial hypertension) and further measures of exercise capacity, symptoms and quality of life can be reduced by ambrisentan 10 mg/die over 6 months.
3) Analyze if the progression (adverse events, hospitalization, initiation of pulmonary hypertension treatment) of borderline-PAH to manifest PH can be avoided by ambrisentan-treatment (descriptive, observational).
4) Assessment of tolerability and safety

Timepoint(s) of evaluation of this end point: At 6 months of treatment start with study medication

Secondary Outcome(s)

Secondary end point(s): Analyze if in patients with SSc and borderline-PAP show an improvement by treatment with ambrisentan 10 mg/die over 6 months in:
- 6-Minute-walking test
- Quality of life (SF-36)
- Lung function tests (DLCo, DLCo/VA, FVC, FEV1, TLC, residual volume)
- Echocardiography (RA-area, RV-area, Tei, TAPSE, sPAP)
- Borg Dyspnea Index
- WHO-functional class
- further invasively measured hemodynamic parameters evaluated by RHC: right atrial pressure, pulmonary vascular resistance, cardiac output (CO), cardiac index (CI), PAWP, venous oxygen saturation (SvO2)
- Raynaud-syndrome and skin involvement, assessed by the modified Rodnan-Skin score and Symptoms of Scleroderma (descriptive)

Timepoint(s) of evaluation of this end point: At 6 months of treatment start with study medication

Secondary ID(s)

2014-05ED

Source(s) of Monetary Support

GlaxoSmithKline GmbH