A study of the effects of macitentan on the heart in patients with elevated blood pressure in blood vessels of the lungs.

• Register: EUCTR
• Last refreshed on: 1 February 2020
• Main ID: EUCTR2014-004066-20-GB
• Date of registration: 12/01/2015
• Prospective Registration: Yes
• Primary sponsor: Actelion Pharmaceuticals Ltd.
• Public title: A study of the effects of macitentan on the heart in patients with elevated blood pressure in blood vessels of the lungs.
• Scientific title: A prospective, multicenter, single-arm, open-label, phase 4 study to evaluate the effects of macitentan on Right vEntricular remodeling in Pulmonary ArterIal hypeRtension assessed by cardiac magnetic resonance imaging - REPAIR: Right ventricular remodeling in pulmonary arterIal hypertension
• Date of first enrolment: 14/05/2015
• Target sample size: 100
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004066-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Australia, France, Germany, Hong Kong, Israel, Italy, Malaysia, Netherlands, Russian Federation, Singapore, United Kingdom, United States

Contacts

• Name: Global Medical Affairs
• Affiliation: Actelion Pharmaceuticals Ltd.

• Name: Global Medical Affairs
• Affiliation: Actelion Pharmaceuticals Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
The full list of inclusion criteria is provided in Section 4.3 of the Protocol and all patients must fulfill all criteria. The main inclusion criteria are:
1. Signed informed consent prior to any study-mandated procedure
2. Symptomatic pulmonary arterial hypertension (PAH)
3. World Health Organization (WHO) Functional Class (FC) III
4. PAH etiology belonging to one of the following groups according to Nice classification:
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- and toxin-induced PAH
1.4.1 PAH associated with connective tissue disease
1.4.4 PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair
5. Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) performed between Day -28 and Day 1 (inclusion RHC; RHC data obtained at study site within this time frame, prior to obtaining signed informed consent, are acceptable) showing:
• mPAP = 25 mmHg and
- PCWP or LVEDP = 12 mmHg and PVR = 4 Wood Units (WU) (320 dyn.sec.cm-5) or
- 12 mmHg = PCWP or LVEDP = 15 mmHg and PVR = 6WU (480 dyn.sec.cm-5)
- 6.6-minute walk distance (6MWD) = 150 m during screening
7. For patients treated with oral loop diuretics, treatment dose must be stable since at least 1 month prior to the inclusion RHC
8. For patients treated with PDE-5 inhibitors, treatment dose must be stable since at least 3 months prior to the inclusion RHC (initiation of PDE-5 inhibitors during screening is allowed after all screening assessments have been performed).
9. For patients treated with beta blockers, treatment dose must be stable since at least 1 month prior to the inclusion RHC
10. Men or women =18 and < 75 years. For patients aged = 65 and < 75 years, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
11. Women of childbearing potential must:
a. Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
b. Agree to use reliable methods of contraception from screening up to 30 days after study treatment discontinuation, and
c. Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation
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 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion criteria:
The full list of exclusion criteria is provided in Section 4.4 of the Protocol and all patients must not fulfill any exclusion criterion. The main exclusion criteria are:
1. Body weight < 40 kg
2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
3. Pregnancy, breastfeeding or intention to become pregnant during the study
4. Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program
5. Known concomitant life-threatening disease with a life expectancy < 12 months
6. Any condition likely to affect protocol or treatment compliance
7. Hospitalization for PAH (except for diagnosis of PAH) within 3 months prior to informed consent signature
8. Left atrial volume indexed for body surface area (BSA) = 43mL/m2 by echocardiography or cardiac MRI
9. Moderate to severe left-heart valvular disease
10. History of pulmonary embolism or deep vein thrombosis
11. Presence of one or more of the following signs of relevant lung disease at any time up to screening:
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
- FVC < 60% of predicted.
- Forced expiratory volume in one second (FEV1) < 60% of predicted.
12. Moderate to severe restrictive lung disease (i.e., total lung capacity < 60% of predicted value) at any time prior to enrollment.
13. Historical evidence of significant coronary artery disease established by:
• History of myocardial infarction or
• More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
• Elevation of the ST segment on electrocardiogram or
• History of coronary artery bypass grafting or
• Stable angina
14. Known uncontrolled diabetes mellitus (in the opinion of the investigator)
15. Severe renal insufficiency (calculated creatinine clearance < 30 mL/min)
16. Cancer
17. Systolic blood pressure < 90 mmHg
18. Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × ULN accompanied by an AST elevation > ULN at Screening.
19. Hemoglobin < 100g/L
20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal range
21. Need for dialysis
22. Responders to acute vasoreactivity test based on medical history
23. Prior use of endothelin receptor antagonists, stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues
24. Treatment with strong inducers of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John’s Wort)
25. Treatment with strong inhibitors of CYP3A4 within 4

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

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension
MedDRA version: 20.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Trade Name: Opsumit
Product Name: macitentan
Product Code: ACT-064992
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: MACITENTAN
CAS Number: 441798-33-0
Current Sponsor code: ACT-064992
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Primary end point(s): Primary efficacy endpoint
The study has two primary efficacy endpoints:
-Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume (RVSV) assessed by cardiac MRI from pulmonary artery flow.
-Ratio of Week 26 to baseline Pulmonary Vascular Resistance (PVR) assessed by RHC.

Timepoint(s) of evaluation of this end point: Week 26

Secondary Objective: Secondary objective:
To evaluate the safety and tolerability of macitentan in patients with symptomatic PAH

Exploratory objectives:
To investigate the effect of macitentan on disease-related circulating biomarkers in patients with symptomatic PAH
To explore a potential association between change in right ventricular properties and clinical outcome in patients with symptomatic PAH
To investigate the effect of macitentan on ventriculo-arterial coupling in patients with symptomatic PAH
To evaluate the effect of macitentan on left ventricular properties in patients with symptomatic PAH

Main Objective: To evaluate the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic PAH.

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints
Change from baseline to Week 26 in:
-RV End Diastolic Volume (RVEDV)
-RV End Systolic Volume (RVESV)
-RV Ejection Fraction (RVEF)
-RV mass
-six-minute walk distance (6MWD)
-World Health Organization (WHO) Functional Class (FC)

Timepoint(s) of evaluation of this end point: Week 26

Secondary ID(s)

AC-055-403

Source(s) of Monetary Support

Actelion Pharmaceuticals Ltd.

Ethics review

Status: Approved
Approval date: 14/05/2015
Contact: