E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure with preserved ejection fraction and pulmonary vascular disease |
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E.1.1.1 | Medical condition in easily understood language |
Left heart failure (inability of the heart to pump enough blood) may lead to increased pressure in the lung blood vessels. This increases the right heart workload and may lead to right heart failure. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076396 |
E.1.2 | Term | Heart failure with preserved ejection fraction |
E.1.2 | System Organ Class | 100000004849 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To describe the long-term safety of macitentan 10 mg in subjects with HFpEF and pulmonary vascular disease. |
|
E.2.2 | Secondary objectives of the trial |
To explore the long-term efficacy of macitentan 10 mg |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed and dated ICF.
2. Subject remained in the main study (SERENADE / AC-055G202, EudraCT number 2016-003653-15) for:
a. 52 weeks after randomization if entered this OL extension study prior to protocol Version 4.
b. At least 24 weeks after randomization if entering this OL extension
study under protocol Version 4.
3. A woman of childbearing potential is eligible only if all of the following apply:
• Negative pre-treatment serum pregnancy test.
• Agreement to undertake monthly pregnancy tests from the enrollment visit up to at least 30 days after study treatment discontinuation.
• Agreement to use reliable contraception from at least 30 days prior to the enrollment visit up to at least 30 days after study treatment discontinuation. |
|
E.4 | Principal exclusion criteria |
1. Premature discontinuation of study treatment in the main study (SERENADE / AC-055G202, EudraCT number 2016-003653-15) due to an adverse event related to:
a. Edema or fluid retention
b. Worsening of heart failure
c. Liver aminotransferase elevation
d. Study treatment, based on 'investigators' discretion
2. Liver aminotransferase elevations outside of normal range at the enrollment visit fulfilling the following criteria:
a. associated clinical symptoms of liver injury, e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever)
b. associated increase in total bilirubin outside of normal range
3. Treatment with the following forbidden medications within 1 month prior to the enrollment visit:
a. Treatments that may interfere with the assessment of efficacy
(i.e., endothelin receptor antagonists, prostanoids, phosphodiesterase-5 inhibitors, guanylate cyclase stimulators)
b. Strong cytochrome P-450 3A4 (CYP3A4) inducers such as rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, or St. John’s wort
c. Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir or a moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole or amiodarone) or co-administration of a combination of moderate CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors (eg, miconazole, piperine), in the 1-month period prior to baseline. This will not necessarily apply to subjects who are already well-managed on such an ongoing combination.
d. any other investigational treatment
4. Pregnant, planning to be become pregnant or lactating.
5. Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease.
6. Known hypersensitivity to macitentan or drugs of the same class, or any of the study drug excipients (e.g. soy lecithin, lactose). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
No primary efficacy endpoint has been defined for this study.
Exploratory efficacy endpoints:
1. Percent of baseline N-terminal pro-brain natriuretic peptide over time
2. Percent of baseline mid-regional pro-atrial natriuretic peptide over time
3. Change from baseline in accelerometer-assessed physical activity
variables over time
4. Change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score as well as clinical summary score and physical limitations score over time
5. Time to WHF event as adjudicated by the Clinical Event committee (CEC) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.: at enrollment, week 24, week 36, week 52 and then every 26 weeks until end of open label treatment
2.: at enrollment, week 24, week 36, week 52 and then every 26 weeks until end of open label treatment
3.: at enrollment, week 24, week 36, week 52 and then every 26 weeks up to end-of-treatment visit (7d after last dose)
4.: at enrollment, Week 1, Week 4, Week 8, Week 16, Week 24, Week 36, Week 52 and then every 26 weeks up to end of treatment followed by end-of-study visit (30 days after last dose) |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Israel |
Russian Federation |
United States |
Austria |
Bulgaria |
Denmark |
France |
Germany |
Hungary |
Poland |
Sweden |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |