E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
To assess the effects of ACT-064992 on morbidity and mortality in patients with symptomatic pulmonary arterial hypertension |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•To demonstrate that either dose of ACT-064992 prolongs the time to the first morbidity or mortality event in patients with symptomatic pulmonary arterial hypertension.
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E.2.2 | Secondary objectives of the trial |
•To demonstrate that either dose of ACT-064992 improves exercise capacity and WHO functional class, and prolongs the time to death or hospitalization for PAH in patients with symptomatic pulmonary arterial hypertension. •To evaluate the safety and tolerability of ACT-064992 in patients with symptomatic pulmonary arterial hypertension.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Signed informed consent prior to initiation of any study mandated procedure. 2.Patients with symptomatic pulmonary arterial hypertension (PAH) in modified WHO functional class II to IV. 3.Patients with the following types of PAH belonging to groups 1.1 to 1.3 of the Venice classification: a.Idiopathic (IPAH); b.Familial (FPAH); or c.Related to: i.Collagen vascular disease; ii.Simple, congenital systemic-to-pulmonary shunts at least 1 year post surgical repair; iii.HIV infection; or iv.Drugs and toxins. 4.PAH diagnosis confirmed by hemodynamic evaluation performed prior to randomization and showing all of the following: a.Mean pulmonary artery pressure (mPAP) >= 25 mmHg at rest; b.Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) < 15 mmHg; and c.Pulmonary vascular resistance (PVR) at rest >= 240 dyn*sec/cm5.
For patients who participate in the pharmacokinetic/ pharmacodynamic substudy, hemodynamic evaluation must have been performed within 3 months prior to randomization. For all other patients, hemodynamic evaluation must have been performed within 1 year prior to randomization. 5.6-minute walk distance (6MWD) >= 50 m and ≤ 475 m. 6.Men or women >= 12 years of age (women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception).
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E.4 | Principal exclusion criteria |
1.PAH associated with portal hypertension, thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy. 2.PAH associated with non corrected simple congenital systemic-to-pulmonary shunts, and combined and complex systemic-to-pulmonary shunts, corrected or non corrected. 3.PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis. 4.Persistent pulmonary hypertension of the newborn. 5.Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification. 6.Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value after bronchodilator administration. 7.Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted value. 8.Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C. 9. Estimated Creatinine clearance <30mL/min 10.Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal. 11.Hemoglobin < 75% of the lower limit of the normal range. 12.Systolic blood pressure < 100 mmHg. 13.Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements. 14.Pregnant or breast-feeding. 15.Known concomitant life-threatening disease with a life expectancy < 12 months. 16.Body weight < 40 kg. 17.Any condition that prevents compliance with the protocol or adherence to therapy. 18.Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise. 19.Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization. 20.Systemic treatment within 4 weeks prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mTOR inhibitors). 21. Treatment with CYP3A inducers within 4 weeks prior to randomization. 22.Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients. 23.Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint Time from start of treatment to first morbidity or mortality event, defined as follows: 1.Death, or 2.Atrial septostomy, or 3.Lung transplantation, or 4.Initiation of intravenous or subcutaneous prostanoids (e.g., epoprostenol, treprostinil), or 5.Other worsening of pulmonary arterial hypertension. Other worsening of pulmonary arterial hypertension is defined by the combination of all of the three following components: •A decrease in 6MWD of at least 15% from baseline that should be confirmed by two 6-minute walk tests, performed on different days, within 2 weeks AND •Worsening of PAH symptoms (1) AND •Need for new treatment(s) for PAH (2) (1) Worsening of PAH symptoms must include at least one of the following: WHO functional class increased, or no change in patients in WHO class IV at baseline Appearance or worsening of signs/symptoms of right heart failure that did not respond to oral diuretic therapy (2) New treatments for PAH are: oral or inhaled prostanoids (e.g., iloprost) oral phosphodiesterase inhibitors (e.g., sildenafil) endothelin receptor antagonists (e.g., bosentan, ambrisentan, sitaxsentan) only after discontinuation of the study drug intravenous diuretics An independent Clinical Event Committee (CEC) will review and confirm all reported mortality and morbidity events in a blinded fashion. The observation period for the primary endpoint will start with first study drug intake, and end with EOT plus 1 week. Patients who prematurely discontinue study treatment without a morbidity or mortality event will be censored at the time of study treatment discontinuation plus 1 week (censoring rate is expected to be 5%/year, and to be similar in all treatment groups). The hazard of a morbidity/mortality event in one group relative to the other is not expected to change with time, and the event rate in the placebo group is expected to be 35% per year. The treatment effect to be detected is a reduction of 40% of the event rate to 21%. Secondary endpoints These will be analyzed in the following sequence: 1.Change from baseline to Month 6 in 6MWD 2.Change from baseline to Month 6 in modified WHO functional class 3.Time to death due to PAH or hospitalization for PAH up to EOT 4.Time to death of all causes up to EOT
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
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 | Information not present in EudraCT |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |