E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Inoperable chronic thromboembolic pulmonary hypertension (CTEPH) |
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MedDRA Classification |
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 bosentan improves exercise capacity and/or pulmonary vascular resistance (PVR) in patients with inoperable CTEPH. |
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E.2.2 | Secondary objectives of the trial |
· To evaluate the effect of bosentan on the time to clinical worsening, NYHA class and cardiac hemodynamics in patients with inoperable CTEPH.
. To evaluate the safety and tolerability of bosentan in this patient population. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
· Symptomatic pulmonary hypertension in modified NYHA functional class II to IV due to CTEPH as demonstrated by ventilation/perfusion lung scanning and pulmonary angiography.
· CTEPH judged inoperable because of peripheral localization of thrombotic material or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) with no evidence of recurrent thromboembolism and not amenable to repeated surgery.
· 6-minute walk test (6MWT) distance < 450 m.
· Hemodynamic evaluation showing: i. Mean pulmonary arterial pressure (mPAP) >= 25 mmHg ii. Pulmonary capillary wedge pressure (PCWP) < 15 mmHg iii. Pulmonary vascular resistance (PVR) at rest >= 300 dyn.sec/cm5
For patients who underwent PEA, hemodynamic evaluation must have been performed more than 6 months after PEA. For all patients, hemodynamic evaluation must have been performed with the 3 months immediately preceding inclusion.
· Men or women >= 18 and =< 80 years of age (Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception).
· Anticoagulants at efficacious dose for at least 3 months prior to randomization.
· Signed informed consent prior to initiation of any study-mandated procedure.
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E.4 | Principal exclusion criteria |
· Other forms of pulmonary hypertension including pulmonary hypertension related to sickle cell disease.
· Obstructive lung disease: FEV1/FVC < 0.5 after bronchodilation · Severe restrictive lung disease: Total Lung Capacity < 60% of predicted value.
· Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication.
· Symptomatic pulmonary embolism within 6 months prior to randomization.
· Pulmonary endarterectomy within 6 months prior to randomization.
· Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
· Illness with a life expectancy of less than 6 months.
· Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
· AST and/or ALT > 3 times the upper limit of normal ranges.
· Hemoglobin concentration < 75% the lower limit of normal ranges.
· Pregnancy or breast-feeding.
. Systolic blood pressure (BP) < 85 mmHg.
· Treatment or planned treatment with another investigational drug and/or pulmonary angioplasty within 3 months prior to randomization.
· Treatment with an endothelin receptor antagonist, a phosphodiesterase inhibitor, L-arginine or with prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization.
· Treatment for pulmonary hypertension within 1 month prior to randomization, excluding calcium channel blockers if present for at least 1 month before randomization.
· Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, glibenclamide (glyburide) within 1 week prior to randomization.
· Known hypersensitivity to bosentan or any of the excipients |
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E.5 End points |
E.5.1 | Primary end point(s) |
There are two Co-Primary Endpoints:
1. Change from baseline to Week 16 in 6MWT distance. A mean difference from placebo of at least 35 m is considered clinically relevant. This parameter is expected to be normally distributed with a standard deviation of 65 m.
2. PVR at rest at Week 16 expressed as percent of the baseline value. A geometric mean in the active group showing a reduction of at least 20% when compared to the placebo geometric mean is considered clinically relevant. The natural logarithm of this parameter is expected to be normally distributed with a standard deviation of 0.280. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |