| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Thromboembolic Pulmonary Hypertension |
|
| 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 | 10037406 |
| E.1.2 | Term | Pulmonary hypertension secondary |
|
| 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 assess the efficacy and safety of oral BAY 63-2521 in patients with inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) or recurrent or persisting pulmonary hypertension after surgical treatment. The optimized dose reached after individual dose titration (starting with 1 mg tid and if tolerated up-titrated after two weeks up to 1.5 mg or 2 mg or 2.5 mg tid) will be compared with placebo. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 18 to 75 years of age at Visit 1. Male and female patients with CTEPH and a 6MWD Test above 150 m either defined as : o Inoperable due to the consideration of an experienced surgeon1, with pulmonary vascular resistance >480 dyn*sec*cm-5 measured at least 3 months after start of full anticoagulation and mean pulmonary artery pressure >25 mmHg or o with persisting or recurrent PH after Pulmonary Endarterectomy (Patients must have a PVR >480 dyn*sec*cm-5 measured at least 6 months after surgery) The diagnosis of CTEPH must have been established based on 2 of the 4 following imaging methods before study entry: Ventilation-Perfusion Scan, Pulmonary Angiogram, Spiral-CT, MR-Angiogram. The diagnosis of inoperability must have been established based on a Pulmonary Angiogram and /or a 64-slice Spiral CT before study entry. Unspecific treatments which may also be used for the treatment of pulmonary hypertension such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants must have been started at least 3 months before Visit 1 and treatment with diuretics needs to be stable for at least one month before Visit 1. Patients who full-fill criteria for a supplemental long-term oxygen therapy (PaO2 < 55 mmHg and/or SaO2 < 88% at rest, sleep and exertion) need to be supplied sufficiently before study entry. The amount of supplemental oxygen and the delivery method need to be stable for at least three months beforeVisit 1. Right-heart catheterization results for the definite diagnosis of PH must not be older than 6 weeks at Visit 1 (will be considered as baseline values), must have been measured after at least 3 months of full anticoagulation, and must have been measured in the participating centre under standardized conditions (refer to the study specific Swan Ganz catheterization manual). If the respective measurements have not been performed in context with the patient’s regular diagnostic work up, they have to be performed as a part of the study during the Pre-Treatment Phase (after the patient signed the informed consent). Women without childbearing potential defined as postmenopausal women aged 55 years or older, women with bilateral tubal ligation, women with bilateral ovarectomy, and women with hysterectomy can be included in the study. Women with childbearing potential can only be included in the study if a serological pregnancy test is negative and a combination of condoms with a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs) is used. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire period. Patients must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures. |
|
| E.4 | Principal exclusion criteria |
| Patients unable to perform a valid 6MWD Test (eg orthopedic disease, peripheral artery occlusive disease, which affects the patient’s ability to walk) Patients with a relative difference of more than 15% between the eligibility- and the baseline 6MWD Test Medication/Treatment Exclusions: Patients who are screened for possible participation in the study must not been withdrawn from treatments which are medically required. If such treatments are not in-line with the entry criteria of this study, the patient must not be enrolled. The following specific medications for treatment of pulmonary hypertension or medications which may exert a pharmacodynamic interaction with the study drug are not allowed: Pre-Treatment within the last 3 months before Visit 1: Endothelin Receptor Antagonists Prostacycline analogues Specific (eg Sildenafil or Tadalafil) or unspecific Phosphodiesterase Inhibitors (eg Dipyridamole, Theophylline) NO donors (eg Nitrates) Pulmonary Disease Exclusions: All types of pulmonary hypertension except subtypes 4.1 and 4.2 of the Venice Clinical Classification of Pulmonary Hypertension Moderate to severe bronchial asthma or COPD (Forced Expiratory Volume < 60% predicted) Severe restrictive lung disease (Total Lung Capacity <70% predicted) Severe congenital abnormalities of the lungs, thorax, and diaphragm Exclusions related to abnormalities in blood gases (measured capillary or arterial): SaO2 < 88% despite supplemental oxygen therapy PaO2 < 55 mmHg despite supplemental oxygen therapy PaCO2 > 45 mmHg Cardiovascular Exclusions: Uncontrolled arterial hypertension (Systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg) Systolic blood pressure <95 mmHg Resting heart rate in the awake patient <50 BPM or >105 BPM History of atrial fibrillation within the last 3 months before Visit 1 Left heart failure with an ejection fraction less than 40% Pulmonary venous hypertension with pulmonary capillary wedge pressure >15 mmHg Hypertrophic obstructive cardiomyopathy Severe proven or suspected coronary artery disease (patients with Canadian Cardiovascular Society Angina Classification class 2-4, and/or requiring nitrates, and/or myocardial infarction within the last 3 months before Visit 1) Clinical evidence of symptomatic atherosclerotic disease (eg peripheral artery disease with reduced walking distance, history of stroke with persistent neurological deficit etc) Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension Evidence for recurrent thromboembolism despite sufficient (documented) oral anticoagulation - also when pulmonary arteries are not affected. Exclusions related to disorders in organ function: Clinical relevant hepatic dysfunction indicated by: - bilirubin >2 times upper limit normal - and / or hepatic transaminases >3 times upper limit normal - and / or signs of severe hepatic insufficiency (eg impaired albumin synthesis with an albumin < 32g/l, hepatic encephalopathy > grade 11) 1West Haven Criteria of Altered Mental Status In Hepatic Encephalopathy Renal insufficiency (glomerular filtration rate <30 mL/min eg calculated based on the Cockcroft formula [refer to appendix 10.13]). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is change from baseline in 6 Minute Walking Distance (6MWD) after 16 weeks. |
|
| 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 | 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 | Yes |
| 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 | 29 |
| 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 |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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