| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Thromboembolic Pulmonary Hypertension |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037406 |
| E.1.2 | Term | Pulmonary hypertension secondary |
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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 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. |
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• 18 to 80 years of age at Visit 1 (please consider age related restrictions with respect to the baseline PCWP see section 4.2.3. Cardiovascular Exclusion Criteria).
The lower age limit may be higher if legally requested in the participating countries.
• Male and female patients with CTEPH and an eligibility and baseline 6MWD Test between 150 m and 450 m either defined as:
o Inoperable, with pulmonary vascular resistance >480 dyn*sec*cm-5 measured at least 90 days after start of full anticoagulation and mean pulmonary artery pressure >25 mmHg
The inoperability of CTEPH patients, considered as ineligible for Pulmonary Endarterectomy (PEA) by the investigators, needs to be confirmed by an experienced surgeon before randomization(for details please refer to section 10.14 Operability Assessment).
or
o with persisting or recurrent PH after Pulmonary Endarterectomy (Patients must have a PVR >480 dyn*sec*cm-5 measured at least 180 days after surgery)
For patients with persisting or recurrent PH after PEA no study related operability assessment must be performed (Note: patients with evidence for recurrent thromboembolism are excluded from the trial / see Section 4.2.3 “Cardiovascular Exclusions”).
Note: With respect to the verification of the inclusion criteria, PAPmean and PVR are considered as calculated parameters. For the respective calculations refer to sections 4.6.4 and 10.5.
• 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 90 days before Visit 1 and treatment with diuretics needs to be stable for at least 30 days before Visit 1.
• Patients with supplemental long-term oxygen therapy can be included, if the amount of supplemental oxygen and the delivery method was stable for at least 90 day before Visit 1.
• Right-heart catheterization results for the definite diagnosis of PH must not be older than 8 weeks at Visit 1 (will be considered as baseline values), must have been measured after at least 90 days of full anticoagulation, and must have been measured in collaboration with the participating center under standardized conditions (refer to the study specific Right Heart 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) or at Visit 1 before randomization.
• Women without childbearing potential defined as postmenopausal women (= permanent absence of monthly periods for more than 2 years), 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 safe contraception methods is used throughout the study.
• 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.
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| E.4 | Principal exclusion criteria |
• Patients unable to perform a valid 6MWD Test (eg patients with a severe peripheral artery occlusive disease). Note: Patients, who require walking aids, may be included, if in the opinion of the investigator the walking distance is not impaired.
• Patients with a relative difference (ie absolute difference/mean) of more than 15% between the eligibility- and the baseline 6MWD test (for further details see section 4.6.3).
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 are not allowed:
Pre-Treatment with the following specific medications is not allowed(a):
• Pre-treatment with NO donors (eg Nitrates) within the last 90days before Visit 1
• Pre-treatment with PAH specific medications:
o Endothelin Receptor Antagonists
o Prostacycline Analogues.
o Specific (eg Sildenafil or Tadalafil) or unspecific Phosphodiesterase Inhibitors (eg Dipyridamole, Theophylline).
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 obstructive lung disease (Forced Expiratory Volume in one second < 60% predicted).
The predicted Forced Expiratory Volume in one second (FEV1) is a calculated value. For the calculation refer to section 10.4
• Severe restrictive lung disease (Total Lung Capacity <70% predicted).
The predicted Total Lung Capacity (TCL) is a calculated value. For the calculation refer to section 10.4
• Severe congenital abnormalities of the lungs, thorax, and diaphragm.
Exclusions related to abnormalities in blood gases (capillary or arterial at rest):
• SaO2 < 88% at Visit 0 despite supplemental oxygen therapy.
• PaO2 < 55 mmHg at Visit 0 despite supplemental oxygen therapy.
• PaCO2 > 45 mmHg at Visit 0.
Cardiovascular Exclusions:
• • History of uncontrolled arterial hypertension within the last 90 days before Visit 1 and/or
• Systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg at Visit 0 and/or Visit 1 before randomization.
• History of uncontrolled arterial hypotension within the last 90 days before Visit 1 and/or
• Systolic blood pressure <95 mmHg at Visit 0 and/or Visit 1 before randomization.
• Resting heart rate in the awake patient <50 BPM or >105 BPM at Visit 0 and/or Visit 1 before randomization.
• Atrial fibrillation / atrial flutter within the last 90 days before Visit 1.
• Left heart failure with an ejection fraction less than 40% within the last 90 days before Visit 1.
• Pulmonary venous hypertension indicated by baseline pulmonary capillary wedge pressure >15 mmHg (if age is between 18 and 75 years at Visit 1) or >12 mmHg (if age is > 75 years at Visit 1) .
• 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 90 days 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 at Visit 0.
- and / or: ALT (Alanine-Amino-Transferase) or AST (Aspartate-Amino-Transferase) >3 times upper limit normal at Visit 0.
- and / or: signs of severe hepatic insufficiency (eg impaired albumin synthesis with an albumin < 32g/l, hepatic encephalopathy > grade 1a) at Visit 0.
aWest Haven Criteria of Altered Mental Status In Hepatic Encephalopathy
Severe renal insufficiency indicated by a glomerular filtration rate <30 mL/min at Visit 0 eg calculated based on the Cockcroft formula [refer to appendix 10.13] or Modification of Diet in Renal Disease Study Group (MDRD) formula.
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| 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 | 50 |
| 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
| |
| 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 | 2 |
| 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 | 2 |
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