| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (PAH) |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with clinical symptoms due to abnormally high blood pressure in the lung blood vessels |
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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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in treatment naive patients and patients pretreated with an Endothelin Receptor Antagonist or a Prostacyclin analogue with symptomatic Pulmonary Arterial Hypertension (PAH) |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male and female patients with symptomatic PAH ( Group I / Venice Clinical Classification of Pulmonary Hypertension), an eligibility and baseline 6MWD test between 150 m and 450 m, a pulmonary vascular resistance (PVR) >300 dyn*sec*cm-5 and a mean pulmonary artery pressure (PAPmean) >25 mmHg either due to:
- Idiopathic PAH
- Familial PAH
- Associated PAH due to connective tissue disease
- Associated PAH due to congenital heart disease (i.e. atrial septal defect, ventricle septal defect, persistent ductus arteriosus), if patients underwent surgical correction more than 360 days before study inclusion
- Associated PAH due to portal hypertension with liver cirrhosis (Note: patients with clinical relevant hepatic dysfunction are excluded; see exclusions related to disorders in organ function)
- Associated PAH due to anorexigen or amphetamine use
• Treatment naive patients (with respect to PAH specific medication) and patients pre-treated with an Endothelin Receptor Antagonist or a Prostacycline Analogue (iv Prostacyclin Analogues excluded; see general exclusions):
- Pretreated Patients need to be stable on Endothelin Receptor Antagonists or Prostacycline treatment for at least 90 days prior toVisit 1. “Stable” is defined as no change in the type of Endothelin Receptor Antagonists or Prostacycline Analogue and the respective daily dose.
• Unspecific treatments which may also be used for the treatment of pulmonary hypertension such as oral anticoagulants, diuretics, digitalis, low to medium dose calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants must have been started at least 30 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 days before Visit 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) and must have been measured in collaboration with the participating centre 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.
• 18 to 80 years of age at Visit 1.
• 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 participating in another clinical trial or who have done so within 30 days before Visit 1.
• Pregnant women (i.e. positive serum ß-human-chorionic-gonadotropin test or other signs of pregnancy), or breast feeding women, or women with childbearing potential not using a combination of safe contraception methods
• Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator
• Patients with substance abuse (e.g. alcohol or drug abuse) within the previous 180 days before Visit 1.
• Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g. active cancer disease with localized and/or metastasized tumor mass)
• Patients with hypersensitivity to the investigational drug or inactive constituents.
• Patients unable to perform a valid 6MWD test (e.g. 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 (i.e. absolute difference / mean) 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 are not allowed:
Pre-Treatment within the last 90 days before Visit 1:
• iv Prostacycline Analogues (oral, inhalative or subcutaneous Prostacyclin Analogues are allowed if pre-treatment is stable, see inclusion criteria).
• Specific (e.g. Sildenafil or Tadalafil) or unspecific Phosphodiesterase Inhibitors (e.g. Dipyridamole, Theophylline).
• NO donors (e.g. Nitrates).
Pulmonary Diseases Exclusions:
• All types of pulmonary hypertension except subtypes of Venice Group I specified in the inclusion criteria.
• Moderate to severe obstructive lung disease (Forced Expiratory Volume in one second < 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 (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 randomisation.
• 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 randomisation
• Resting heart rate in the awake patient <50 BPM or >105 BPM at Visit 0 and/or Visit 1 before randomisation.
• Atrial fibrillation or 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 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 (e.g. 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.
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 (e.g. 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 e.g. calculated based on the Cockcroft formula or the 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 12 weeks |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline, Day 14, Day 28, Day 42, Day 56 and after 12 weeks therapy |
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| E.5.2 | Secondary end point(s) |
- change from baseline in Pulmonary Vascular Resistance after 12 weeks
- change from baseline in NT-proBNP after 12 weeks
- change from baseline in WHO functional class after 12 weeks
- Time to Clinical Worsening
- change from baseline in Borg CR10 Scale after 12 weeks
- change from baseline in EQ-5D questionnaire after 12 weeks
- change from baseline in LPH questionnaire after 12 weeks
Additional HEOR endpoints:
- change in use of healthcare resources after 12 weeks
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline, Day 14, Day 28, Day 42, Day 56 and after 12 weeks therapy |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Russian Federation |
| Singapore |
| Switzerland |
| Taiwan |
| Thailand |
| United States |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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