| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (PAH) |
|
| 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 |
|
| 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) |
|
| E.2.2 | Secondary objectives of the trial | |
| 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), a 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 (ie atrial septal defect, ventricle septal defect, persistent ductus arteriosus), if patients underwent surgical correction more than 12 months before study inclusion
- Associated PAH due to portal hypertension with liver cirrhosis CHILD-Pugh class A (B and C excluded) and proven alcohol abstinence for >6 months and no active hepatitis
- 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 Prostacyclinanalogue*:
- Pretreated Patients need to be stable on Endothelin Receptor Antagonists or Prostacyclin treatment for at least three months prior toVisit 1. “Stable” is defined as no change in the type of Endothelin Receptor Antagonists or Prostacyclinanalogue 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 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 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), 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-Study Phase (after the patient signed the informed consent).
• 18 to 75 years of age at Visit 1.
• 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 |
• Participation in another clinical trial during the preceding 3 months.
• Pregnant women, or breast feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs)
• 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 underlying medical disorders with an anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass)
• Patients with a history of severe allergies or multiple drug allergies.
• Patients with hypersensitivity to the investigational drug or inactive constituents.
• 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 variance 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:
• iv Prostacycline Analogues.
• Specific (eg Sildenafil or Tadalafil) or unspecific Phosphodiesterase Inhibitors
(eg Dipyridamole, Theophylline).
• NO donors (eg Nitrates).
Pulmonary Diseases Exclusions:
• All types of pulmonary hypertension except subtypes of Venice Group I
specified in the inclusion criteria.
• 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.
• Clinical or radiological evidence of Pulmo-Veno-Occlusive Disease (PVOD) or
Pulmonary Capillary Haemangiomatosis (PCH).
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.
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 1a
aWest 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 12 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 | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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