Randomized, double-blind, placebo-controlled, multi-centre, multi-national study to evaluate the efficacy and safety of oral BAY 63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in patients with symptomatic Pulmonary Arterial Hypertension (PAH). - PATENT-1 Study

• Register: EUCTR
• Last refreshed on: 4 February 2013
• Main ID: EUCTR2008-003482-68-DK
• Date of registration: 02/02/2009
• Prospective Registration: Yes
• Primary sponsor: Bayer HealthCare AG, D-51368 Leverkusen
• Public title: Randomized, double-blind, placebo-controlled, multi-centre, multi-national study to evaluate the efficacy and safety of oral BAY 63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in patients with symptomatic Pulmonary Arterial Hypertension (PAH). - PATENT-1 Study
• Scientific title: Randomized, double-blind, placebo-controlled, multi-centre, multi-national study to evaluate the efficacy and safety of oral BAY 63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in patients with symptomatic Pulmonary Arterial Hypertension (PAH). - PATENT-1 Study
• Date of first enrolment: 16/03/2009
• Target sample size: 462
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-003482-68
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, France, Germany, Greece, Ireland, Italy, Netherlands, Portugal, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

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 (ie 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 naïve patients (with respect to PAH specific medication) or patients pre-treated with an Endothelin Receptor Antagonist or a Prostacyclin Analogue (iv Prostacyclin Analogues excluded; see general exclusions):
- Pretreated Patients need to be stable on Endothelin Receptor Antagonists or Prostacyclin treatment for at least 90 days prior to Visit 1. “Stable” is defined as no change in the type of Endothelin Receptor Antagonists or Prostacyclin 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.


Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.
Exclusion criteria:
• Patient’s 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 (eg 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 (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.
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 Prostacyclin Analogues (oral, inhalative or subcutaneous Prostacyclin Analogues are allowed if pre- treatment is stable, see inclusion criteria).
• 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 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 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 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 is between 18 and 75 years at Visit 1)
or > 12 mmHg (if age is > 75 years at Visit 1)
• Hypertrophic obstructive cardiomyopathy

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension (PAH)
MedDRA version: 9.1 Level: LLT Classification code 10064911 Term: Pulmonary arterial hypertension

Intervention(s)

Product Name: BAY 63-2521 tablets 0.5 mg
Product Code: BAY 63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY 63-2521
Other descriptive name: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: BAY 63-2521 tablets 1 mg
Product Code: BAY 63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY 63-2521
Other descriptive name: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: BAY 63-2521 tablets 1.5 mg
Product Code: BAY 63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY 63-2521
Other descriptive name: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: BAY 63-2521 tablets 2 mg
Product Code: BAY 63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY 63-2521
Other descriptive name: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-
Pharmaceutical form of the placebo: Film-coated tabl

Primary Outcome(s)

Main Objective: 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)

Primary end point(s): The primary endpoint is change from baseline in 6 Minute Walking Distance (6MWD) after 12 weeks

Secondary Objective:

Secondary ID(s)

2008-003482-68-DE

BAY 63-2521/12934