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: 28 November 2016
• Main ID: EUCTR2008-003482-68-IE
• Date of registration: 10/10/2008
• Prospective Registration: Yes
• Primary sponsor: Bayer HealthCare AG
• 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: 13/01/2009
• 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
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): 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), 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.


Are the trial subjects under 18? no
Number of subjects
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 insuffi

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: 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: 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: 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: Tablet
Route of administration of the placebo: Oral

Primary Outcome(s)

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

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)

Secondary Objective:

Secondary ID(s)

2008-003482-68-DE

BAY 63-2521/12934