Pulmonary arterial hypertension MedDRA version: 14.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Conditions
Interventions
Product Name: BAY 63-2521 IR tablets 1.0 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
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Sponsors
Bayer HealthCare AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: •18 to 75 years of age at Visit 1 (the lower age limit may be higher if legally requested in the participating countries). •Male and female subjects with symptomatic PAH (Group I Dana Point Updated Clinical Classification 2008), a 6-min walking distance (6MWD) of more than 150 m, a pulmonary vascular resistance (PVR) >300 dyn*s*cm-5, and a mean pulmonary artery pressure (PAPmean) = 25 mmHg either due to: -Idiopathic PAH. -Heritable 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 subjects underwent surgical correction >360 days before study inclusion. -Associated PAH due to portal hypertension with liver cirrhosis. (Note: subjects with clinical relevant hepatic dysfunction are excluded; see exclusions related to disorders in organ function.) -Associated PAH due to anorexigen or amphetamine use. Note: Other PAH subtypes of Dana Point Updated Clinical Classification Group I than the ones listed above, for example (eg) PAH associated with human immunodeficiency virus (HIV) infection, are excluded from the trial (see exclusion criteria). Note: With respect to the verification of the inclusion criteria, PAPmean and PVR are considered as calculated parameters. Note: Subjects who originally failed screening due to the upper limit of the 6MWD in the original study protocol can be re-screened. •For Study Part 1: subjects on stable pretreatment with sildenafil at a dose of 20 mg tid. “Stable” is defined as no change in the respective daily dose for at least 90 days prior to randomization. •Unspecific treatments which may also be used for the treatment of PAH such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants (if indicated) 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. •Subjects with supplemental long-term oxygen therapy may be included, if the amount of supplemental oxygen and the delivery method was stable on average for at least 90 days before Visit 1. •SBP >/=95 mmHg and heart rate (HR) =65 years) yes F.1.3.1
Exclusion criteria
Exclusion criteria: •Subject’s participating in another clinical trial or who have done so within 30 days before Visit 1. •Previous assignment to treatment during this study. •Pregnant women (ie positive serum beta-human-chorionic-gonadotropin test or other signs of pregnancy), or breast feeding women, or women with childbearing potential not using a combination of 2 effective methods of birth control (eg prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method, male partner sterilization) throughout the study. •Subjects with a medical disorder, condition, or history of such that would impair the subject’s ability to participate or complete this study in the opinion of the investigator. •Subjects with substance abuse (eg alcohol or drug abuse) within the previous 180 days before Visit 1. •Subjects with underlying medical disorders with an anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass). •Subjects with a history of severe allergies or multiple drug allergies. •Subjects with hypersensitivity to the investigational drug or any of the excipients. •Subjects unable to perform a valid 6MWD test, eg subjects with a severe peripheral artery occlusive disease. (Note: Subjects, who require walking aids, may be included if in the opinion of the investigator the walking distance is not impaired.) •Subjects with a relative difference (ie absolute difference/mean) of more than 15% between the eligibility- and the baseline 6MWD test •All types of pulmonary hypertension except subtypes of Updated Clinical Classification of PH (Dana Point 2008) Group I specified in the inclusion criteria. •Moderate to severe obstructive lung disease (forced expiratory volume 45 mmHg. •Uncontrolled arterial hypertension (SBP >180 mmHg and /or diastolic blood pressure >110 mmHg). [exclusion criteria about SBP and Resting heart rate deleted] •Atrial fibrillation within the last 90 days before Visit 1. •Pulmonary venous hypertension with pulmonary capillary wedge pressure ?15 mmHg. •Hypertrophic obstructive cardiomyopathy. •Severe proven or suspected coronary artery disease (subjects with Canadian Cardiovascular Society Angina Classification class 2 to 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. •Clinical relevant hepatic dysfunction indicated by: - Bilirubin >2 times upper limit normal (ULN) - and/or ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3 times ULN - and/or signs of severe hepatic insufficiency (eg impaired albumin sy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of 1, 1.5, 2, and 2.5 mg riociguat tid (dose titration) administered simultaneously with sildenafil on blood pressure in subjects with symptomatic pulmonary arterial hypertension.;Secondary Objective: To investigate the safety of the riociguat/sildenafil combination and changes in 6-minute walk test, WHOf unctional class, N terminal pro-brain natriuretic peptide, and variables obtained during right-heart catheterization after 12 weeks of treatment; pharmacokinetics of riociguat and sildenafil.;Primary end point(s): •Maximum change in supine SBP from baseline within 4 h of dosing with riociguat for the individual dose steps or placebo.;Timepoint(s) of evaluation of this end point: Every two weeks over 8 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary pharmacodynamic endpoints: - Maximum change in standing SBP from baseline within 4 h of dosing with study medication. - Maximum change in standing diastolic blood pressure (DBP) from baseline within 4 h of dosing with study medication. - Maximum change in supine DBP from baseline within 4 h of dosing with study medication. - Maximum change in supine and standing HR from baseline within 4 h of dosing with study medication. - Area under effect curve (AUEC) for change from baseline in standing and supine systolic and diastolic BP, and HR within 6 h of dosing with riociguat or placebo. Exploratory efficacy endpoints: - Change from baseline in 6MWD 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 CR 10 scale (measured at the end of the 6MWD test) after 12 weeks. Safety endpoints: Safety of riociguat/sildenafil combination ;Timepoint(s) of evaluation of this end point: Secondary pharmacodynamic endpoints Every 2 weeks over 8 weeks: -Maximum change in standing SBP... -Maximum change in standing diastolic blood pressure... -Maximum change in supine DBP... -Maximum change in supine and standing HR... Within 6 h of dosing with riociguat or placebo: -AUEC for change from baseline in standing and supine systolic and diastolic BP, and HR Exploratory efficacy endpoints: After 12 weeks: -Change from baseline in 6MWD -Change from baseline in NT-proBNP -Change from baseline in WHO functional class -Time to clinical worsening. -Change from baseline in Borg CR 10 scale Safety endpoints: At every visit | — |
Countries
Austria, Czech Republic, Germany, Italy, Poland, Spain, United Kingdom
Contacts
Public ContactBayer Clinical Trials Contact
Bayer HealthCare AG
Outcome results
None listed