Evaluation of the pharmacodynamic effect of the combination of Sildenafil and Riociguat on blood pressure and other safety parameters

Conditions: Pulmonary arterial hypertension
MedDRA version: 14.1Level: PTClassification code 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2010-018863-40-CZ

Lead Sponsor: Bayer HealthCare AG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 36

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) •Women without child-bearing potential defined as postmenopausal women (ie 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 may only be included in the study if a serological pregnancy test is negative and 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) are used throughout the study.
•Subjects who are able to understand and follow instructions and who are able to participate in the study for the entire period.
•Subjects 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 36
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subject

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 <60% predicted). The predicted forced expiratory volume in 1 second (FEV1) is a calculated value.
•Severe restrictive lung disease (total lung capacity <70% predicted). The predicted total lung capacity (TLC) is a calculated value.
•Severe congenital abnormalities of the lungs, thorax, and diaphragm.
•Oxygen saturation (SaO2) <88% despite supplemental oxygen therapy.
•Arterial partial oxygen pressure (PaO2) <55 mmHg despite supplemental oxygen therapy.
•Arterial partial pressure of carbon dioxide (PaCO2) >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 synthesis with an albumin <32

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method

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