Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters.

Study Overview
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Brief Summary
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Pulmonary Arterial Hypertension (PAH) is a severe progressive disease with a high mortality. Although several drugs are available for the treatment of PAH none offer a cure, therefore there is still a high medical need for new treatments. Soluble guanylate cyclase (sGC) is one of the chemicals involved in the pathways controlling vascular tone, which is impaired in patients with PAH. This causes constriction and thickening of the blood vessels wall in the lungs and increase of blood pressure in the lungs. This can lead to the very debilitating symptoms of PAH such as tiredness, shortness of breath on exertion, collapse and often the inability of the patient to perform their daily life activities. Inhalation of Nitric Oxide, which activates sGC is used to treat PAH, but its effect wears off as soon as inhalation stops. Direct stimulation of sGC using this new compound Riociguat may be a new approach for the treatment of PAH. The phosphodiesterase 5 (PDE5)-inhibitor Sildenafil is one of licensed treatments for PAH. The Patent Plus is a double-blind, placebo-controlled safety study, designed to investigate the effect of Riociguat on blood pressure in patients with PAH when given in combination with Sildenafil.

Detailed Description
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Main objective: Evaluation of the pharmacodynamic effect of the combination of Sildenafil and Riociguat on blood pressure and other safety parameters in patients with symptomatic PAH Secondary objectives:To investigate the safety of the riociguat/sildenafil combination and changes in 6-minute walk test, World Health Organization (WHO) functional class, N terminal pro-brain natriuretic peptide, and variables obtained during right-heart catheterization after 12 weeks of treatment; pharmacokinetics of riociguat and sildenafil. The study consists of one part. In study Part 1 only subjects (18) on stable sildenafil treatment of 20 mg tid have been enrolled. Study Part 2 will not start.

Official Title
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An Interaction Study to Evaluate Changes in Blood Pressure Following 1, 1.5, 2, and 2.5 mg Riociguat Tid (Dose Titration) Compared to Placebo Treatment on the Background of Stable Sildenafil Pretreatment in Subjects With Symptomatic Pulmonary Arterial Hypertension

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: Riociguat (Adempas, BAY63-2521)
* Drug: Placebo
* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 75 years of age at Visit 1 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 For Study Part 1: subjects on stable pretreatment with sildenafil at a dose of 20 mg tid 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) </=105 beats per minute (BPM) in the first 2 h after intake of sildenafil (measured at Visits 0 and 1) Women without child-bearing potential 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 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 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 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 pulmonary hypertension (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 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 Clinical evidence of symptomatic atherosclerotic disease 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 g/L, hepatic encephalopathy > grade 1 Renal insufficiency (glomerular filtration rate <30 mL/min, eg calculated based on the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT<br>Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions. | Drug: Riociguat (Adempas, BAY63-2521)<br>* BAY63-2521: 1 mg tid - 2,5 mg tid oral for 12 weeks.<br>Drug: Sildenafil<br>* Participants continued to take daily stable sildenafil background treatment according to their prescriptions.<br>|
| Placebo Comparator: Placebo<br>Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions. | Drug: Placebo<br>* Placebo for 12 weeks<br>Drug: Sildenafil<br>* Participants continued to take daily stable sildenafil background treatment according to their prescriptions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change From Baseline in Supine Systolic Blood Pressure (SBP) Within 4 Hours Post-dose at Visit 6 (Week 12) | Systolic blood pressure (SBP) was measured as standard vital sign parameter. Range allowed in this study: <= 180 mmHg. In addition, SBP must be >=95 mmHg in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent SBP measurements in that profile) within 4 hours post-dose. Baseline was the last SBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change From Baseline in Standing Systolic Blood Pressure (SBP) Within 4 Hours Post-dose at Visit 6 (Week 12) | Systolic blood pressure (SBP) was measured as standard vital sign parameter. Range allowed in this study: <= 180 mmHg. In addition, SBP must be >=95 mmHg in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent SBP measurements in that profile) within 4 hours post-dose. Baseline was the last SBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Maximum Change From Baseline in Supine Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12) | Diastolic blood pressure (DBP) was measured as standard vital sign parameter. Range allowed in this study: <= 110 mmHg. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent DBP measurements in that profile) within 4 hours post-dose. Baseline was the last DBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Maximum Change From Baseline in Standing Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12) | Diastolic blood pressure (DBP) was measured as standard vital sign parameter. Range allowed in this study: <= 110 mmHg. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent DBP measurements in that profile) within 4 hours post-dose. Baseline was the last DBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Maximum Change From Baseline in Supine Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12) | Heart rate (HR) was measured as standard vital sign parameter. Range allowed in this study: <= 105 beats per minute (bpm) in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum increase from baseline (or zero if baseline was higher than all subsequent HR measurements in that profile) within 4 hours post-dose. Baseline was the last HR recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Maximum Change From Baseline in Standing Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12) | Heart rate (HR) was measured as standard vital sign parameter. Range allowed in this study: <= 105 beats per minute (bpm) in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum increase from baseline (or zero if baseline was higher than all subsequent HR measurements in that profile) within 4 hours post-dose. Baseline was the last HR recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Area Under Effect Curve (AUEC) of Supine SBP Within 4 Hours Post-dose at Visit 6 (Week 12) | The area under the effect curve (AUEC) at each visit of supine SBP describes an average within-subject change in SBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last SBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Area Under Effect Curve (AUEC) of Standing SBP Within 4 Hours Post-dose at Visit 6 (Week 12) | The area under effect curve (AUEC) at each visit of standing SBP describes an average within-subject change in SBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last SBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Area Under Effect Curve (AUEC) of Supine DBP Within 4 Hours Post-dose at Visit 6 (Week 12) | The area under effect curve (AUEC) at each visit of supine DBP describes an average within-subject change in DBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last DBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Area Under Effect Curve (AUEC) of Standing DBP Within 4 Hours Post-dose at Visit 6 (Week 12) | The area under effect curve (AUEC) at each visit of standing DBP describes an average within-subject change in DBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last DBP recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Area Under Effect Curve (AUEC) of Supine HR Within 4 Hours Post-dose at Visit 6 (Week 12) | The area under effect curve (AUEC) at each visit of supine HR describes an average within-subject change in HR from baseline over a time-period of 4 hours post-dose (Note that the area only takes values above the individual baseline for the respective visit into account. The area that would result from a decrease from baseline is not taken into account for the calculation of the area). Baseline was the last HR recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 
| Area Under Effect Curve (AUEC) of Standing HR Within 4 Hours Post-dose at Visit 6 (Week 12) | The area under effect curve (AUEC) at each visit of standing HR describes an average within-subject increase in HR from baseline over a time-period of 4 hours post-dose (Note that the area only takes values above the individual baseline for the respective visit into account. The area that would result from a decrease from baseline is not taken into account for the calculation of the area). Baseline was the last HR recorded at and within 30 minutes before intake of study drug. | Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Hypertension, Riociguat, Blood Pressure