Study Completed

Pulmonary Hypertension

Bayer Identifier:

15096

ClinicalTrials.gov Identifier:

NCT01179334

EudraCT Number:

2010-018863-40

EU CT Number:

Not Available

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

Trial purpose

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.

Key Participants Requirements

Sex

Both

Age

18 - 75 Years

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) - 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

Trial summary

Enrollment Goal

Trial Dates

August 2010 - May 2013

Phase

Phase 2

Could I Receive a placebo

Yes

Products

Adempas (Riociguat, BAY63-2521)

Accepts Healthy Volunteer

Where to participate

Status	Institution	Location
Terminated		Gießen, 35392, Germany
Terminated		Berlin, 13353, Germany
Completed		Hamburg, 20246, Germany
Completed		Köln, 50924, Germany
Completed		Dresden, 01307, Germany
Completed		Regensburg, 93042, Germany
Completed		Heidelberg, 69126, Germany
Terminated		Mönchengladbach, 41063, Germany
Terminated		Warszawa, 01-138, Poland
Completed		Bologna, 40138, Italy
Completed		Pavia, 27100, Italy
Completed	Vseobecna fakultni nemocnice	Praha 2, 12808, Czech Republic
Terminated		Innsbruck, 6020, Austria
Terminated		Villach, 9500, Austria
Completed		Würzburg, 97074, Germany
Terminated		Hannover, 30625, Germany
Terminated		Clydebank, G81 4DY, United Kingdom
Completed	Papworth Hospital	Cambridge, CB23 3RE, United Kingdom
Terminated		Providence, 02903, United States
Terminated		Columbus, 43221, United States
Completed		Barcelona, 08036, Spain
Terminated		Aurora, 80045, United States
Terminated		Christchurch, 8011, New Zealand
Terminated		Auckland, 1051, New Zealand
Terminated		Otwock, 05-400, Poland

Primary Outcome

Maximum change from baseline in supine systolic blood pressure (SBP) within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes

Secondary Outcome

Maximum change from baseline in standing systolic blood pressure (SBP) within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Maximum change from baseline in supine diastolic blood pressure (DBP) within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Maximum change from baseline in standing diastolic blood pressure (DBP) within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Maximum change from baseline in supine heart rate (HR) within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Maximum change from baseline in standing heart rate (HR) within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Area under effect curve (AUEC) of supine SBP within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Area under effect curve (AUEC) of standing SBP within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Area under effect curve (AUEC) of supine DBP within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Area under effect curve (AUEC) of standing DBP within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Area under effect curve (AUEC) of supine HR within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes
Area under effect curve (AUEC) of standing HR within 4 hours post-dose at visit 6 (week 12)
Time Frame:
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Safety Issue:
Yes

Trial design

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

Trial Type

Interventional

Intervention Type

Drug

Trial Purpose

Treatment

Allocation

Randomized

Blinding

Double Blind

Assignment

Parallel Assignment

Trial Arms

Additional Information

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