Riociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor

Study Overview
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Brief Summary
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BAY63-2521 Riociguat leads to the relaxation of smooth muscle cells in pulmonary arteria and may also inhibit abnormal remodeling of lung blood vessels. In patients with pulmonary arterial hypertension Riociguat showed to reduce the pulmonary blood pressure and improved the right heart function without unacceptable side effects. Here dose of Riociguat will be adjusted over 8 weeks then a Maintenance Phase of 16 weeks follows. Patients with Pulmonary Arterial Hypertension treated with stable doses of Phosphodiesterase Type-5 Inhibitors (Eg Sildenafil, Tadalafil) not appropriately responding to therapy will be included. Based on previous evidence and on the different modes of action an improvement of exercise capacity, heart function and quality of life may be expected if PDE5i treatment is transitioned to riociguat. Where Riociguat is pending market approval or reimbursement once the treatment phase is completed drug can be made available for another 18 months (Extended Drug Supply Phase - EDSP) under study conditions. Patients may also transition at the end of the maintenance period or any time during the EDSP to any program that is intended to provide riociguat until drug approval/reimbursement, e.g. a long-term extension study, compassionate use or named patient program. Study termination is also possible at any time.

Official Title
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An Open-label, International, Multicenter, Single-arm, Uncontrolled, Phase IIIb Study of Riociguat in Patients With Pulmonary Arterial Hypertension (PAH) Who Demonstrate an Insufficient Response to Treatment With Phosphodiesterase-5 Inhibitors (PDE-5i)

Conditions
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Hypertension, Pulmonary

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients (18 -75 years of age) with idiopathic, familial, drug/toxin induced and associated PAH due to congenital heart disease (Group I / Dana Point Classification of PH) demonstrating insufficient response to treatment with PDE-5i for at least 3 months Patients with and without endothelin receptor antagonist (ERA) therapy World Health Organization Functional Class (WHO FC) III at screening 6-minute walking distance (6MWD) of 165-440 m Cardiac index <3.0 L/min/m*2. Exclusion Criteria: All types of PH except subtypes of Dana Point Group I specified in the inclusion criteria Evidence of clinically significant restrictive or obstructive parenchymal lung diseases Diffusing capacity of the lung for carbon monoxide (DLCO) <30% predicted History or active state of serious hemoptysis / pulmonary hemorrhage including those managed by bronchial artery embolization Patients unable to perform a valid 6MWD test Pregnant women (i.e. positive pregnancy 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, for example a combination of condoms with a safe and highly effective contraception method (prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device) or a double barrier method is used throughout the study.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat<br>Subjects received riociguat film coated immediate-release (IR) tablet 3 times a day (tid) with or without food at a starting dose of 1.0 milligram (mg) and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase). An optimal dose was determined based on systolic blood pressure (SBP) and well-being. Thereafter, riociguat continued at the optimal individual dose until Week 24 (Main phase). Dose reductions or stop of study medication for safety reasons were allowed at any time. Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) were possible at the investigator's discretion weighing the benefit with potential risks implied. Subjects were offered participation in EDSP and received riociguat 2.5 mg film coated IR tablet 3 tid with or without food for 18 months or until reimbursement. | Drug: Riociguat (Adempas, BAY63-2521)<br>* Riociguat / BAY63-2521 film-coated tablets will be used in this study at a dosage of either 0.5, 1.0, 1.5, 2.0, and 2.5 mg. 3 times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in 6 Minute Walking Distance (6MWD) | 6MWD test was used to measure the subjects functional exercise capacity. Subjects were instructed to walk alone, not run, from one end to the other end of the walking course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. No warm-up period was performed before the test. Investigators have not walked with the subjects. This was an encouraged test (the person conducting the test encouraged subjects to walk farther or faster by using only standardized phrases). | Baseline, Week 12 and Week 24 |