Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Riociguat (Adempas, BAY63-2521); Sildenafil; Tadalafil
Intervention description: Film-coated tablets will be used in this study at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg. Tablets will be administered orally.The starting dose is 1 mg TID; the intervals between drug intakes should be 6 to 8 hours. The dosage should be increased by 0.5 mg increments in 2 week intervals to 1.5 mg, 2.0 mg, and 2.5 mg TID (maximal total daily dose).; Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator.; Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator.
Intervention MeSH terms: Sildenafil Citrate; Tadalafil; Riociguat
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 225.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      To demonstrate the effectiveness of riociguat as replacement of phosphodiesterase-5
      inhibitors (PDE-5i) therapy in pulmonary arterial hypertension (PAH) patients
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male and female patients aged 18 to 75 years.

          -  Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) > 400
             dyn*sec*cm-5, mean pulmonary artery pressure ≥ 25 mmHg, and pulmonary capillary wedge
             pressure (PCWP) ≤ 15 mmHg as assessed by the most recent right heart catheterization
             (RHC) from medical history prior to screening to confirm the diagnosis. Alternatively,
             PCWP can be replaced by left ventricular end-diastolic pressure (≤ 15 mmHg). PAH of
             the following types:

               -  Idiopathic

               -  Hereditary

               -  Drug and toxin induced PAH

               -  Associated with PAH due to:

                    -  Connective tissue disease (CTD)

                    -  Congenital heart disease, but only if the patient underwent surgical repair
                       more than one year before enrolment

                    -  Portal hypertension with liver cirrhosis (Note: patients with clinical
                       relevant hepatic dysfunction are excluded; see exclusions related to
                       disorders in organ function)

          -  Patients who are on stable doses of a PDE-5i and ERA combination therapy or on stable
             PDE-5i monotherapy 6 weeks prior to and at randomization but not at treatment goal
             (tadalafil 20 to 40 mg once daily or sildenafil at least 60 mg daily dose).

          -  WHO FC III at screening and at randomization.

          -  6MWD test between 165 m and 440 m at screening and at randomization.

          -  Stable dose of diuretics, if used, for at least 30 days prior to and at randomization.

          -  Patients who are able to understand and follow instructions and who are able to
             participate in the study for the entire study.

          -  Women of childbearing potential must agree to use adequate contraception when sexually
             active. Adequate contraception is defined as any combination of at least 2 effective
             methods of birth control, of which at least 1 is a physical barrier (e.g. condom with
             hormonal contraception like implants or combined oral contraceptives, condom with
             intrauterine devices). This applies beginning with signing of the informed consent
             form until 30 (+5) days after the last administration of study drug.

          -  Patients 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:

          -  Participation in another interventional clinical study within 30 days prior to
             screening.

          -  All types of PH (including PH-IIP) except subtypes of Dana Point Group I specified in
             the inclusion criteria.

          -  Previous treatment with riociguat.

          -  Pregnant women (i.e., positive serum ß-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 contraception methods (as laid out in inclusion
             criterion) throughout the study.

          -  Patients with a medical disorder, condition, or history of such that would impair the
             patient's ability to participate or complete this study, in the opinion of the
             investigator.

          -  Relevant obstructive and restrictive or other lung diseases.

          -  Patients with underlying medical disorders with an anticipated life expectancy below 2
             years (e.g., active cancer disease with localized and/or metastasized tumor mass).

          -  Cardiovascular exclusion criteria like left ventricular disease, coronary heart
             disease or stroke within previous 3 months.

          -  Patients with hypersensitivity to the investigational drug or any of the excipients.

          -  Patients unable to perform a valid 6MWD test (e.g., orthopedic disease, peripheral
             artery occlusive disease, which affects the patient's ability to walk). Note:
             Patients, who require walking aids, may be included if in the opinion of the
             investigator the walking distance is not impaired. Patients with a variance of more
             than 15% between the screening and the randomization (i.e., baseline) 6MWD test.