Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy

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

Detailed Description
-----------------
Data from a previous single arm study (RESPITE) indicate that transition from PDE5i to riociguat may be feasible, safe and beneficial in patients not adequately responding to PDE5i. REPLACE is a randomized controlled study to confirm the potential clinical benefit of transition from PDE5i to riociguat. Satisfactory clinical response in patients who are on a stable dose of phosphodiesterase-5inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal will be compared between one group of patients randomized to maintain current treatment and another group where the PDE5i is replaced by riociguat.

Official Title
-----------------
A Prospective, Randomized, International, Multicenter, Double-arm, Controlled, Open-label Study of Riociguat in Patients With Pulmonary Arterial Hypertension (PAH) Who Are on a Stable Dose of Phosphodiesterase-5 Inhibitors (PDE-5i) With or Without Endothelin Receptor Antagonist (ERA), But Not at Treatment Goal

Conditions
-----------------
Pulmonary Arterial Hypertension

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


Participation Criteria
=================
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.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat<br>PDE5i treatment will be stopped and riociguat treatment initiated following a defined washout period with a starting dose of 1 mg riociguat TID followed by an 8 weeks dose adjustment phase according to the approved riociguat dose adjustment scheme. | Drug: Riociguat (Adempas, BAY63-2521)<br>* 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).<br>|
| Active Comparator: PDE-5i<br>Patients will continue to receive PDE5i treatment as well as other standard of care treatments at the discretion of the investigator up to Week 24. Patients in the experimental and active comparator treatment arms follow the same visit schedule. | Drug: Sildenafil<br>* 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.<br>Drug: Tadalafil<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Satisfactory Clinical Response at Week 24 | The treatment is assessed as efficient (participants with satisfactory clinical response) in case at least 2 out of the following 3 criteria were fulfilled 6 Minute Walking Distance increase by ≥ 10% or ≥ 30 m from baseline to Week 24 World Health Organization Functional Class (WHO FC) I or II at Week 24 N-terminal pro-brain natriuretic peptide (NT-proBNP) reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7) and in absence of the defined criteria of clinical worsening | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks | Six-minute walk distance (6MWD) was conducted to test the physical limitations of the participant by assessing the participant's exercise capacity. The distance walked by the participant in 6 minutes was measured. | From baseline and up to 24 weeks | 
| Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24 | N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure. | From baseline and up to 24 weeks | 
| Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24 | The participant's functional class was determined by using the WHO classification. Possible classes range from I (patients with pulmonary hypertension (PH) but without resulting limitation of physical activity) to IV (patients with PH with inability to carry out any physical activity without symptoms). | From baseline and up to 24 weeks | 
| Number of Participants With Adjudicated Clinical Worsening at Week 24 | Clinical worsening was defined as death of any cause, hospitalization due to worsening pulmonary arterial hypertension (PAH) (adjudicated) or disease progression (adjudicated). | Up to 24 weeks |