Efficacy and Safety of Riociguat in Patients With Symptomatic Pulmonary Hypertension (PH) Associated With Idiopathic Interstitial Pneumonias (IIP)

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of 26-weeks of treatment with riociguat vs. placebo in patients with symptomatic PH (pulmonary hypertension) associated with IIP (idiopathic interstitial pneumonias).

Detailed Description
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Number of participants with Adverse Events (AEs) will be reported in Adverse Events section.

Official Title
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A Randomized, Double-blind, Placebo-controlled Phase II Study to Investigate the Efficacy and Safety of Riociguat (0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID) in Patients With Symptomatic Pulmonary Hypertension Associated With Idiopathic Interstitial Pneumonias (IIP).

Conditions
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Idiopathic Interstitial Pneumonias / Hypertension,Pulmonary

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women aged from ≥18 to ≤80 years Diagnosed with one of the following (confirmed using a multidisciplinary approach, as per ATS(American Thoracic Society) / ERS(European Respiratory Society) / JRS (Japanese Respiratory Society) / ALAT(Latin American Thoracic Association) guidelines: Major IIPs (idiopathic interstitial pneumonias) diagnosis or suspected as one of the following: Idiopathic pulmonary fibrosis Idiopathic nonspecific interstitial pneumonia Respiratory bronchiolitis-interstitial lung disease Desquamative interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Rare IIPs diagnosis by one of the following: Idiopathic lymphoid interstitial pneumonia Idiopathic pleuroparenchymal fibroelastosis Unclassifiable idiopathic interstitial pneumonias Forced Vital Capacity (FVC) ≥ 45 % 6MWD (6 minutes walking distance) ≥ 150 m to ≤ 450 m {under stable O2(oxygen) supplementation via nasal cannula} Diagnosis of PH (pulmonary hypertension) confirmed by right heart catheter (RHC) with (mean artery pulmonary artery pressure )mPAP ≥ 25 mmHg and (pulmonary artery wedge pressure)PAWP ≤15 mmHg at rest Systolic blood pressure (SBP) ≥ 95 mmHg and no signs or symptoms of hypotension WHO functional class II-IV Women of childbearing potential can only be included in the study if a pregnancy test is negative. 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 one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration Exclusion Criteria: Known significant left heart disease: Pulmonary venous hypertension indicated by baseline pulmonary capillary wedge pressure > 15 mmHg Symptomatic coronary artery disease Systolic left-ventricular dysfunction with an left ventricular ejection fraction (LVEF) <45% Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization Any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening. Massive hemoptysis being defined as acute bleeding >240 mL in a 24-hour period or recurrent bleeding >100 mL/d over several days Difference > 15% between the eligibility and the baseline 6MWD test Forced expiratory volume in one second (FEV1) / Forced Vital Capacity (FVC) <0.65 after bronchodilator administration Initiation in cytotoxic, immunosuppressive, cytokine modulating therapy initiated within 3 months prior to screening. Such agents might include. azathioprine, cyclophosphamide, corticosteroids, etanercept, tumor necrosis factor alpha (TNFα) inhibitors and others Any specific treatment for (pulmonary arterial hypertension) PAH/PH (pulmonary hypertension )within 3 months prior to screening Concomitant use of the following medication: nitrates or (nitric oxide) NO donors (such as amyl nitrite) in any form, phosphodiesterase 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole), Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women, or women of childbearing potential not using adequate contraception (as defined in the aforementioned inclusion criterion) and not willing to agree to 4 weekly pregnancy testing from Visit 1(first administration of study drug) onwards until 4 weeks after last study drug intake

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat (Adempas, BAY63-2521)<br>In the main study treatment phase participants received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase participants were to be treated with Riociguat until commercial access in the indication of pulmonary hypertension (PH) associated with idiopathic interstitial pneumonias (IIP) or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor's global team. | Drug: Riociguat (Adempas, BAY63-2521)<br>* Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient's systolic blood pressure and well-being.<br>|
| Placebo Comparator: Placebo<br>In the main study treatment phase participants received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase participants were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor's global team. | Drug: Riociguat (Adempas, BAY63-2521)<br>* Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient's systolic blood pressure and well-being.<br>Drug: Placebo<br>* Inactive dosed at 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration for 26 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26 | The 6MWD test is designed to evaluate a patient's exercise capacity while performing an everyday activity. | Baseline to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Worsening | The combined endpoint time to clinical worsening, made up of the following components, defined by the first occurrence: all-cause mortality; need for hospitalization due to worsening cardiopulmonary (CP) status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling); >15% decrease in the 6MWD test; worsening of WHO functional class. | From baseline to week 26 |