Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study)

Study Overview
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Brief Summary
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This is a randomised, double-blind, placebo-controlled, multicentre, multinational, prospective study in patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) prior to pulmonary endarterectomy (PEA) with high preoperative pulmonary vascular resistance (PVR). Patients will be randomised in a 1:1 ratio to receive riociguat or matching placebo for 3 months before undergoing PEA. The primary objective of this study is to assess the efficacy of riociguat on preoperative PVR compared to placebo in patients with operable CTEPH.

Official Title
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A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Multicentre, Prospective Study to Assess Efficacy of Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy With High Preoperative Pulmonary Vascular Resistance

Conditions
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Chronic Thromboembolic Pulmonary Hypertension, CTEPH

Intervention / Treatment
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* Drug: Riociguat
* Drug: Placebo
* Procedure: Pulmonary endarterectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is a male or nonpregnant and nonlactating female patient aged from 18 to 80 years, both inclusive Is diagnosed with operable CTEPH and anticipating symptomatic and/or prognostic benefit from PEA Has pulmonary vascular resistance (PVR) >800 dyn·s·cm-5 Has undergone right heart catheterisation not more than 180 days before randomisation visit Has been treated with anticoagulants for at least 90 days before randomisation visit Has ability to swallow oral medication Has ability and willingness to participate and access the health facility Is capable of understanding the written informed consent and provides signed and witnessed written informed consent Female patient must be either surgically sterile, postmenopausal (no menses for the previous 12 months), or must be practicing an effective method of birth control as determined by the investigator (eg, oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or male partner with vasectomy or complete abstinence) Exclusion Criteria: Has unstable disease in need of urgent PEA surgery as determined by the treating physician Has known hypersensitivity, allergic, or adverse reactions to riociguat or any of the excipients comprising riociguat tablets. Has known active hepatitis A IgM (HAV-IgM), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV Ab) Is human immunodeficiency virus positive Has pulmonary veno-occlusive disease Has symptomatic hypotension Has symptomatic carotid disease Has significant coronary atherosclerotic disease in need of intervention Has severe left heart disease in need of intervention Has redo sternotomy Has received any background therapy for pulmonary arterial hypertension (PAH) in the preceding 30 days before randomisation visit including endothelin receptor antagonists (ERAs), phosphodiesterase 5 (PDE5) inhibitors, or prostanoids Is receiving nitrates, nitric oxide donors (e.g. amyl nitrite), ERAs, prostanoids, specific PDE5 inhibitors, nonspecific phosphodiesterase inhibitors (e.g. dipyridamole, theophylline) Is receiving strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance protein inhibitors Is receiving strong CYP3A inducers Has creatinine clearance <15 mL/min or on any form of dialysis Has severe hepatic impairment classified as Child-Pugh C Has received an investigational drug within the past 4 weeks before randomisation visit Is a lactating or pregnant (as demonstrated by a serum pregnancy test) woman, and not willing to take measures for not to become pregnant during the 3 months treatment study period and one month after the last dose of study drug administered Has smoked or used tobacco in any form, including snuff or chewing within 3 months prior to randomisation visit Has idiopathic interstitial pneumonitis

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Riociguat<br>Patients will receive riociguat for 3 months followed by pulmonary endarterectomy. | Drug: Riociguat<br>* Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.<br>* Other names: BAY 63-2521;Procedure: Pulmonary endarterectomy<br>* PEA will be performed at the end of medical treatment (Day 90)<br>* Other names: PEA;|
| Placebo Comparator: Placebo<br>Patients will receive placebo for 3 months followed by pulmonary endarterectomy. | Drug: Placebo<br>* Placebo will be given analogue to riociguat with matching tablets.<br>Procedure: Pulmonary endarterectomy<br>* PEA will be performed at the end of medical treatment (Day 90)<br>* Other names: PEA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA) | Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA) | Pulmonary vascular resistance (PVR) will be assessed at baseline and 6 months post pulmonary endarterectomy (PEA). The change in PVR will be assessed as percentage. | 270 days | 
| Number of Patients With Either All-cause Death, PH-related Hospitalization, Need for PAH-targeted Therapy or WHO Functional Class Unchanged or Worse Between Randomization and 6 Months Post Pulmonary Endarterectomy (Composite Endpoint) | All deaths occurring post-randomization until the last visit will be included. All PH-related hospitalizations except the in-hospital care during and after pulmonary endarterectomy (PEA) from randomization until 6 months after PEA will be included. The worst value for World Health Organization (WHO) functional class after treatment will be used. | 270 days | 
| Intraoperative Circulatory Arrest Time | Circulatory arrest time will be measured in minutes | intraoperative | 
| Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint) | The occurrence of any of the following complications will be assessed: Bleeding and/or blood loss >1 L in 12 hours Airway bleed with need for extracorporeal membrane oxygenation Any use of extracorporeal membrane oxygenation for respiratory or hemodynamic support, specified as veno-venous or veno-arterial Prolonged ventilation >96 hours Need for tracheostomy Need for drainage of pericardial effusion Neurological complications, ie, stroke, cerebral, subdural bleeding Reintubation or noninvasive ventilation for reperfusion response Hemoptysis requiring any intervention Renal failure requiring dialysis Wound infections Pneumonia Prolonged need for inotropic support (≥ 5 days) | intraoperative | 
| Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane | Classed as easier than normal (1); normal (2); more difficult than normal (3) | intraoperative | 
| Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance | Classed as better than expected (1); as expected (2); worse than expected (3) | intraoperative | 
| Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall | Classed as more solid than usual (1); normal (2); more friable than usual (3) | intraoperative | 
| Number of Patients Who Died During the Course of the Study | All deaths occurring during the whole course of the study | 270 days | 
| Patients Who Withdraw During the Randomized Treatment Phase | Only withdrawals after randomization but before PEA will be included | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary endarterectomy, PEA, Medical therapy