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

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

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Thromboembolic Pulmonary Hypertension; CTEPH
• Intervention / Treatment: Drug: Riociguat; Procedure: Pulmonary endarterectomy; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Hopital de Bicetre
• Germany
  • Bad Nauheim, Germany, 61231
    • Kerckhoff-Klinik GmbH
• United Kingdom
  • Cambridge, United Kingdom, CB3 8RE
    • Papworth Hospital
• United States
  • California
    • La Jolla, California, United States, 92037-7892
      • UC San Diego

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Riociguat; Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.	Drug: Riociguat; 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.; Other Names: Adempas; BAY 63-2521; Procedure: Pulmonary endarterectomy; PEA will be performed at the end of medical treatment (Day 90); Other Names: PEA
Placebo Comparator: Placebo; Patients will receive placebo for 3 months followed by pulmonary endarterectomy.	Procedure: Pulmonary endarterectomy; PEA will be performed at the end of medical treatment (Day 90); Other Names: PEA; Drug: Placebo; Placebo will be given analogue to riociguat with matching tablets.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NT-proBNP From Baseline Until the End of Medical Treatment	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	90 days
Change in NT-proBNP From Baseline Until 6 Months Post-surgery	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	270 days
Change in Cardiac Index From Baseline Until the End of Medical Treatment	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	90 days
Change in Cardiac Index From Baseline Until 6 Months Post-surgery	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	270 days
Change in Mean Right Atrial Pressure From Baseline Until the End of Medical Treatment	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	90 days
Change in Mean Right Atrial Pressure From Baseline Until 6 Months Post-surgery	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	270 days
Change in Mean Pulmonary Atrial Pressure From Baseline Until the End of Medical Treatment	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	90 days
Change in Mean Pulmonary Atrial Pressure From Baseline Until 6 Months Post-surgery	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	270 days
Change in Pulmonary Artery Wedge Pressure From Baseline Until the End of Medical Treatment	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	90 days
Change in Pulmonary Artery Wedge Pressure From Baseline Until 6 Months Post-surgery	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	270 days
Length of Hospital Stay for Pulmonary Endarterectomy	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	intraoperative
Length of Intensive Care Unit Stay for Pulmonary Endarterectomy	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	intraoperative
WHO Functional Class at the End of Medical Treatment	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	90 days
WHO Functional Class 6 Months Post Pulmonary Endarterectomy	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	270 days
Need for PAH-targeted Therapy 6 Months Post-surgery	Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study	270 days

Collaborators and Investigators

• Sponsor: International CTEPH Association
• Investigators: Principal Investigator: David Jenkins, MD, Papworth Hospital NHS Foundation Trust, Cambridge, UK

Publications and helpful links

Helpful Links

• Website of the International CTEPH Association

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2018
• Primary Completion (Actual): May 5, 2020
• Study Completion (Actual): May 5, 2020

Study Registration Dates

• First Submitted: August 25, 2017
• First Submitted That Met QC Criteria: September 4, 2017
• First Posted (Actual): September 6, 2017

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: May 31, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: PEA; Pulmonary endarterectomy; Medical therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: PEA Bridging Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: IPD sharing is not foreseen

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No