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

• ClinicalTrials.gov Identifier: NCT03273257
• Recruitment Status: Terminated
• First Posted: September 6, 2017
• Results First Posted: June 22, 2021
• Last Update Posted: June 22, 2021
• Sponsor: International CTEPH Association
• Information provided by (Responsible Party): International CTEPH Association

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Thromboembolic Pulmonary Hypertension; CTEPH	Drug: Riociguat; Drug: Placebo; Procedure: Pulmonary endarterectomy	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: Double-blind
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 17, 2018
• Actual Primary Completion Date: May 5, 2020
• Actual Study Completion Date: May 5, 2020

Arms and Interventions

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 Name: PEA
Placebo Comparator: Placebo; Patients will receive placebo for 3 months followed by pulmonary endarterectomy.	Drug: Placebo; Placebo will be given analogue to riociguat with matching tablets.; Procedure: Pulmonary endarterectomy; PEA will be performed at the end of medical treatment (Day 90); Other Name: PEA

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA) [ Time Frame: 270 days ]
   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.
2. 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) [ Time Frame: 270 days ]

   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.

3. Intraoperative Circulatory Arrest Time [ Time Frame: intraoperative ]
   Circulatory arrest time will be measured in minutes
4. Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint) [ Time Frame: intraoperative ]

   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)
5. Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane [ Time Frame: intraoperative ]
   Classed as easier than normal (1); normal (2); more difficult than normal (3)
6. Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance [ Time Frame: intraoperative ]
   Classed as better than expected (1); as expected (2); worse than expected (3)
7. Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall [ Time Frame: intraoperative ]
   Classed as more solid than usual (1); normal (2); more friable than usual (3)
8. Number of Patients Who Died During the Course of the Study [ Time Frame: 270 days ]
   All deaths occurring during the whole course of the study
9. Patients Who Withdraw During the Randomized Treatment Phase [ Time Frame: 90 days ]
   Only withdrawals after randomization but before PEA will be included

Other Outcome Measures:

1. Change in NT-proBNP From Baseline Until the End of Medical Treatment [ Time Frame: 90 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
2. Change in NT-proBNP From Baseline Until 6 Months Post-surgery [ Time Frame: 270 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
3. Change in Cardiac Index From Baseline Until the End of Medical Treatment [ Time Frame: 90 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
4. Change in Cardiac Index From Baseline Until 6 Months Post-surgery [ Time Frame: 270 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
5. Change in Mean Right Atrial Pressure From Baseline Until the End of Medical Treatment [ Time Frame: 90 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
6. Change in Mean Right Atrial Pressure From Baseline Until 6 Months Post-surgery [ Time Frame: 270 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
7. Change in Mean Pulmonary Atrial Pressure From Baseline Until the End of Medical Treatment [ Time Frame: 90 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
8. Change in Mean Pulmonary Atrial Pressure From Baseline Until 6 Months Post-surgery [ Time Frame: 270 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
9. Change in Pulmonary Artery Wedge Pressure From Baseline Until the End of Medical Treatment [ Time Frame: 90 days ]
   Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
10. Change in Pulmonary Artery Wedge Pressure From Baseline Until 6 Months Post-surgery [ Time Frame: 270 days ]
    Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
11. Length of Hospital Stay for Pulmonary Endarterectomy [ Time Frame: intraoperative ]
    Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
12. Length of Intensive Care Unit Stay for Pulmonary Endarterectomy [ Time Frame: intraoperative ]
    Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
13. WHO Functional Class at the End of Medical Treatment [ Time Frame: 90 days ]
    Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
14. WHO Functional Class 6 Months Post Pulmonary Endarterectomy [ Time Frame: 270 days ]
    Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
15. Need for PAH-targeted Therapy 6 Months Post-surgery [ Time Frame: 270 days ]
    Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, California

UC San Diego

La Jolla, California, United States, 92037-7892

France

Hopital de Bicêtre

Paris, France

Germany

Kerckhoff-Klinik GmbH

Bad Nauheim, Germany, 61231

United Kingdom

Papworth Hospital

Cambridge, United Kingdom, CB3 8RE

Sponsors and Collaborators

International CTEPH Association

Investigators

• Principal Investigator: David Jenkins, MD; Papworth Hospital NHS Foundation Trust, Cambridge, UK

  Study Documents (Full-Text)

Documents provided by International CTEPH Association:

Study Protocol  [PDF] April 26, 2018

Statistical Analysis Plan  [PDF] December 14, 2020

More Information

Additional Information:

Website of the International CTEPH Association 

• Responsible Party: International CTEPH Association
• ClinicalTrials.gov Identifier: NCT03273257
• Other Study ID Numbers: PEA Bridging Study
• First Posted: September 6, 2017
• Results First Posted: June 22, 2021
• Last Update Posted: June 22, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: IPD sharing is not foreseen

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by International CTEPH Association:

Pulmonary endarterectomy; PEA; Medical therapy

Additional relevant MeSH terms:

Hypertension, Pulmonary; Hypertension; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Riociguat; Enzyme Activators; Molecular Mechanisms of Pharmacological Action