Back to resultsRiociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study)
Primary Purpose
Chronic Thromboembolic Pulmonary Hypertension, CTEPH
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Riociguat
Placebo
Pulmonary endarterectomy
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Thromboembolic Pulmonary Hypertension focused on measuring Pulmonary endarterectomy, PEA, Medical therapy
Eligibility 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
Sites / Locations
- UC San Diego
- Hopital de Bicêtre
- Kerckhoff-Klinik GmbH
- Papworth Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Riociguat
Placebo
Arm Description
Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.
Patients will receive placebo for 3 months followed by pulmonary endarterectomy.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
Intraoperative Circulatory Arrest Time
Circulatory arrest time will be measured in minutes
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)
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)
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)
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)
Number of Patients Who Died During the Course of the Study
All deaths occurring during the whole course of the study
Patients Who Withdraw During the Randomized Treatment Phase
Only withdrawals after randomization but before PEA will be included
Full Information
NCT ID
NCT03273257
First Posted
August 25, 2017
Last Updated
May 31, 2021
Sponsor
International CTEPH Association
1. Study Identification
Unique Protocol Identification Number
NCT03273257
Brief Title
Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study)
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2021
Overall Recruitment Status
Terminated
Why Stopped
The study was stopped due to slower than expected recruitment and the additional limitations on clinical research imposed by the COVID-19 pandemic, both of which made study completion within a reasonable timeframe appear unlikely.
Study Start Date
August 17, 2018 (Actual)
Primary Completion Date
May 5, 2020 (Actual)
Study Completion Date
May 5, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
International CTEPH Association
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Thromboembolic Pulmonary Hypertension, CTEPH
Keywords
Pulmonary endarterectomy, PEA, Medical therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Masking Description
Double-blind
Allocation
Randomized
Enrollment
14 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Riociguat
Arm Type
Active Comparator
Arm Description
Patients will receive riociguat for 3 months followed by pulmonary endarterectomy.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will receive placebo for 3 months followed by pulmonary endarterectomy.
Intervention Type
Drug
Intervention Name(s)
Riociguat
Other Intervention Name(s)
Adempas, BAY 63-2521
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo will be given analogue to riociguat with matching tablets.
Intervention Type
Procedure
Intervention Name(s)
Pulmonary endarterectomy
Other Intervention Name(s)
PEA
Intervention Description
PEA will be performed at the end of medical treatment (Day 90)
Primary Outcome Measure Information:
Title
Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA)
Description
Pulmonary vascular resistance (PVR) will be assessed at baseline and immediately before pulmonary endarterectomy. The change in PVR will be assessed as percentage.
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA)
Description
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.
Time Frame
270 days
Title
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)
Description
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.
Time Frame
270 days
Title
Intraoperative Circulatory Arrest Time
Description
Circulatory arrest time will be measured in minutes
Time Frame
intraoperative
Title
Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint)
Description
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)
Time Frame
intraoperative
Title
Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane
Description
Classed as easier than normal (1); normal (2); more difficult than normal (3)
Time Frame
intraoperative
Title
Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance
Description
Classed as better than expected (1); as expected (2); worse than expected (3)
Time Frame
intraoperative
Title
Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall
Description
Classed as more solid than usual (1); normal (2); more friable than usual (3)
Time Frame
intraoperative
Title
Number of Patients Who Died During the Course of the Study
Description
All deaths occurring during the whole course of the study
Time Frame
270 days
Title
Patients Who Withdraw During the Randomized Treatment Phase
Description
Only withdrawals after randomization but before PEA will be included
Time Frame
90 days
Other Pre-specified Outcome Measures:
Title
Change in NT-proBNP From Baseline Until the End of Medical Treatment
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
90 days
Title
Change in NT-proBNP From Baseline Until 6 Months Post-surgery
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
270 days
Title
Change in Cardiac Index From Baseline Until the End of Medical Treatment
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
90 days
Title
Change in Cardiac Index From Baseline Until 6 Months Post-surgery
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
270 days
Title
Change in Mean Right Atrial Pressure From Baseline Until the End of Medical Treatment
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
90 days
Title
Change in Mean Right Atrial Pressure From Baseline Until 6 Months Post-surgery
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
270 days
Title
Change in Mean Pulmonary Atrial Pressure From Baseline Until the End of Medical Treatment
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
90 days
Title
Change in Mean Pulmonary Atrial Pressure From Baseline Until 6 Months Post-surgery
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
270 days
Title
Change in Pulmonary Artery Wedge Pressure From Baseline Until the End of Medical Treatment
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
90 days
Title
Change in Pulmonary Artery Wedge Pressure From Baseline Until 6 Months Post-surgery
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
270 days
Title
Length of Hospital Stay for Pulmonary Endarterectomy
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
intraoperative
Title
Length of Intensive Care Unit Stay for Pulmonary Endarterectomy
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
intraoperative
Title
WHO Functional Class at the End of Medical Treatment
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
90 days
Title
WHO Functional Class 6 Months Post Pulmonary Endarterectomy
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
270 days
Title
Need for PAH-targeted Therapy 6 Months Post-surgery
Description
Data are not reported for this exploratory endpoint because of limited sample size due to early termination of the study
Time Frame
270 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Jenkins, MD
Organizational Affiliation
Papworth Hospital NHS Foundation Trust, Cambridge, UK
Official's Role
Principal Investigator
Facility Information:
Facility Name
UC San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92037-7892
Country
United States
Facility Name
Hopital de Bicêtre
City
Paris
Country
France
Facility Name
Kerckhoff-Klinik GmbH
City
Bad Nauheim
ZIP/Postal Code
61231
Country
Germany
Facility Name
Papworth Hospital
City
Cambridge
ZIP/Postal Code
CB3 8RE
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
IPD sharing is not foreseen
Links:
URL
https://www.cteph-association.org/
Description
Website of the International CTEPH Association
Learn more about this trial
Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study)
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