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

Study Description

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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

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	80 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
Estimated Primary Completion Date :	July 2020
Estimated Study Completion Date :	July 2020

Arms and Interventions

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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. 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

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Primary Outcome Measures :

1. Change from baseline in pulmonary vascular resistance (PVR) to immediately before pulmonary endarterectomy (pre-PEA) [ Time Frame: 90 days ]
   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 ]
   Change in PVR will be assessed as percentage
2. Number of patients with either all-cause death, PH-related hospitalisation, need for PAH-targeted therapy or WHO functional class unchanged or worse between randomisation and 6 months post pulmonary endarterectomy (composite endpoint) [ Time Frame: 270 days ]

   All deaths occuring post-randomisation until the last visit will be included. All PH-related hospitalisations except the in-hospital care during and after pulmonary endarterectomy (PEA) from randomisation until 6 months after PEA will be included.

   The worst value for 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. Frequency of intraoperative surgery-related complications (composite endpoint) [ Time Frame: intraoperative ]

   The occurence 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 haemodynamic 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
   • Haemoptysis requiring any intervention
   • Renal failure requiring dialysis
   • Wound infections
   • Pneumonia
   • Prolonged need for inotropic support (≥ 5 days)
5. Surgical evaluation of specimen: 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: 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: appearance of clot and vessel wall [ Time Frame: intraoperative ]
   Classed as more solid than usual (1); normal (2); more friable than usual (3)
8. Frequency of all-cause death [ Time Frame: 270 days ]
   All deaths occuring during the whole course of the study
9. Frequency of withdrawal during randomised treatment phase [ Time Frame: 90 days ]
   Only withdrawals after randomisation 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 ]
2. Change in NT-proBNP from baseline until 6 months post-surgery [ Time Frame: 270 days ]
3. Change in cardiac index from baseline until the end of medical treatment [ Time Frame: 90 days ]
4. Change in cardiac index from baseline until 6 months post-surgery [ Time Frame: 270 days ]
5. Change in mean right atrial pressure from baseline until the end of medical treatment [ Time Frame: 90 days ]
6. Change in mean right atrial pressure from baseline until 6 months post-surgery [ Time Frame: 270 days ]
7. Change in mean pulmonary atrial pressure from baseline until the end of medical treatment [ Time Frame: 90 days ]
8. Change in mean pulmonary atrial pressure from baseline until 6 months post-surgery [ Time Frame: 270 days ]
9. Change in pulmonary artery wedge pressure from baseline until the end of medical treatment [ Time Frame: 90 days ]
10. Change in pulmonary artery wedge pressure from baseline until 6 months post-surgery [ Time Frame: 270 days ]
11. Length of hospital stay for pulmonary endarterectomy [ Time Frame: intraoperative ]
    The hospital length of stay in days from the first date the patient is hospitalised for pulmonary endarterectomy until the patient is discharged
12. Length of intensive care unit stay for pulmonary endarterectomy [ Time Frame: intraoperative ]
    The intensive care unit (ICU) length of stay in days from the first ICU day for pulmonary endarterectomy until the patient is discharged from the ICU unit
13. WHO functional class at the end of medical treatment [ Time Frame: 90 days ]
14. WHO functional class 6 months post pulmonary endarterectomy [ Time Frame: 270 days ]
15. Need for PAH-targeted therapy 6 months post-surgery [ Time Frame: 270 days ]

Eligibility Criteria

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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 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

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Contacts

Contact: Fabrizio Canonaco, Dr	+ 41 41 379 79 70	fabrizio.canonaco@cteph-association.org
Contact: Simone Lerch, Dr	+ 41 41 379 79 70	simone.lerch@cteph-association.org

Locations

United States, California
UC San Diego	Not yet recruiting
La Jolla, California, United States, 92037-7892
Contact: Nick H Kim, Prof
Contact: Michael M Madani, Prof
France
Hopital de Bicêtre	Not yet recruiting
Paris, France
Contact: Gérald Simonneau, Prof
Contact: Elie Fadel, Prof
Germany
Kerckhoff-Klinik GmbH	Recruiting
Bad Nauheim, Germany, 61231
Contact: Eckhard Mayer, Prof
United Kingdom
Papworth Hospital	Not yet recruiting
Cambridge, United Kingdom, CB3 8RE
Contact: David Jenkins, MD
Contact: Joanna Pepke-Zaba, MD

Sponsors and Collaborators

International CTEPH Association

Investigators

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

More Information

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Additional Information:

Website of the International CTEPH Association 

Responsible Party:	International CTEPH Association
ClinicalTrials.gov Identifier:	NCT03273257 History of Changes
Other Study ID Numbers:	PEA Bridging Study
First Posted:	September 6, 2017
Last Update Posted:	September 13, 2018
Last Verified:	September 2018
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; Lung Diseases; Respiratory Tract Diseases