Clinical trial NCT03273257: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Thromboembolic Pulmonary Hypertension
CTEPH
Keywords: Pulmonary endarterectomy
PEA
Medical therapy
Lead sponsor: International CTEPH Association
Sponsor class: OTHER
First posted: 2017-09-06
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR) to Immediately Before Pulmonary Endarterectomy (Pre-PEA)
timeFrame: 90 days
Secondary outcomes:
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR) to 6 Months Post Pulmonary Endarterectomy (PEA)
timeFrame: 270 days
measure: 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)
timeFrame: 270 days
measure: Intraoperative Circulatory Arrest Time
timeFrame: intraoperative
measure: Number of Patients With Intraoperative Surgery-related Complications (Composite Endpoint)
timeFrame: intraoperative
measure: Surgical Evaluation of Specimen: Stratification of Patients According to Ease of Dissection Plane
timeFrame: intraoperative
measure: Surgical Evaluation of Specimen: Stratification of Patients According to Completeness of Disease Clearance
timeFrame: intraoperative
measure: Surgical Evaluation of Specimen: Stratification of Patients According to Appearance of Clot and Vessel Wall
timeFrame: intraoperative
measure: Number of Patients Who Died During the Course of the Study
timeFrame: 270 days
measure: Patients Who Withdraw During the Randomized Treatment Phase
timeFrame: 90 days
Other outcomes:
measure: Change in NT-proBNP From Baseline Until the End of Medical Treatment
timeFrame: 90 days
measure: Change in NT-proBNP From Baseline Until 6 Months Post-surgery
timeFrame: 270 days
measure: Change in Cardiac Index From Baseline Until the End of Medical Treatment
timeFrame: 90 days
measure: Change in Cardiac Index From Baseline Until 6 Months Post-surgery
timeFrame: 270 days
measure: Change in Mean Right Atrial Pressure From Baseline Until the End of Medical Treatment
timeFrame: 90 days
measure: Change in Mean Right Atrial Pressure From Baseline Until 6 Months Post-surgery
timeFrame: 270 days
measure: Change in Mean Pulmonary Atrial Pressure From Baseline Until the End of Medical Treatment
timeFrame: 90 days
measure: Change in Mean Pulmonary Atrial Pressure From Baseline Until 6 Months Post-surgery
timeFrame: 270 days
measure: Change in Pulmonary Artery Wedge Pressure From Baseline Until the End of Medical Treatment
timeFrame: 90 days
measure: Change in Pulmonary Artery Wedge Pressure From Baseline Until 6 Months Post-surgery
timeFrame: 270 days
measure: Length of Hospital Stay for Pulmonary Endarterectomy
timeFrame: intraoperative
measure: Length of Intensive Care Unit Stay for Pulmonary Endarterectomy
timeFrame: intraoperative
measure: WHO Functional Class at the End of Medical Treatment
timeFrame: 90 days
measure: WHO Functional Class 6 Months Post Pulmonary Endarterectomy
timeFrame: 270 days
measure: Need for PAH-targeted Therapy 6 Months Post-surgery
timeFrame: 270 days
Locations:
city: La Jolla
country: United States
facility: UC San Diego
state: California
city: Paris
country: France
facility: Hopital de Bicêtre
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik GmbH
city: Cambridge
country: United Kingdom
facility: Papworth Hospital
Study officials:
affiliation: Papworth Hospital NHS Foundation Trust, Cambridge, UK
name: David Jenkins, MD
role: PRINCIPAL_INVESTIGATOR
References: