Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension

Prospective, Randomized, Placebo-controlled, Double-blind, Multicenter, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Bosentan in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

The present trial investigates a possible use of oral bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH), to patients suffering from inoperable chronic thromboembolic pulmonary hypertension (CTEPH) because of (i) peripheral localization of thrombotic material or (ii) persistent or recurrent pulmonary hypertension after pulmonary endarterectomy.

Study Overview

• Status: Completed
• Conditions: Chronic Thromboembolic Pulmonary Hypertension
• Intervention / Treatment: Drug: bosentan

• Study Type: Interventional
• Enrollment (Actual): 157
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia, 4032
    • The Prince Charles Hospital
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Austria
  • Vienna, Austria, 1180
    • General Hospital of Vienna
• Belgium
  • Brussels, Belgium, 1070
    • University Hospital Erasme
  • Leuven, Belgium, 3000
    • University Hospital Gathuisberg
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4W7
      • The Ottawa Hospital
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital Pulmonary & Critical Care Medicine
  • Quebec
    • Sainte-Foy, Quebec, Canada, G1V 4G5
      • Centre de Pneumonologie de L'Hospital Laval
    • Sainte-Foy, Quebec, Canada, G1V 4G5
      • University of Western Ontario
• Czech Republic
  • Praha 2, Czech Republic, 128 08
    • Charles University, Internal Medicine Department, (PAH unit)
• France
  • Bron Cedex, France, 69677
    • Hopital Cardiologique Louis-Pradel
  • Clamart, France, 92140
    • Hopital Antoinw Beclere
• Germany
  • Giessen, Germany, 35392
    • University Hospital Giessen
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Mainz, Germany, 55101
    • Johannes Gutenberg University Hospital
• Italy
  • Bologna, Italy, 40138
    • Policlinico S. Orsola-Malpighi
  • Orbassano, Italy, 10043
    • Azienda Ospedailera San Luigi
  • Pavia, Italy, 27100
    • San Matteo Hospital
  • Trieste, Italy, 34149
    • Ospedale di Cattinara
• Netherlands
  • Amsterdam, Netherlands, 1100 DE
    • Academic Medical Center
  • Nieuwegein, Netherlands, 3430 EM
    • St. Antonius Ziekennuis
• Poland
  • Warszawa, Poland, 01-138
    • Medical University of Warsaw
• Spain
  • Barcelona, Spain, 08035
    • Hospital Clinico i Provincial
• United Kingdom
  • Cambridge, United Kingdom, CB3 8RE
    • Papworth Hospital
  • Glasgow, United Kingdom, G11 5AA
    • Western Infirmary
• United States
  • California
    • LaJolla, California, United States, 92037-1300
      • University of California at San Diego
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic, Division of Cardiovascular Diseases and Internal Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27701
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Symptomatic pulmonary hypertension in modified NYHA functional class II to IV due to CTEPH as demonstrated by ventilation/perfusion lung scanning and pulmonary angiography.
• CTEPH judged inoperable because of peripheral localization of thrombotic material or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) with no evidence of recurrent thromboembolism and not amenable to repeated surgery.
• 6-minute walk test (6MWT) distance < 450 m.
• Hemodynamic evaluation showing: Mean pulmonary arterial pressure (mPAP) >= 25 mmHg; Pulmonary capillary wedge pressure (PCWP) < 15 mmHg; Pulmonary vascular resistance (PVR) at rest >= 300 dyn×sec/cm5
• For patients who underwent PEA, hemodynamic evaluation must have been performed more than 6 months after PEA.
• For all patients, hemodynamic evaluation must have been performed with the 3 months immediately preceding inclusion.
• Men or women >= 18 and =< 80 years of age (Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception).
• Anticoagulants at efficacious dose for at least 3 months prior to randomization.
• Signed informed consent prior to initiation of any study-mandated procedure.

Exclusion Criteria:

• Other forms of pulmonary hypertension including pulmonary hypertension related to sickle cell disease.
• Obstructive lung disease: FEV1/FVC < 0.5 after bronchodilator.
• Severe restrictive lung disease: Total Lung Capacity < 60% of predicted value.
• Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication.
• Symptomatic pulmonary embolism within 6 months prior to randomization.
• Pulmonary endarterectomy within 6 months prior to randomization.
• Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
• Illness with a life expectancy of less than 6 months.
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
• AST and/or ALT > 3 times the upper limit of normal ranges.· Hemoglobin concentration < 75% the lower limit of normal ranges.
• Pregnancy or breast-feeding.
• Systolic blood pressure (BP) < 85 mmHg.
• Treatment or planned treatment with another investigational drug and/or pulmonary angioplasty within 3 months prior to randomization.
• Treatment with an endothelin receptor antagonist, a phosphodiesterase inhibitor, L-arginine or with prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization.
• Treatment for pulmonary hypertension within 1 month prior to randomization, excluding calcium channel blockers if present for at least 1 month before randomization.
• Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, glibenclamide (glyburide) within 1 week prior to randomization.
• Known hypersensitivity to bosentan or any of the excipients.

Study Plan

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline to Week 16 in 6-Minute Walk Test distance	Week 16
Change from Baseline to Week 16 in Pulmonary Vascular Resistance at rest	Week 16

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline to Week 16 in modified NYHA functional class	Week 16
Time to clinical worsening	Time to clinical worsening

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• Jais X, D'Armini AM, Jansa P, Torbicki A, Delcroix M, Ghofrani HA, Hoeper MM, Lang IM, Mayer E, Pepke-Zaba J, Perchenet L, Morganti A, Simonneau G, Rubin LJ; Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension Study Group. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol. 2008 Dec 16;52(25):2127-34. doi: 10.1016/j.jacc.2008.08.059.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): February 1, 2007
• Study Completion (Actual): March 1, 2007

Study Registration Dates

• First Submitted: April 10, 2006
• First Submitted That Met QC Criteria: April 10, 2006
• First Posted (Estimated): April 12, 2006

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 31, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: bosentan; CTEPH
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: AC-052-366