Clinical trial NCT00071461: Efficacy and Safety of Oral Bosentan in Patients With Idiopathic Pulmonary Fibrosis
Official title: A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Bosentan in Patients With Idiopathic Pulmonary Fibrosis, Open Label Extension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Idiopathic pulmonary fibrosis
Interstitial lung disease
Bosentan
BUILD
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2003-10-24
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Endothelin-1 (ET-1) is expressed in a variety of pulmonary pathological conditions including pulmonary vascular disease and pulmonary fibrosis.

Bosentan (an oral dual ET-1 receptor antagonist) could delay the progression of idiopathic pulmonary fibrosis (IPF), a condition for which no established treatment is available.

The present trial investigates a possible use of bosentan, which is currently approved for the treatment of symptoms of pulmonary arterial hypertension (PAH) WHO class III and IV, to a new category of patients suffering from IPF.

It was decided to offer Open Label treatment (bosentan) for patients willing to continue in the BUILD 1 study.


Eligibility criteria: Inclusion Criteria:

1. Male or female patients over 18 years of age.

   * Women must be either postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile.
   * Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination.
2. IPF proven diagnosis \< 3 years documented according to ATS/ERS international multidisciplinary consensus, with or without surgical (thoracoscopic or open) chest lung biopsy
3. Duration of illness ≥ 3 months.
4. Six-minute walk test distance (limited by dyspnea) ≥ 150 meters and \< 500 meters
5. Patients who have signed the informed consent form prior to initiation of any study procedure.

Exclusion Criteria:

1. Interstitial lung disease due to conditions other than IPF, including but not limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans with organizing pneumonia, and cancer.
2. History of clinically significant environmental exposure known to cause pulmonary fibrosis (drugs, asbestos, beryllium, radiation, domestic birds, etc.).
3. Severe concomitant illness limiting life expectancy (\< 1 year).
4. FVC ≥ 90% predicted.
5. Severe restrictive lung disease: FVC \< 50% predicted or FVC \< 1.2 l, or DLco \< 30% predicted or residual volume ≥ 120% predicted.
6. Severe obstructive lung disease: FEV1/FVC\< 0.65.
7. Documented improvement of patient's condition within 12 months prior to randomization with or without IPF-specific therapy (e.g., corticosteroids, immunosuppressive, cytotoxic or antifibrotic drugs, TNFa blocker, interferon g).
8. Recent pulmonary or upper respiratory track infection (within 4 weeks of randomization).
9. PaO2 \< 55 mm Hg (sea level) or 50 mm Hg (altitude) at rest on room air.
10. Echocardiographic evidence of severe pulmonary hypertension (PH): systolic pulmonary pressure ≥ 50 mm Hg or tricuspid regurgitation velocity ≥ 3.2 m/sec (unless severe PH is invalidated by a right heart catheterization). If the pulmonary pressure is not quantifiable, presence of significant right ventricular enlargement or hypertrophy or right ventricular dysfunction.
11. Severe chronic heart failure, e.g., NYHA class III or IV and/or left ventricular ejection fraction \< 25%.
12. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements, e.g., the 6MWT or the PFTs.

    (e.g., angina pectoris, intermittent claudicating, chronic arthritis).
13. Baseline values of liver transaminases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) \> 3 times the upper limit of normal ranges.
14. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
15. Serum creatinine ≥ 2.5 mg/dl (221 mmol/l) or dialysis.
16. Hemoglobin concentration \< 75% the lower limit of normal ranges.
17. Systolic blood pressure \< 85 mm Hg.
18. Pregnancy or breast-feeding.
19. Current drug or alcohol dependence.
20. Smoker (≥ 5 cigarettes per day) or former smoker (≥ 5 cigarettes per day) having stopped less than 6 months prior to randomization.
21. Recently started (\< 8 weeks from Screening visit) or planned cardio-pulmonary rehabilitation program based on exercise.
22. Treatment with oral corticosteroids (\> 15 mg/day prednisone or equivalent), immunosuppressive, cytotoxic or antifibrotic drugs such as TNF alpha blocker, or interferon gamma within 4 weeks of randomization.within 4 weeks of randomization.
23. Treatment with glibenclamide (glyburide), cyclosporine A or tacrolimus within 1 weeks of randomization.
24. Treatment with an endothelin receptor antagonist within 3 months of randomization.
25. Treatment within 3 months of randomization or planned treatment with another investigational drug.
26. Known hypersensitivity to bosentan or any of the excipients.

Primary outcomes:
measure: Change in 6-minute walk distance
timeFrame: Baseline to End-of-Period 1
Secondary outcomes:
measure: Death or treatment failure
timeFrame: Up to End-of-Period 1
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham - Pulmonary Division
state: Alabama
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA - Division of Pulmonary and Critical Care Medicine
state: California
city: San Diego
country: United States
facility: UCSD Medical Center
state: California
city: San Francisco
country: United States
facility: University of California - Ambulatory Care Center
state: California
city: Denver
country: United States
facility: National Jewish Medical and Research Center
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Miami
country: United States
facility: Jackson Memorial Hospital
state: Florida
city: Iowa city
country: United States
facility: University of Iowa Hospitals & Clinics - Department of Internal Medicine
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan Health System - Division of Pulmonary & Critical Care Medicine
state: Michigan
city: Rochester
country: United States
facility: Mayo Medical School - Mayo Clinic
state: Minnesota
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: University of Washington - Division of Pulmonary & Critical Care Medicine
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospitals & Clinics - Section of Pulmonary and Critical Care Medicine
state: Wisconsin
city: Vancouver
country: Canada
facility: University of British Columbia - St. Paul's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Rosedale Medical Center
state: Ontario
city: Montreal
country: Canada
facility: Notre-Dame Hospital - Clinique du Thorax
state: Quebec
city: Bobigny
country: France
facility: Hôpital Avicenne - Université de Paris
city: Grenoble
country: France
facility: Médecine Spécialisée Aigüe - CHU Grenoble
city: Lyon
country: France
facility: Hôpital Louis Pradel
city: Freiburg
country: Germany
facility: Abt. Pneumologie Medizinische Klinik Universitätsklinikum Freiburg
city: Loewenstein
country: Germany
facility: Klinik Löwenstein gGmbH
city: Munchen
country: Germany
facility: Medizinische Klinik und Poliklinik I Klinikum der Universität München
city: Tel-Hashomer
country: Israel
facility: Sheba Medical Center
city: Siena
country: Italy
facility: Section of Respiratory Diseases - Policlinico Le Scotte - Siena University
city: Bern
country: Switzerland
facility: Inselspital
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
References:
citation: Raghu G, King TE Jr, Behr J, Brown KK, du Bois RM, Leconte I, Roux S, Swigris J. Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1). Eur Respir J. 2010 Jan;35(1):118-23. doi: 10.1183/09031936.00188108. Epub 2009 Aug 13.
citation: King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, Stahler G, Leconte I, Roux S, Raghu G. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008 Jan 1;177(1):75-81. doi: 10.1164/rccm.200705-732OC. Epub 2007 Sep 27.