Efficacy and Safety of Oral Bosentan in Patients With Idiopathic Pulmonary Fibrosis

NCT ID: NCT00071461

Last Updated: 2012-02-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 158 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-08-31
• Study Completion Date: 2010-05-31

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.

Conditions

Idiopathic Pulmonary Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Initial dose: 62.5 mg b.i.d. for 4 weeks.

• Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).
• body weight < 40 kg (90 lb): 62.5 mg b.i.d.

Group Type: EXPERIMENTAL

bosentan

Intervention Type: DRUG

Initial dose: 62.5 mg b.i.d. for 4 weeks.

• Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).
• body weight < 40 kg (90 lb): 62.5 mg b.i.d.

2

Initial dose: 62.5 mg b.i.d. for 4 weeks.

• Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).
• body weight < 40 kg (90 lb): 62.5 mg b.i.d.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Initial dose: 62.5 mg b.i.d. for 4 weeks.

• Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).
• body weight < 40 kg (90 lb): 62.5 mg b.i.d.

Interventions

bosentan

Initial dose: 62.5 mg b.i.d. for 4 weeks.

• Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).
• body weight < 40 kg (90 lb): 62.5 mg b.i.d.

Intervention Type: DRUG

Placebo

Initial dose: 62.5 mg b.i.d. for 4 weeks.

• Target dose: - body weight > 40 kg (90 lb): 125 mg b.i.d., (if the initial dose is well tolerated).
• body weight < 40 kg (90 lb): 62.5 mg b.i.d.

Intervention Type: DRUG

Other Intervention Names

Tracleer

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Actelion

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Alabama at Birmingham - Pulmonary Division

Birmingham, Alabama, United States

David Geffen School of Medicine at UCLA - Division of Pulmonary and Critical Care Medicine

Los Angeles, California, United States

UCSD Medical Center

San Diego, California, United States

University of California - Ambulatory Care Center

San Francisco, California, United States

National Jewish Medical and Research Center

Denver, Colorado, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Jackson Memorial Hospital

Miami, Florida, United States

University of Iowa Hospitals & Clinics - Department of Internal Medicine

Iowa City, Iowa, United States

University of Michigan Health System - Division of Pulmonary & Critical Care Medicine

Ann Arbor, Michigan, United States

Mayo Medical School - Mayo Clinic

Rochester, Minnesota, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor College of Medicine

Houston, Texas, United States

University of Washington - Division of Pulmonary & Critical Care Medicine

Seattle, Washington, United States

University of Wisconsin Hospitals & Clinics - Section of Pulmonary and Critical Care Medicine

Madison, Wisconsin, United States

University of British Columbia - St. Paul's Hospital

Vancouver, British Columbia, Canada

Rosedale Medical Center

Toronto, Ontario, Canada

Notre-Dame Hospital - Clinique du Thorax

Montreal, Quebec, Canada

Hôpital Avicenne - Université de Paris

Bobigny, , France

Médecine Spécialisée Aigüe - CHU Grenoble

Grenoble, , France

Hôpital Louis Pradel

Lyon, , France

Abt. Pneumologie Medizinische Klinik Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Klinik Löwenstein gGmbH

Löwenstein, , Germany

Medizinische Klinik und Poliklinik I Klinikum der Universität München

München, , Germany

Sheba Medical Center

Tel Litwinsky, , Israel

Section of Respiratory Diseases - Policlinico Le Scotte - Siena University

Siena, , Italy

Inselspital

Bern, , Switzerland

Royal Brompton Hospital

London, , United Kingdom

Countries

United States; Canada; France; Germany; Israel; Italy; Switzerland; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 19679600 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 17901413 (View on PubMed)

Other Identifiers

BUILD 1

Identifier Type: -

Identifier Source: secondary_id

AC-052-320

Identifier Type: -

Identifier Source: org_study_id