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

Idiopathic Pulmonary Fibrosis Clinical Trial

— BUILD 1  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00071461
• Other study ID #: AC-052-320
• Secondary ID: BUILD 1
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: October 23, 2003
• Last updated: February 22, 2012
• Start date: August 2003
• Est. completion date: May 2010

Study information

• Verified date: February 2012
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 158
• Est. completion date: May 2010
• Est. primary completion date: September 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Interstitial Pneumonias
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
Canada	Notre-Dame Hospital - Clinique du Thorax	Montreal	Quebec
Canada	Rosedale Medical Center	Toronto	Ontario
Canada	University of British Columbia - St. Paul's Hospital	Vancouver	British Columbia
France	Hôpital Avicenne - Université de Paris	Bobigny
France	Médecine Spécialisée Aigüe - CHU Grenoble	Grenoble
France	Hôpital Louis Pradel	Lyon
Germany	Abt. Pneumologie Medizinische Klinik Universitätsklinikum Freiburg	Freiburg
Germany	Klinik Löwenstein gGmbH	Loewenstein
Germany	Medizinische Klinik und Poliklinik I Klinikum der Universität München	Munchen
Israel	Sheba Medical Center	Tel-Hashomer
Italy	Section of Respiratory Diseases - Policlinico Le Scotte - Siena University	Siena
Switzerland	Inselspital	Bern
United Kingdom	Royal Brompton Hospital	London
United States	University of Michigan Health System - Division of Pulmonary & Critical Care Medicine	Ann Arbor	Michigan
United States	University of Alabama at Birmingham - Pulmonary Division	Birmingham	Alabama
United States	National Jewish Medical and Research Center	Denver	Colorado
United States	Baylor College of Medicine	Houston	Texas
United States	University of Iowa Hospitals & Clinics - Department of Internal Medicine	Iowa city	Iowa
United States	David Geffen School of Medicine at UCLA - Division of Pulmonary and Critical Care Medicine	Los Angeles	California
United States	University of Wisconsin Hospitals & Clinics - Section of Pulmonary and Critical Care Medicine	Madison	Wisconsin
United States	Jackson Memorial Hospital	Miami	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Mayo Medical School - Mayo Clinic	Rochester	Minnesota
United States	UCSD Medical Center	San Diego	California
United States	University of California - Ambulatory Care Center	San Francisco	California
United States	University of Washington - Division of Pulmonary & Critical Care Medicine	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in 6-minute walk distance		Baseline to End-of-Period 1	No
Secondary	Death or treatment failure		Up to End-of-Period 1	No