Effects of bosentan on morbidity and mortality in patients with Idiopathic Pulmonary Fibrosis - a multicenter, double-blind, randomized, placebo-controlled, parallel group, event-driven, group sequential, phase III study - BUILD-3

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-001183-24-BE
• Date of registration: 14/11/2006
• Prospective Registration: Yes
• Primary sponsor: ACTELION PHARMACEUTICALS LTD
• Public title: Effects of bosentan on morbidity and mortality in patients with Idiopathic Pulmonary Fibrosis - a multicenter, double-blind, randomized, placebo-controlled, parallel group, event-driven, group sequential, phase III study - BUILD-3
• Scientific title: Effects of bosentan on morbidity and mortality in patients with Idiopathic Pulmonary Fibrosis - a multicenter, double-blind, randomized, placebo-controlled, parallel group, event-driven, group sequential, phase III study - BUILD-3
• Date of first enrolment: 12/12/2006
• Target sample size: 460
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-001183-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Event-driven and group-sequential If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
*Signed informed consent.

*Male or female patients aged 18 years or older (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception).

*Proven diagnosis of IPF according to ATS/ERS statement, of < 3 years, with surgical lung biopsy (SLB).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
*Interstitial lung disease due to conditions other than IPF.
*Presence of extensive honeycomb (HC) on Baseline high-resolution computed tomography (HRCT) scan. The patient is not allowed in BUILD 3 if HC involves more than 5 % of the parenchyma in 3 or more of the 6 zones (i.e., right and left lung, viewed at the levels of tracheal carina, inferior pulmonary veins, and 1 cm above the dome of the diaphragm), whether the involvement is unilateral or bilateral.
*Severe concomitant illness limiting life expectancy (< 1 year).
*Severe restrictive lung disease: forced vital capacity (FVC) < 50% predicted, or FVC < 1.2 liter.
*Diffusing capacity of the lung for carbon monoxide (DLCO) < 30% predicted.
*Residual volume = 120% predicted.
*Obstructive lung disease: forced expiratory volume in 1 second (FEV1)/FVC < 0.65.
*Documented sustained improvement of patient's IPF condition up to 12 months prior to randomization with or without IPF-specific therapy.
*Recent pulmonary or upper respiratory tract infection (up to 4 weeks prior to randomization).
*Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests).
*Chronic heart failure with NYHA class III/IV or known left ventricular ejection fraction < 25%.
*ALT/SGPT and/or AST/SGOT > 1.5 times the upper limit of the normal ranges (ULN).
*Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
*Serum creatinine = 2.5 mg/dl (221 mmol/l) or chronic dialysis.
*Hemoglobin concentration < 75% the lower limit of the normal ranges.
*Systolic blood pressure < 85 mmHg.
*Pregnancy or breast-feeding.
*Current drug or alcohol dependence.
*Chronic treatment with the following drugs prescribed for IPF (within 4 weeks of randomization):
-Oral corticosteroids (> 20 mg/day of prednisone or equivalent),
-Immunosuppressive or cytotoxic drugs,
-Antifibrotic drugs including pirfenidone, D-penicillamine, colchicine, TNFa blocker, imatinib, interferon g, cyclophosphamide, azathioprine,
-Chronic use of N-acetylcysteine (prescribed for IPF).
*Oral anticoagulants other than those indicated for a venous or arterial thrombotic disease.
*Treatment with glibenclamide (glyburide) and calcineurin inhibitors (cyclosporine A, tacrolimus) up to 1 week prior to randomization.
*Treatment with an endothelin receptor antagonist up to 3 months prior to randomization.
*Participation in the BUILD 1 trial.
*Treatment with another investigational drug up to 3 months prior to randomization or planned treatment.
*Known hypersensitivity to bosentan or any of the excipients.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Idiopathic Pulmonary Fibrosis (IPF)
MedDRA version: 8.1 Level: LLT Classification code 10021240 Term: Idiopathic pulmonary fibrosis

Intervention(s)

Trade Name: Tracleer
Product Name: Bosentan
Product Code: Ro 47-0203
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BOSENTAN
CAS Number: 147536978
Current Sponsor code: Ro 47-0203
Other descriptive name: Tracleer
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 62.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Tracleer
Product Name: Bosentan
Product Code: Ro 47-0203
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BOSENTAN
CAS Number: 147536978
Current Sponsor code: Ro 47-0203
Other descriptive name: Tracleer
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 125-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: - To demonstrate that bosentan delays disease worsening or death in patients with idiopathic pulmonary fibrosis (IPF).

Secondary Objective: - To assess the effects of bosentan on quality of life, dyspnea, and pulmonary function tests (PFTs) in this patient population.

-To assess the safety and tolerability of bosentan in this patient population.

Primary end point(s): *Time to occurrence of disease worsening or death up to EOS.
-Disease worsening is defined as worsening of PFTs or acute exacerbation of IPF.

1) Worsening of PFTs (confirmed by two tests at least 4 weeks apart) is defined as the occurrence of both:
-Decrease from baseline = 10% in FVC (absolute values, i.e., liters) and
-Decrease from baseline =15% in DLco (absolute values, i.e., ml×mmHg 1×min-1)

A patient unable to perform PFTs at a planned visit due to worsening of IPF will be considered as having a worsening of PFTs if the latter are not invalidated by a test at a follow-up visit.

2) Acute exacerbation of IPF is defined as:An unexplained rapid deterioration of patient’s condition within 4 weeks with an increasing shortness of breath requiring hospitalization and oxygen supplementation = 5 liters/min to maintain a resting SaO2=90% or PaO2 = 55 mmHg (sea level) or 50 mmHg (high altitude).

A documented acute exacerbation of IPF will be considered to be an event, irrespective of the results of any follow-up PFTs or fatal outcome.

Patients who are transplanted (without a prior documented disease worsening), or who withdraw their consent, or those lost to follow-up before the EOS will be censored at the patient’s EOS visit date.

Patients starting forbidden IPF medications (without prior documented disease worsening as defined above) will not be considered as having reached an event.

The risk of an event in one group relative to the other is not expected to change with time. The risk of an event in the placebo group is expected to be 25% / year. The treatment effect to be detected is a 40 % relative risk reduction in event rate and corresponds to a Hazard Ratio for bosentan/placebo of 0.565, i.e., the risk is expected to be 15% / year in the bosentan group.

Secondary ID(s)

2006-001183-24-NL

AC-052-321