The objective of this trial is to demonstrate that bosentan delays disease worsening or death in patients with IPF.
Source
Brief title
BUILD-3
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
Primary end-point: 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)
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).
Secondary outcome
• Proportion of patients who experienced either disease worsening or death at 1
year.
• Change from Baseline to 1 year in Quality of Life assessed by the SF-36
questionnaire (individual dimensions and overall score).
• Change from Baseline to 1 year in Quality of Life assessed by the EQ-5D
questionnaire.
• Transition dyspnea index (TDI) at 1 year.
• Time to occurrence of disease worsening up to EOS.
• Time to death up to EOS.
Exploratory Endpoints
• Change from Baseline to EOT and EOS in Quality of Life assessed by the SF 36
questionnaire (individual dimensions and overall score).
• Change from Baseline to EOT and EOS in Quality of Life assessed by the EQ 5D
questionnaire.
• Transition dyspnea index at EOT and EOS.
• Proportion of patients who improve in TDI with at least 1 unit at 1 year.
• Change from baseline to 1 year, EOT, and EOS in PFTs (FVC, DLCO).
• Time to occurrence of disease worsening or death up to EOS in the pooled
BUILD 1 (patients diagnosed with surgical lung biopsy) and BUILD 3 patient
population.
Background summary
Idiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing
alveolitis, is a distinct clinical disorder belonging to the spectrum of
interstitial lung diseases (ILD). IPF is a progressive disease characterized by
the presence of a histological pattern of usual interstitial pneumonia (UIP) on
surgical lung biopsy.
IPF was considered a chronic inflammatory disease resulting in parenchymal
fibrosis. However, recent evidence suggests a mechanism of abnormal wound
healing, with progressive extracellular matrix accumulation, decreased
fibroblast-myoblast cell death, continuous epithelial cell apoptosis and
abnormal re-epithelialization. Progressive fibrotic tissue deposition in the
interstitial areas of the lung leads to decreased lung compliance and reduced
gas exchanges.
The onset of symptoms is usually gradual and patients complain of
non-productive cough, shortness of breath occurring first on exercise and then
at rest. Cyanosis, cor pulmonale, and peripheral edema may be observed in the
late phase of the disease.
No therapies have been shown to improve the survival or quality of life for
patients with IPF and none is registered. Current treatment is still based on
the former assumption that IPF is an inflammatory process with concurrent
remodeling of the lung by fibrosis. Consequently, it involves anti-inflammatory
therapy, including corticosteroids (e.g., prednisone, prednisolone),
immunosuppressive/cytotoxic agents (e.g., azathioprine, cyclophosphamide) or a
combination of both. However, because of the marginal benefit and serious side
effects of the current therapies, along with newer insights into the
pathogenesis of IPF, there is an important need for novel therapeutic
approaches.
Study objective
The objective of this trial is to demonstrate that bosentan delays disease
worsening or death in patients with IPF.
Study design
This is a prospective, randomized, multicenter, double-blind, parallel group,
placebo-controlled, event-driven, group sequential, phase III superiority study.
The BUILD 3 study is designed to assess the efficacy and safety of bosentan 125
mg b.i.d. in patients with IPF. Eligible patients will be randomized to receive
bosentan or placebo (2 : 1, bosentan : placebo). No drug has been approved for
the treatment of IPF. At least 390 patients will be enrolled.
The double-blind treatment period is of variable duration. Patients will be
called for an End of Study visit when 131 events have been observed. Two
efficacy interim analyses are planned after the 50% and 75% of the planned
events have been observed. The study will be terminated for superiority of one
treatment or for futility (binding), i.e., if the appropriate nominal critical
boundaries are crossed.Patients will be followed-up until the BUILD 3 EOS visit
and for 28 days after study drug discontinuation. If the patient experiences a
documented disease worsening the investigator must permanently discontinue the
double-blind study drug.
Intervention
Bosentan 62.5 mg b.i.d. administered orally for 4 weeks, followed by the
maintenance dose of 125 mg b.i.d. (62.5 mg b.i.d. if body weight < 40 kg/90 lb).
Or
Placebo
At any time and for tolerability reasons, the double-blind study drug can be
down-titrated to 62.5 mg b.i.d.
Study burden and risks
At screening the following assessments will be done: a full medical
examination, pulmonary function tests, arterial blood gas and laboratory tests.
An electrocardiogram (ECG), and a HRCT scan will only be performed if not done
within the last three months prior to randomisation. A Pregnancy test for women
of childbearing capacity will be performed monthly and up to 3 months after End
Of Treatment.
The initial diagnosis (done by the pathologist) is to be documented by a
surgical biopsy < 3 years. No surgical biopsy should be taken for the sole sake
of BUILD-3 participation.
Risks associated with participation i.e. the use of bosentan are abnormal liver
function tests, and transient low hemoglobin levels. Therefore, all patients
will have monthly blood samples taken for LFT monitoring. Hemoglobin will be
monitored monthly up to Month 4, every 4 months thereafter up to End Of
Treatment. There is a risk of bruising or pain, at the site from where the
blood was drawn.
Every 4 months, patients will be seen at the outpatient*s department, for a
physical examination, pulmonary function test and to take some blood samples.
See also protocol page 22, Visit and Assessment Schedule.
There is no guarantee that patients will benefit directly from this research.
Information obtained during the course of this clinical research study may
contribute to a better understanding of the disease and may be useful in
selecting medicines for future treatment. Regardless of any individual benefit,
the knowledge gained from this study may contribute to information that would
allow the use of this drug or similar drugs in later treatment for patients
suffering from IPF.
Nederland
Nederland
Listed location countries
Age
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).
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 *mol/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,TNFalfa blocker, imatinib, interferon *, 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | 2006-001183-24-NL |
CCMO | NL14521.078.06 |