Idiopathic Pulmonary Fibrosis
Conditions
Keywords
BUILD 3, Idiopathic Pulmonary Fibrosis, Tracleer, Interstitial Lung Disease, bosentan, Actelion
Brief summary
BUILD 3 is a prospective, multicenter, randomized, double-blind, parallel group, placebo-controlled, event-driven, group sequential, phase III superiority study. The primary objective is to demonstrate that bosentan delays disease worsening or death in patients with Idiopathic Pulmonary Fibrosis.
Interventions
DRUGBosentan
Bosentan 62.5 mg tablets twice daily (b.i.d.) for 4 weeks followed by bosentan 125 mg tablets b.i.d (if body weight \> 40 kg) or bosentan 62.5 mg tablets b.i.d. (if body weight \< 40 kg)
DRUGPlacebo
Placebo matching bosentan 62.5 mg tablets and 125 mg tablets
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * Male or female 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 American Thoracic Society / European Respiratory Society (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 honeycombing (HC) on baseline high-resolution computed tomography (HRCT) scan. * Severe concomitant illness limiting life expectancy (\<1 year). * Severe restrictive lung disease. * Obstructive lung disease. * Diffusing capacity of the lung for carbon monoxide \<30% predicted. * Residual volume \> or = 120% predicted. * 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. * Chronic heart failure with New York Heart Association (NYHA) class III/IV or known left ventricular ejection fraction \<25%. * Alanine aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) \> 1.5 times the upper limit of the normal ranges. * Moderate to severe hepatic impairment. * Serum creatinine \> or = 2.5 mg/dl 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, 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 outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Occurrence of Disease Worsening or Death up to End of Study. | 36 months | Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Experienced Either Disease Worsening or Death at 1 Year. | 12 months | Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Initial dose: 62.5 mg twice daily (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. | 209 |
| Bosentan Initial dose: 62.5 mg twice daily (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. | 407 |
| Total | 616 |
Baseline characteristics
| Characteristic | Placebo | Bosentan | Total |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 9.1 | 63.8 years STANDARD_DEVIATION 8.4 | 63.6 years STANDARD_DEVIATION 8.6 |
| Age, Customized > 70 years | 44 participants | 88 participants | 132 participants |
| Age, Customized Between 18 and 40 years | 4 participants | 5 participants | 9 participants |
| Age, Customized Between 41 and 60 years | 74 participants | 119 participants | 193 participants |
| Age, Customized Between 61 and 70 years | 87 participants | 195 participants | 282 participants |
| Region of Enrollment Australia | 11 participants | 22 participants | 33 participants |
| Region of Enrollment Austria | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Belgium | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Canada | 14 participants | 30 participants | 44 participants |
| Region of Enrollment Croatia | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Czech Republic | 5 participants | 9 participants | 14 participants |
| Region of Enrollment France | 9 participants | 14 participants | 23 participants |
| Region of Enrollment Germany | 10 participants | 26 participants | 36 participants |
| Region of Enrollment Ireland | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Israel | 7 participants | 16 participants | 23 participants |
| Region of Enrollment Italy | 8 participants | 14 participants | 22 participants |
| Region of Enrollment Japan | 14 participants | 26 participants | 40 participants |
| Region of Enrollment Korea, Republic of | 9 participants | 23 participants | 32 participants |
| Region of Enrollment Netherlands | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Serbia | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Spain | 7 participants | 15 participants | 22 participants |
| Region of Enrollment Switzerland | 5 participants | 8 participants | 13 participants |
| Region of Enrollment United Kingdom | 3 participants | 7 participants | 10 participants |
| Region of Enrollment United States | 99 participants | 185 participants | 284 participants |
| Sex: Female, Male Female | 76 Participants | 111 Participants | 187 Participants |
| Sex: Female, Male Male | 133 Participants | 296 Participants | 429 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 200 / 209 | 386 / 406 |
| serious Total, serious adverse events | 74 / 209 | 129 / 406 |
Outcome results
Primary
Time to Occurrence of Disease Worsening or Death up to End of Study.
Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF).
Time frame: 36 months
Population: The primary analysis was performed on the Intent To Treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Time to Occurrence of Disease Worsening or Death up to End of Study. | month12 (366 days) | 43 participants with event |
| Placebo | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 24 (732 days) | 88 participants with event |
| Placebo | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 8 (244 days) | 22 participants with event |
| Placebo | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 30 (915 days) | 94 participants with event |
| Placebo | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 18 (549 days) | 74 participants with event |
| Placebo | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 36 (1098 days) | 94 participants with event |
| Placebo | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 4 (122 days) | 10 participants with event |
| Bosentan | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 36 (1098 days) | 158 participants with event |
| Bosentan | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 4 (122 days) | 18 participants with event |
| Bosentan | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 8 (244 days) | 40 participants with event |
| Bosentan | Time to Occurrence of Disease Worsening or Death up to End of Study. | month12 (366 days) | 74 participants with event |
| Bosentan | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 18 (549 days) | 117 participants with event |
| Bosentan | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 24 (732 days) | 145 participants with event |
| Bosentan | Time to Occurrence of Disease Worsening or Death up to End of Study. | month 30 (915 days) | 156 participants with event |
p-value: 0.21195% CI: [0.658, 1.097]Log Rank
Secondary
Percentage of Patients Who Experienced Either Disease Worsening or Death at 1 Year.
Disease worsening was defined as an event of worsening of pulmonary function tests (PFT) or acute exacerbation of idiopathic pulmonary fibrosis (IPF).
Time frame: 12 months
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients Who Experienced Either Disease Worsening or Death at 1 Year. | 23.9 percentage of participants with event |
| Bosentan | Percentage of Patients Who Experienced Either Disease Worsening or Death at 1 Year. | 19.9 percentage of participants with event |
p-value: 0.254295% CI: [-0.13, 0.39]Fisher Exact