E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic Pulmonary Fibrosis (IPF) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021240 |
E.1.2 | Term | Idiopathic pulmonary fibrosis |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To demonstrate that bosentan delays disease worsening or death in patients with idiopathic pulmonary fibrosis (IPF). |
|
E.2.2 | Secondary objectives of the trial |
- 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. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Fibrosis markers: Change from Baseline to Month 4 and EOT of plasma markers of fibrosis, e.g., KL 6, SP-A, SP-D, MCP-1. The decision to analyze the markers will be taken jointly with the steering committee based on the study results. This sub-study will be conducted in selected centers. The data will be reported in a study report separate from the clinical report. |
|
E.3 | Principal 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). |
|
E.4 | Principal 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. |
|
E.5 End points |
E.5.1 | 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. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Event-driven and group-sequential |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of Study (EOS) will occur for all patients when the target number of morbidity/mortality events has been reached. End of Treatment (EOT), at an individual patient’s level, coincides with EOS or occurs earlier in case of premature discontinuation of study drug. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |