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    Summary
    EudraCT Number:2006-001183-24
    Sponsor's Protocol Code Number:AC-052-321
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-11-16
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2006-001183-24
    A.3Full title of the trial
    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
    A.3.2Name or abbreviated title of the trial where available
    BUILD-3
    A.4.1Sponsor's protocol code numberAC-052-321
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorACTELION PHARMACEUTICALS LTD
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tracleer
    D.2.1.1.2Name of the Marketing Authorisation holderActelion Registration Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBosentan
    D.3.2Product code Ro 47-0203
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBOSENTAN
    D.3.9.1CAS number 147536978
    D.3.9.2Current sponsor codeRo 47-0203
    D.3.9.3Other descriptive nameTracleer
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number62.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tracleer
    D.2.1.1.2Name of the Marketing Authorisation holderActelion Registration Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBosentan
    D.3.2Product code Ro 47-0203
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBOSENTAN
    D.3.9.1CAS number 147536978
    D.3.9.2Current sponsor codeRo 47-0203
    D.3.9.3Other descriptive nameTracleer
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Idiopathic Pulmonary Fibrosis (IPF)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level LLT
    E.1.2Classification code 10021240
    E.1.2Term Idiopathic pulmonary fibrosis
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To demonstrate that bosentan delays disease worsening or death in patients with idiopathic pulmonary fibrosis (IPF).
    E.2.2Secondary 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.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.3Principal 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.4Principal 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.5.1Primary 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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Event-driven and group-sequential
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA53
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-11-16. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 265
    F.4.2.2In the whole clinical trial 390
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    ·Double-blind study extension: (See protocol)

    ·Post-treatment follow-up:

    - Up to 28 days after EOT (Serious Adverse Event follow up).
    - Long-term survival up to 5 years after the last patient randomized (based on study results).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-01-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-04-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-04-29
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