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    EudraCT Number:2014-002022-12
    Sponsor's Protocol Code Number:EPOS-CT-001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-11-03
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2014-002022-12
    A.3Full title of the trial
    A European multi-centre, randomised, double-blind trial of pirfenidone in bronchiolitis-obliterans-syndrome grade 1-3 in lung transplant recipients.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    European Trial of Pirfenidone in BOS (EPOS).
    A.3.2Name or abbreviated title of the trial where available
    EPOS Trial
    A.4.1Sponsor's protocol code numberEPOS-CT-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorClinical Trials Unit, Rigshospitalet
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann La Roche Ltd
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRigshopitalet
    B.5.2Functional name of contact pointDr. Michael Perch
    B.5.3 Address:
    B.5.3.1Street AddressBlegdamsvej 9
    B.5.3.2Town/ cityCopenhagen
    B.5.3.3Post code2100
    B.5.4Telephone number004535459702
    B.5.5Fax number004535452931
    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. name Esbriet
    D. of the Marketing Authorisation holderF. Hoffmann La Roche Ltd
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namePirfenidone
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    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 INNPIRFENIDONE
    D.3.9.1CAS number 53179-13-8
    D.3.9.2Current sponsor codePIR
    D.3.9.3Other descriptive name5-Methyl-1-Phenyl-2-1-(H)-Pyridone
    D.3.9.4EV Substance CodeSUB09907MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number267
    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) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 placeboCapsule, hard
    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
    Bronchiolitis Obliterans Syndrome (BOS) in patients following lung transplantation. This syndrome occurs due to rejection of the transplanted organ (s).
    E.1.1.1Medical condition in easily understood language
    A lung disease in which the small airway branches (bronchioles) are compressed and narrowed by scar tissue (fibrosis) and/or inflammation. This leads to partial or complete blockage of the airways.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10049202
    E.1.2Term Bronchiolitis obliterans
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of Pirfenidone on the change in FEV1 over 6 months in lung transplant recipients with bronchiolitis obliterans syndrome, who are treated with Azithromycin.
    E.2.2Secondary objectives of the trial
    • Categorical percentage change in FEV1 [Categorical percentage change in FEV1 ≥ 10 % (increase or decrease) relative to FEV1 (ml) at baseline]
    • Change of FVC in liters
    • Change in TLC in liters
    • FEV1/FVC ratio change
    • Number of patients with treatment failure
    • Change in BOS grade
    • Change in percent predicted DLco.
    • Change in functional level as assessed by the 6MWT
    • Hospital admission for any reason
    • Death or re-transplantation rates
    • Change in EQ5D scale
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients >18 years of age
    2. Azithromycin therapy for at least 4 weeks prior to study start, with an Azithromycin dose of minimum 250mg /day at least 3 times per week
    3. Double lung transplantation is required;
    4. Patients must be at least 6 months after transplantation and must have documented post-transplant, base-line value of FEV1 (mean of the 2 highest values measured at least 3 weeks apart according to ISHLT criteria)
    5. Patients must have BOS grade 1 - 3.
    6. Patients must have documented progressive disease as demonstrated by:
    • At least 3 FEV1 measurements in the last 6 months each at least 3 weeks apart
    • a total decline of at least 200mL in FEV1 in the last six months
    • a mean decline of at least 50 mL in the last two measurements
    E.4Principal exclusion criteria
    1. Patients with redo lung transplantation or combined transplantation (including heart and lung transplantation) Or Single lung recipients
    2. Patients with any severe comorbidity complicating BOS which might determine the prognosis and functional level of the patient (e.g. invasive aspergillosis, active malignant disease within last 12 months (i.e. disease free since at least 12 months))
    3. FEV1 decline related to other non BOS causes (eg pneumothorax, bronchial stenosis, effusion, etc.)
    4. Screening ECG shows QTc > 500 ms
    5. Patients who on Thorax CT at entry demonstrate new significant findings which are not compatible with BOS like interstitial fibrosis, consolidation, appearances suggesting restrictive Allograft Syndrome (RAS) and acute pulmonary infection as cause of decline in lung function
    6. Documented acute perivascular rejection higher than grade A1 or findings compatible with antibody mediated rejection at the last trans-bronchial biopsy performed .
    7. Pregnancy or lactation.
    8. Renal insufficiency (Creatinine clearance <30 ml/min calculated by the CKD-Epi formula).
    9. Any of the following liver test criteria above the specified limit:
    • Total bilirubin above the upper limit of the normal range (ULN), except in patients with predominantly unconjugated hyperbilirubinemia (e.g., Gilbert’s syndrome)
    • Aspartate or alanine aminotransferase (AST or ALT) >3 × ULN
    • Subjects with severe liver impairment (Child Pugh C)
    10. Known allergy or hypersensitivity to Pirfenidone
    11. Ongoing use or expected use of any of the following therapies:
    • Strong inhibitors of CYP1A2 (fluvoxamine or enoxacin)
    • Moderate inhibitors of CYP1A2 (mexiletine, thiabendazole, oral contraceptives or phenylpropanolamine [Note: ciprofloxacin will be allowed only at doses ≤500 mg BID])
    • Moderate inducers (montelukast, phenytoin)
    • Cimetidine
    • Previous treatment with Pirfenidone after transplantation
    12. Patients who have resumed smoking after transplantation
    13. Initiation of a new bronchodilator therapy or treatment with Montelukast within 4 weeks prior to randomization
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the change in FEV1 (ml) from baseline to 6 months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This endpoint will be evaluated at the end of the study (the 6 month visit for each patient).
    E.5.2Secondary end point(s)
    • Categorical percentage change in FEV1 [Categorical percentage change in FEV1 ≥ 10 % (increase or decrease) relative to FEV1 (ml) at baseline]
    • Change of FVC in liters
    • Change in TLC in liters
    • FEV1/FVC ratio change
    • Number of patients with treatment failure
    • Change in BOS grade
    • Change in percent predicted DLco.
    • Change in functional level as assessed by the 6MWT
    • Hospital admission for any reason
    • Death or re-transplantation rates
    • Change in EQ5D scale
    E.5.2.1Timepoint(s) of evaluation of this end point
    All secondary endpoints will be evaluated at the end of the study (the 6 month visit for each patient).
    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 No
    E.6.13Others No
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    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.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 No
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 80
    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)
    Treatment will be given as per routine care. Subjects who have completed the EPOS trial will also be offered open label Pirfenidone for up to 1 year if they wish to receive this treatment.
    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 Decision2014-11-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-01-31
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