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    Summary
    EudraCT Number:2015-000640-42
    Sponsor's Protocol Code Number:1199.222
    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:2015-08-18
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-000640-42
    A.3Full title of the trial
    A twelve week, open-label, randomised, parallel-group study evaluating safety, tolerability and pharmacokinetics (PK) of oral nintedanib in combination with oral pirfenidone, compared to treatment with nintedanib alone, in patients with idiopathic pulmonary fibrosis (IPF)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety, tolerability and PK of nintedanib in combination with pirfenidone in IPF
    A.3.2Name or abbreviated title of the trial where available
    Safety, tolerability and PK of nintedanib iin combination with pirfenidone in IPF
    A.4.1Sponsor's protocol code number1199.222
    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 SponsorBoehringer Ingelheim bv
    B.1.3.4CountryNetherlands
    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 supportBoehringer Ingelheim bv
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim
    B.5.2Functional name of contact pointQRPE PSC CT Information Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressBinger Strasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55216
    B.5.3.4CountryGermany
    B.5.4Telephone number+18002430127
    B.5.5Fax number+18008217119
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.com
    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 Ofev
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1123
    D.3 Description of the IMP
    D.3.1Product nameOfev 100 mg capsule
    D.3.2Product code nintedanib
    D.3.4Pharmaceutical form Capsule, soft
    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 INNnintedanib
    D.3.9.1CAS number 656247-17-5
    D.3.9.3Other descriptive nameNINTEDANIB
    D.3.9.4EV Substance CodeSUB120728
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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.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 Ofev
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1123
    D.3 Description of the IMP
    D.3.1Product nameOfev 150 mg capsule
    D.3.2Product code nintedanib
    D.3.4Pharmaceutical form Capsule, soft
    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 INNnintedanib
    D.3.9.1CAS number 656247-17-5
    D.3.9.3Other descriptive nameNINTEDANIB
    D.3.9.4EV Substance CodeSUB120728
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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.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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Esbriet
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/04/241
    D.3 Description of the IMP
    D.3.1Product namepirfenidone
    D.3.2Product code pirfenidone
    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 codePIRFENIDONE
    D.3.9.3Other descriptive namePIRFENIDONE
    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.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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Idiopathic Pulmonary Fibrosis
    E.1.1.1Medical condition in easily understood language
    Idiopathic pulmonary fibrosis
    N/A
    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 18.1
    E.1.2Level PT
    E.1.2Classification code 10021240
    E.1.2Term Idiopathic pulmonary fibrosis
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of the trial will be to assess safety and tolerability of combined treatment with nintedanib and pirfenidone
    E.2.2Secondary objectives of the trial
    A secondary objective is to assess the exposure, based on pharmacokinetic trough concentration values, to nintedanib either given alone or in combination with pirfenidone and to assess the assess the exposure of pirfenidone when combined with nintedanib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Written informed consent consistent with ICH-GCP and local laws, signed prior to any study procedures being performed (including any required washout)
    -Male or female patients aged greater than or equal to 40 years at visit 1
    -Idiopathic Pulmonary Fibrosis (IPF) diagnosis, based upon the ATS/ERS/JRS/ALAT 2011 guideline and confirmed by the investigator based on chest high resolution computed tomography (HRCT) scan performed within 12 months of visit 1
    -FVC greater than or equal to 50% of predicted normal at visit 1
    E.4Principal exclusion criteria
    -ALT, AST > 1.5 fold upper limit of normal (ULN) at visit 1
    -Total bilirubin > 1.5 fold ULN at visit 1
    -Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC <0.7) at visit 1
    -History of myocardial infarction within 6 months of visit 1 or unstable angina within 1 month of visit 1
    -Bleeding Risk: Known genetic predisposition to bleeding, Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, dabigatran, heparin, hirudin etc) or high dose antiplatelet therapy, History of haemorrhagic central nervous system event within 12 months prior to visit 1, History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to visit 1, International normalised ratio (INR) > 2 at visit 1, Prothrombin time and partial thromboplastin time (PTT) > 150% of
    institutional ULN at visit 1
    -Planned major surgery during the trial participation, including lung transplantation,major abdominal or major intestinal surgery.
    -History of thrombotic event (including stroke and transient ischemic attack) within 12
    months of visit 1
    -Severe renal impairment (Creatinine clearance <30 mL/min calculated
    by Cockcroft–Gault formula6 at visit 1) or end-stage renal disease
    requiring dialysis.
    -Treatment with NAC, prednisone >15 mg daily or >30 mg every 2 days OR equivalent
    dose of other oral corticosteroids and/or fluvoxamine within 2 weeks of visit 2
    -Treatment with azathioprine, cyclophosphamide, cyclosporine as well as any other
    investigational drug within 8 weeks of visit 2
    -Previous treatment with pirfenidone
    -Permanent discontinuation of nintedanib in the past due to AEs considered drug-related
    -Known hypersensitivity to nintedanib, pirfenidone, peanut or soya or to any of the
    excipients
    -A disease or condition which in the opinion of the investigator may interfere with testing procedures or put the patient at risk when participating in this trial
    -Alcohol or drug abuse which in the opinion of the treating physician would interfere with treatment
    -Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
    -Women of childbearing potential not willing or able to use highly effective methods of
    birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year
    when used consistently and correctly5 for 28 days prior to and 3 months after nintedanib administration
    -Patients not able to understand and follow study procedures including completion of selfadministered questionnaires without help
    -Patients who require dose reduction and/or temporary interruption during the run-in
    period with nintedanib 150 mg bid
    -Patients with underlying chronic liver disease (Child Pugh A, B or C
    hepatic impairment)
    E.5 End points
    E.5.1Primary end point(s)
    1: The primary endpoint is the percentage of patients with on-treatment gastrointestinal (GI) AEs (SOC GI disorders) from baseline to week 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    1: 12 weeks
    E.5.2Secondary end point(s)
    1: Pre-dose plasma concentrations at steady state (Cpre,ss) of nintedanib at baseline, weeks
    2 and 4

    2: Pre-dose plasma concentrations at steady state (Cpre,ss) of pirfenidone at weeks 2 and 4.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1: baseline, week 2 and week 4

    2: week 2 and week 4
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    France
    Germany
    Italy
    Netherlands
    United States
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    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 months2
    E.8.9.1In the Member State concerned days21
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days21
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 95
    F.4.2.2In the whole clinical trial 135
    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)
    Patients will be treated according to clinical practice
    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 Decision2015-08-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-13
    P. End of Trial
    P.End of Trial StatusCompleted
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