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    Summary
    EudraCT Number:2015-003360-37
    Sponsor's Protocol Code Number:1199.247
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-12-09
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-003360-37
    A.3Full title of the trial
    A double blind, randomized, placebo-controlled trial evaluating the efficacy and safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of nintedanib in patients with PF-ILD
    A.3.2Name or abbreviated title of the trial where available
    Nintedanib in PF-ILD
    A.4.1Sponsor's protocol code number1199.247
    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 SponsorSCS Boehringer Ingelheim Comm. V
    B.1.3.4CountryBelgium
    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 supportSCS Boehringer Ingelheim Comm. V
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    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 Internactional 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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNintedanib 100 mg capsules
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNintedanib 150 mg capsules
    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.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, soft
    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 placeboCapsule, soft
    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
    The aim of the current study is to investigate the efficacy and safety of 150 mg bid nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) defined as patients who present with features of diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography (HRCT) and whose lung function and respiratory symptoms or chest imaging have worsened despite treatment with unapproved medications used in clinical practice to treat ILD.
    E.1.1.1Medical condition in easily understood language
    Patients having progressive fibrosing interstitial lung disease
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    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 a reduction of lung function decline, as measured by the annual rate of decline in FVC for nintedanib compared to placebo.
    E.2.2Secondary objectives of the trial
    The main secondary objectives of the trial are to investigate the effect of treatment on quality of life using the King's Brief Interstitial Lung Disease Questionnaire (K-BILD), and to assess the effect of nintedanib on time to first acute ILD exacerbation and overall survival over 52 weeks.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written Informed Consent consistent with ICH-GCP and local laws signed prior to entry into the study (and prior to any study procedure including shipment of HRCT to reviewer).
    2. Male or female patients aged = 18 years at Visit 1.
    3. Patients with physician diagnosed ILD who fulfil at least one of the following criteria for PF-ILD within 24 months of screening visit (Visit 1) despite treatment with unapproved medications used in clinical practice to treat ILD, as assessed by the investigator (refer to Exclusion Criteria):
    a. Clinically significant decline in FVC % pred based on a relative decline of =10%
    b. Marginal decline in FVC % pred based on a relative decline of =5-<10% combined with worsening of respiratory symptoms
    c. Marginal decline in FVC % pred based on a relative decline of =5-<10% combined with increasing extent of fibrotic changes on chest imaging
    d. Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging
    [Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus].
    4. Fibrosing lung disease on HRCT, defined as reticular abnormality with traction bronchiectasis with or without honeycombing, with disease extent of >10%, performed within 12 months of Visit 1 as confirmed by central readers.
    5. For patients with underlying CTD: stable CTD as defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.
    6. DLCO corrected for Haemoglobin (Hb) [visit 1] = 30% and <80% predicted of normal at Visit 2.
    7. FVC = 45% predicted at Visit 2.
    E.4Principal exclusion criteria
    1. AST, ALT > 1.5 x ULN at Visit 1
    2. Bilirubin > 1.5 x ULN at Visit 1
    3. Creatinine clearance <30 mL/min calculated by Cockcroft¿Gault formula at Visit 1.
    4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
    5. Previous treatment with nintedanib or pirfenidone.
    6. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (Visit 1).
    7. Use of any of the following medications for the treatment of ILD: azathioprine (AZA), cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and the combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide within 8 weeks of Visit 2, rituximab within 6 months of Visit 2.
    8. Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 Guidelines.
    9. Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:
    a. Previous clinical or echocardiographic evidence of significant right heart failure
    b. History of right heart catheterization showing a cardiac index = 2 l/min/m²
    c. PAH requiring parenteral therapy with epoprostenol/treprostinil
    10. Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at Visit 1).
    11. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
    12. Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)
    13. Cardiovascular diseases, any of the following:
    a. Severe hypertension, uncontrolled under treatment (=160/100 mmHg), within 6 month of Visit 1
    b. Myocardial infarction within 6 months of Visit 1
    c. Unstable cardiac angina within 6 months of Visit 1
    14. Bleeding risk, any of the following:
    a. Known genetic predisposition to bleeding.
    b. Patients who require
    i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)
    ii. High dose antiplatelet therapy.
    c. History of haemorrhagic central nervous system (CNS) event within 12 months of Visit 1.
    d. Any of the following within 3 months of Visit 1:
    i. Haemoptysis or haematuria
    ii. Active gastro-intestinal (GI) bleeding or GI ¿ ulcers
    iii. Major injury or surgery (Investigators judgment).
    e. Coagulation parameters: International normalized ratio (INR) >2, prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x ULN at Visit 1.
    15. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1.
    16. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
    17. Patients with peanut allergy.
    18. Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
    19. Life expectancy for disease other than ILD < 2.5 years (Investigator assessment).
    20. Planned major surgical procedures.
    21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
    22. 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 correctly as well as one barrier method for 28 days prior to and 3 months after nintedanib administration. A list of contraception methods meeting these criteria is provided in the patient information.
    23. In the opinion of the Investigator, active alcohol or drug abuse.
    24. Patients not able to understand or follow trial procedures including completion of self-administered questionnaires without help.
    E.5 End points
    E.5.1Primary end point(s)
    1: Annual rate of decline in Forced Vital Capacity
    E.5.1.1Timepoint(s) of evaluation of this end point
    1: 52 weeks
    E.5.2Secondary end point(s)
    1: Absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score at week 52

    2: Time to first acute ILD exacerbation or death over 52 weeks

    3: Time to death over 52 weeks

    4: Time to death due to respiratory cause over 52 weeks

    5: Time to progression (defined as a equal or more than 10 percent absolute decline in FVC percent pred) or death over 52 weeks

    6: Proportion of patients with a relative decline from baseline in FVC percent pred of more than 10 percent at week 52

    7: Proportion of patients with a relative decline from baseline in FVC percent pred of more than 5 percent at week 52

    8: Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms dyspnea domain score at week 52

    9: Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms cough domain score at week 52
    E.5.2.1Timepoint(s) of evaluation of this end point
    1: 52 weeks

    2: 52 weeks

    3: 52 weeks

    4: 52 weeks

    5: 52 weeks

    6: 52 weeks

    7: 52 weeks

    8: 52 weeks

    9: 52 weeks
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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) 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 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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Argentina
    Belgium
    Canada
    Chile
    China
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Poland
    Russian Federation
    Spain
    United Kingdom
    United States
    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
    LVLS
    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 days2
    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 days2
    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: 450
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 223
    F.4.2.2In the whole clinical trial 600
    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)
    All patients who have regularly completed the trial will be offered open-label treatment with nintedanib in a separate study.
    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 Decision2017-01-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-12
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