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    Summary
    EudraCT Number:2014-004938-25
    Sponsor's Protocol Code Number:BAY86-5321/17613
    National Competent Authority:Slovakia - SIDC (Slovak)
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-03-02
    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 ConcernedSlovakia - SIDC (Slovak)
    A.2EudraCT number2014-004938-25
    A.3Full title of the trial
    An open-label, randomized, active-controlled, parallel-group, Phase-3b
    study of the efficacy, safety, and tolerability of three different treatment
    regimens of 2 mg aflibercept administered by intravitreal injections to
    subjects with diabetic macular edema (DME).
    Otvorená, randomizovaná štúdia fázy IIIb s aktívnou kontrolou a
    paralelnou skupinou, skúmajúca účinnosť, bezpečnosť a znášanlivosť troch
    rôznych liečebných režimov s 2 mg afliberceptu podávaného
    intravitreálnymi injekciami pacientom s diabetickým makulárnym edémom
    (DME)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of three different aflibercept regimens in subjects with DME.
    A.3.2Name or abbreviated title of the trial where available
    VIOLET
    A.4.1Sponsor's protocol code numberBAY86-5321/17613
    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 SponsorBayer AG
    B.1.3.4CountryGermany
    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 supportBayer AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer AG
    B.5.2Functional name of contact pointBayer Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street Address-
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number+4930300139003
    B.5.6E-mailclinical-trials-contact@bayer.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 Eylea 40mg/ml solution for injection in a vial
    D.2.1.1.2Name of the Marketing Authorisation holderBayer AG
    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 nameAflibercept
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravitreal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAflibercept
    D.3.9.1CAS number 862111-32-8
    D.3.9.2Current sponsor codeBAY86-5321
    D.3.9.3Other descriptive nameAFLIBERCEPT
    D.3.9.4EV Substance CodeSUB26987
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Diabetic macular edema (DME)
    E.1.1.1Medical condition in easily understood language
    Diabetic macular edema (DME) is a manifestation of Diabetic
    Retinopathy - damage to the blood vessels of the retina caused by
    complications of diabetes.
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10057934
    E.1.2Term Diabetic macular edema
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10015919
    E.1.2Term Eye disorders
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal (IVT) treatment regimens to subjects with DME pre-treated with 2 mg aflibercept every 8 weeks after 5 initial monthly injections for approximately 1 year or more (according to the EU label for the first year of treatment)
    E.2.2Secondary objectives of the trial
    The secondary objective is to assess the safety and tolerability of different treatment regimens of aflibercept in this population.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be met at screening and baseline for this study
    1. Adults of either sex, ≥ 18 years of age
    2. The subject’s history of aflibercept treatment meets all of the following:
    a. Treatment in the study eye was initiated with five monthly (-1 week / +2 weeks) doses of 2 mg aflibercept and improvements of visual and anatomic outcomes were observed and documented.
    b. Following the above initiation phase, the intervals between treatments were between 6 weeks and 12 weeks (one exception will be allowed).
    c. The interval between the last two pre-study injections was ≥ 8 weeks, and visual and anatomic outcomes have been stable over this interval.
    d. The subject received the last IVT injection of aflibercept in the study eye 8 weeks (±10 days) before the first planned treatment / randomization in this study.
    e. Total prior treatment duration with aflibercept (i.e. from first aflibercept treatment ever to enrollment into this study) was 1 year or longer.
    3. Willingness and ability to comply with clinic visits and study-related procedures
    4. Women and men of reproductive potential must agree to a method of highly effective contraception (as defined by the Clinical Trials Facilitation group [CTFG] from 15 SEP 2014)
    5. Negative pregnancy test (serum test at screening; urine dip stick test at baseline; women of childbearing potential only)
    6. Signed written informed consent

    To be met at initiation of pre-study aflibercept treatment:
    7. Type-1 or -2 diabetes mellitus
    8. Diagnosis of DME secondary to diabetes mellitus involving the center of the macula
    (defined as the area of the center subfield on OCT) in the study eye
    9. Decrease in vision determined to be primarily the result of DME in the study eye
    10. BCVA in the study eye of ETDRS letter score 73 to 24. This corresponds to a Snellen equivalent of approximately 20/40 to 20/320.
    E.4Principal exclusion criteria
    A subject must not meet any of the following exclusion criteria as applicable to be eligible for enrollment into this study.

    At initiation of pre-study aflibercept treatment
    1. Previous treatment with anti-angiogenic drugs in study eye (e.g. pegaptanib sodium, bevacizumab, ranibizumab or aflibercept) within the last 12 weeks before initiation of aflibercept pre-study treatment.

    At all of the following time points:
     Initiation of pre-study aflibercept treatment
     Screening for this study
     Baseline for this study

    2. History of vitreoretinal surgery and/or including scleral buckling in the study eye
    3. Prior treatment of the study eye with
     - Long acting steroids, either periocular or intraocular, in the preceding 120 days or
    - Iluvien® intravitreal implant at any time
    4. Active proliferative diabetic retinopathy (PDR), current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment in the study eye
    5. Aphakia in the study eye
    6. Cataract surgery within 90 days before aflibercept treatment in the study eye
    7. Yttrium-aluminum-garnet capsulotomy in the study eye within 30 days before aflibercept treatment
    8. Any other intraocular surgery within 90 days of aflibercept treatment in the study eye
    9. Ocular inflammation (including trace or above) or history of uveitis in the study eye
    10. Vitreomacular traction or epiretinal membrane in the study eye evident biomicroscopically or on OCT that was thought to affect central vision
    11. Pre-retinal fibrosis involving the macula of the study eye
    12. Structural damage to the center of the macula in the study eye that was likely to preclude improvement in BCVA following the resolution of macular edema including atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or organized hard exudates
    13. Concurrent disease in the study eye, other than DME, that could compromise VA, require medical or surgical intervention during the study period, or could confound interpretation of the results (including advanced glaucoma, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause)
    14. Myopia of a spherical equivalent prior to any possible refractive or cataract surgery of ≥ 8 diopters in the study eye
    15. Administration of systemic anti angiogenic agents within 180 days before aflibercept treatment
    16. Uncontrolled diabetes mellitus as defined by hemoglobin (Hb)A1c > 12.0%
    17. Uncontrolled blood pressure (defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 95 mmHg while subject is sitting confirmed in two separate measurements)
    18. Presence of any contraindications indicated in the EU commission/locally approved label for aflibercept

    At all of the following time points
     Screening for this study
     Baseline for this study.
    19. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye
    20. Any ocular or periocular infection in the preceding 4 weeks in either eye
    21. Filtration surgery for glaucoma in the past or likely to be needed in the future on the study eye
    22. Uncontrolled glaucoma (defined as intraocular pressure [IOP] > 25 mmHg despite treatment with antiglaucoma medication) in the study eye
    23. Allergy or hypersensitivity to fluorescein
    24. Current treatment for a serious systemic infection
    25. History of either cerebral vascular accident and/or myocardial infarction within 180 days before aflibercept treatment
    26. Renal failure requiring dialysis or renal transplant
    27. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, might affect interpretation of the results of the study, or renders the subject at high risk for treatment complications
    28. Significant media opacities, including cataract, in the study eye that interferes with visual acuity, fundus photography or OCT imaging.
    29. Breast-feeding women
    30. Previous receipt of at least 1 dose of study drug under this protocol
    31. Concomitant participation in another clinical study with investigational medicinal product(s). Exception: A temporal overlap with participation in Bayer study protocol 17850 is acceptable.
    32. Close affiliation with the investigational site; e.g. a close relative of the investigator,
    dependent person (e.g. employee or student of the investigational site).
    E.5 End points
    E.5.1Primary end point(s)
    The change in best corrected visual acuity (BCVA; as measured by the ETDRS letter score) from baseline (i.e. randomization) to Week 52
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 52 weeks of randomized treatment
    E.5.2Secondary end point(s)
    The secondary efficacy variables are
    - Change from baseline in ETDRS BCVA letter score for the study eye to Week 100
    - Change from baseline in CRT in the study eye to Week 52
    - Change from baseline in CRT in the study eye to Week 100
    - Proportion of subjects who gained ≥ 10, ≥ 15 letters
    - Proportion of subjects who lost ≥ 30 letters
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 52 and 100 weeks of randomized treatment
    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.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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Two alternative regimens of Afliberceptwill be compared to the reference arm.
    E.8.2.4Number of treatment arms in the trial3
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA86
    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
    Austria
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Italy
    Lithuania
    Poland
    Portugal
    Slovakia
    Spain
    Switzerland
    United Kingdom
    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
    The end of the study as a whole will be reached as soon as the last visit of the last subject has been reached in all centers in all participating countries (EU and non-EU).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days8
    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: 367
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 123
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 449
    F.4.2.2In the whole clinical trial 490
    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)
    After the final visit or after early termination, all subjects return to standard-of-care treatment outside of this 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 Decision2016-04-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-04-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-09-24
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