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    Summary
    EudraCT Number:2014-003132-39
    Sponsor's Protocol Code Number:BAY86-5321/17508
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-12-04
    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 ConcernedFrance - ANSM
    A.2EudraCT number2014-003132-39
    A.3Full title of the trial
    Managing neovascular age-related macular degeneration (nAMD) over 2 years with a Treat and Extend (T&E) regimen of 2 mg intravitreal (IVT) aflibercept - a randomized, open-label, active-controlled, parallel-group phase IV/IIIb study (ARIES)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Managing neovascular age-related macular degeneration over 2 years using of different schedules of 2 mg aflibercept injected in the eye (ARIES)
    A.3.2Name or abbreviated title of the trial where available
    Managing nAMD with a T&E IVT aflibercept regimen
    A.4.1Sponsor's protocol code numberBAY86-5321/17508
    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 HealthCare 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 HealthCare AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer healthcare AG
    B.5.2Functional name of contact pointClinical Trials Contact, CTP EU CTR
    B.5.3 Address:
    B.5.3.1Street AddressBayer Pharma AG
    B.5.3.2Town/ city Berlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.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 Pharma 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 codeBAY 86-5321
    D.3.9.3Other descriptive nameVEGF Trap-Eye / AFLIBERCEPT
    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
    Neovascular age-related macular degeneration (nAMD)
    E.1.1.1Medical condition in easily understood language
    Degeneration of the part of the retina responsible for the sharp, central vision caused by growth of new blood vessels and leakage in the area.
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess whether 2 mg IVT aflibercept administered in an early-start T&E regimen (initiated after the first 8-weekly treatment interval) is non-inferior to 2 mg IVT aflibercept administered in a late-start T&E regimen (initiated at the end of Year 1, per label) in subjects with nAMD
    E.2.2Secondary objectives of the trial
    To assess the percentage of subjects requiring retreatment with IVT aflibercept less frequently than every 8 weeks (2Q8)
    To assess the safety and tolerability of IVT aflibercept
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent.
    2. Men and women ≥ 50 years of age.
    3. Active primary subfoveal CNV lesions secondary to nAMD, including juxtafoveal lesions that affect the fovea as evidenced by FA in the study eye. Patients with polypoidal choroidal vasculopathy or retinal angiomatous proliferation are eligible to participate in the study, and their condition should be captured in the eCRF.
    4. ETDRS BCVA of 73 to 25 letters (20/40 to 20/320 Snellen equivalent) in the study eye.
    5. Willing, committed, and able to return for all clinic visits and complete all study-related procedures.
    6. Able to read, (or, if unable to read due to visual impairment, be read to verbatim by the person administering the informed consent or a family member) understand and willing to sign the ICF.
    7. The area of CNV must occupy at least 50% of the total lesion.
    8. Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period between signing of the ICF and 3 months after the last administration of study drug. The definition of adequate contraception will be based on the judgment of the investigator and on local requirements. Acceptable methods of contraception include, but are not limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii) diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv) hormone-based contraception. Subjects must agree to utilize two reliable and acceptable methods of contraception simultaneously.
    E.4Principal exclusion criteria
    1. Any prior ocular (in the study eye) or systemic treatment or surgery for nAMD, except dietary supplements or vitamins.
    2. Any prior or concomitant therapy with another investigational agent to treat nAMD in the study eye.
    3. Prior treatment with anti-VEGF agents as follows:
    • Prior treatment with anti-VEGF therapy in the study eye is not allowed
    • Prior treatment with anti-VEGF therapy in the fellow eye with an investigational agent (not approved, e.g. bevacizumab) within the last 3 months before the first dose in the study. Such treatment will also not be allowed during the study. Prior treatment with an approved anti-VEGF therapy in the fellow eye is allowed.
    • Prior systemic anti-VEGF therapy, investigational or approved, within the last 3 months before the first dose in the study, and such treatment will not be allowed during the study.
    4. Total lesion size >12 disc areas (30.5 mm2, including blood, scars and neovascularization) as assessed by FA in the study eye.
    5. Subretinal hemorrhages that are either 50% or more of the total lesion area, or if the blood is under the fovea and is 1 or more disc areas in size in the study eye. (If the blood is under the fovea, then the fovea must be surrounded by 270 degrees by visible CNV).
    6. Scar or fibrosis making up >50% of the total lesion in the study eye.
    7. Scar, fibrosis, or atrophy involving the center of the fovea in the study eye.
    8. Presence of retinal pigment epithelial tears or rips involving the macula in the study eye.
    9. History of any vitreous hemorrhage within 4 weeks before screening in the study eye.
    10. Presence of other causes of CNV in the study eye.
    11. Prior vitrectomy in the study eye.
    12. History of retinal detachment or treatment or surgery for retinal detachment in the study eye.
    13. Any history of macular hole of stage 2 and above in the study eye.
    14. Any intraocular surgery, periocular surgery, or cataract surgery within 90 days before Day 1 in the study eye, except lid surgery, which may not have taken place within 1 month of screening, as long as it is unlikely to interfere with the injection.
    15. Only 1 functional eye even if that eye is otherwise eligible for the study.
    16. Prior trabeculectomy or other filtration surgery in the study eye.
    17. Uncontrolled glaucoma (defined as IOP ≥25 mm Hg despite treatment with antiglaucoma medication) in the study eye.
    18. Aphakia or pseudophakia with absence of posterior capsule (unless it occurred as a result of a yttrium aluminum garnet posterior capsulotomy) in the study eye.
    19. Previous therapeutic radiation in the region of the study eye.
    20. History of corneal transplant or corneal dystrophy in the study eye.
    21. Significant media opacities, including cataract, in the study eye which might interfere with visual acuity, assessment of toxicity or FP.
    22. History or clinical evidence of diabetic retinopathy, diabetic macular edema or any retinal vascular disease other than AMD in either eye.
    23. Active intraocular, extraocular and periocular inflammation or infection in either eye.
    24. Any ocular or periocular infection within the last 2 weeks before screening in either eye.
    25. Any history of ocular or periocular Herpes simplex in either eye.
    26. Any history of uveitis in either eye.
    27. Presence of scleromalacia in either eye.
    28. Any concurrent intraocular condition in the study eye that could require either medical or surgical intervention during the 104-week study period.
    29. Any concurrent ocular condition in the study eye which, in the opinion of the investigator, could either increase the risk to the subject safety or which otherwise may interfere with evaluation of efficacy or safety.
    30. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug.
    31. Participation as a subject in any clinical study within 12 weeks before screening.
    32. Any systemic or ocular treatment with an investigational agent in the past 3 months before screening.
    33. The use of long-acting steroids, either systemically or intraocularly, in the past 6 months before screening.
    34. Any history of allergy to the antiseptic used during preparation of the eye for the IVT injection in the investigational site (e.g. povidone iodine or chlorhexidine).
    35. Known serious allergy to the fluorescein sodium for injection in angiography.
    36. Hypersensitivity to the active substance aflibercept or to any of the excipients.
    37. Pregnancy or breastfeeding.
    38. 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)
    39. Previous assignment to treatment during this study.
    E.5 End points
    E.5.1Primary end point(s)
    Change in BCVA as measured by the ETDRS letter score from Week 16 to Week 104
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change from Week 16 to Week 104
    E.5.2Secondary end point(s)
    Key-secondary efficacy variable:
    • Proportion of subjects maintaining vision (<3 lines loss) at Week 104 compared with baseline
    Secondary efficacy variables:
    • Change in BCVA as measured by the ETDRS letter score from baseline to Weeks 52 and 104 and from Week 16 to Week 52
    • Change in central retinal thickness (CRT) from baseline to Weeks 52 and 104 and from Week 16 to Weeks 52 and 104
    • Number of study drug injections from baseline to Weeks 52 and 104
    • Duration of last treatment interval
    • Proportion of subjects requiring retreatment at 8, 10, 12, 14, and 16 weeks as the last treatment interval
    • Proportion of 3-line gainers at Weeks 52 and 104 compared with baseline
    • Proportion of subjects maintaining vision (<3 lines loss) at Week 52 compared with baseline
    Exploratory efficacy variables:
    • Change in CNV size and total lesion size from baseline to Weeks 52 and 104
    • Proportion of subjects with non-deteriorating OCT morphology (as assessed by the central reading center) at Weeks 52 and 104 compared with baseline
    • Proportion of subjects showing no IRF and no SRF at Weeks 8, 16, 52 and 104
    • Proportion of subjects showing no IRF and no SRF exceeding 50 µm in thickness at Weeks 52 and 104
    • Percentage of subjects requiring retreatment with IVT aflibercept less frequently than every 8 weeks (2Q8)
    A complete list of variables to be analyzed for this study will be provided in the statistical analysis plan (SAP).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints of evaluation of secondary end point are given in section E5.2
    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) 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    aflibercept
    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 EEA28
    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
    Australia
    Canada
    France
    Germany
    Italy
    Netherlands
    Spain
    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
    LVLS
    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 months2
    E.8.9.1In the Member State concerned days4
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days4
    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: 41
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 227
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    In case of incapacitated adults the consent of the legally acceptable representative will be requested
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 208
    F.4.2.2In the whole clinical trial 268
    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 end of the study, subjects will be treated with either IVT aflibercept or other treatment according to their physician's decision and standard of care
    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 Decision2015-11-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-04-26
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