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    Summary
    EudraCT Number:2018-002611-99
    Sponsor's Protocol Code Number:20090
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-04-28
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-002611-99
    A.3Full title of the trial
    Open-label, randomized, two–arm, controlled study to assess the efficacy, safety, and tolerability of intravitreal (IVT) aflibercept compared to laser photocoagulation in patients with retinopathy of prematurity (ROP)
    Studio controllato, randomizzato, in aperto, a due bracci volto alla valutazione dell'efficacia, della sicurezza e della tollerabilità di aflibercept intravitreale (IVT) rispetto alla fotocoagulazione laser in pazienti affetti da retinopatia del prematuro (ROP)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Aflibercept for retinopathy of prematurity – intravitreal injection versus laser therapy
    Aflibercept per la ROP – iniezione IVT verso terapia laser
    A.3.2Name or abbreviated title of the trial where available
    FIREFLeYe
    FIREFLeYe
    A.4.1Sponsor's protocol code number20090
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/115/2019
    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 AddressCTP Team/Ref: 'EU CTR' /Bayer AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.3.4CountryGermany
    B.5.4Telephone number4930300139003
    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 codeBAY 86-5321
    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 Yes
    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
    Retinopathy of prematurity
    retinopatia del prematuro (ROP)
    E.1.1.1Medical condition in easily understood language
    Retinopathy of prematurity
    retinopatia del prematuro (ROP)
    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 PT
    E.1.2Classification code 10038933
    E.1.2Term Retinopathy of prematurity
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of aflibercept in subjects diagnosed with retinopathy of prematurity (ROP) in comparison to laser
    Valutare l'efficacia di aflibercept in soggetti con diagnosi di retinopatia del prematuro (ROP) rispetto al laser
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of aflibercept
    To assess the treatment burden of aflibercept and laser
    To describe the systemic exposure to aflibercept
    Valutare la sicurezza e la tollerabilità di aflibercept
    Valutare l'onere associato al trattamento con aflibercept e con il laser
    Descrivere l'esposizione sistemica ad aflibercept
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Gestational age at birth ≤ 32 weeks or birth weight ≤ 1500 g
    Type of Participant and Disease Characteristics
    2.Subjects with treatment-naïve ROP classified according to the International Classification for ROP in at least one eye as:
    - Zone I Stage 1 plus, or 2 plus, or 3 non-plus or 3 plus, or Zone II Stage 2 plus or 3 plus, or AP-ROP
    3.Weight at baseline (day of treatment) ≥ 800 g
    4.Male or female
    5.Signed informed consent from parent(s)/legally authorized representative(s) as described in Section 10.1.3 of the clinical trial protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical trial protocol
    1.Gestational age at birth ≤ 32 weeks or birth weight ≤ 1500 g
    Type of Participant and Disease Characteristics
    2.Subjects with treatment-naïve ROP classified according to the International Classification for ROP in at least one eye as:
    - Zone I Stage 1 plus, or 2 plus, or 3 non-plus or 3 plus, or Zone II Stage 2 plus or 3 plus, or AP-ROP
    3.Weight at baseline (day of treatment) ≥ 800 g
    4.Male or female
    5.Signed informed consent from parent(s)/legally authorized representative(s) as described in Section 10.1.3 of the clinical trial protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical trial protocol
    E.4Principal exclusion criteria
    Subjects are excluded from the study if any of the following “per subject” criteria are met. A potential study eye is excluded from the study if any of the “per eye” criteria are met:
    Medical Conditions – per subject
    1.Known or suspected chromosomal abnormality, genetic disorder or syndrome
    2.Previous exposure to any IVT or systemic anti-VEGF agent, including maternal exposure during pregnancy and/or during breastfeeding
    3.Clinically significant neurological disease (eg, intraventricular hemorrhage grade 3 or higher, periventricular leukomalacia, congenital brain lesions significantly impairing optic nerve function, severe hydrocephalus with significantly increased intracranial pressure)
    4.Pediatric conditions rendering the infant ineligible for study intervention at baseline or for repeated blood draws as evaluated by a NICU specialist and a study ophthalmologist
    5.Presence of active ocular infection within 5 days of the first treatment
    Medical Conditions – per eye
    6.Advanced stages of ROP with partial or complete retinal detachment (ROP Stages 4 and 5)
    7.ROP involving only Zone III
    8.Ocular abnormalities that may interfere with the administration of study intervention or assessment of the study primary endpoint Prior/Concomitant Therapy – per subject
    9.Postnatal treatment with oral or intravenous corticosteroids at an equivalent dose of prednisone ≥ 1 mg/kg/day for > 2 weeks within 14 days of the first study intervention
    Prior/Concomitant Therapy – per eye
    10.Previous surgical or nonsurgical treatment for ROP (IVT anti-VEGF injection, ablative laser therapy, cryotherapy, and vitrectomy) Prior/Concurrent Clinical Study Experience
    11.Participation of the subject or the mother in other clinical trials requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening, or within 30 days or 5 half-lives of administration of the previous study drug, whichever is longer
    Subjects are excluded from the study if any of the following “per subject” criteria are met. A potential study eye is excluded from the study if any of the “per eye” criteria are met:
    Medical Conditions – per subject
    1.Known or suspected chromosomal abnormality, genetic disorder or syndrome
    2.Previous exposure to any IVT or systemic anti-VEGF agent, including maternal exposure during pregnancy and/or during breastfeeding
    3.Clinically significant neurological disease (eg, intraventricular hemorrhage grade 3 or higher, periventricular leukomalacia, congenital brain lesions significantly impairing optic nerve function, severe hydrocephalus with significantly increased intracranial pressure)
    4.Pediatric conditions rendering the infant ineligible for study intervention at baseline or for repeated blood draws as evaluated by a NICU specialist and a study ophthalmologist
    5.Presence of active ocular infection within 5 days of the first treatment
    Medical Conditions – per eye
    6.Advanced stages of ROP with partial or complete retinal detachment (ROP Stages 4 and 5)
    7.ROP involving only Zone III
    8.Ocular abnormalities that may interfere with the administration of study intervention or assessment of the study primary endpoint Prior/Concomitant Therapy – per subject
    9.Postnatal treatment with oral or intravenous corticosteroids at an equivalent dose of prednisone ≥ 1 mg/kg/day for > 2 weeks within 14 days of the first study intervention
    Prior/Concomitant Therapy – per eye
    10.Previous surgical or nonsurgical treatment for ROP (IVT anti-VEGF injection, ablative laser therapy, cryotherapy, and vitrectomy) Prior/Concurrent Clinical Study Experience
    11.Participation of the subject or the mother in other clinical trials requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening, or within 30 days or 5 half-lives of administration of the previous study drug, whichever is longer
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint
    Proportion of patients with absence of active ROP and unfavorable structural outcomes at 24 weeks after starting study treatment
    Percentuale di pazienti senza ROP attiva ed esiti strutturali sfavorevoli 24 settimane dopo l'inizio del trattamento in studio
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 24 weeks after starting study Treatment
    24 settimane dopo inizio trattamento sperimentale
    E.5.2Secondary end point(s)
    Secondary Endpoints addressing primary objectives
    Requirement for intervention with a second treatment modality from baseline to Week 24
    Recurrence of ROP from baseline to Week 24
    To explore new Retinopathy of Prematurity Activity Scale proposed by the International Neonatal Consortium

    Secondary Endpoints addressing secondary objectives
    •Number of aflibercept administrations from baseline to Week 24
    •Number of laser treatments from baseline to Week 24
    •Proportion of participants with ocular TEAEs and SAEs from baseline to Week 24
    •Proportion of participants with systemic TEAEs and SAEs from baseline to Week 24
    •Systemic exposure to free aflibercept (at expected maximum plasma concentration and during elimination period from plasma) determined by sparse sampling
    •Presence of anti-drug antibodies before and 12 weeks after aflibercept injection
    Necessità di intervento con una seconda modalità di trattamento dal basale alla Settimana 24
    Recidiva di ROP dal basale alla Settimana 24
    Esame della nuova Scala di attività nella retinopatia del prematuro (Retinopathy of Prematurity Activity Scale) proposta dall'International Neonatal Consortium
    Endpoint secondari associati agli obiettivi secondari:

    Numero di somministrazioni di aflibercept dal basale alla Settimana 24
    Numero di trattamenti laser dal basale alla Settimana 24
    Percentuale di partecipanti con TEAE e SAE oculari dal basale alla Settimana 24
    Percentuale di partecipanti con TEAE e SAE sistemici dal basale alla Settimana 24
    Esposizione sistemica ad aflibercept libero (alla concentrazione plasmatica massima prevista e durante il periodo di eliminazione dal plasma) determinata con il prelievo di campioni sporadici
    Presenza di anticorpi anti-farmaco prima e 12 settimane dopo l'iniezione di aflibercept
    E.5.2.1Timepoint(s) of evaluation of this end point
    • From baseline to Week 24
    dal basale alla settimana 24
    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 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
    Laser Therapy
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA67
    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
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Czech Republic
    Estonia
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Israel
    Italy
    Japan
    Korea, Democratic People's Republic of
    Latvia
    Lithuania
    Malaysia
    Netherlands
    Poland
    Portugal
    Romania
    Russian Federation
    Singapore
    Slovakia
    Spain
    Sweden
    Switzerland
    Taiwan
    Turkey
    Ukraine
    United Kingdom
    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
    The end of the study as a whole is defined as the date of the last visit of the last subject in the study in all centers in all participating countries (EU and non-EU).
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 135
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 135
    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) No
    F.1.3Elderly (>=65 years) No
    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 No
    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
    Preterm newborn infants will be involved
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 74
    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)
    A Phase 3b study (Study 20275; extension study) is planned to assess the long-term outcomes of subjects who received study intervention in this study and accept participation in the extension study.
    A Phase 3b study (Study 20275; extension study) is planned to assess
    the long-term outcomes of subjects who received study intervention in
    this study and accept participation in the extension 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 Decision2019-07-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-14
    P. End of Trial
    P.End of Trial StatusCompleted
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