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    Summary
    EudraCT Number:2012-005418-20
    Sponsor's Protocol Code Number:CRFB002G2302
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-09-05
    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 ConcernedGermany - PEI
    A.2EudraCT number2012-005418-20
    A.3Full title of the trial
    A 12-month, randomized, double-masked, sham-controlled, multicenter
    study to evaluate the efficacy and safety of 0.5 mg ranibizumab intravitreal
    injections in patients with visual impairment due to vascular endothelial
    growth factor (VEGF) driven macular edema (ME)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 12-month study to evaluate the efficacy and safety of injections of 0.5
    mg ranibizumab into the eye of patients with vision loss caused by
    increased accumulation of fluid within the intraretinal layers of the macula
    (macular edema) and for which ranibizumab may have a positive impact
    A.4.1Sponsor's protocol code numberCRFB002G2302
    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 SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma GmbH
    B.5.2Functional name of contact pointMedizinischer Infoservice (MCC)
    B.5.3 Address:
    B.5.3.1Street AddressRoonstraße 25
    B.5.3.2Town/ cityNürnberg
    B.5.3.3Post code90429
    B.5.3.4CountryGermany
    B.5.4Telephone number+491802232300
    B.5.5Fax number+49911273 12160
    B.5.6E-mailinfoservice.novartis@novartis.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 Lucentis
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLucentis
    D.3.2Product code RFB002
    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 INNRANIBIZUMAB
    D.3.9.1CAS number 347396-82-1
    D.3.9.2Current sponsor codeRFB002
    D.3.9.4EV Substance CodeSUB22314
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Visual impairment due to vascular endothelial growth factor (VEGF)
    driven macular edema (ME)
    E.1.1.1Medical condition in easily understood language
    Impaired vision due to increased accumulation of fluid in the back of the
    eye (macula) caused by an intrinsic substance, so-called vascular
    endothelial growth factor (VEGF)
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10025415
    E.1.2Term Macular oedema
    E.1.2System Organ Class 10015919 - Eye disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10047571
    E.1.2Term Visual impairment
    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
    To demonstrate that an individualized regimen of intravitreal injection of
    0.5 mg ranibizumab has superior efficacy compared to sham treatment
    in adult patients with visual impairment due to VEGF-driven ME.
    The primary objective will be assessed by the BCVA change from
    baseline to Month 2.
    E.2.2Secondary objectives of the trial
    Evaluate efficacy of ranibizumab vs sham treatment by
    •BCVA change from baseline (BL) by visit to Mo 2
    •change in CSFT and CSFV (by OCT) from BL over time to Mo 2
    •presence of intra-/sub-retinal fluid (by OCT) and of active ME leakage (by FA) at Mo 2
    •rescue treatment requirement at Mo 1
    Evaluate efficacy of ranibizumab by original treatment assignment by
    •average BCVA change from BL to Mo1 thru Mo6 and to Mo1 thru Mo12
    •change from BL in CSFT and CSFV (by OCT) by visit
    •presence of intra-/sub-retinal fluid (by OCT) and of active ME leakage (by FA) at Mo 2,6 and 12 compared to BL
    •proportion of patients with ≥1, ≥5, ≥10 and ≥15 letters gain or reaching 84 letters, from BL at Mo 2, 6 and 12
    •proportion of patients with >1, >5,>10 and >15 letters loss at Mo 2,6 and 12 Assess number of ranibizumab (re)treatments by Mo 2,6 and 12
    Evaluate:
    •safety of ranibizumab (ocular and non-ocular AE) vs sham at Mo 2 and over time at Mo 6 and 12
    •reasons for treatment decision
    E.2.3Trial contains a sub-study No
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    To describe the efficacy and safety of ranibizumab in adolescent patients
    E.3Principal inclusion criteria
    • Diagnosis of active ME secondary to any causes (for adult patients: except DME, AMD and RVO) that is primary, chronic (i.e., ME is present for > 3 months) or recurrent, confirmed by at least one of three
    following criteria:
    a) Presence of posterior pole changes compatible with active ME seen by fundus ophthalmoscopy, biomicroscopy and fundus photography
    b) Presence of leakage from ME seen by fluorescein angiography (FA)
    c) Presence of intra-retinal fluid/cysts seen by optical coherence tomography (OCT)
    • BCVA must be between ≥ 24 and ≤ 83 letters tested at 4 meters starting distance using ETDRS-like visual acuity charts (approximate Snellen chart equivalents of 20/25 and 20/320) in the study eye
    • Visual loss in the study eye should be mainly due to the presence of any eligible types of ME (for adult patients: non-DME, non-AMD and non- RVO) based on ocular clinical, as well as FA and OCT findings





    E.4Principal exclusion criteria
    For both eyes
    • Active diabetic retinopathy, active ocular/periocular infectious disease or active severe intra-ocular inflammation (e.g., anterior chamber cells (ACC) >2+ and/or vitreous haze (VH) >2+). Rescreening is permitted after intra-ocular inflammation is successfully treated with antiinflammatory therapy that does not compromise eligibility
    • Confirmed intraocular pressure (IOP) ≥ 25 mmHg for any reason
    • Neovascularization of the iris or neovascular glaucoma
    • Inability to obtain fundus photographs, fluorescein angiograms or OCT images of sufficient quality to be analyzed
    For study eye
    • ME secondary to DME, AMD or RVO (for adult patients only). RAP lesions are exclusionary in patients 50 years of age or older
    • Ocular disorders that could confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the 12-month study period. These include for example:
    a. Presence or history of retinal detachment, macular hole, epi-retinal membrane (if the membrane is involving the fovea)
    b. Presence of cataract, leading to marked visual impairment and/or requiring surgery during the study
    c. Presence of vitreomacular traction (VMT) as the primary reason for the ME in the opinion of the investigator
    d. Diagnosis of retinitis pigmentosa (RP)
    e. Diagnosis of Central Serous Chorioretinopathy (CSC, CSR)
    • Any type of advanced, severe or unstable ocular disease or its treatment, that could interfere with the primary and/or secondary outcome evaluations including any medical condition that could be expected to progress, recur, or change to such an extent that it could bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk.
    • ME with a high likelihood of spontaneous resolution (e.g., central serous chorioretinopathy (CSC) or pseudophakic ME) unless the ME persists for > 3 months or has not improved upon topical treatment with steroids or NSAIDsHistory of laser photocoagulation with involvement of the macular area at any time
    • Verteporfin photodynamic therapy (vPDT) at any time
    • History of intraocular treatment with any anti-angiogenic drugs within 6 months of the baseline visit (e.g., bevacizumab [Avastin®], aflibercept [Eylea®], pegaptanib [Macugen®], ranibizumab [Lucentis®])
    • History of intravitreal treatment with steroids, e.g. triamcinolone within 6 months prior to baseline
    • History of treatment with intravitreal implants (e.g., Illuvien®, Ozurdex®, Retisert®) at any time
    • History of vitreoretinal surgery at any time (cataract surgery is not an exclusion criterion unless a large removal of vitreous or removal of posterior vitreous has occurred)
    E.5 End points
    E.5.1Primary end point(s)
    Best corrected visual acuity (BCVA) change from baseline to Month 2
    E.5.1.1Timepoint(s) of evaluation of this end point
    month 2
    E.5.2Secondary end point(s)
    Compared to sham treatment
    • BCVA change from baseline by visit up to Month 2 in study eye
    • Change in central subfield thickness (CSFT) and central subfield volume (CSFV) in study eye from baseline over time to Month 2
    • Presence of intra-/subretinal fluid in study eye at Month 2
    • Presence of active chorioretinal leakage assessed by FA at Month 2
    • Requirement for rescue treatment at Month 1 By original treatment assigment
    • Average BCVA change in study eye from baseline to Month 1 through Month 12
    • Change from baseline in CSFT and CSFV in study eye by visit
    • Presence of intra-/subretinal fluid in study eye at Month 2, Month 6 and Month 12 compared to Baseline
    • Presence of active chorioretinal leakage in study eye at Month 2,Month 6 and Month 12 compared to Baseline
    • Proportion of patients with ≥ 1, ≥ 5, ≥ 10 and ≥ 15 letters gain or reaching 84 letters in study eye, from baseline at Month 2, Month 6 and Month 12
    • Proportion of patients with > 1, > 5, > 10 and > 15 letters loss at Month 2, Month 6 and Month 12
    • Number of ranibizumab treatments and retreatments to study eye by Month 2, Month 6 and Month 12
    • Type, frequency and severity of ocular and non-ocular adverse events in the study eye up to Month 2, up to Month 6 and up to Month 12
    • Reasons for treatment decision by investigator clinical judgement and investigator-assessed evidence of disease activity from OCT and FA images


    E.5.2.1Timepoint(s) of evaluation of this end point
    see above
    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 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 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 Yes
    E.8.1.7.1Other trial design description
    open label group for adolescents
    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
    sham injection (adults only)
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA49
    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
    Belgium
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Ireland
    Israel
    Italy
    Korea, Republic of
    Latvia
    Netherlands
    Russian Federation
    Singapore
    Slovakia
    South Africa
    Spain
    Switzerland
    Turkey
    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 years1
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    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: 10
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 157
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 120
    F.4.2.2In the whole clinical trial 187
    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)
    None
    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 Decision2013-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-09-09
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