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    Summary
    EudraCT Number:2013-003272-12
    Sponsor's Protocol Code Number:SIVS1012
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-03-31
    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 ConcernedUK - MHRA
    A.2EudraCT number2013-003272-12
    A.3Full title of the trial
    Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy
    A.3.2Name or abbreviated title of the trial where available
    CLARITY Version 1.0
    A.4.1Sponsor's protocol code numberSIVS1012
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN32207582
    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 SponsorMoorfields Eye Hospital
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNIHR MRC - EME grant
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportBayer PLC
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMoorfields Eye Hospital
    B.5.2Functional name of contact pointNatasha Ajraam
    B.5.3 Address:
    B.5.3.1Street Address162, City Road
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeEC1V 2PD
    B.5.4Telephone number020 7253 3411 x2937
    B.5.5Fax number02075662315
    B.5.6E-mailnatasha.ajraam@moorfields.nhs.uk
    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
    D.2.1.1.2Name of the Marketing Authorisation holderBayer Pharma AG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.2Product code EMA/CHMP/299413/2012
    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.3.9.3Other descriptive nameEylea
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2mg
    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 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Proliferative Diabetic Retinopathy (PDR)
    E.1.1.1Medical condition in easily understood language
    An advanced diabetic eye condition caused by abnormal growth of new blood vessels in the eye.
    E.1.1.2Therapeutic area Body processes [G] - Ocular Physiological Phenomena [G14]
    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 evaluate whether mean change in best corrected visual acuity following intravitreal aflibercept therapy is non-inferior to panretinal photocoagulation (PRP) in eyes with proliferative diabetic retinopathy (PDR) at 52 weeks as measured by ETDRS letters.
    E.2.2Secondary objectives of the trial
    1.To measure the effect of intravitreal aflibercept therapy, relative to panretinal photocoagulation on additional visual functions and quality of life outcomes including
    i)Unilateral and Binocular Esterman visual fields defects
    ii)Binocular visual acuity
    iii)Low luminance visual acuity
    iv)Visual acuity outcomes in terms of visual gain or loss
    v)Contrast sensitivity using Pelli Robson charts
    vi)Vision-related quality of life measured by VFQ-25 and RetDQoL
    vii)Diabetic retinopathy treatment satisfaction outcomes (RetTSQ)
    viii)Generic health-related quality of life using the EQ-5D, ICECAP-A, and CSRI.

    2.To estimate incremental cost-effectiveness of intravitreal aflibercept versus standard PRP treatment at 52 weeks.

    3.To determine the proportions of naïvePDR and non-naïve PDR eyes in both arms that do not require panretinal photocoagulation through 52 weeks after basic treatment of 3 loading doses of aflibercept or initial completion of PRP.
    4.To compare between a
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Embedded in the CLARITY trial version 1 is a mechanistic sub-study. 40 participants will undergo retinal photography and image analysis at screening, 12 and 52 weeks to explore the effect of aflibercept on the retina and blood vessels.
    E.3Principal inclusion criteria
    1.Subjects of either sex aged 18 years or over.
    2.Diagnosis of diabetes mellitus (type 1 or type 2).
    3.Best corrected visual acuity in the study eye better than or equal to 54 ETDRS letters (Snellen visual acuity 6/24).
    Please see section 6.3 Re-screening of patients
    4.Visual acuity in fellow eye ≥ 2/60
    5.PDR with no evidence of previous PRP or presence of new or persistent retinal neovascularisation despite prior PRP that (a) requires treatment in the opinion of the investigator and (b) there is sufficient space in the peripheral retina to perform more PRP treatment. In patients with both eye involvement, the eye with no PRP or the least number of PRP burns will be randomised as the study eye. If both eyes have had no PRP before, the eye with the better visual acuity will be randomised as the study eye. However, patients will be offered a choice and can opt for the ‘worse seeing eye’ to be randomised
    6.Media clarity, pupillary dilation and subject cooperation sufficient for adequate fundus photographs. Eyes with mild pre-retinal haemorrhage or mild vitreous haemorrhage that does not interfere with clear visualisation of the macula and optic disc are eligible for this study.
    7.Ability to give informed consent
    8.Women should use effective contraception, be post-menopausal for at least 12 months prior to trial entry, or surgically sterile
    E.4Principal exclusion criteria
    1.Co-existent ocular disease that will affect visual outcome.
    2.Moderate or dense vitreous haemorrhage that prevents clear visualisation of the macula and/or optic disc or prevents PRP treatment.
    3.Significant fibrovascular proliferation or tractional retinal detachment in the posterior pole.
    4.Prior vitrectomy.
    5.Presence of macular oedema at baseline confirmed by 3D OCT-1000 (Topcon) SD-OCT as central subfield thickness of more than 300µm due to the presence of morphological evidence of diffuse or cystoid oedema. The equivalent measurement for Spectralis OCT is 320µm and Cirrus HD-OCT is 300µm. Please see rescreening of patients.
    6.Other causes of retinal neovascularisation.
    7.Iris or angle neovascularisation and neovascular glaucoma.
    8.Anticipated need for cataract extraction or vitrectomy within the next 12 months.
    9.Known allergy to fluorescein or any components of aflibercept formulation.
    10.Previous intravitreal anti-VEGF or steroid treatment for diabetic macular oedema in the last 4 months. (Previous Iluvien therapy is an exclusion).
    11.Panretinal photocoagulation within the last 8 weeks.
    12.Aphakia.
    13.Uncontrolled glaucoma as per investigator’s judgement.
    14.Severe external ocular infection.

    Exclusion criteria also apply to systemic conditions as follows:

    15.The participant should not have an HbA1c level of more than 12%. Please see section 6.3 Re-screening of patients.
    16.The participant should not have a blood pressure of more than 170/110mmHg. Please see section 6.3 Re-screening of patients.
    17.A medical condition that, in the opinion of the investigator, would preclude participation in the study.
    18.Myocardial infarction, stroke, transient ischaemic attack, acute congestive cardiac failure or any acute coronary event within 6 months of randomisation.
    19.Dialysis or renal transplant.
    20.Pregnant women.
    21.Women of child bearing potential who do not agree to use effective contraception during the study and for at least 3 months after the study has finished.
    22.Breast feeding women.
    23.Males who do not agree to use an effective form of contraception for the duration of the study and for 3 months after the study has finished.
    24.Participation in an investigational trial involving an investigational medicinal product within 30 days of randomisation.
    E.5 End points
    E.5.1Primary end point(s)
    To evaluate whether mean change in best corrected visual acuity following intravitreal aflibercept therapy is non-inferior to panretinal photocoagulation (PRP) in eyes with proliferative diabetic retinopathy (PDR) at 52 weeks as measured by ETDRS letters.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Participants will have visual acuity tests at every visit, but best corrected visual acuity will be assessed at screening, week 12, week 52 and at the point of withdrawal.
    E.5.2Secondary end point(s)
    1.To measure the effect of intravitreal aflibercept therapy, relative to panretinal photocoagulation on additional visual functions and quality of life outcomes including
    i)Unilateral and Binocular Esterman visual fields defects
    ii)Binocular visual acuity
    iii)Low luminance visual acuity
    iv)Visual acuity outcomes in terms of visual gain or loss
    v)Contrast sensitivity using Pelli Robson charts
    vi)Vision-related quality of life measured by VFQ-25 and RetDQoL
    vii)Diabetic retinopathy treatment satisfaction outcomes (RetTSQ)
    viii)Generic health-related quality of life using the EQ-5D, ICECAP-A, and CSRI.

    2.To estimate incremental cost-effectiveness of intravitreal aflibercept versus standard PRP treatment at 52 weeks.

    3.To determine the proportions of naïvePDR and non-naïve PDR eyes in both arms that do not require panretinal photocoagulation through 52 weeks after basic treatment of 3 loading doses of aflibercept or initial completion of PRP.

    4.To compare between arms the regression pattern at 12 weeks and the regression and reactivation patterns of retinal neovascularisation at 52 weeks.

    5.To compare the proportion of patients with 1-step and 3-step improvement or worsening of diabetic retinopathy between treatment arms at 12 and 52 weeks as per schedule of assessment.

    6.To explore the difference in safety profile between intravitreal aflibercept and panretinal photocoagulation at 52 weeks, in terms of proportion of patients developing macular oedema (defined as central subfield thickness of >300µm on 3DOCT-1000 (Topcon) SD-OCT due to clinical evidence of macular oedema) or Spectralis OCT >320µmor Cirrus HD-OCT >300 µm or its equivalent if any other OCT devices are used, any de novo or increase in existing vitreous haemorrhage, de novo or increasing tractional retinal detachment, neovascular glaucoma, and requirement for vitrectomy. The indication for vitrectomy will be reported.

    Mechanistic evaluation objectives:
    1.To explore whether intravitreal aflibercept compared to panretinal photocoagulation causes measurable regression of area of retinal neovascularisation at 12 and 52 weeks.

    2.To explore differences in the mean change in retinal vessel oxygen saturation and retinal vessel calibre in eyes treated with intravitreal aflibercept compared to panretinal photocoagulation at 12 and 52 weeks.

    3.To explore whether intravitreal aflibercept reduces angiographically quantifiable areas of retinal non-perfusion compared to panretinal photocoagulation through 52 weeks.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1)& 2) Screening, week 52 and point of withdrawal.
    3) Week 12, week 52 and point of withdrawal.
    4), 5) & 6) Screening, week 12, week 52 and point of withdrawal.

    Mechanistic evaluation
    1), 2) and 3) Screening, week 12, week 52 and point of withdrawal.
    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) Yes
    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 Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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
    Panretinal procogulation laser treatment - standard care
    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 concerned17
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    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.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 110
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 110
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state220
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 220
    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)
    Aflibercept is not available to participants at the end of trial. This is specified in the patient information sheet. Patients will be offered PRP treatment, which is standard treatment for this condition, if the disease recurs after the trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-03-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-12-21
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