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    Summary
    EudraCT Number:2015-003418-25
    Sponsor's Protocol Code Number:CTU/2014/120
    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:2016-01-04
    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 ConcernedUK - MHRA
    A.2EudraCT number2015-003418-25
    A.3Full title of the trial
    An Open-label, Multi-centre, Phase I/II Dose Escalation Trial of an Adeno-Associated Virus Vector (AAV2/5-OPTIRPE65) for Gene Therapy of Adults and Children with Retinal Dystrophy associated with Defects in RPE65 (LCA2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Gene Therapy Trial for LCA2 OPTIRPE65
    A.3.2Name or abbreviated title of the trial where available
    Gene Therapy Trial for LCA2 OPTIRPE65 (AAV2/5-OPTIRPE65)
    A.4.1Sponsor's protocol code numberCTU/2014/120
    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 SponsorMeiraGTx UK II Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportMeiraGTx UK II Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMeiraGTx UK II Ltd
    B.5.2Functional name of contact pointJulie Bakobaki
    B.5.3 Address:
    B.5.3.1Street Address92 Britannia Walk
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeN1 7NQ
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailocularinfo@meiragtx.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/15/177
    D.3 Description of the IMP
    D.3.1Product nameAAV2/5-OPTIRPE65
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraocular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAAV2/5-OPTIRPE65
    D.3.9.2Current sponsor codeAAV2/5-OPTIRPE65
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit billion organisms/ml billion organisms/millilitre
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number1000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    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
    Leber Congenital Amaurosis (LCA) caused by mutations in RPE65
    E.1.1.1Medical condition in easily understood language
    Retinal degeneration caused by mutations in RPE65
    E.1.1.2Therapeutic area Diseases [C] - Eye Diseases [C11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10070667
    E.1.2Term Leber's congenital amaurosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary research objective is to assess the safety of a new optimised virus vector for RPE gene replacement in the retina. Safety is defined as an ATIMP related:
    - Reduction in visual acuity by 15 ETDRS letters or more
    - Severe unresponsive inflammation (defined below)
    - Infective endophthalmitis
    - Ocular malignancy
    - Grade III or above non-ocular SUSAR

    Classification of severe unresponsive inflammation will be according to the SUN (standardisation of uveitis nomenclature) Working Group grading system (Am J Ophthalmol. 2005 Sep;140(3):50916.) i.e.
    - anterior chamber cells 3+ (26-50 cells in a field size of 1mm x 1-mm slit-beam), or
    - anterior chamber flare 3+ (marked, iris and lens details hazy) or
    - vitreous haze 3+ (Ophthalmology 1985; 92:467-71)

    that fail to improve by 2 steps (or to grade 0) during a 6 week period.
    E.2.2Secondary objectives of the trial
    The secondary research objective is to determine whether the new AAV2/5-OPTIRPE65 is effective at improving sight in terms of both visual and retinal function, and quality of life.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion in the trial will be limited to individuals who:
    • Are aged 3 years or older
    • Have early-onset severe retinal dystrophy consistent with RPE65 deficiency
    • Have homozygous or compound heterozygous missense or null mutations in RPE65 confirmed in accredited laboratory
    • Have functional or structural evidence of photoreceptor preservation as assessed by static perimetry (for visual field assessment) and SD-OCT scanning respectively
    • Are able to give informed consent or assent, with the guidance of their parent/guardian where appropriate
    • Are able to undertake age-appropriate clinical assessments
    • If female and of child bearing potential, are willing to use an effective form of birth control (hormonal or barrier method of birth control; or abstinence) for at least 12 months following ATIMP administration
    • If male, are willing to use barrier and spermicide form of contraceptive or maintain sexual abstinence for at least 12 months following ATIMP administration
    • Females of childbearing potential will have a negative pregnancy test on the day of ATIMP administration. Participants are considered not of childbearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy or bilateral oophorectomy) or post-menopausal
    • Are willing to give consent for the use of blood and blood components collected throughout the trial for the investigation of immune responses to the ATIMP
    E.4Principal exclusion criteria
    Individuals will be excluded who:
    • Are females who are pregnant or breastfeeding
    • Have contraindications for transient immune-suppression by systemic corticosteroids (including uncontrolled hypertension, diabetes mellitus, tuberculosis, renal impairment, osteoporosis, gastric ulceration, severe affective disorder) or are immunocompromised
    • Have a previous history (within 5 years) of gastric or duodenal ulceration, hiatus hernia, uncontrolled gastro-oesphageal reflux or are using non-steroidal anti-inflammatory drugs on a regular basis at the time of screening
    • Have a known allergy to any of the non-investigational drugs to be used in the trial
    • Have participated in another research study involving an investigational medicinal therapy for ocular disease within the last 6 months
    • Have any other condition that the PI considers makes them inappropriate for entry into the trial
    • Have had intraocular surgery within 6 months of screening
    • Have an ocular or systemic disorder that may preclude subretinal surgery and/or interfere with interpretation of the study results
    • Are unwilling to consider the possibility of entry into a subsequent longer term follow up study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is defined as any of the below occurring during the 6 weeks following administration, at least possibly related to the ATIMP, not surgery alone:
    - Reduction in visual acuity by 15 ETDRS letters or more
    - Severe unresponsive inflammation
    - Infective endophthalmitis)
    - Ocular malignancy
    - Grade III or above non-ocular SUSAR.
    E.5.1.1Timepoint(s) of evaluation of this end point
    This endpoint will be evaluated at 1 day, 3 days, 1 week, 2 weeks, 4 weeks, 6 weeks, 9 weeks, 3 months, and 6 months after subretinal administration of the intervention.
    E.5.2Secondary end point(s)
    The secondary outcomes are measures of the efficacy of the intervention; these will be performed on an individual participant basis and will be descriptive in nature. Efficacy will be defined as:

    - Any improvement in visual function from baseline that is greater that the test-retest variation for that test and is sustained for at least two consecutive assessments.
    - Any improvement in retinal function from pre-intervention that is greater than the test-retest variation and measurable by electroretinography (ERG).
    - If no ERG is previously detectable, then the presence of any reproducible response with appropriate waveform would be significant. If an ERG is there to start with, any of the following would be significant: an improvement in amplitude of >50 % in DA 0.01 b-wave (rod system sensitivity); bright flash DA 10 a- wave (photoreceptor improvement); the 30Hz flicker; and the LA 3.0 photopic a- and b-waves. In terms of timing: > 3ms improvement in photopic parameters
    and bright flash DA 10 a-wave; 3-6ms for the DA 0.01 and DA 10.0 b-waves. Quality of life will be measured by the Impact of Visual Impairment (IVI) questionnaire and the EQ5D-5Land EQ-5D-Y.
    2.3) Quality of life will be measured by the Impact of Visual Impairment (IVI) questionnaire and the EQ5D-5L and with vision bolt on.
    E.5.2.1Timepoint(s) of evaluation of this end point
    This endpoint will be evaluated at 3 months and 6 months after subretinal administration of the intervention.
    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 Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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
    United Kingdom
    United States
    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 years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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 Yes
    F.1.1Number of subjects for this age range: 9
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 4
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 9
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Children
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 27
    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)
    The intervention will only be provided one time to participants. At the end of this trial, participants will be invited to enrol in a separate long-term follow-up study that will continue to monitor safety and efficacy for 5 years after administration of the intervention.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-12-07
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