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    Summary
    EudraCT Number:2014-001874-32
    Sponsor's Protocol Code Number:RDC-CNGA3-01
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2015-02-16
    Trial 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 number2014-001874-32
    A.3Full title of the trial
    Safety and efficacy of a bilateral single subretinal injection of rAAV.hCNGA3 in adult and minor patients with CNGA3-linked achromatopsia investigated in a randomized, wait list controlled, observer-masked trial
    Sicherheit und Wirksamkeit einer beidseitigen, einzelnen subretinalen Injektion von rAAV.hCNGA3 bei Erwachsenen und Kindern mit CNGA3-chromosomaler Achromatopsie, untersucht in einer randomisierten Wartelisten-kontrollierten, einfach verblindeten Studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy of a bilateral, single injection of a genetically modified virus particle under the retina in adults and children with achromatopsia (an eye disease caused by a defect in the genetic material), investigated in a clinical trial.
    Sicherheit und Wirksamkeit einer einzelnen Verabreichung eines genetisch veränderten Viruspartikels bei Patienten mit Achromatopsie (einer durch einen Defekt im Genmaterial bedingten Augenerkrankung); untersucht in einer klinischen Studie
    A.4.1Sponsor's protocol code numberRDC-CNGA3-01
    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 SponsorUniversitätsklinikum Tübingen
    B.1.3.4CountryGermany
    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 supportTistou und Charlotte Kerstan-Stiftung (trial preparation), BMBF (trial conduct)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSTZ eyetrial am Department für Augenheilkunde
    B.5.2Functional name of contact pointHead of STZ eyetrial, Dr. T. Peters
    B.5.3 Address:
    B.5.3.1Street AddressElfriede-Aulhorn-Str. 7
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72076
    B.5.3.4CountryGermany
    B.5.4Telephone number4970712984894
    B.5.5Fax number497071295021
    B.5.6E-mailtobias.peters@stz-eyetrial.de
    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 numberEMA/746037/2016
    D.3 Description of the IMP
    D.3.1Product namerAAV.hCNGA3 vector
    D.3.2Product code ACHM2
    D.3.4Pharmaceutical form Concentrate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOcular use
    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
    CNGA3-linked achromatopsia
    E.1.1.1Medical condition in easily understood language
    Degenerative disease of the retina
    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 LLT
    E.1.2Classification code 10000454
    E.1.2Term Achromatopsia
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main objective: The primary aim of the trial is the investigation of the safety of rAAV.hCNGA3 after bilateral subretinal injection in adult and minor patients with CNGA3-linked achromatopsia.
    E.2.2Secondary objectives of the trial
    The investigation of treatment effects as reflected by patient/parent reported outcomes and the efficacy of the intervention on visual functions are secondary aims of the trial.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • clinical diagnosis of achromatopsia
    • 6-12 years of age
    • ≥ 18 years of age
    • bi-allelic pathogenic or likely pathogenic mutations in CNGA3
    • BCVA ≥ 20/400
    • a minimal outer nuclear layer thickness of 10µm at 3° eccentricity (normal = 38±6µm)
    • ability to understand and willingness to consent to study protocol
    • no infection with Human Immundeficiency Virus (HIV)
    • Male patients must agree to use condoms during the first 6 months post treatment.
    • Female patients of childbearing potential must agree to use an effective method of birth control during the first 6 months post treatment.
    • negative pregnancy test in women with childbearing potential (a woman who is two years post-menopausal or surgically sterile is not considered to be of childbearing potential)
    E.4Principal exclusion criteria
    • any other retinopathy due to other diseases e.g. (but not limited to) arterial hypertension, trauma or acquired inflammatory diseases (uveitis serology) , retinopathy of the premature
    • systemic conditions (e.g. coronary heart disease, congenital/genetic conditions, autoimmune disorders) which may affect study participation or outcome measures
    • current or recent participation in other study or administration of biologic agent within the last three months
    • recent (within the last 6 months) ocular surgery, intravitreal or subretinal implantation of a medical device
    • known sensitivity to any compound used in the study
    • contraindications to systemic immunosuppression
    • subject/partner of childbearing potential unwilling to use adequate contraception for six months after dosing
    • nursing or pregnant female subject
    • any other cause that, in the investigator‘s opinion, renders potential subjects not suitable for the study
    • causal mutations in other genes for hereditary retinal diseases
    • contraindications in view of the planned surgery (e.g. anaemia Hb<8g/dl, severe coagulopathy, severe blood pressure fluctuations) including intolerance and contraindications to general anaesthesia
    • ocular opacity and mature cataract
    • ocular infection with herpes simplex virus in medical history
    • history of ocular malignancies
    • disorders of the inner retina (e.g. retinal vascular occlusions in the patients history)
    • glaucoma defined as damage of the optic nerve
    • history of poorly controlled (HbA1c > 7%) Diabetes Mellitus type 1 or type 2
    • patients treated with systemic corticoids within 14 days prior inclusion
    • systemic illness or medically significant abnormal laboratory values >3 UNL in blood analysis including renal and hepatic functions at inclusion
    • absence of vision on the contralateral eye
    • contraindication to pharmacological mydriasis (e.g. history of angle block glaucoma)
    E.5 End points
    E.5.1Primary end point(s)
    E.5.1 Primary End Point (repeat as necessary) :
    Primary Endpoint safety:
    • Incidence and severity of ocular adverse events
    • Incidence and severity of non-ocular adverse events

    Safety will be assessed by clinical examination of ocular inflammation (slit lamp, fundus biomicroscopy), fundus photography, fundus autofluorescence and by evaluation of rod function in the treated area (DAC and scotopic CPC). Systemic safety will be assessed by vital signs, routine clinical chemistry testing (including CRP, ESR) and full/differential blood counts. Immunopathology essays will include specific enzyme-linked immunosorbent assays for humoral antibodies against rAAV8 capsid protein.

    Adverse events of special interest (AESI)
    - Adverse immunological reaction both systemic and ocular, defined by e.g. - but not limited to - blood parameters, findings in slit lamp examination.
    - Severe vision loss, defined by more than 15 ETDRS letters loss compared to screening more than 56 days after surgery.

    SAEs and AESIs must be reported to the sponsor within 24h, the sponsor is obliged to inform the DMC immediately. The procedure is defined on the SAE worksheet.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint safety: Safety assessment 12 months after treatment (incidence and severity of ocular and non-ocular adverse events)
    Primary endpoint efficacy: Contrast sensitivity (Pelli Robson 3 m) 6 months after treatment
    E.5.2Secondary end point(s)
    Secondary endpoints efficacy:
    • Contrast sensitivity (Pelli Robson 3 m)
    • BCVA assessed using the ETDRS visual acuity protocol
    • FrACT (Freiburg Visual Acuity & Contrast Test)
    • Roth FM28 sat
    • VA-CAL (Visual acuity under different conditions of contrast and ambient light)
    • Patient reported outcomes (VFQ25/CVFQ, A3-PRO)
    • Electroretinography
    • Chromatic pupil campimetry (CPC) cone protocol – exploratory - functional

    Secondary endpoints safety:
    • Changes in various outcome measures, as determined by
    • Spectral domain optical coherence tomography (SD-OCT) morphological
    • Chromatic pupil campimetry (CPC) rod protocol – exploratory - functional
    • Dark-adapted chromatic perimetry (DAC) – exploratory - functional
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoint(s) of evaluation of this endpoint: 12 months after treatment
    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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I/IIb study
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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
    Waiting group design
    E.8.2.4Number of treatment arms in the trial2
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years13
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned 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: 6
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    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: 8
    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 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 state14
    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)
    Trial subjects will be controlled by regular routine examinations only or treated in subsequent studies. Currently, there is no treatment alternative available and not enough scientific data available for a compassionate use program. Close monitoring of subjects may be required in the follow-up period after the study to ensure patient safety. In any case, it is expected that subjects will continue to be treated by the investigational site.
    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 Decision2015-09-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-29
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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