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    Summary
    EudraCT Number:2010-023111-34
    Sponsor's Protocol Code Number:TDU13583(SG1/001/10)
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-07-22
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2010-023111-34
    A.3Full title of the trial
    A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected SAR422459, Administered to Patients with Stargardt's Macular Degeneration.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/IIa Study of SAR422459 in Patients With Stargardt's Macular Degeneration

    A.4.1Sponsor's protocol code numberTDU13583(SG1/001/10)
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/213/2019
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of Sponsorsanofi-aventis recherche et développement
    B.1.3.4CountryNetherlands
    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 supportsanofi-aventis recherche et développement
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationsanofi-aventis recherche et développement
    B.5.2Functional name of contact point-
    B.5.3 Address:
    B.5.3.1Street Address-
    B.5.3.2Town/ city-
    B.5.3.3Post code-
    B.5.3.4CountryFrance
    B.5.6E-mailContact-Us@sanofi-aventis.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 numberEMEA/OD/127/09
    D.3 Description of the IMP
    D.3.1Product nameSAR422459
    D.3.2Product code Lentiviral vector containing ABCA4 gene
    D.3.4Pharmaceutical form Suspension 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 INNSAR422459
    D.3.9.2Current sponsor codeSAR422459
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number180000 to 1800000
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberGene Therapy Medicinal Product CAT reference number : EMEA/CAT/801443/2009
    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
    Stargardt Macular Degeneration, also known as Stargardt Macular Dystrophy, fundus flavimaculatus or Stargardt disease.
    E.1.1.1Medical condition in easily understood language
    Inherited juvenile macular degeneration, leading to deterioration of central vision, and legally-defined blindness in young adults.
    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 10062766
    E.1.2Term Stargardt's disease
    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
    To assess the safety and tolerability of ascending doses of SAR422459 in patients with Stargardt's Macular Degeneration.
    E.2.2Secondary objectives of the trial
    To evaluate for possible biological activity of SAR422459.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Signed and dated written informed consent obtained from the patient and/or the patient's legally acceptable representative.

    -Diagnosis of Stargardt's Macular Degeneration (SMD), with at least one pathogenic mutant ABCA4 allele on each chromosome.

    -Women of childbearing potential must have a negative pregnancy test at Day -1, and agree to use an effective form of contraception for at least three months, or be surgically sterile or postmenopausal, with the last menstrual period being over two years prior to enrollment .

    -Males must agree with their partner to use two forms of contraception for at least three months following SAR422459 administration.

    -Patients must agree to not donate blood, organs, tissues or cells for at least three months following SAR422459 administration

    -Patients enrolled in France must be affiliated to or benefit from a social security regimen.

    -Specific Inclusion Criteria Patient Group A:
    -Patients (18 years or older) with Advanced Stargardt's Macular degeneration.
    -Visual acuity ≤20/200 in the worst eye
    -Severe cone-rod dysfunction with no detectable or severely abnormal full-field electroretinogram responses.

    -Specific Inclusion Criteria Patient Group B:
    -Patients (18 years or older) with Stargardt’s Macular Degeneration.
    -Visual Acuity ≤20/200 in the worst eye.
    -Abnormal full-field electroretinogram responses.

    -Specific Inclusion Criteria Patient Group C:
    -Patients (18 years or older) with Stargardt’s Macular Degeneration.
    -Visual acuity ≤20/100 in the worst eye.
    -Abnormal full-field electroretinogram responses.

    -Specific Inclusion Criteria Patient Group D:
    -Symptomatic patients (from 6 years to 26 years old) with early or childhood-onset SMD (age at disease onset < 18 years) with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by direct sequencing and co-segregation analysis within the patient’s family.
    -Visual acuity of ≥20/200 in both eyes at the time of the screening visit.
    -Patients are anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an annual progression rate in at least one of the following parameters occurring in at least one eye (assessments recorded up to 2 years prior to the screening visit date may be considered to document evidence of rapid deterioration):
    -Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters).
    -Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry.
    -Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by >14 dB-sr as assessed by static perimetry.
    -Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate of ≥0.5 mm^2.
    -Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a rate of ≥0.5 mm^2.
    -All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform required study procedures as judged and confirmed by the study investigator.

    - Specific inclusion criteria Patient Group E
    -Symptomatic patients (between 6 years and 17 years old) with early or childhood-onset SMD with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by direct sequencing and co-segregation analysis within the patient's family.
    -Visual acuity of ≥20/100 in both eyes at the time of screening visit.
    -Patients are anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an annual progression rate in at least one of the following parameters occurring in at least one eye (assessments recorded up to 2 years prior to the screening visit date may be considered to document evidence of rapid deterioration):
    -Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters).
    -Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry.
    -Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by >14 dB-sr as assessed by static perimetry.
    -Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate of ≥0.5 mm2.
    -Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a rate of ≥0.5 mm2.
    -All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform required study procedures as judged and confirmed by the study investigator.



    E.4Principal exclusion criteria
    -Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints.

    -Cataract surgery with intraocular lens implantation within 6 months of enrolment.

    -Aphakia or prior vitrectomy in the study eye.

    -Concomitant systemic diseases including those in which the disease itself, or the treatment for the disease, can alter ocular function.

    -Any intraocular surgery or laser in either eye planned within 6 months of Day 0.

    -Any contraindication to pupil dilation in either eye.

    -Any known allergy to any component of the delivery vehicle or diagnostic agents used during the study, or medications planned for use in the peri-operative period, particularly topical, injected or systemic corticosteroids.

    -Any injectable intravitreal treatment to the treated eye or intravitreal device in the treated eye within 6 months prior to screening.

    -Any periocular injections of corticosteroids to the treated eye within 4 months prior to screening.

    -Laboratory test abnormalities or abnormalities in electrocardiogram, chest X rays that in the opinion of the principal investigator, would make the patient unsuitable for participation in the study.

    -Significant intercurrent illness or infection during the 28 days prior to enrolment.

    -Pre-menopausal or non-surgically sterile women who are unwilling to use an effective form of contraception such as the contraceptive pill or intrauterine device.

    -Alcohol or other substance abuse.

    -Contraindications to use of anaesthesia (local or general, as appropriate).

    -Concurrent anti-retroviral therapy that would inactivate the investigational agent.

    -History of any investigational agent within 28 days prior to SAR422459 administration.

    -Participation in a prior ocular gene transfer therapy study.

    -Enrollment in any other clinical treatment study throughout the duration of the SAR422459 study.

    -Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks prior to surgery.

    -A past medical history of human immunodeficiency virus (HIV) or hepatitis A, B or C infection.

    -Women who are pregnant or are breastfeeding.

    -History or signs consistent with unilateral amblyopia (strabismic, anisometropic or stimulus deprivation).
    E.5 End points
    E.5.1Primary end point(s)
    Number of patients with treatment emergent adverse events

    Change from baseline in ocular safety assessments

    Measured as change from baseline in Best Corrected Visual Acuity, Slit-lamp, Ophthalmoscopy, Fundus Photography, Intraocular Pressure, Microperimetry, full-field static and kinetic perimetry, OCT and ERG


    E.5.1.1Timepoint(s) of evaluation of this end point
    at 48 weeks
    E.5.2Secondary end point(s)
    Delay in retinal degeneration

    Measured as change from baseline in function relative to untreated contralateral eye on: BCVA, microperimetry, full-field static/kinetic perimetry, OCT and FAF
    E.5.2.1Timepoint(s) of evaluation of this end point
    at 48 weeks
    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) Yes
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    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 Will this trial be conducted at a single site globally? Yes
    E.8.4 Will this trial be conducted at multiple sites globally? No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    France
    Italy
    Netherlands
    United States
    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
    Last visit last subject in the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    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: 18
    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: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Pediatric patients, needing parental consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 41
    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)
    At the end of the study, the patient will be invited to enter in an open-label safety study (LTS13588) and long-term follow-up visits including ophthalmological examinations and recording of adverse events for up to 15 years.
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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