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    Summary
    EudraCT Number:2013-002112-27
    Sponsor's Protocol Code Number:MD1003CT2013-01MS-ON
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-29
    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 ConcernedFrance - ANSM
    A.2EudraCT number2013-002112-27
    A.3Full title of the trial
    Effect of MD1003 in chronic visual loss related to optic neuritis in multiple sclerosis: a pivotal randomized double masked placebo controlled study
    Effet MD1003 dans le traitement des séquelles visuelles des névrites optiques de la sclerose en plaques: Etude pivot randomisée en double insu versus placebo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of MD1003 on visuel impairement of multiple sclerosis
    Effet du MD1003 les troubles visuels de la sclérose en plaques
    A.3.2Name or abbreviated title of the trial where available
    MS-ON
    MS-ON
    A.4.1Sponsor's protocol code numberMD1003CT2013-01MS-ON
    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 SponsorMEDDAY SAS
    B.1.3.4CountryFrance
    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 supportMEDDAY SAS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMEDDAY SAS
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address26 rue des rigoles
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75020
    B.5.3.4CountryFrance
    B.5.6E-mailguillaume.brion@medday-pharma.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namebiotin
    D.3.2Product code MD1003
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBIOTIN
    D.3.9.1CAS number 58-85-5
    D.3.9.2Current sponsor codeMD
    D.3.9.4EV Substance CodeSUB05841MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 No
    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
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    chronic visual loss related to optic neuritis in multiple sclerosis
    séquelles visuelles des névrites optiques de la sclerose en plaques
    E.1.1.1Medical condition in easily understood language
    multiple sclerosis
    sclerose en plaques
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10030942
    E.1.2Term Optic neuritis
    E.1.2System Organ Class 10029205 - Nervous system 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 demonstrate the superiority of biotin 300 mg/day over placebo in the visual improvement of patients suffering from chronic visual loss after optic neuritis related to multiple sclerosis
    Démontrer la supériorité de la biotine 300 mg/jour comparée à un placebo sur l'amélioration des troubles de la vision chez des patients avec séquelles de névrite optique de la sclérose en plaques
    E.2.2Secondary objectives of the trial
    To evaluate the acceptability and the safety of biotin 300 mg/day
    Evaluer la tolérance et la sécurité de la biotine à 300 mg/jour
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Diagnosis criteria of MS fulfilling revised Mc Donald criteria (2010)
    2) Uni-or bilateral optic neuropathy with worst eye VA≤ 5/10 confirmed at 6 months
    3) Worsening of visual acuity during the last two years
    4) Informed consent prior to any study procedure
    5) Patient aged 18-64 years
    1) Diagnostic de SEP sur les criteres diagnostiques de MacDonald
    2) Neuropathie optique unilaterale ou bilaterale avec acuite visuelle (AV) de l'oeil le plus atteint ≤ 5/10 confirmée à 6 mois
    3) Déterioration de l'acuité visuelle au cours des deux dernières années
    4) Consentement éclairé
    5) Patient majeur de moins de 65 ans
    E.4Principal exclusion criteria
    1) Optic neuritis relapse within the three months before inclusion
    2) Normal RNFL at OCT
    3) Presence of other ocular pathology (glaucoma, cataract, retinopathy, anterior uveitis, myopia>7 dioptrics, intraocular pressure>20, amblyopia, retinal or optic head abnormalities (drusen, dysversion)
    4) Bilateral visual acuity <1/20
    5) Visual impairment caused by ocular flutter or nystagmus
    6) Pregnancy or childbearing potential woman without contraception:
    - Both male and female subjects who are not either surgically sterile (tubal ligation/obstruction or removal of ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year confirmed by a negative hormone panel) must commit to using TWO highly effective method of birth control for the duration of the study and for two months after the treatment termination. A highly effective method of birth control is defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectable or combined oral contraceptives, IUDs, sexual abstinence or vasectomized partner. Acceptable forms of effective contraception include:
    - Established use oral, injected or implanted hormonal methods of contraception.
    - Placement of an intrauterine device (IUD) or intrauterine system (IUS).
    - Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. Notice that, when used alone, the diaphragm and condom are not highly effective forms of contraception.
    - The use of additional spermicides does confer additional theoretical contraceptive protection. Spermicides alone are inefficient at preventing pregnancy when the whole ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and should not be used alone.
    - True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    - Male sterilisation: subjects must present with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. For female subjects on the study, the vasectomised male partner should be the sole partner for that subject.
    7) Any general chronic handicapping disease other than MS
    8) New treatment introduced less than 3 months prior to inclusion or less than 1 month for Fampridine
    1) Rechute de névrite optique dans les 3 mois précédant l'inclusion
    2) Couche des fibres nerveuses de la rétine normale sur l'OCT
    3) Presence d'autre maladie ophtalmique (glaucome, cataract, retinopathie, uveite anterieure, myopie > 7d, pression intra-oculaire >20, amblyopie, anomalies de la rétine ou de la papille optique (drusen, dysversion papillaire...)
    4) Acuité visuelle bilaterale < 1/20
    5) Baisse de l'acuité visuelle en rapport avec un nystagmus ou un flutter oculaire
    6) Grossesse ou femme en age de procreation sans double contraception efficace : les hommes et les femmes qui ne sont pas stériles ou qui ne sont pas en période post ménopausique doivent utiliser deux méthodes de contraception efficaces. Ces méthodes incluent la contraception orale (pilules contraceptives), un dispositif intra-utérin (stérilet), l’abstinence sexuelle, la vasectomie, l’utilisation de diaphragmes avec spermicides et l’utilisation de préservatifs. Noter que l’utilisation de préservatifs ou d’un diaphragme avec spermicide ne sont pas des méthodes suffisamment efficaces si elles sont utilisées seules. L’abstinence périodique (par exemple en fonction du calendrier d’ovulation ou de la courbe thermique), ainsi que le retrait (coït interrompu) ne sont pas des méthodes efficaces de contraception.
    7) Maladie avec handicap neurologique autre que la sclérose en plaques
    8) Introduction d'un nouveau traitement dans les 3 mois précédents l'inclusion, ou dans le mois précédent pour la fampridine
    E.5 End points
    E.5.1Primary end point(s)
    Mean change in best corrected visual acuity (logMAR) at 100% contrast between baseline and month 6 of the diseased eye (where the diseased eye is defined as the eye with the worst visual acuity (<5/10) at baseline and with evidence of worsening during the past three years)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Selection visit M-1,
    Inclusion visit M0,
    Interim visit M3,
    End of blinded period visit M6,
    Interim visit M9,
    Interim visit M12
    Interim visit M18
    Biannual follow-up visits
    E.5.2Secondary end point(s)
    1. A Fisher’s exact test will be used to compare the proportions of patients with improvement of VA of the diseased eye of at least 0.3 logMAR at M6
    2. A Fisher’s exact test will be used to compare the proportions of patients with improvement of bilateral AV from <5(70 ETDRS visual acuity score) to ≥5/10 (70 visual acuity score)) at 100% contrast at M6
    3. A logistic model using a generalized estimating equations (GEE) approach will be used to compare the proportions of eyes with reappearance of P100 waves or improvement of P100 latencies≥10 ms at M6
    4. Mann-Whitney’s U test will be performed to compare the mean values of CGI at M6 (clinical global impression evaluated by the patient (SGI) and by the clinician (CGI),
    5. Mann-Whitney’s U test will be used to compare the mean change in NEIFVQ-25 (functional vision questionnaire) between baseline and M6,
    6. Mann-Whitney’s U test will be used to compare the mean change in the SF36 subscores between baseline and M6

    In addition, the following endpoints will be used as exploratory endpoints to provide additional support.

    End of the placebo-controlled period at M6:
    - The proportion of patients with improvement of VA of the selected eye of at least 0.1 and 0.2 logMAR at 100% contrast at M6 will be displayed by treatment group. A Fisher’s exact test will be used to compare the proportions of patients with improvement of VA of the selected eye of at least 0.1 and 0.2 logMAR at M6.
    - Mean changes in visual acuity of the non-selected eye between M0 and M6 at 100% contrast. An ANCOVA on mean changes with adjustment on visual acuity at baseline will be performed as well as a Welch t-test and a Wilcoxon-Mann-Whitney test;
    - Mean changes in visual acuity of all eyes between M0 and M6 at 100% contrast. A generalized estimating equations (GEE) approach will be performed;
    - Mean change in bilateral visual acuity at 100% contrast between baseline and M6 (M12 and M18 for the extension phase). An ANCOVA on mean changes with adjustment on visual acuity at baseline will be performed
    - Mean change in visual acuity of the selected eye at 5% contrast between baseline and M6 (M12 and M18 for the extension phase). An ANCOVA on mean changes with adjustment on visual acuity at baseline will be performed as well as a Welch t-test and a Wilcoxon-Mann-Whitney test.
    - Mean change in visual acuity of all eyes at 5% contrast between baseline and M6 (M12 and M18 for the extension phase). LogMAR at 5% contrast as well as mean changes in visual acuity of all eyes between baseline and M6 will be summarized by treatment group. A GEE model will be also performed adjusting on center and baseline values.
    - The proportion of patients with at least one eye improved by at least 0.3 logMAR at 5% contrast at M6 will be displayed by treatment group. A Fisher’s exact test will be used to compare the proportions of patients with at least one eye improved by at least 0.3 logMAR at 5% contrast at M6. The same analyses will be performed other cut off values of 0.1 and 0.2 logMAR.
    - Mean changes in the mean deviation visual field defects of the selected eye between baseline and M6 will be summarized by treatment group. An ANCOVA on mean changes with adjustment on baseline values will be performed.
    - Mean changes in the mean deviation visual field defects of all eyes between M0 and M6 (generalized estimating equations (GEE) approach);
    - Mean changes in the Pattern Standard Deviation between M0 and M6 (generalized estimating equations (GEE) approach);
    - Mean changes in RNFL values of all eyes between baseline and M6 (generalized estimating equations (GEE) approach);
    - Mean changes in temporal RNFL values of all eyes between baseline and M6 (generalized estimating equations (GEE) approach);
    - Mean changes in macula volume between baseline and M6 (generalized estimating equations (GEE) approach);
    - Mean changes in selected latencies of all eyes between M0 and M6 will be compared between the treatment groups using a GEE approach with adjustment on baseline values. Mean changes between M0 and M12 will be also described by treatment group.
    - Mean changes in selected amplitudes of all eyes between M0 and M6 will be compared between the treatment groups using a GEE approach with adjustment on baseline values. Mean changes between M0 and M12 will be also described by treatment group.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Selection visit M-1,
    Inclusion visit M0,
    Interim visit M3,
    End of blinded period visit M6,
    Interim visit M9,
    Interim visit M12
    Interim visit M18
    Biannual follow-up visits until market authorization application, i.e. M36
    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) 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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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 concerned19
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Last visit last patient
    Dernière visite dernier patient
    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 months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 105
    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 state95
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 105
    F.4.2.2In the whole clinical trial 0
    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
    Aucun
    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 Decision2013-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-01
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