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    Summary
    EudraCT Number:2016-000700-29
    Sponsor's Protocol Code Number:MD1003CT2016-01MS-SPI2
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-12-09
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2016-000700-29
    A.3Full title of the trial
    Effect of MD1003 in progressive multiple sclerosis: a randomized double blind placebo controlled study.
    Efecto de MD1003 en la esclerosis múltiple progresiva: estudio aleatorizado, en doble ciego y controlado con placebo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of MD1003 in progressive multiple sclerosis with walking impairment
    Efecto de MD1003 en esclerosis múltiple con dificultad para caminar.
    A.3.2Name or abbreviated title of the trial where available
    SPI2
    SPI2
    A.4.1Sponsor's protocol code numberMD1003CT2016-01MS-SPI2
    A.5.4Other Identifiers
    Name:ClinicalTrials.govNumber:NCT02936037
    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 PHARMACEUTICALS SA
    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 pharmaceuticals SA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedday Pharmaceuticals
    B.5.2Functional name of contact pointclinical trials information desk
    B.5.3 Address:
    B.5.3.1Street Address96 boulevard Haussmann
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75008
    B.5.3.4CountryFrance
    B.5.4Telephone number+3301 81 51 66 66
    B.5.5Fax number+3301 81 51 66 77
    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 nameD-Biotin
    D.3.2Product code MD1003
    D.3.4Pharmaceutical form Capsule, hard
    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 INND-BIOTIN
    D.3.9.1CAS number 58-85-5
    D.3.9.2Current sponsor codeMD1003
    D.3.9.4EV Substance CodeSUB32335
    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, hard
    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
    Multiple sclerosis
    Esclerosis Múltiple
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis
    Esclerosis Múltiple
    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 19.0
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To confirm the superiority of MD1003, 300 mg/day, over placebo to clinically improve patients with progressive multiple sclerosis (MS).
    Demostrar la superioridad de MD1003, 300 mg/día, respecto al placebo para mejorar clínicamente a los pacientes con esclerosis múltiple (EM) progresiva.
    E.2.2Secondary objectives of the trial
    To evaluate the safety of MD1003
    Evaluar la seguridad de MD1003
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient aged 18-65 years old
    2. Signed and dated written informed consent form in accordance with local regulations: having freely given their written informed consent to participate in the study
    3. Diagnosis of primary or secondary progressive MS fulfilling revised McDonald criteria (2010) and Lublin criteria (2014)
    4. Documented evidence of clinical disability progression within the 2 years prior to inclusion, i.e. a) progression of EDSS during the past two years of at least 1 point sustained for at least 6 months if inclusion EDSS is from 3.5 to 5.5 or at least 0.5 point increase sustained for at least 6 months if inclusion EDSS is from 6 to 6.5 or b) increase of TW25 by at least 20% in the last two years sustained for at least 6 months or c) other well-documented objective worsening validated by the Adjudication Committee
    5. EDSS at inclusion from 3.5 to 6.5
    6. TW25 < 40 seconds
    7. Kurtzke pyramidal functional subscore ≥2 defined as “minimal disability: patient complains of motor-fatigability or reduced performance in strenuous motor tasks (motor performance grade 1) and/or BMRC grade 4 in one or two muscle groups”
    1. Paciente de 18-65 años
    2. Documento de consentimiento informado por escrito firmado y fechado de acuerdo con las regulaciones locales: consentimiento informado por escrito para participar en el estudio otorgado libremente
    3. Diagnóstico de EM progresiva primaria o secundaria que cumpla los criterios de McDonald revisados (2010) y los criterios de Lublin (2014)
    4.Evidencia documentada de progresión de la discapacidad clínica en los 2 años previos a la inclusión, es decir, a) progresión en la EDSS en los dos últimos años de al menos 1 punto sostenida durante un mínimo de 6 meses si la EDSS en la inclusión es de 3,5 a 5,5, o de al menos 0,5 puntos sostenida durante un mínimo de 6 meses si la EDSS en la inclusión es de 6 a 6,5, o b) aumento del TW25 de al menos 20% en los dos últimos años sostenido durante un mínimo de 6 meses, o c) otro empeoramiento objetivo bien documentado validado por el Comité de Adjudicación
    5.EDSS en la inclusión de 3,5 a 6,5
    6.TW25 < 40 segundos
    7.Subescala de la función piramidal de Kurtzke ≥2 definida como “discapacidad mínima: el paciente se queja de fatiga motora o reducción funcional en tareas motoras vigorosas (función motora de grado 1) y/o BMRC de grado 4 en uno o dos grupos musculares”
    E.4Principal exclusion criteria
    1. Clinical evidence of a relapse in 24 months prior to inclusion
    2. Treatment with any product containing biotin as single ingredient within six months prior to inclusion (multivitamin supplementation authorized if biotin < 1mg per day)
    3. Concomitant treatment with fampridine at inclusion or in the 30 days prior to inclusion
    4. New immunosuppressive/immunomodulatory drug initiated less than 90 days prior to inclusion
    5. Treatment with botulinium toxin (except for cosmetic purpose) initiated within 6 months prior to inclusion
    6. In-patient rehabilitation program within the 3 months prior to inclusion
    7. Pregnancy, breastfeeding or women with childbearing potential without acceptable form of contraception
    8. Men unwilling to use an acceptable form of contraception
    9. Any general chronic handicapping/incapacitating disease other than MS
    10. Any serious disease necessitating biological follow-up with biological tests using biotinylated antibodies or substrates
    11. Past history of rhabdomyolysis/metabolic myopathy
    12. Known fatty acids beta oxidation defect
    13. Known hypersensitivity or intolerance to biotin, analogues or excipients, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
    14. Patients with hypersensitivity or any contra-indication to Gadolinium
    15. Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer
    16. Laboratory tests out of normal ranges considered by the investigator as clinically significant with regards to the study continuation
    17. Patients with history or presence of alcohol abuse or drug addiction
    18. Untreated or uncontrolled psychiatric disorders, especially suicidal risk assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
    19. Participation in another research study involving an investigational product (IP) in the 90 days prior to inclusion, or planned use during the study duration
    20. Patients likely to be non-compliant to the study procedures or for whom a long-term follow-up seems to be difficult to achieve
    21. Relapse that occurs between inclusion and randomization visit
    1.Evidencia clínica de recidiva en los 12 meses previos a la inclusión
    2.Tratamiento con cualquier producto que contenga biotina como único ingrediente en los seis meses previos a la inclusión (se autorizan suplementos multivitamínicos si la biotina es < 1 mg/día)
    3.Tratamiento concomitante con fampridina en la inclusión o en los 30 días previos a la inclusión
    4.Nuevo inmunosupresor/inmunomodulador introducido menos de 90 días antes de la inclusión
    5.Tratamiento con toxina botulínica (excepto con fines cosméticos) introducido en los 6 meses previos a la inclusión
    6.Programa hospitalario de rehabilitación en los 3 meses previos a la inclusión
    7.Embarazo, lactancia o mujeres potencialmente fértiles sin un método de anticoncepción adecuado
    8.Varones que no deseen utilizar un método de anticoncepción adecuado
    9.Cualquier enfermedad general crónica discapacitante/incapacitante que no sea la EM
    10.Cualquier enfermedad grave que requiera seguimiento biológico con pruebas biológicas que utilicen anticuerpos o sustratos biotinilados
    11.Antecedentes de rabdomiólisis/miopatía metabólica
    12.Defecto conocido de la beta-oxidación de ácidos grasos
    13.Hipersensibilidad o intolerancia conocidas a la biotina, sus análogos o excipientes, pacientes con problemas hereditarios raros de intolerancia a la galactosa, déficit de lactasa de Lapp o malabsorción de glucosa-galactosa
    14.Pacientes con hipersensibilidad o cualquier contraindicación al gadolinio
    15.Pacientes con trastorno hepático no controlado, enfermedad renal o cardiovascular no controlada, o cáncer
    16.Resultados de pruebas de laboratorio fuera de los límites normales que el investigador considere clínicamente importantes respecto a la continuación del estudio
    17.Pacientes con antecedentes o presencia de alcoholismo o drogadicción
    18.Trastornos psiquiátricos no tratados o no controlados, especialmente riesgo de suicidio evaluado con la Columbia-Suicide Severity Rating Scale (C-SSRS)
    19.Participación en otro estudio de investigación con un producto en investigación (PI) en los 90 días previos a la inclusión, o utilización prevista durante el período del estudio
    20.Pacientes que probablemente no cumplirán con los procedimientos del estudio o en los que se prevé difícil lograr un seguimiento a largo plazo
    21.Recidiva que se produce entre la visita de inclusión y la visita de aleatorización
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint:
    Proportions of patients:
    - with decreased EDSS at M12 confirmed at M15 (where decreased EDSS is defined as a decrease of at least 1 point if initial EDSS from 3.5 to 5.5 and of at least 0.5 point if initial EDSS from 6 to 6.5)
    or
    - with improved TW25 of at least 20% at M12 and M15
    compared to the lowest of the two EDSS and TW25* scores among inclusion and randomization visits
    Criterio principal de evaluación de la eficacia:
    Porcentaje de pacientes:
    -Con disminución de la EDSS el M12 confirmada el M15 (la disminución de la EDSS se define como una disminución de al menos 1 punto si la EDSS inicial es de 3,5 a 5,5 y de al menos 0,5 puntos si la EDSS inicial es de 6 a 6,5)
    o
    -Con mejoría del TW25 de al menos 20% el M12 y el M15
    en comparación con el valor más bajo de las dos puntuaciones de EDSS y TW25* en las visitas de inclusión y de aleatorización.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - month 12 and 15
    Mes 12 y 15
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints
    1. Time to EDSS progression confirmed at 12 weeks
    - CGI-I score (clinical global impression of change – improvement), evaluated both by the patient (SGI) and by the evaluating physician (CGI)
    - Mean change in TW25 between M0 and M15

    Exploratory endpoints
    - Brain MRI changes between M0 and M15
    a. Thalamic volume change
    b. Percent brain volume change
    c. Cortical grey matter volume change
    d. Brain water content change evaluated by Pseudo T2 relaxation time
    e. NAA/Cr in a subset of sites acquiring MRS
    - Remote monitoring of ambulation
    - Multiple Sclerosis Quality of Life-54 (MSQOL54) and Caregiver health-related quality of life in Multiple Sclerosis (CAREQOL-MS) subscores and composite scores
    - Subscores of the Kurtzke functional score
    - Symbol digit modalities test (SDMT)

    Safety evaluation
    - Recording of AEs
    - Laboratory testing (standard hematology and biochemistry panel)
    - ECG: PR interval, QRS, QT/QTc
    - Brain MRI
    - Columbia-Suicide Severity Rating Scale
    Criterios secundarios de evaluación de la eficacia
    1. Tiempo hasta la progresión de la EDSS confirmada a las 12 semanas
    -Puntuación de la CGI-I (clinical global impression of change – improvement; impresión clínica global de cambio – mejoría), evaluada por el paciente (SGI) y por el médico (CGI)
    - Cambio medio del TW25 entre M0 y M15

    Criterios de evaluación exploratorios
    -Cambios en la RM cerebral entre M0 y M15
    a.Cambio del volumen del tálamo
    b.Cambio porcentual del volumen del cerebro
    c.Cambio del volumen de la sustancia gris de la corteza
    d.Cambio del contenido hídrico del cerebro evaluado mediante el tiempo de pseudorelajación en T2
    e.NAA/Cr en un subgrupo de centros que dispongan de espectroscopia por resonancia magnética (MRS)
    -Monitorización remota de la deambulación
    -Subescalas de calidad de vida en la esclerosis múltiple 54 (MSQOL54) y calidad de vida relacionada con la salud del cuidador en la esclerosis múltiple (CAREQOL-MS) y puntuaciones compuestas
    -Subescalas de la escala funcional de Kurtzke
    -Prueba de modalidades de símbolos y dígitos (SDMT)


    Evaluación de la seguridad
    -Registro de los acontecimientos adversos
    -Analítica de laboratorio (pruebas estándar de hematología y bioquímica)
    -ECG: Intervalo PR, QRS, QT/QTc
    -RM cerebral
    -Columbia-Suicide Severity Rating Scale (Escala de clasificación de la severidad del riesgo de suicidio de Columbia)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Month 12, month 15
    Mes 12, mes 15
    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) 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Canada
    Czech Republic
    Germany
    Italy
    Spain
    Sweden
    United Kingdom
    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
    LVLS
    Última visita última paciente
    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 months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    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: 370
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 103
    F.4.2.2In the whole clinical trial 375
    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)
    Standard of care
    Práctica habitual
    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 Decision2017-02-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-03
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-03-10
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