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    Summary
    EudraCT Number:2018-002648-10
    Sponsor's Protocol Code Number:7109
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-04-03
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-002648-10
    A.3Full title of the trial
    TestOsterone TreatmEnt on neuroprotection and Myelin repair in Relapsing Remitting Multiple Sclerosis
    Traitement de la SEP récurrente-rémittente (SEP-RR) par la testostérone :
    effets potentiels sur la neuroprotection et la remyélinisation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TestOsterone TreatmEnt in Relapsing Remitting Multiple Sclerosis
    Traitement de la SEP récurrente-rémittente (SEP-RR) par la testostérone
    A.3.2Name or abbreviated title of the trial where available
    TOTEM-RRMS
    TOTEM-RRMS
    A.4.1Sponsor's protocol code number7109
    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 SponsorHôpitaux Universitaires de Strasbourg
    B.1.3.4CountryFrance
    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 supportDGOS
    B.4.2CountryFrance
    B.4.1Name of organisation providing supportBAYER PHARMA AG
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportFHU Neurogenycs
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHôpitaux Universitaires de Strasbourg
    B.5.2Functional name of contact pointEric DEMONSANT
    B.5.3 Address:
    B.5.3.1Street Address1 place de l'Hôpital
    B.5.3.2Town/ cityStrasbourg
    B.5.3.4CountryFrance
    B.5.6E-maildpidrci@chru-strasbourg.fr
    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 Yes
    D.2.1.1.1Trade name NEBIDO
    D.2.1.1.2Name of the Marketing Authorisation holderBAYER HEALTHCARE
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTestosterone
    D.3.9.3Other descriptive nameTESTOSTERONE UNDECANOATE
    D.3.9.4EV Substance CodeSUB04744MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000/4
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntramuscular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsing Remitting Multiple sclerosis
    Sclérose en Plaques Récurrente Rémittente
    E.1.1.1Medical condition in easily understood language
    Multiple sclerosis
    Sclérose 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 20.0
    E.1.2Level PT
    E.1.2Classification code 10063399
    E.1.2Term Relapsing-remitting 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 evaluate the remyelinating and neuroprotective effect of testosterone treatment used for 54 weeks in natalizumab-treated RRMS patients (Tysabri®) using a combination of thalamus atrophy and diffusion tensor measured by MRI.
    Evaluer l’effet remyélinisant et neuro-protecteur d’un traitement par la testostérone utilisé pendant 54 semaines chez des patients atteints de SEP-RR traités par natalizumab (Tysabri®) sur un critère combinant l'analyse de l’atrophie du thalamus et du tenseur de diffusion mesurés par IRM.
    E.2.2Secondary objectives of the trial
    - To Evaluate the effectiveness of the treatment on advanced parameters in MRI.
    - To evaluate the clinical effectiveness of the treatment and its tolerance.
    - Evaluer l’efficacité du traitement sur des paramètres avancés en IRM.
    - Evaluer l'efficacité clinique du traitement et sa tolérance.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Identify new biomarkers predictive of the evolution of the disease through the establishment of a biobank of blood samples.
    Identifier de nouveaux biomarqueurs prédictifs de l’évolution de la maladie grâce à la constitution d’une biobanque d’échantillons sanguins.
    E.3Principal inclusion criteria
    - Man between 18 and 55 years
    - Confirmed and documented diagnosis of MS, as defined by the revised McDonald criteria
    - Patient treated with intravenous infusions of natalizumab (Tysabri®, 300 mg) once every 4 weeks for at least 1 year prior to randomization
    - Biological hypogonadism defined by serum total testosterone levels below 15 nmol / L (checked by blood sampling during the screening visit)
    - Negative status for JC virus or JC virus synthesis index ≤ 1.5 (within 6 months prior to screening visit)
    - No relapses in the year prior to inclusion
    - Disability status during the selection visit with an EDSS score of 0 to 7 (verified by questionnaire during the inclusion visit)
    - Stable neurological state in the month preceding randomization
    - Homme âgé de 18 à 55 ans inclus
    - Diagnostic de SEP-RR confirmé et documenté, tel que défini par les critères de McDonald révisés
    - Patient ayant comme traitement de fond des perfusions intraveineuses de natalizumab (Tysabri®, 300 mg) une fois toutes les 4 semaines depuis au moins un an avant la randomisation
    - Hypogonadisme biologique défini par un taux de testostérone totale sérique strictement inférieur à 15 nmol/L (vérifié par prélèvement sanguin à la visite de sélection)
    - Statut négatif pour le virus JC ou un index de synthèse de virus JC ≤ 1,5 (dans les 6 mois précédant la visite de sélection)
    - Absence de poussées dans l’année qui précède la randomisation
    - Etat neurologique stable dans le mois précédant la randomisation
    E.4Principal exclusion criteria
    - Patients with progressive MS (primary or secondary)
    - Patients with hypogonadism with clinical symptoms and treated with androgens
    - Patients with PSA (prostate specific antigen)> 2.5 ng / ml (for an age less than 49 years old) or> 3.5 ng / ml (for age ≥ 50 years) (checked by a blood test at screening visit)
    - Patients with a hemoglobin concentration> 16 g / dL (checked by blood sampling during the screening visit)
    - Patients with any other disease other than MS that may contribute to neurological symptoms and signs or affect their evaluation
    - Patients with neurological signs compatible with PML or confirmed PML
    - Patients diagnosed with untreated sleep apnea
    - Patients with or having had cancer or tumors of the liver, heart, kidney, prostate or mammary gland
    - Patients with cardiovascular, renal, hepatic, hematological, gastrointestinal, pulmonary, uncontrolled diseases
    - Patients with chronic infectious disease
    - Patients with a history of hypersensitivity to Nebido® or any of the excipients, or drugs of similar chemical classes
    - Patients who used experimental drugs and / or who participated in clinical drug trials in the 6 months prior to selection
    -Patient atteint de SEP progressive (primaire ou secondaire)14
    -Patient souffrant d’hypogonadisme avec symptômes cliniques et traités avec des androgènes
    -Patient ayant un taux de PSA (Prostate specific antigen) > 2,5 ng/ml (pour un âge inférieur à 49 ans) ou > 3,5 ng/ml (pour un âge supérieur ou égal à 50 ans) (dans les 3 mois précédant la sélection ou vérifié par prélèvement sanguin à la visite de sélection)
    -Patient ayant une concentration d’hémoglobine > 16 g/dL (dans les 3 mois précédant la sélection ou vérifié par prélèvement sanguin à la visite d’inclusion)
    -Patient sous anticoagulants oraux nécessitant un INR >3
    -Patient souffrant de toute autre maladie autre que la SEP pouvant contribuer aux symptômes et signes neurologiques ou en affecter l’évaluation
    -Patient présentant des signes neurologiques compatibles avec une LEMP ou une LEMP confirmée
    -Patient diagnostiqué pour une apnée du sommeil non traitée
    -Patient atteint ou ayant souffert de cancer ou de tumeurs hépatiques, cardiaques, rénales, de la prostate ou des glandes mammaires
    -Patient présentant des pathologies cardio-vasculaires, une insuffisance rénale ou hépatique, hématologiques, gastro-intestinales, pulmonaires, incontrôlées
    -Patient atteint d’une maladie infectieuse chronique
    -Patient atteint d’une maladie organique ou psychiatrique compromettant sa capacité à comprendre les informations données et à suivre le protocole
    -Patient présentant des antécédents d’hypersensibilité au Nébido® ou à l’un des excipients, ou aux médicaments de classes chimiques similaires
    -Patient ayant utilisé des médicaments expérimentaux et/ou ayant participé à des études cliniques portant sur des médicaments dans les 6 mois précédant la sélection
    E.5 End points
    E.5.1Primary end point(s)
    Binary criterion comparing the success rate in each treatment group, defined by thalamic atrophy less than 0.5% per year and / or a decrease in transverse diffusivity in lesions less than 0.5% per year.
    Critère binaire comparant le taux de succès dans chaque groupe de traitement, défini par une atrophie thalamique inférieure à 0.5% par an et/ou une diminution de la diffusivité transversale dans les lésions inférieure à 0.5% par an.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 54 weeks of study drug (Visit 6)
    Après 54 semaines de traitement (Visite 6)
    E.5.2Secondary end point(s)
    Efficiency of treatment by imaging:
    • evolution of conventional MRI parameters: volume and number of T1 hypointense lesions, volume and number of new or enlarged T2 lesions, total volume of hyper-intensity FLAIR.
    • evolution of unconventional MRI parameters: diffusion tensor imaging (NODDI), quantitative magnetization transfer imaging (MPF).

    Clinical efficiency of treatment:
    • Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) test consisting of the symbol digit modalities test (SDMT), the California Verbal Learning Test Second Edition (CVLT2), and the Brief Visuospatial Memory Test Revised (BVMTR) test,
    • Changes in quality of life and health-related quality of life as measured by the SF-36 and EQ-5D (European quality of life in 5 dimensions) questionnaires respectively.
    • Impact of MS on workplace productivity and day-to-day activities, as assessed by the WPAI (Work productivity and activity impairment) questionnaire.
    • Impact on fatigue, as measured by the Multi-Dimensional Fatigue Impact Scale (MFIS),
    • Hospital assessment scale for anxiety and depression, as measured by the hospital anxiety and depression scale (HADS) questionnaire.
    • Evolution of handicap by the EDSS Score

    Safe use of the treatment: number and nature of adverse events, evaluation of vital signs at each visit, clinical and neurological examinations, biological results, locally interpreted MRI for tolerance (non-MS pathology of the CNS) and monitoring of concomitant medications ( outside Tysabri®).
    Efficacité du traitement à l’imagerie :
    • évolution des paramètres d'IRM conventionnels : volume et nombre des lésions hypointenses en T1, volume et nombre des lésions T2 nouvelles ou élargies, volume total de l’hyper-intensité FLAIR.
    • évolution des paramètres d’IRM non conventionnels : imagerie de tenseur de diffusion (NODDI), imagerie quantitative du transfert de magnétisation (MPF).

    Efficacité clinique du traitement :
    • Test BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) composé du test de modalité de chiffres et de symboles (SDMT, Symbol digit Modalities Test), du test d’apprentissage verbal de Californie (CVLT2, California Verbal Learning Test second edition), et du test de la mémoire visuo-spatiale brève-version révisée (BVMTR, Brief Visuospatial Memory Test Revised),
    • Modifications en termes de qualité de vie, et de qualité de vie liée à la santé, mesurées par les questionnaires SF-36 et EQ-5D (European quality of life in 5 dimensions) respectivement,
    • Impact de la SEP sur la productivité au travail et les activités quotidiennes, telles qu'évaluées par le questionnaire WPAI:MS (Work productivity and activity impairment).
    • Impact sur la fatigue, tel que mesuré par l’inventaire multi-dimensionnel de la fatigue (MFIS, Modified fatigue impact scale),
    • Échelle hospitalière d’évaluation de l'anxiété et de la dépression, telle que mesurée par le questionnaire HADS (Hospital anxiety and depression scale).
    • Evolution du handicap par le Score EDSS

    Sécurité d'emploi du traitement : nombre et nature des évènements indésirables, évaluation des signes vitaux à chaque visite, examens cliniques et neurologiques, résultats biologiques, IRM interprétées localement pour la tolérance (pathologies du SNC non-SEP) et suivi des médicaments concomitants (hors Tysabri®).
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 54 weeks of study drug (Visit 6)
    Après 54 semaines de traitement (Visite 6)
    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) 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 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 concerned4
    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 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 of the last subject
    dernière visite du dernier sujet participant à l'étude
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months43
    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: 80
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state80
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-04-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-15
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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