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    Summary
    EudraCT Number:2017-000635-13
    Sponsor's Protocol Code Number:EMMA
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-02-22
    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 - BfArM
    A.2EudraCT number2017-000635-13
    A.3Full title of the trial
    Escalating therapy in steroid-refractory relapses of multiple sclerosis – comparison of methylprednisolone to immunoadsorption
    Eskalationstherapie des MS-Schubs mit Methylprednisolon vs. Immunadsorption
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Escalating therapy in steroid-refractory relapses of multiple sclerosis – comparison of methylprednisolone to immunoadsorption
    Eskalationstherapie des MS-Schubs mit Methylprednisolon vs. Immunadsorption
    A.4.1Sponsor's protocol code numberEMMA
    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 SponsorUniversität Leipzig
    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 supportDeutsche Forschungsgesellschaft DFG
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportFresenius Medical Care GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportMiltenyi Biotec GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportDIAMED Medizintechnik GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversität Leipzig
    B.5.2Functional name of contact pointKlinik und Poliklinik für Neurologi
    B.5.3 Address:
    B.5.3.1Street AddressLiebigstr. 20
    B.5.3.2Town/ cityLeipzig
    B.5.3.3Post code04103
    B.5.3.4CountryGermany
    B.5.4Telephone number004903419724307
    B.5.5Fax number004903419724219
    B.5.6E-mailthenbergf@medizin.uni-leipzig.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Powder and solution for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMethylprednisolone
    D.3.9.3Other descriptive nameMETHYLPREDNISOLONE
    D.3.9.4EV Substance CodeSUB08872MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2000
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple Sclerosis (MS), acute episode
    Multiple Sklerose (MS), akuter Schub
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis (MS), acute episode
    Multiple Sklerose (MS), akuter Schub
    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 HLT
    E.1.2Classification code 10052785
    E.1.2Term Multiple sclerosis acute and progressive
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To prove the superiority of immunoadsorption over a 2nd course of methylprednisolone as an escalating treatment of steroid refractory relapses in RRMS and CIS.
    Nachweis der Überlegenheit der Immunadsorption über eine zweite Gabe von Methylprednisolon als eskalierende Steroidbehandlung von therapierefraktären Schüben bei schubförmiger Multipler Sklerose und klinisch isolierten Syndrom einer Demyelinisierung des ZNS (clinically isolated syndrome of CNS demyelination, CIS).
    E.2.2Secondary objectives of the trial
    Validation of the superiority of immunoadsorption based on further neurological evaluations (e.g. MS functional composite/MSFC) and comparison of the two treatment modalities regarding safety and patient satisfaction (acceptance, well-being, quality of life).
    Validierung der Überlegenheit der Immunadsorption anhand weiterer neurologischer Auswertungen und Vergleich der beiden Behandlungsmodalitäten in Bezug auf Sicherheit und Patienten-zufriedenheit (Akzeptanz, Wohlbefinden, Lebensqualität
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Analyses of prognostic measures for response to 1st IVMP course
    In addition, there is an external responder group defined as patients screened but not randomized because of a satisfactory response to the 1st IVMP escalation therapy (data capture at screening and on day 180 will be performed).
    Analyse von prognostischen Faktoren für das Ansprechen auf die erste IVMP Therapie
    Zusätzlich gibt es eine "external responder Group" von Patienten, die gescreent wurden, aber nicht randomisiert wurden, da die erste IVMP Eskalationstherapie zufriedenstellend gewirkt hat. Von diesen Patienten werden Daten zu Screening und nach 180 Tagen erfasst.
    E.3Principal inclusion criteria
    1. ≥ 18 years
    2. Diagnosis of MS (according to McDonald criteria, revision of 2017) or of clinically isolated syndrome of CNS demyelination
    3. Acute relapse (new or recurring symptoms lasting at least 24 hrs, affecting the subject’s activities of daily living [ADL])
    4. Initial therapy of current relapse with IVMP (2500 - 5000 mg total dose) with unsatisfactory response
    5. EDSS at screening 2.0-8.0
    6. At screening, interval since onset of current relapse maximum 28 days
    7. At screening, interval since end of initial course of IVMP** at least 7 days
    8. Before onset of qualifying MS relapse, clinically stable for at least 30 days
    9. Written informed consent
    1. ≥ 18 Jahre alt
    2. Diagnose MS (gem. McDonald criteria, revision of 2017) oder klinisch isoliertes Syndrom (KIS) einer ZNS-Demyelinisierung
    3. Akuter Schub (neue oder wiederkehrende Symptome, die mindestens 24 Stunden anhalten und die täglichen Aktivitäten des Patienten beeinträchtigen) [activities of daily living, ADL]
    4. Initiale Therapie des aktuellen Schubs mit intravenöses Methylprednisolon (IVMP, 2500 - 5000 mg Gesamtdosis) mit unzureichendem Ansprechen
    5. EDSS beim Screening 2,0-8,0
    6. Beim Screening: Intervall seit Beginn des aktuellen Schubs maximal 28 Tage
    7. Beim Screening: Intervall seit Ende der ersten IVMP-Gabe mindestens 7 Tage
    8. Vor Beginn des MS-Schubs: klinisch stabil für mindestens 30 Tage
    9. Schriftliche Einverständniserklärung
    E.4Principal exclusion criteria
    1. Primary (PPMS) or secondary progressive MS (SPMS)
    2. Pseudo-relapse associated with fever or infection. Assessment of a potential pseudo-relaose will be performed at screening and include a) history, b) clinical findings on physical examination, c) vital signs and d) laboratory results.
    3. Known chronic autoimmune disorder (except for autoimmune thyroidits with hypothyroidism under sufficient substitution treatment) or deteriorating neurological condition except for MS
    4. Known malignant disease within 5 years of screening (except for localized basal cell carcinoma)
    5. Current or past relevant psychiatric disease (dementia, dissociative disorder, psychotic features, schizophrenia)
    6. Current depression (if BDI > 17 pts., thorough clinical evaluation is necessary to determine if MP therapy is feasible)
    7. Known allergies against methylprednisolone, a component of the MP product to be used locally; or against any components of immunoadsorption columns potentially used at the study site (i.e. camelid immunoglobulins or agarose if TheraSorb® may be used; protein A/ Peptid GAM if Immunosorba/Globaffin® may be used)
    8. Side-effects from MP during the initial treatment course that would, if recurring, foreseeably lead to MP discontinuation
    9. Contraindications to the use of methylprednisolone:
    • Insufficiently controlled diabetes
    • Insufficiently controlled arterial hypertension;
    • active infection with elevated inflammation parameters (e.g. hemogram, CrP);
    • tuberculosis (According to the Fachinformation (SmPC) for methylprednisolone, tuberculosis should be ruled out before any administration of i.v. methylprednisolone; unless a chest X-ray was performed and found unremarkable within the past year, a chest X-ray is recommended. Such chest X-ray constitutes part of clinical routine and is not a study procedure. )
    • vaccination with a live vaccine within 2 weeks before randomization;
    • severe osteoporosis / osteopenia;
    10. Contraindications to the use of IA:
    • Current use of ACE-inhibitors or sartans (taken within 3 d prior to visit 3/beginning of treatment), which can neither be replaced nor paused
    • Known disorders of the hemostatic system of vascular (e.g. von Willebrand syndrome), coagulation (e.g. hemophilia) or cellular (e.g. thrombocytopenia) origin
    • Conditions that prohibit anticoagulation using heparin and/or citrate
    11. Abnormal results of coagulation tests, or thrombocytopenia at Screening acc. to local laboratory reference values
    12. Known active infection with hepatitis B, C or HIV
    13. Any condition which is, at the time of screening and foreseeably for the remaining study period, severely compromising immune function (e.g. AIDS, severe systemic infection)
    14. Current drug abuse
    15. Pregnant or breast feeding women
    16. Women of child bearing potential without highly effective contraceptive measures (Clinical Trial Facilitation Group (CTFG) 9/15/2014) during the interval between screening and day 45.
    17. Anticipated poor compliance (e.g. due to long travel distance to the trial site)
    18. Current participation in other interventional clinical trial
    19. Patients under legal supervision or guardianship.
    20. Patients placed in an institution by official or court order
    1. Primär oder sekundär progrediente MS
    2. Pseudo-Schub in Verbindung mit Fieber oder Infektion. Das Vorhandenseins eines Pseudo-Schubs wird bei Screening beurteilt unter Berücksichtigung a) der Anamnese, b) klinische Befunde der körperlichen Untersuchungen, c) Vitalparameter und d) Laborbefunde.
    3. Bekannte chronische Autoimmunerkrankung (mit Ausnahme von Autoimmunthyreopathien mit Hypothyreose bei ausreichender Substitutionsbehandlung) oder progrediente neurologische Erkrankung mit Ausnahme von MS
    4. Bekannte maligne Erkrankung innerhalb der letzten 5 Jahren vor Screening(außer lokalisierte Basalzellkarzinome)
    5. Aktuelle oder frühere relevante psychiatrische Erkrankung (Demenz, dissoziative Störung, psychotische Symptome, Schizophrenie)
    6. Aktuelle Depression (wenn BDI* >17 Punkte, ist eine gründliche klinische Bewertung notwendig, um die MP-Therapie-Option einzuschätzen)
    7. Bekannte Methylprednisolon-Allergie, sowie gegen lokal zu verwendende Komponenten des Medizin-Produktes oder gegen Komponenten der Immunadsorptionssäulen (TheraSorb®: Cameliden Immunglobuline oder Agarose; Immunosorba/Globaffin®: Protein A/Peptid GAM)
    8. Nebenwirkungen von Methylprednisolon, die bereits während des anfänglichen Behandlungsverlaufs aufgetreten sind und bei Wiederholung perspektivisch zu einem Abbruch der MP-Behandlung führen würden
    9. Kontraindikationen für die Verwendung von Methylprednisolon:
    • unzureichend kontrollierter Diabetes
    • unzureichend kontrollierte arterielle Hypertonie
    • aktive Infektion mit erhöhten Entzündungsparametern (z. B. Blutbild, CRP)
    • Tuberkulose (Patienten mit einer Tuberkulose sind gemäß der Fachinformation von Methylprepnisolon von der Studie auszuschließen bevor jeglicher Verabreichung von Methylprednisolon i.v.. Falls nicht im letzten Jahr ein Röntgen-Thorax durchgeführt worden ist und als unauffällig befunden wurde, wird die Durchführung eines Röntgen-Thorax empfohlen. Eine solche Röntgen-Thorax-Untersuchung gehört zur klinischen Routine und ist keine Studienprozedur).
    • Impfung mit einem Lebendimpfstoff innerhalb von 2 Wochen vor der Randomisierung
    • schwere Osteoporose/Osteopenie
    10. Kontraindikationen für die Verwendung von IA:
    • Aktuelle Anwendung von ACE-Hemmern oder Sartanen (Einnahme innerhalb von 3 Tagen vor der Visite 3/Beginn der Behandlung), die weder ersetzt noch pausiert werden können
    • Bekannte Erkrankungen des hämostatischen Systems: vaskulären (z.B. von Willebrand-Syndrom), Gerinnungs- (z.B. Hämophilie) oder zellulären (z.B. Thrombozytopenie) Ursprungs
    • Bedingungen, bei denen eine Antikoagulation mit Heparin und/oder Citrat kontraindiziert ist
    11. Abnorme Ergebnisse von Gerinnungstests oder Thrombozytopenie beim Screening gemäß den lokalen Laborwerten
    12. Bekannte aktive Infektion mit Hepatitis B, C oder HIV
    13. Jeder Zustand, der zum Zeitpunkt des Screenings und vorhersehbar für den verbleibenden Studienzeitraum eine stark beeinträchtigende Immunfunktion darstellt (z.B. AIDS, schwere systemische Infektion).
    14. Derzeitiger Drogenmissbrauch
    15. Schwangere oder stillende Frauen
    16. Frauen im gebärfähigen Alter ohne hochwirksame Empfängnisverhütung zwischen Screening und Tag 45
    17. Erwartete mangelnde Kooperationsbereitschaft (z.B. aufgrund eines langen Anfahrtsweges zum Prüfzentrum
    18. Aktuelle Teilnahme an anderen interventionellen klinischen Prüfungen
    19. Patienten unter Rechtsaufsicht oder Vormundschaft
    20. Patienten, die aufgrund behördlicher oder gerichtlicher Anordnung in einer Anstalt untergebracht sind
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint: EDSS on day 45 or before start of any rescue treatment after EoT (if applicable)
    EDSS (Expanded Disability Status Scale) am Tag 45 oder vor Beginn einer „Rescue“-Behandlung nach Therapie-Ende (EoT, falls zutreffend).
    E.5.1.1Timepoint(s) of evaluation of this end point
    On day 45 or before start of any rescue treatment after EoT (if applicable)
    Am Tag 45 oder vor Beginn einer „Rescue“-Behandlung nach Therapie-Ende (EoT, falls zutreffend).
    E.5.2Secondary end point(s)
    Key secondary endpoints (sEP)
    • subscore in the functional system predominantly affected by the current relapse (pFS)
    • MSFC
    • visual acuity (by Snellen score); in optic neuritis
    • HRQoL measures
    Wichtige sekundäre Endpunkte:
    • Subscore im Funktionssystem, das überwiegend vom aktuellen Schub betroffen ist (pFS)
    • MSFC (MS Functional Score)
    • Sehschärfe (nach Snellen-Score) bei Optikusneuritis
    • Gesundheitsbezogenen Lebensqualitätsmessungen
    E.5.2.1Timepoint(s) of evaluation of this end point
    On days 45, 90 and 180.
    Am Tag 45, 90 und 180.
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Immunadsorption
    immunoadsorption
    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 concerned10
    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
    Letzte Visite des letzten Patienten
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    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: 140
    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 state140
    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)
    Patients will be treated at the investigator´s discretion.
    Die Patienten werden gemäß der Einschätzung des Prüfers weiterbehandelt.
    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 Decision2018-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-08
    P. End of Trial
    P.End of Trial StatusOngoing
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