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    EudraCT Number:2019-002078-30
    Sponsor's Protocol Code Number:NL70122.078.20
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-03-24
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2019-002078-30
    A.3Full title of the trial
    Autoimmune epilepsy Modulated by IVIg – effects on Cortical Excitability, the AMICE study
    Auto-immuun epilepsie gemoduleerd door IVIg - effect op corticale exciteerbaarheid, de AMICE studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Epilepsie caused by auto antibodies modulated by Privigen - effects on brain excitability
    Epilepsie veroorzaakt door lichaamseigen antistoffen waarvoor behandeling met Privigen - effect op prikkelbaarheid van de hersenen
    A.3.2Name or abbreviated title of the trial where available
    AMICE study
    AMICE studie
    A.4.1Sponsor's protocol code numberNL70122.078.20
    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 SponsorErasmus MC
    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 supportEpilepsiefonds
    B.4.1Name of organisation providing supportInterlaken Leadership Award
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointAutoimmune Encephalitis workgroup
    B.5.3 Address:
    B.5.3.1Street AddressDoctor Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 GD
    B.5.4Telephone number0031107043980
    B.5.5Fax number0031107044727
    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. name Privigen
    D. of the Marketing Authorisation holderCSL Behring GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 namePrivigen
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    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
    Auto-immune epilepsy
    Auto-immuun epilepsy
    E.1.1.1Medical condition in easily understood language
    Epilepsy caused by auto antibodies
    Epilepsie veroorzaakt door lichaamseigen antistoffen
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Providing proof of a therapeutic effect of IVIg in autoimmune epilepsy, both clinically and serologically.
    Het leveren van bewijs voor een therapeutisch van IVIg in auto-immuun epilepsie, zowel klinisch als serologisch.
    E.2.2Secondary objectives of the trial
    - Identifying an objective marker of therapy response in epilepsy, measuring cortical excitability by TMS-EEG, in vivo.
    - Providing evidence that patients’ antibodies affect cortical hyperexcitability, in vitro.
    - Het identificeren van een objectieve marker voor therapie respons in epilepsie, middels het meten van corticale exciteerbaarheid d.m.v. TMS-EEG (in vivo).
    - Het bewijzen dat de antistoffen van patiënten invloed hebben op corticale exciteerbaarheid (in vitro).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age of 18 years and older.
    - Epilepsy, with at least one seizure per week at baseline.
    - Antibodies proven in serum and/or CSF in cell-based assay and/or ELISA and on immunohistochemistry. In case of anti-GAD antibodies, antibody titer with ELISA has to be >10,000 IU in serum or >100 IU in CSF.
    - Leeftijd van 18 of ouder.
    - Epilepsie, met aanvalsfrequentie van tenminste 1 insult per week.
    - Antistoffen aangetoond in serum en/of liquor in cell-based assay en/of ELISA en middels immunohistochemie. In het geval van anti-GAD antistoffen, antistof titer met ELISA moet >10,000 IE zijn in serum en >100 IE in liquor.
    E.4Principal exclusion criteria
    - Another identified cause of epilepsy (i.e. viral/bacterial encephalitis, stroke, tumor).
    - Severe encephalitis in which escalation of therapy (second-line immunotherapy, i.e. Rituximab or Cyclophosphamide) is expected within the study period (mainly anti-NMDAR encephalitis with mRS 5, at the ICU).
    - Use of immunotherapy < 3 months ago.
    - Use of monoclonal antibodies < 1 year ago.
    - Premorbid mRS ≥3.
    - Known hypersensitivity to Privigen or contraindication for Privigen, i.e. IgA deficiency.
    - Patient and/or legal representative is withholding informed consent.
    - Patient objects after initial informed consent.
    - Andere aangetoonde oorzaak van epilepsie (bijv. virale of bacteriële encefalitis, beroerte, tumor).
    - Ernstige encefalitis waarbij indicatie voor escalatie van behandeling (tweedelijns immunotherapie zoals Rituximab of Cyclofosfamide) wordt verwacht in de studieperiode (met name anti-NMDAR encefalitis met mRS 5, op de intensive care).
    - Gebruik van immunotherapie < 3 maanden geleden.
    - Gebruik van monoclonale antistoffen < 1 jaar geleden.
    - Premorbide mRS ≥3.
    - Bekende overgevoeligheid voor Privigen of contra-indicaties voor Privigen, zoals IgA deficiëntie.
    - Patiënt en/of wettelijke vertegenwoordiger weigeren informed consent.
    - Patiënt weigert deelname aan onderzoek na initieel informed consent te hebben gegeven.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients with a seizure frequency reduction >50% and the proportion of patients that achieve full freedom of seizures in week 6, 7 and 8 (compared to the baseline frequency), for all patients with autoimmune epilepsy and compared by subgroup.
    Proportie van patiënten met reductie van de epilepsiefrequentie van >50% en proportie van patiënten die epilepsievrij wordt
    Dit wordt gemeten in week 6, 7 en 8 en wordt vergeleken met de baseline frequentie
    Voor alle patiënten met auto-immuun epilepsie en vergeleken tussen subgroepen.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Seizure frequency is determined by the patient’s diary; by which the average seizure frequency at baseline (baseline frequency is determined by the seizure frequency in the 3 weeks prior to the start of the study) can be compared with week 6, 7, and 8. These averages of 3 weeks give a good impression of the epilepsy frequency.
    Epilepsiefrequentie wordt bepaald d.m.v. het patiëntdagboek. De gemiddelde epilepsiefrequentie op baseline (bepaald door de epilepsiefrequentie in de 3 weken voorafgaande aan de studie) wordt vergeleken met de epilepsiefrequentie in week 6, 7 en 8. Deze gemiddelden van 3 weken geven een goede impressie van de epilepsiefrequentie.
    E.5.2Secondary end point(s)
    - Antibody levels pre- and post-treatment correlated to the seizure frequency, for all patients with autoimmune epilepsy and compared by subgroup. In addition, the amount of patients with antibody titer reduction >50% and the amount of patients that become antibody free, for all patients with autoimmune epilepsy and compared by subgroup.
    - Clinical improvement:
    - Changes in the PNS neurological scale and FAB at 3, 6, 12 and 18 weeks, for all patients with autoimmune epilepsy and compared by subgroup.
    - Changes in the MOCA at 6, 12 and 18 weeks, for all patients with autoimmune epilepsy and compared by subgroup.
    - Changes in the QOLIE-31-P at 3, 6, 12 and 18 weeks, for all patients with autoimmune epilepsy and compared by subgroup.
    - Proportion of patients with a relapse within 18 weeks, for all patients with autoimmune epilepsy and compared by subgroup at 18 weeks.
    - Antistoflevels voor en na behandeling gecorreleerd aan de epilepsiefrequentie, voor alle patiënten met auto-immuun epilepsie en vergeleken tussen de subgroepen. Daarnaast het aantal patiënten die een antistof titer reductie van >50% hebben en het aantal patiënten die antistofvrij worden, voor alle patiënten met auto-immuun epilepsie en vergeleken tussen de subgroepen.
    - Klinische verbetering:
    - Veranderingen in de PNS neurologische schaal en FAB na 3, 6, 12 en 18 weken, voor alle patiënten met auto-immuun epilepsie en vergeleken tussen de subgroepen
    - Veranderingen in de MOCA na 6, 12 en 18 weken, voor alle patiënten met auto-immuun epilepsie en vergeleken tussen de subgroepen
    - Veranderingen in de QOLIE-31-P na 3, 6, 12 en 18 weeks, voor alle patiënten met auto-immuun epilepsie en vergeleken tussen de subgroepen
    - Proportie van patiënten met een terugval binnen 18 weken, voor alle patiënten met auto-immuun epilepsie en vergeleken tussen de subgroepen na 18 weken.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Antibody levels: Blood samples will be achieved at baseline and after 5 days, 3 weeks, 3 weeks and 5 days, 6, 12, and 18 weeks. CSF will be achieved by lumbar puncture at baseline and after 6 weeks.
    - Seizure frequency: will be measured by the patient's diary.
    - Clinical improvement: the PNS neurological scale, FAB and QOLIE-31-P will be performed at baseline and 3, 6, 12 and 18 weeks. The MOCA will be performed at baseline and 6, 12 and 18 weeks.
    - Antistof levels: bloed wordt afgenomen op baseline en na 5 dagen, 3 weken, 3 weken en 5 dagen, 6, 12, en 18 weken. Liquor wordt middels lumbaalpunctie afgenomen op baseline en na 6 weken.
    - Epilepsiefrequentie: wordt bepaald middels het patiëntdagboek.
    - Klinische verbetering: PNS neurologsche schaal, FAB and QOLIE-31-P worden afgenomen op baseline en na 3, 6, 12 en 18 weken. De MOCA wordt afgenomen op baseline en na 6, 12 en 18 weken.
    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. 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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    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 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
    LVLS (laatste controle van de laatste patiënt)
    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 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: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 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 Yes
    F. of subjects incapable of giving consent
    Some patients with autoimmune encephalitis/epilepsy will have cognitive deficits and/or a lower level of consciousness due to the autoimmune encephalitis, and are incapacitated because of this.
    Sommige patiënten met auto-immuun epilepsie/encefalitis zullen cognitieve stoornissen hebben en/of een verlaagd bewustzijn t.g.v. de auto-immuun encefalitis. Zij zullen hierdoor wilsonbekwaam zijn.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state55
    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)
    After the study period patients will be treated conform the advise of the treating doctor (neurologist), this can include IVIg.
    Na de studieperiode zullen patiënten behandeld worden conform het advies van de behandelend arts (neuroloog), dit kan ook IVIg omvatten.
    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 Decision2020-03-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-19
    P. End of Trial
    P.End of Trial StatusOngoing
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