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    Summary
    EudraCT Number:2012-005723-33
    Sponsor's Protocol Code Number:amantadineSCEDI.
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-10-01
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2012-005723-33
    A.3Full title of the trial
    Efficacy of amantadine on behavioural and emotional problems and impairment of executive functioning
    due to acquired brain injury to the frontal lobes: a series of single case experimental design studies.
    Effect van amantadine op gedrags- en emotionele problemen en executieve functiestoornissen veroorzaakt door verworven frontaal hersenletsel: een serie van Single Case Experimental Design onderzoeken
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of amantadine in acquired brain injury.
    Onderzoek naar het effect van amantadine op gedragsproblemen na hersenletsel
    A.4.1Sponsor's protocol code numberamantadineSCEDI.
    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 SponsorGGZ Oost Brabant
    B.1.3.4CountryNetherlands
    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 supportGGZ Oost Brabant
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGGZ Oost Brabant
    B.5.2Functional name of contact pointOpleiding & Onderzoek
    B.5.3 Address:
    B.5.3.1Street AddressBerlicumseweg 8
    B.5.3.2Town/ cityRosmalen
    B.5.3.3Post code5248 NT
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031738447500
    B.5.6E-mailopleidingen@ggzoostbrabant.nl
    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 symmetrel
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis BV
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    behavioural and emotional problems and impairment of executive functioning due to acquired brain injury to the frontal lobes
    gedrags- en emotionele problemen en executieve functiestoornissen veroorzaakt door verworven frontaal hersenletsel
    E.1.1.1Medical condition in easily understood language
    acquired brain injury
    gedragsproblemen na verworven hersenletsel
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Brain injury due to different causes is common and can have severe functional impact. Frontal lesions often lead to cognitive impairments, but also to behavioural consequences, e.g. apathy, agitation, aggression, and emotional lability. Amantadine may be effective in the treatment of these cognitive and behavioural consequences. Anatomical and neurochemical theory support these findings and amantadine is clinically used albeit without the support of scientific evidence. The aim of this study is to find scientific evidence to support the clinical use of amantadine in the brain injured.
    hersenletsel door verschillende oorzaken komt veel voor en heeft een groot effect op het functioneren. Frontaal letsel leidt vaak tot cognitieve beperkingen maar ook tot gedragsproblemen.
    Amantadine zou effectief kunnen zijn in de behandeling van deze problemen. Anatomische en neurochemie theorieen ondersteunen deze vooronderstelling. Amantadine wordt klinisch gebruikt maar zonder de ondersteuning van wetenschappelijk bewijs. Het doel van dit onderzoek is wetenschappelijk bewijs te vergaren om daarmee het klinisch gebruik van amantadine te ondersteunen.
    E.2.2Secondary objectives of the trial
    not applicable
    niet van toepassing
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subjects have suffered acquired brain damage due to various aetiologies as verified by CT or MRI • Subjects suffer from emotional lability/irritability, aggressiveness, apathy as established through clinical observation and/or impairment of executive functioning as established by clinical judgement or on the basis of neuropsychological assesment. • Subjects are >3 months post injury • Subjects are 18 years or older • Written informed consent is given
    -Verworven hersenletsel door verschillende oorzaken aangetoond met CT of MRI -Emotionele labiliteit, agressiviteit, apathie vastgesteld door klinische observatie en/of beperkingen in het executief functioneren vastgesteld door het klinisch oordeel of via neuropsychologisch onderzoek -minstens 3 maanden na het letsel -18 jaar of ouder -schriftelijk informed consent is gegeven
    E.4Principal exclusion criteria
    Current drug addiction
    • Current psychoses • The current use of incompatible medications: methylphenidate, typical or atypical antipsychotics, combination diuretics (hydrochlorthiazide + potassium sparing diuretics) or Levodopa. • Pregnancy and lactation • Cardiac disease. Inclusion only after the consulting cardiologists consent • Refractory epilepsy • Kidney failure (eGFR<10 ml/min) • A history of gastric ulceration • Current glaucoma • Hypersensitivity to amantadine or any of the excipients
    - actuele verslaving
    -actuele psychose -actueel gebruik van niet compatibele medicatie -zwangerschap en lactatie -hartaandoeningen -onbehandelbare epilepsie
    acquired brain injury
    01-01-2015
    Ga naar boven
    -nierfalen -maagzweer in de voorgeschiedenis -actueel glaucoom -overgevoeligheid voor amantadine of een van de toevoegingen
    E.5 End points
    E.5.1Primary end point(s)
    The main study parameters will be the behavioural disturbance and the impairment in executive functioning due to the brain injury involved.
    The behavioural problems will be measured on the one hand with a standardized instrument (the Neuropsychiatric Inventory (NPI)); on the other hand we will establish an individual target behaviour in cooperation between the investigator, the patient and the significant other. This individual target behaviour will be the most problematic behaviour for the patient or his environment, and will be measured by a Visual Analogue Scale (VAS), scoring by severity on a 1-100 scale. Individual target behaviours could for example be the number of aggressive incidents per day, apathy or sexual inappropriate behaviour.
    The VAS is particularly suitable for the assessment of subjective phenomena. [43]
    Nijman et al used a VAS to measure the severity of aggressive incidents on psychiatric wards. [44]
    Morrison used a VAS to allow relatives and professionals to rate the behaviour of elderly patients. He proved the scale to have good inter-rater reliability, test-retest reliability and validity.[45]

    The NPI [32] [33] targets neuropsychiatric symptoms, amongst them apathy, irritability/lability, agitation/aggression and disinhibition, in brain injured patients. The NPI consists of 12 subscales scoring both frequency and severity of each behaviour and caregiver distress. It covers 12 behavioural domains; for each behaviour frequency is scored from 1 (sometimes) to 4 (very often), the severity from 1 (mild) to 3 (severe) and the caregiver distress from 1 (minimal) to 5 (extreme or very severe). A total score is reached by multiplying and adding the frequency and severity scores (0-144)
    The NPI scores behavioural changes since injury or since the last scoring.
    The NPI is validated for patients with dementia and brain injury. Cummings et al [32] [33] demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable.
    Information for the NPI is obtained from a caregiver familiar with the patient's behaviour (in this experiment the significant other or nurse). It takes 15 minutes to conduct the interview.

    The impairment in executive functioning will be measured with the Behaviour Rating Inventory of Executive Function (BRIEF)-A.
    The Hogrefe Translation into Dutch Test of executive functioning, standardised to Flemish and Dutch population standards will be used. B. Huizinga & Smidts [34] found good internal consistency and test-retest reliability.
    Caregivers (significant other or nurse) are asked to fill out the “form for informants” which contains 75 questions and takes 15 min.
    The BRIEF-A contains 9 subscales. Each question from a subscale is scored from 1 (never) to 3 (often). The 9 subscales are clustered in 3 indexes (behavioural index, metacognitive index and total score). There are 3 validity scales.
    Raw scale scores can be converted to T-scores. T-scores higher than 65 are clinically significant.
    In this experiment a decrease in T-score from above 65 to below 60 (normal score) will be indicative of efficacy of amantadine. T-scores between 60 and 65 are subclinical.
    Gedragsproblemen en beperkingen in het executief functioneren als gevolg van hersenletsel zijn de primaire uitkomstmaten.
    Gedragsproblemen worden aan de ene kant gemeten met de NPI. Aan de andere kant wordt individueel doelgedrag vastgesteld en gemeten met een VAS 1-100.
    De beperkingen in het cognitief functioneren worden gemeten met de BRIEF-A
    E.5.1.1Timepoint(s) of evaluation of this end point
    17 weeks after the start of the study the end points will be evaluated
    17 weken na de start van het onderzoek worden de uitkomstmaten geëvalueerd.
    E.5.2Secondary end point(s)
    - Cognitive impairments (MMSE-24)
    The MMSE will be administered to measure objective cognitive impairments.[36]
    The MMSE consists of 21 items and is divided in two parts. All the items of the first part will be verbally answered. The verbal section measures memory, orientation and attention domains. The second part of the MMSE subjects will have to name, read, write and copy. 30 Points is the maximum score that subjects can achieve.[36]
    The MMSE is proven to be valid and reliable.[36] The concurrent validity was proven good for as well the verbal scale as the performal scale of the Wechsler Adult Intelligence Scale (respectively r = .78 and r = .66).[37] The test-retest reliability of the MMSE was high (Pearson coefficient ranging from .83 till .98).
    De andere cognitieve beperkingen worden gescreend met de MMSE.
    E.5.2.1Timepoint(s) of evaluation of this end point
    17 weeks after the start of the study this endpoint will be evaluated.
    17 weken na de start van het onderzoek wordt deze uitkomstmaat geëvalueerd.
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Single case Experimentele onderzoeksopzet
    Single Case Experimental Design
    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 trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 bezoek van de laatste proefpersoon
    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 months12
    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: 40
    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 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.3.3.6.1Details of subjects incapable of giving consent
    Due to cognitive impairments some subjects may be incompetent to give informed consent, because of not being able to comprehend the information given to them.
    Vanwege cognitieve beperkingen kunnen sommige proefpersonen de aangeboden informatie niet begrijpen en zij daarom niet instaat om informed consent te geven.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    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)
    If effective amantadine can be given after the individual subject ended participation in the trial.
    Als amantadine effectief is bij de individuele proefpersoon, dan kan het middel na deelname worden gegeven.
    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 Decision2014-10-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-03-15
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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