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    Summary
    EudraCT Number:2014-005088-34
    Sponsor's Protocol Code Number:1372-14
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-18
    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 ConcernedUK - MHRA
    A.2EudraCT number2014-005088-34
    A.3Full title of the trial
    A randomised controlled, double blind trial investigating the efficacy of fluoxetine treatment in improving memory and learning impairments in patients with mesial temporal lobe epilepsy: Fluoxetine, Learning and Memory in Epilepsy (FLAME).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial investigating the effect of the anti-depressant fluoxetine on learning and memory in people with epilepsy.
    A.3.2Name or abbreviated title of the trial where available
    FLAME
    A.4.1Sponsor's protocol code number1372-14
    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 SponsorCardiff University
    B.1.3.4CountryUnited Kingdom
    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 supportEpilepsy Research UK
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSouth East Wales Trial Unit
    B.5.2Functional name of contact pointCheney Drew
    B.5.3 Address:
    B.5.3.1Street Address7th Floor, Neuadd Merionydd, Heath Park
    B.5.3.2Town/ cityCardiff
    B.5.3.3Post codeCF14 4YS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02920687295
    B.5.6E-mailDrewC5@cardiff.ac.uk
    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 fluoxetine
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Labs
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameFluoxetine
    D.3.4Pharmaceutical form Capsule
    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 INNfluoxetine hydrochloride
    D.3.9.1CAS number 56296-78-7
    D.3.9.2Current sponsor codeN/A
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Mesial Temporal Lobe Epilepsy
    E.1.1.1Medical condition in easily understood language
    Epilepsy
    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 18.0
    E.1.2Level PT
    E.1.2Classification code 10043209
    E.1.2Term Temporal lobe epilepsy
    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 determine if treatment with oral fluoxetine can change spatial learning in patients with mesial temporal lobe epilepsy after a two month period of treatment.
    E.2.2Secondary objectives of the trial
    To determine the effect of oral treatment with fluoxetine on:;
    1. verbal learning in patients with mesial temporal lobe epilepsy after a two
    month period of treatment.
    2. spatial and/or verbal learning in patients with mesial temporal lobe
    epilepsy two months after treatment withdrawal.
    3. spatial and/or verbal memory in patients with mesial temporal lobe epilepsy
    after a two month period of treatment.
    4. spatial and/or verbal memory in patients with mesial temporal lobe epilepsy
    two months after treatment withdrawal.

    To determine whether:

    5. patients differ in the severity of their learning deficit depending on
    which side the hippocampal sclerosis occurs
    6. patients with TLE show deficits in pattern separation and if such
    deficits predict a response to fluoxetine
    7. hippocampal microstructure correlates with allocentric learning and
    memory deficits and/or the response to fluoxetine
    8. fluoxetine alters seizure freque
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The inclusion criteria for this trial are;

    • Adult patients between the ages of 18-65yrs
    Adult persons over the age of 65 will not be included as neurogenesis (the postulated biological target) diminishes significantly after this age and this subgroup therefore may not benefit. If benefit is shown under 65 then a subsequent study to assess benefit in this age group may be carried out.
    • diagnosis of mesial temporal lobe epilepsy
    • unilateral hippocampal sclerosis (confirmed by MRI)

    E.4Principal exclusion criteria
    Exclusion Criteria for this trial are;

    • bilateral hippocampal sclerosis on MRI
    • presence of significant active depression and/ or anxiety as determined by
    HADS scoring (11 or above on either subscale)
    • Persons lacking capacity or an IQ score of 80 or below as assessed by the
    WASI
    • presence of poorly controlled seizures in patients undergoing active AED
    changes
    • any participant not suitable for MRI
    • pregnancy
    • Wishing to breast feed during the trial
    • participation in another clinical trial of an investigational medicinal
    product (IMP)
    • previous adverse reaction to fluoxetine
    • contraindicated concomitant medication – such as Monoamine Oxidase Inhibitors
    • hepatic impairment that would require any dose adjustment for fluoxetine
    (elevated liver Enzymes (- 2.5 or more times the upper limit of the normal
    range).
    • congenital long QT syndrome, a family history of QT prolongation or other
    clinical conditions that predispose to arrhythmias (e.g., hypokalemia,
    hypomagnesemia, bradycardia, acute myocardial infarction or uncompensated
    heart failure). An ECG will be performed in patients with a stable cardiac
    history. Most patients in our database have already been screeened for
    prolonged Q-T syndrome as part of their epilepsy evaluation.
    • Patients on Tamoxifen as concomitant Fluoxetine may lead to reduced
    concentrations of its active metabolite endoxifen.
    • Participants taking St John’s Wort should agree to discontinue it before
    taking the IMP. If not, they will be excluded, as St John’s Wort potentiates
    the serotonergic effects of Fluoxetine.


    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure for this study is the measure of verbal and spatial learning
    E.5.1.1Timepoint(s) of evaluation of this end point
    This measure will be evaluated at baseline, 60 days after starting IMP treatment and again 60 days after IMP has been stopped.
    E.5.2Secondary end point(s)
    Secondary endpoints for this trial are:

    - Pattern separation measures
    - Brain MRI microstructure
    - seizure frequency
    E.5.2.1Timepoint(s) of evaluation of this end point
    Pattern separation measures will be evaluated at baseline, 60 days after starting IMP treatment and 60 days after finishing IMP treatment.

    Brain MRI structure will be measured at baseline only

    Seizure frequency will be evaluated at each patient visit.
    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 No
    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 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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 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 state60
    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)
    We do not plan on making the trial treatment available to trial participants once the research is finished. However, participants may receive fluoxetine treatment from their GP in the future for the treatment of depression.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Brain Repair and Intracranial Neurotherapeutics Unit
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-06-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-29
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