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    Summary
    EudraCT Number:2012-001552-19
    Sponsor's Protocol Code Number:TOPMATEPY4067
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-09-05
    Trial results View 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-001552-19
    A.3Full title of the trial
    A Randomized, Active-Controlled, Open-Label, Flexible-Dose Study to Assess the Safety and Tolerability of Topiramate as Monotherapy Compared With Levetiracetam as Monotherapy in Pediatric Subjects With New or Recent-Onset Epilepsy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the effects and safety of the drugs topiramate and levetiracetam in treating children recently diagnosed with epilepsy
    A.3.2Name or abbreviated title of the trial where available
    Long term Safety TOPAMAX monotherapy in pediatric patients
    A.4.1Sponsor's protocol code numberTOPMATEPY4067
    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 SponsorJanssen-Cilag International N.V.
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen Research and Development
    B.5.2Functional name of contact pointClinical Registry Group-JB BV
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310715242166
    B.5.5Fax number+310715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.com
    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 Topamax
    D.2.1.1.2Name of the Marketing Authorisation holderCilag AG Switzerland
    D.2.1.2Country which granted the Marketing AuthorisationSwitzerland
    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 Coated tablet
    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 INNTopiramate
    D.3.9.2Current sponsor codeRWJ-17021-000
    D.3.9.3Other descriptive nameTOPIRAMATE
    D.3.9.4EV Substance CodeSUB11190MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 2
    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 Topamax
    D.2.1.1.2Name of the Marketing Authorisation holderCilag AG Switzerland
    D.2.1.2Country which granted the Marketing AuthorisationSwitzerland
    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 Coated tablet
    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 INNtopiramate
    D.3.9.2Current sponsor codeRWJ-17021-000
    D.3.9.3Other descriptive nameTOPIRAMATE
    D.3.9.4EV Substance CodeSUB11190MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 3
    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 Topamax
    D.2.1.1.2Name of the Marketing Authorisation holderCilag AG Switzerland
    D.2.1.2Country which granted the Marketing AuthorisationSwitzerland
    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 Coated tablet
    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 INNtopiramate
    D.3.9.2Current sponsor codeRWJ-17021-000
    D.3.9.3Other descriptive nameTOPIRAMATE
    D.3.9.4EV Substance CodeSUB11190MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.IMP: 4
    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 Topamax
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag S.p.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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, hard
    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 INNTopiramate
    D.3.9.2Current sponsor codeRWJ-17021-000
    D.3.9.3Other descriptive nameTOPIRAMATE
    D.3.9.4EV Substance CodeSUB11190MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 5
    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.2.1.1.1Trade name Keppra
    D.2.1.1.2Name of the Marketing Authorisation holderUCB Pharma SA
    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.3.4Pharmaceutical form Oral solution
    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 INNLEVETIRACETAM
    D.3.9.1CAS number 102767-28-2
    D.3.9.3Other descriptive namelevetiracetam
    D.3.9.4EV Substance CodeSUB08459MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.IMP: 6
    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.2.1.1.1Trade name Keppra
    D.2.1.1.2Name of the Marketing Authorisation holderUCB Pharma SA
    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.3.4Pharmaceutical form Tablet
    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 INNLEVETIRACETAM
    D.3.9.1CAS number 102767-28-2
    D.3.9.3Other descriptive namelevetiracetam
    D.3.9.4EV Substance CodeSUB08459MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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.IMP: 7
    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.2.1.1.1Trade name Keppra
    D.2.1.1.2Name of the Marketing Authorisation holderUCB Pharma SA
    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.3.4Pharmaceutical form Tablet
    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 INNLEVETIRACETAM
    D.3.9.1CAS number 102767-28-2
    D.3.9.3Other descriptive namelevetiracetam
    D.3.9.4EV Substance CodeSUB08459MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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.IMP: 8
    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.2.1.1.1Trade name Keppra
    D.2.1.1.2Name of the Marketing Authorisation holderUCB Pharma SA
    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.3.4Pharmaceutical form Tablet
    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 INNLEVETIRACETAM
    D.3.9.1CAS number 102767-28-2
    D.3.9.3Other descriptive namelevetiracetam
    D.3.9.4EV Substance CodeSUB08459MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number750
    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
    New-onset or recent-onset 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 17.0
    E.1.2Level PT
    E.1.2Classification code 10015037
    E.1.2Term 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
    The primary objective is to evaluate the effects of topiramate monotherapy compared with levetiracetam, another standard antiepileptic drug (AED), as monotherapy for new-onset or recent-onset epilepsy on pediatric growth and maturation, bone mineralization, and kidney stone formation in children 2 to 15 years of age.
    E.2.2Secondary objectives of the trial
    Overall safety will be assessed
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1 Subject must be a child or adolescent (male or female) 2 to 15 years of age with a clinical diagnosis of new-onset or recent-onset epilepsy characterized by POS (with or without secondary generalization) or PGTCS in accordance with criteria of the International League Against Epilepsy. The epilepsy diagnosis must be within the previous 2 years before screening.2 Subject must have clinical or electroencephalogram (EEG) evidence of POS (simple or complex), with or without secondary generalization, or PGTCS at least 3 months prior to the first day of screening. Subjects should have at least 1, but no more than 2, unprovoked seizures during the 3 months prior to screening. Acceptable evidence of POS includes 1 of the following:
    •Documented recurrent clinical seizures with asymmetric motor features or characteristic behavioral alterations. The interictal EEGs may be negative or inconclusive, provided that the clinical criterion for POS is met.
    •A routine EEG or video EEG showing focal or asymmetric EEG findings (epileptiform discharges, focal slowing, focal attenuation, or a combination), with or without secondary generalization. Clinical seizures with symmetric or behavioral features are acceptable in the presence of EEG evidence of an asymmetric origin.
    Acceptable evidence of PGTCS includes 1 of the following:
    •Documented recurrent clinical seizures with seizures that are initially generalized, associated with tonic contractions and clonic movements
    •EEG expression that is a generalized, synchronous, symmetrical discharge
    •Interictal EEGs may be normal or show generalized discharges such as spikes, polyspike, spike-wave, and polyspike wave.
    3 At screening, subject must have weight and height values within the 5th to 95th percentile for chronological age (based on standard Child Height and Weight Charts from the CDC). 4 Subject must never have been treated for epilepsy (treatment-naïve) or have been treated with no more than 1 standard AED if temporary or urgent AED use was necessary. Previous AED exposure must not exceed either of the following:
    •Thirty-one days immediately preceding enrollment, or
    •A total of 6 months of previous AED exposure in the past if the AED has been discontinued for at least 1 year prior to enrollment
    5 If subject is currently treated with an AED, inadequacy of current epilepsy treatment must be documented on a worksheet provided to the investigator. Criteria for inadequacy include:
    •AED dosage is considered optimized (including, if clinically appropriate, recent demonstration of adequate blood levels) in the opinion of the investigator and unchanged for at least 5 half-lives prior to the first day of screening and found to be:
    -Inadequate in controlling seizures in the opinion of the investigator, as shown in part by a retrospective history of at least 1 seizure in the 3 months prior to screening, or
    -Not well tolerated
    6 Parents (or legally acceptable representatives) of the subject must sign an informed consent/permission document, indicating that they understand the purpose of and procedures required for the study and are willing to give permission for their child to participate in the study. Subjects 7 years of age and older, capable of understanding the nature of the study, must provide assent for their participation. 7 Caregivers (parents or legally acceptable representatives) of the subject must be able to accurately maintain the subject take-home record and seizure diary. 8 Subject must have had a computerized tomography or magnetic resonance imaging scan within 2 years prior to study entry, to confirm the absence of a progressive lesion, such as a tumor, with the exception of lesions of tuberous sclerosis and Sturge-Weber syndrome, which are allowed. The report must be included in the source documents. 9 Subject must have an electrocardiogram (ECG) at screening with no “abnormal, clinically significant” interpretations by a local cardiologist. 10 Subject must be otherwise healthy on the basis of physical examination, medical history, vital signs, clinical laboratory tests, and 12-lead ECG performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population. This determination must be recorded in the subject's source documents and initialed by the investigator. 11 Subject must be ambulatory and must have normal activity levels based on the Habitual Activity Estimation Scale (HAES; see Attachment 1) at screening, according to recommended levels. 12 Before randomization, a girl must be either:
    •Not of childbearing potential: premenarchal; permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable of pregnancy
    Please refer to protocol for all Inclusion Criteria
    E.4Principal exclusion criteria
    1 Subject has a surgically implanted and functioning vagus nerve stimulator. 2 Subject has a history of seizures as a result of a correctable medical condition, such as metabolic disturbance, toxic exposure, neoplasm, or active infection within 2 weeks prior to the first day of screening. 3 Subject has had uncontrolled seizures while previously taking either topiramate or levetiracetam. 4 Subject has a history of nonepileptic seizures within 2 weeks prior to the first day of screening. 5 Subject has myoclonic or absence seizures. 6 Subject has a history of status epilepticus within 2 weeks prior to first day of screening. Status epilepticus is defined as 30 minutes of continuous motor seizures. 7 Subject has had epilepsy surgery within 3 months prior to the first day of screening. 8 Subject has any progressive neurologic disorder, including malignancy, brain tumor, active central nervous system infection, demyelinating disease, or degenerative or progressive central nervous system disease, with the exception of tuberous sclerosis and Sturge Weber syndrome. 9 Subject has any clinically significant uncontrolled medical illness, including hepatic or renal failure, ischemic cardiac disease, bone disorders, growth and maturation disorders of any type, malignancy, physical impairments that prevent normal ambulation, or any disorder that, in the opinion of the investigator, places the subject at risk through participation in a clinical study. 10 Subject has nephrocalcinosis, renal stones of any type, or hydronephrosis, as evidenced by medical history or screening examination. 11 Subject has a history of ≥2 long bone fractures if the subject is ≤10 years old; ≥3 long bone fractures if the subject is >10 years old, where at least 1 of the fractures was a low-impact fracture, defined as slight trauma that may include:
    •Falling to the ground from <0.5 m (standing height)
    •Falling to a resilient surface (rubber or sand) from 0.5 to 3 m
    •Falling from a bed or cot
    •Playing injuries, including playground scuffles
    12 Subject has indwelling hardware, or has an abnormality of the skeleton or spine, such as scoliosis of 20 degrees or more, kyphosis, or skeletal dysplasia. 13 Subject has clinically relevant abnormalities noted on renal ultrasound or DEXA scans. Subjects with baseline BMD Z-scores ≤-2, for either posterior-anterior lumbar spine (L1 L4) or total body less head, will not be enrolled. 14 Subject has congenital glaucoma or known ocular deficits, or is receiving any ocular medications except lubricating eye drops or topical antibiotics. 15 Subject has a known history of central hyperthermia, dysautonomia, or other disturbances of autonomic function. 16 Subject has a known history of inborn errors of metabolism, mitochondrial dysfunction, or prior evidence of hyperammonemia. 17 Subject has any clinically significant abnormality in laboratory tests at screening, including but not limited to:
    •WBC count <3,000/mL or absolute neutrophil count <1,000 /mL in the last 6 months
    •Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-glutamyltransferase (GGT) 3 times the ULN
    •Total bilirubin 1.5 mg/dL or conjugated bilirubin 20% of total
    •Venous ammonia 2 times the ULN
    •25-hydroxy-vitamin D (normal reference range is ≥20.0 ng/mL)
    •Parathyroid hormone (normal reference range is 14.0 to 72.0 pg/mL)
    •1,25-dihydroxy-vitamin D, as determined by the age-dependent reference ranges (see lab manual)
    •Insulin-like growth factor 1 (IGF-1), as determined by the age-dependent reference ranges (see lab manual)
    18 Subject has a bicarbonate level <20 mEq/L, has a diagnosis of metabolic acidosis, or is on alkali therapy. 19 Subject has refractory epilepsy and requires adjunctive AED therapy or is receiving >1 concurrent AED (including benzodiazepines, regardless of the reason for prescription). 20 Subject is being treated with furosemide, hydrochlorothiazide, vigabatrin, vitamin B6 therapy for epilepsy, monoamine oxidase (A or B) inhibitors, felbamate, zonisamide, or any other medication that is a potent carbonic anhydrase inhibitor (eg, acetazolamide). Past treatment with furosemide for more than 2 weeks must be discussed with the sponsor and the discussion documented. 21 Subject is being treated with other drugs that may affect bone metabolism, eg, steroids (intravenous or oral steroids), growth hormone, antacids, or nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic or underlying disorders for more than 7 consecutive days at least 1 month prior to the first day of screening. 22 Subject has been treated with an investigational drug within 5 half-lives prior to the first day of screening. please refer to Protocol for all the exclusion criteria
    E.5 End points
    E.5.1Primary end point(s)
    •Percentage of subjects with kidney stones
    •Change from baseline in weight Z-score over time
    •The following height analyses will be conducted for prepubertal subjects (2 to 9 years of age), subjects 10 to 15 years of age, and subjects 2 to 15 years of age:
    -Height at 1 year postbaseline
    -Height change from baseline over time
    -Height Z-score at 1 year postbaseline
    -Change from baseline in height Z-score over time
    -Height velocity at 1 year postbaseline
    -Height velocity Z-score at 1 year postbaseline
    -Percentage of outlier subjects with height Z-score decrease of >0.5, >1.0, and >2.0 over time
    •The following BMD and bone mineral content (BMC) endpoints:
    -BMD and BMC over time
    -BMD and BMC change from baseline over time
    -Z-score for BMD and BMC over time
    -Change from baseline in Z-score for BMD and BMC over time
    -Percent change from baseline in BMD and BMC over time
    -Percentage of outlier subjects with BMD Z-score decrease of >0.5, >1.0, and >2.0 over time
    •Change from baseline in biochemical markers of bone mineralization including: serum levels of alkaline phosphatase, calcium, phosphorus, parathyroid hormone (intact), 25-hydroxy-vitamin D, 1,25-dihyroxy vitamin D, and IGF-1
    •Change from baseline in serum and urine laboratory tests, eg, bicarbonate, ammonia, renal function tests, and LFTs
    •Change from baseline in bone age
    E.5.1.1Timepoint(s) of evaluation of this end point
    The timepoints for the primary is baseline 6 months and 12 months or last visit in case of early termination.

    E.5.2Secondary end point(s)
    Longitudinal endpoints will be analyzed using a mixed-model repeated measures (MMRM) analysis. The MMRM model will include treatment group, age group, visit, treatment-by-visit interaction, baseline measure, and baseline-by-visit interaction. An unstructured covariance will be used. Other appropriate covariance structures will be explored as needed. Confidence intervals with 95% confidence for the estimated treatment differences will be provided at each time point as appropriate. For proportion endpoints, 95% confidence intervals will be provided for the treatment difference. Each of the endpoints will also be summarized by age group.
    Seizure counts and cognitive, developmental, and behavioral assessments will be summarized by treatment group and age group. The incidence of suicide-related thoughts and behaviors as determined by the C-SSRS will be summarized by treatment group and age group.
    In addition to the above endpoints, other safety-related endpoints may be included in the analyses if deemed necessary.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Labs are done: screen, month 1, Month 3, 6, 9 and 12 or last visit.
    Suicidality assessment is done at baseline, months 1-12, each visit.
    Behavior assessments are done at baseline, month 3, month 6 and month 12
    Seizure counts are done at months 1-12, each visit
    Bone age x ray will be done at baseline and month 12
    Bone marker assessments will be done at screen, month 6 and 12
    The cognitive battery will be done at screen, baseline and months 6 and 12.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    levetiracetam
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Brazil
    Canada
    Chile
    China
    Colombia
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Latvia
    Lithuania
    Malaysia
    Mexico
    Netherlands
    New Zealand
    Norway
    Peru
    Philippines
    Poland
    Portugal
    Puerto Rico
    Russian Federation
    Singapore
    South Africa
    Spain
    Sweden
    Taiwan
    Thailand
    Ukraine
    United Kingdom
    United States
    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
    The study is considered completed with the last study assessment for the last subject participating in the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 282
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 141
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 141
    F.1.2Adults (18-64 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minor: Parents (or legally acceptable representatives) of the subject must sign an informed consent. Subjects 7 years of age and older, capable of understanding the nature of the study, must provide assent for their participation.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 76
    F.4.2.2In the whole clinical trial 282
    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)
    There may be an optional post-study follow-up phase to obtain dual energy x-ray absorptiometry (DEXA) measurements in a subgroup of subjects who experience a clinically important reduction in BMD after 1 year of treatment with topiramate, to determine whether a decrease in BMD after or during 1 year of treatment with topiramate is reversible. These subjects will have a repeat DEXA scan 6 months after discontinuation of study drug. An additional consent/ Assent will be required for this phase.
    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 Decision2014-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-18
    P. End of Trial
    P.End of Trial StatusOngoing
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