E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Epilepsy, partial onset or generalised tonic-clonic seizures. |
Epilessia,in soggetti con nuova o recente diagnosi di epilessia e con crisi epilettiche parziali (POS) o tonico-cloniche generalizzate. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015037 |
E.1.2 | Term | Epilepsy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of this study is to compare the efficacy and safety of Lacosamide (LCM) (200 to 600mg/day) to Carbamazepine Controlled release CBZ CR (400 to 1200mg/day) used as monotherapy for at least 1 year, efficacy being measured as a primary endpoint by 6 month seizure freedom, in newly or recently diagnosed epilepsy subjects. The study will employ a noninferiority design to show at least a similar benefit risk balance for LCM compared with CBZ CR, using 6-month seizure freedom as primary endpoint. |
L'obiettivo primario di questo studio è confrontare l'efficacia e la sicurezza di lacosamide (LCM) (200 - 600 mg/die) e di carbamazepina a rilascio controllato (CBZ-CR) (400 - 1200 mg/die), utilizzate in monoterapia per almeno 1 anno. L'efficacia è misurata come endpoint primario utilizzando come parametro l'assenza di crisi epilettiche per 6 mesi, in soggetti epilettici diagnosticati de novo o di recente. Lo studio utilizzerà un disegno di non inferiorità per dimostrare un bilancio rischio-beneficio quantomeno analogo per LCM rispetto a CBZ-CR, avvalendosi della libertà da crisi epilettiche per 6 mesi quale endpoint primario. |
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E.2.2 | Secondary objectives of the trial |
4.1.2 Other efficacy variables Other efficacy variables are as follows:• Proportion of subjects remaining seizure free for 12 consecutive months of treatment following stabilization at the last evaluated dose for each subject; • Retention rate evaluated as time to withdrawal of treatment due to AE or lack of efficacy(LOE) relative to the first dose of study medication;• Time to first seizure or discontinuation due to AE/LOE during 12 months of treatment following stabilization at the first evaluated dose for each subject...continue;4.2.2 Other safety variables.The other safety variables are as follows: • Changes in hematology, chemistry, and urinalysis parameters;• Changes in 12-lead electrocardiograms (ECGs); • Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate).....continue. |
Prot. sez.4.1.2 Altre variabili di efficacia sono come segue:•Percentuale di soggetti che rimangono liberi da crisi epilettiche per 12 mesi consecutivi di trattamento, dopo stabilizzazione all'ultima dose valutata per ciascun soggetto;•Tasso di ritenzione valutato come tempo alla sospensione del trattamento a causa di evento avverso (AE) o mancanza di efficacia (LOE) rispetto alla prima dose del medicinale in studio;•Tempo alla prima crisi epilettica o sospensione del trattamento a causa di AE/LOE durante 12 mesi di trattamento, dopo stabilizzazione alla prima dose valutata per ciascun soggetto...continua;Prot.sez.4.2.2 Le altre variabili di sicurezza sono le seguenti:•Alterazioni dei parametri ematologici, chimici e urinari; •Cambiamenti negli ECG a 12 derivazioni;•Variazioni dei parametri vitali (ossia pressione arteriosa [BP] e frequenza del polso);...continua. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must fulfill the following inclusion criteria to be eligible to participate in this study: 1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the subject or by the parent(s) or legal representative. The Consent form or a specific Assent form, where required, will be signed and dated by minors. 2. Subject is willing and able to comply with all study requirements. 3. Subject is male or female and ≥16 years of age. Minors will be included in some countries only if legally permitted. 4. Subject has newly or recently diagnosed epilepsy having experienced unprovoked POS (IA, IB, IC with clear focal origin) or generalized tonic-clonic seizures (without clear focal origin) that are classifiable according to the ILAE Classification of Epileptic Seizures, 1981. The discrimination between IC and IIE is not requested for inclusion. 5. Subject has experienced at least 2 unprovoked seizures (separated by a minimum of 48 hours) in the year preceding randomization out of which at least 1 unprovoked seizure occurred in the 3 months preceding randomization. 6. Subject has had an electroencephalogram (EEG) (that is normal or consistent with the diagnosis of partial-onset epilepsy) and a brain computed tomography (CT) scan or magnetic resonance imaging (MRI) exam of the brain consistent with the diagnosis of partial onset or generalized tonic-clonic seizures (without clear focal origin) within the past year. If the EEG and brain CT scan or MRI exam were not performed prior to Visit 1, they need to be completed and results must be available prior to randomization at Visit 2. E. |
eleggibili alla partecipazione a questo studio: 1. Un modulo di consenso informato, in forma scritta e approvato dal Comitato Etico Indipendente (IEC), è stato firmato e datato dal soggetto o dal suo genitore (o genitori) o rappresentante legale. Il modulo di consenso o uno specifico modulo di assenso, ove necessario, sarà firmato e datato dai soggetti minorenni. 2. Il soggetto è disposto e in grado di soddisfare tutti i requisiti dello studio. 3. Il soggetto è maschio o femmina e la sua età è maggiore o uguale a 16 anni. Solo se consentito a norma di legge, in alcuni paesi saranno inclusi soggetti minorenni. 4. Il soggetto ha una diagnosi nuova o recente di epilessia e ha avuto POS non provocate (IA, IB, IC con chiara origine focale) o crisi epilettiche tonico-cloniche generalizzate (senza una chiara origine focale) classificabili secondo le linee guida ILAE Classification of Epileptic Seizures, 1981. Per l'inclusione non è necessaria alcuna distinzione fra IC e IIE. 5. Il soggetto ha avuto almeno 2 crisi epilettiche non provocate (a distanza di almeno 48 ore) nell'anno che precede la randomizzazione, di cui almeno 1 crisi non provocata avvenuta nei 3 mesi precedenti la randomizzazione. 6. Il soggetto è stato sottoposto ad encefalogramma (EEG) (che appare normale e coerente con la diagnosi di epilessia parziale) e a una tomografia computerizzata (TAC cerebrale o risonanza magnetica (RM) dell'encefalo, coerente con la diagnosi di crisi epilettiche parziali o tonico-cloniche generalizzate (senza una chiara origine focale) durante l’ultimo anno. Se EEG e TAC o RM cerebrale non sono stati effettuati prima della Visita 1, occorrerà eseguirli e gli esiti devono essere disponibili prima della randomizzazione alla Visita 2. |
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E.4 | Principal exclusion criteria |
Subjects are not permitted to enroll in the study if any of the following criteria are met: 1. Subject has previously participated in this study or subject has previously been assigned to treatment in a study of the drugs under investigation in this study. 2. Subject is currently participating or has participated within the last 2 months in any study of an investigational drug or experimental device. 3. Subject has a history or presence of seizures of other types than partial-onset (IA, IB, IC with clear focal origin) and generalized tonic-clonic (without clear focal origin) seizures (eg, myoclonic, absence). 4. Subject has a history or presence of seizures occurring only in clustered patterns, defined as repeated seizures occurring over a short period of time (ie, <20 minutes) with or without function regained between 2 ictal events.5. Subject has a history, clinical, or EEG finding suggestive of idiopathic generalized epilepsy (IGE) at randomization (according to the ILAE Classification of Epileptic Seizures, 1989). 6. Subject has current or previous diagnosis of pseudoseizures, conversion disorders, or other nonepileptic ictal events which could be confused with seizures. 7. Subject has any medical or psychiatric condition, which in the opinion of the investigator, could jeopardize the subject’s health or would compromise the subject’s ability to participate in this study. 8. Subject has a history of suicide attempt, has received professional counseling for suicidal ideation, or is currently experiencing active suicidal ideation. 9. Subject has a known hypersensitivity to any components of the investigational product(s). 10. Subject has ever been treated (for any indication) with LCM or CBZ in the past. 11. Subject has been treated for epilepsy with any AED (including benzodiazepines) in the last 6 months before Visit 1. • However, acute and subacute seizure treatment is accepted with a maximum of 2 weeks duration and if treatment was stopped at least 1 week before Visit 1. • Prior use of felbamate or vigabatrin is not allowed. • Benzodiazepines as rescue therapy for epilepsy may have been used as needed in this time period, but not more frequently than once per week. 12. Subject has received treatment with phenobarbital or primidone within 28 days prior to Visit 1. 13. Subject is taking benzodiazepines for a nonepilepsy indication. 14. The use of monoamine oxidase inhibitors (MAOIs) is not allowed within 14 days of Visit 1. 15. Subject has experienced seizure(s) while treated with any AED for an indication other than epilepsy. 16. Subject is taking any drug or product (eg, grapefruit) that may influence CBZ metabolism. 17. Subject has a known history of severe anaphylactic reaction, serious blood dyscrasias, or hepatic porphyrias. 18. Subject has an acute or sub-acutely progressive central nervous system disease. 19. Subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels ≥2× the upper limit of normal (ULN) or has alkaline phosphatase levels ≥3× the ULN. 20. Subject has a medical condition that could reasonably be expected to interfere with drug absorption, distribution, metabolism, or excretion. 21. Subject has a history of alcohol or drug abuse within the previous 2 years. 22. Subject is of Asian ancestry and tests positive for HLA-B*1502 allele. 23. Subject has impaired renal function, ie, creatinine clearance (CLcr) is lower than 30mL/min at Visit 1. Creatinine clearance will be estimated as follows: Adult males: CLcr=(140-age)×weight in kg/(72×serum creatinine in mg/dL) Adult females: CLcr=[(140-age)×weight in kg/(72×serum creatinine in mg/dL)]×0.85 24. Subject has sick sinus syndrome without a pacemaker, or second- or third-degree atrioventricular (AV) block,or subject has any other clinically significant ECG abnormalities.Segue |
Ai soggetti non è permesso l’arruolamento nello studio se soddisfano uno qualsiasi dei criteri seguenti: 1. Il soggetto ha partecipato in precedenza a questo studio, o è stato precedentemente assegnato al trattamento all'interno di uno studio sui farmaci esaminati nell'ambito del presente studio. 2. Attualmente il soggetto partecipa, oppure ha partecipato negli ultimi 2 mesi, a qualunque studio su un farmaco o un dispositivo di tipo sperimentale. 3. Il soggetto evidenzia anamnesi, oppure presenza, di crisi epilettiche tipologicamente diverse dalle crisi parziali (IA, IB, IC con chiara origine focale) e tonico-cloniche generalizzate (senza una chiara origine focale) (per es. miocloniche, di assenza). 4. Il soggetto evidenzia anamnesi, oppure presenza, di crisi epiletticheche si verificano esclusivamente in pattern a grappolo, definite come crisi ripetute insorte nell'arco di un breve periodo di tempo (ossia <20 minuti), con o senza recupero della funzione tra 2 eventi ictali. 5. Il soggetto presenta anamnesi o esiti clinici o encefalografici che suggeriscono epilessia idiopatica generalizzata (IGE) alla randomizzazione (sulla base delle linee guida ILAE Classification of Epileptic Seizures, 1989). 6. Il soggetto presenta una diagnosi attuale o pregressa di pseudocrisi, disturbi di conversione o altri eventi ictali non epilettici che possono essere confusi con crisi epilettiche. 7. Il soggetto soffre di una condizione medica o psichiatrica che, a giudizio dello sperimentatore, potrebbe compromettere la sua salute o la sua capacità di partecipare a questo studio.Segue. |
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E.5 End points |
E.5.1 | Primary end point(s) |
•Proportion of subjects remaining seizure free for 6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject.The primary safety variables are as follows• AEs reported spontaneously by the subject and/or caregiver or observed by the investigator • Subject withdrawals due to AEs • Serious AEs (SAEs) |
• Percentuale di soggetti che rimangono liberi da crisi epilettiche per 6 mesi consecutivi (26 settimane consecutive) di trattamento, dopo stabilizzazione all'ultima dose valutata per ciascun soggetto.• AE segnalati spontaneamente dal soggetto e/o da chi se ne prende cura, oppure osservati dallo sperimentatore.Le variabili primarie di sicurezza sono le seguenti:• Ritiri dei soggetti a causa di AE • AE gravi (SAE) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Proportion of subjects remaining seizure free for 12 consecutive months of treatment following stabilization at the last evaluated dose for each subject • Retention rate evaluated as time to withdrawal of treatment due to AE or lack of efficacy (LOE) relative to the first dose of study medication • Time to first seizure or discontinuation due to AE/LOE during 12 months of treatment following stabilization at the first evaluated dose for each subject • Time to first seizure or discontinuation due to AE/LOE during 12 months of treatment following stabilization at the last evaluated dose for each subject • Time to first seizure during 12 months of treatment from the first dose of study medication • Time to first seizure or discontinuation during 12 months of treatment from the first dose of study medication Safety variables are as follows: • Changes in hematology, chemistry, and urinalysis parameters Changes in 12-lead electrocardiograms (ECGs) • Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate) • Changes in physical or neurological examination findings • Changes in body weight • Changes in fasting serum lipid levels, and thyroid and sex hormone concentrations |
Altre variabili di efficacia sono come segue:•Percentuale di soggetti che rimangono liberi da crisi epilettiche per 12 mesi consecutivi di trattamento, dopo stabilizzazione all'ultima dose valutata per ciascun soggetto;•Tasso di ritenzione valutato come tempo alla sospensione del trattamento a causa di evento avverso (AE) o mancanza di efficacia (LOE) rispetto alla prima dose del medicinale in studio;•Tempo alla prima crisi epilettica o sospensione del trattamento a causa di AE/LOE durante 12 mesi di trattamento, dopo stabilizzazione alla prima dose valutata per ciascun soggetto; •Tempo alla prima crisi epilettica o sospensione a causa di AE/LOE durante 12 mesi di trattamento, dopo stabilizzazione all'ultima dose valutata per ciascun soggetto; •Tempo alla prima crisi epilettica durante 12 mesi di trattamento, dalla prima dose del medicinale in studio; •Tempo alla prima crisi epilettica o sospensione durante 12 mesi di trattamento, dalla prima dose del medicinale in studio.Le altre variabili di sicurezza sono le seguenti:•Alterazioni dei parametri ematologici, chimici e urinari •Cambiamenti negli ECG a 12 derivazioni;•Variazioni dei parametri vitali (ossia pressione arteriosa [BP] e frequenza del polso); •Cambiamenti negli esiti degli esami obiettivi o neurologici;•Variazioni ponderali;•Cambiamenti nei livelli del lipidi sierici a digiuno, e nelle concentrazioni di ormoni tiroidei e sessuali. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of trial. |
Termine dello studio. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
double dummy |
double dummy |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 115 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Mexico |
Russian Federation |
Ukraine |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 39 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 39 |
E.8.9.2 | In all countries concerned by the trial days | 0 |