| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Epileptic Encephalopathy with developmental delay |
| Encefalopatie epilettiche con ritardo di sviluppo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mental retardation with seizures |
| Ritardo mentale associato a convulsioni |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015039 |
| E.1.2 | Term | Epilepsy congenital |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10010331 |
| E.1.2 | Term | Congenital, familial and genetic disorders |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029205 |
| E.1.2 | Term | Nervous system disorders |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 |
To assess the efficacy of the drugs gabapentine, fluoxetine, metformin, amitriptyline and fampridine in reducing seizure frequency in children with developmental and epileptic encephalopathy (DEE) respectively due to mutations in the potassium channels KCNQ2, KCNC1, KCNB1, KCNQ3 and KCNA1/2 whose sensitivity to these drugs has been ascertained in electrophysiological tests performed in vitro.
To assess the efficacy of gabapentine, fluoxetine, metformin, amitriptyline and fampridine in improving behavioural disturbance, and in particular autism spectrum diroder phenotypes, in children affected by DEEs due to mutations in the potassium channels KCNQ2, KCNC1, KCNB1, KCNQ3 and KCNA1/2 whose sensitivity to these drugs has been ascertained in electrophysiological tests performed in vitro. |
Valutare l’efficacia antiepilettica dei farmaci Gabapentina, Fluoxetina, Metformina, Amitriptilina e Fampridina in pazienti affetti da DEE rispettivamente dovute a mutazione nei geni codificanti per canali del potassio KCNQ2, KCNC1, KCNB1, KCNQ3 e KCNA1/2 la cui sensibilità a detti farmaci sia stata accertata in test elettrofisiologici effettuati in vitro.
Valutare l’efficacia dei farmaci Gabapentina, Fluoxetina, Metformina, Amitriptilina e Fampridina nel migliorare i disturbi del comportamento ed in particolare quelli dello spettro autistico, in pazienti affetti da DEE rispettivamente dovuta a mutazioni nei geni codificanti per canali del potassio KCNQ2, KCNC1, KCNB1, KCNQ3 e KCNA1/2 la cui sensibilità a detti farmaci sia stata accertata in test elettrofisiologici effettuati in vitro |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of the drugs gabapentine, fluoxetine, metformin, amitriptyline and fampridine in children with DEE due to mutations in the genes encoding for the potassium channels KCNQ2, KCNC1, KCNB1, KCNQ3 e KCNA1/2, respectively, whose sensitivity to said drugs has been ascertained in electrophysiological tests carried out in vitro:
- in improving neurocognitive development
- in improving body growth
- in improving the quality of life of the patient and caregiver |
Valutare l’efficacia dei farmaci Gabapentina, Fluoxetina, Metformina, Amitriptilina e Fampridina in bambini affetti da DEE rispettivamente dovuta a mutazione nei geni codificanti per canali del potassio KCNQ2, KCNC1, KCNB1, KCNQ3 e KCNA1/2, la cui sensibilità a detti farmaci sia stata accertata in test elettrofisiologici effettuati in vitro:
- nel migliorare lo sviluppo neurocognitivo
- nel migliorare la crescita corporea
- nel migliorare la qualità di vita del paziente e del caregiver |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis of DEE with evidence of developmental delay associated with drug-resistant epilepsy as per ILAE criteria (ie failure to control epileptic activity despite the administration of two antiepileptic drugs appropriate for the condition in place) or diagnosis of autism spectrum disorder;
Presence in genotypic analysis of mutations in genes coding for voltage-gated potassium channels KCNQ2, KCNQ3, KCNA1/2, KCNB1, KCNC1;
Concentrations of antiepileptic drugs present in therapy that have already reached steady state at the time of recruitment. |
• Età >2mesi e < 14 anni
• Diagnosi di DEE con evidenza di ritardo di sviluppo associato ad epilessia farmaco-resistente come da criteri ILAE (ovvero mancato controllo dell’attività epilettica malgrado la somministrazione di due farmaci antiepilettici appropriati per la condizione in essere) oppure diagnosi di disturbo dello spettro autistico;
• Presenza all’analisi genotipica di mutazioni in geni codificanti per canali del potassio voltaggio-dipendenti KCNQ2, KCNQ3, KCNA1/2, KCNB1, KCNC1;
• Concentrazioni dei farmaci antiepilettici presenti in terapia che abbiano già raggiunto lo stato stazionario al momento del reclutamento. |
|
| E.4 | Principal exclusion criteria |
- Infectious encephalitis, demyelinating or degenerative diseases of the central nervous system;
- Pharmacological treatment with four or more antiepileptic drugs in combination, during the 60 days prior to enrollment in the study;
- Treatment with the test drug during the 60 days prior to enrollment;
- Presence of any clinical condition that represents a contraindication to the use of the drug that will be used for the trial (specifically, for all the molecules under study: hypersensitivity to the active ingredient, hepatic (AST, ALT, alkalyine phosphatase, gammaGT > 4 ULN) or renal insufficiency (KDOQI stage> III); for amitriptyline: the presence of convulsive pathology, congenital forms of long QT syndrome, glaucoma or obstructive pathologies of the urinary tract; for fampridine: the presence of convulsive pathology, the concomitant intake of drugs that block the OCT1 transporter such as cimetidine or quinidine; for fluoxetine: concomitant treatment with MAOIs or other drugs that interfere with serotonin uptake, presence of congenital forms of long QT syndrome; for gabapentine: the presence of pulmonary obstructive pathology or neuromuscular diseases and in particular myasthenia gravis; for metformin: any condition and increases the risk of lactic acidosis such as, in addition to liver and kidney failure, already mentioned as general contraindications, heart failure and acute or chronic ketoacidosis;
- Participation in an ongoing clinical study involving the administration of any other experimental drug for the treatment of ED;
- Uncooperative caregiver who does not ensure consistency and accuracy in keeping the epileptic seizures register, in the home administration of the drug or in the surveillance of the appearance of adverse events |
E.4.IT - Criteri di esclusione principali (elencare i più importanti)
- Presenza di encefaliti infettive, malattie demielinizzanti o degenerative del sistema nervoso centrale;
- Trattamento con il farmaco test nel corso dei 60 giorni precedenti il reclutamento;
- Presenza di una qualunque condizione clinica che rappresenti una controindicazione all’uso del farmaco che verrà utilizzato per la sperimentazione (specificamente, per tutte le molecole oggetto di studio: ipersensibilità accertata al principio attivo, insufficienza epatica AST, ALT,
- fosfatasi alcalina, gammaGT > 4 ULN)o renale (KDOQI stadio> III); per l’amitriptilina: la presenza di patologia convulsiva, di forme congenite di sindrome del QT lungo, di glaucoma o di patologie ostruttive delle vie urinarie; per la fampridina: la presenza di patologia convulsiva, la concomitante assunzione di farmaci che bloccano il trasportatore OCT1 come la cimetidina o la chinidina; per la fluoxetina: concomitante trattamento con IMAO od altri farmaci che interferiscono con la captazione della serotonina, presenza di forme congenite di sindrome del QT lungo; per la gabapentina: la presenza di patologia ostruttiva polmonare o di malattie neuromuscolari ed in particolare di miastenia gravis; per la metformina: qualunque condizione aumenti il rischio di lattico acidosi quali, oltre alla insufficienza epatica e renale, già menzionate come controindicazioni generali, l’insufficienza cardiaca e la chetoacidosi acuta o cronica;
- Partecipazione a in atto ad altro studio clinico che preveda la somministrazione di qualsivoglia altro farmaco sperimentale per il trattamento delle DEE;
- Caregiver non collaborativo che non assicuri costanza ed accuratezza nel tenere il registro delle crisi epilettiche, nella somministrazione domiciliare del farmaco o nella sorveglianza della comparsa di eventi avversi. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Percentage change after 3 months of treatment in the number of epileptic seizures recorded by the caregiver over a 24-hour period as reported in a special diary with respect to the baseline values compared to entry into the study.
- Percentage change after 3 months of treatment of the score measured on the assessment scales of the autism spectrum disorder ADOS-2, CARS-2 and Pep3 compared to the values measured upon entry into the study |
- Variazione percentuale dopo 3 mesi di trattamento del numero di crisi epilettiche settimanali registrate dal caregiver come riportate su di un apposito diario rispetto ai valori basali rispetto rilevati all’ingresso nello studio.
- Variazione percentuale dopo 3 mesi di trattamento dello score misurato alle scale di valutazione del disturbo di spettro autistico ADOS-2, CARS-2 e Pep3 rispetto ai valori rilevati all’ingresso nello studio. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Three months from the first day of treatment |
| Tre mesi dall’inizio del trattamento |
|
| E.5.2 | Secondary end point(s) |
Percentage change in scores measured on the following neurocognitive development scales: Griffiths Mental Development Scales Extended Revised (GMDS-ER) and Child Behavior Checklist for ages 1 ½-5 by T. Achenbach and L. Rescoria.
Percentage variations in auxological parameters (weight, height, head circumference)
Percentage change in scores on the following scales of the patient's quality of life (measured with the PedsQL scale) and of the caregiver Caregiver Quality Of Life Questionnaire (Physical & Emotional) (CQLQ). |
• Variazione percentuale negli score misurati alle seguenti scale di valutazione dello sviluppo neurocognitivo: Griffiths Mental Development Scales Extended Revised (GMDS-ER) e Child Behavior Checklist for ages 1 ½-5 di T. Achenbach e L. Rescoria.
• Variazioni percentuali nei parametri auxologici (peso, altezza, circonferenza cranica)
• Variazione percentuale negli score alle seguenti scale di valutazione della qualità di vita del paziente (misurata con la scala PedsQL) e del caregiver Caregiver Quality Of Life Questionnaire (Physical & Emotional) (CQLQ ). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Three months from the first day of treatment |
| Tre mesi dall’inizio del trattamento |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| n of 1 trial |
| n of 1 trial |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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