| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Refractory epilepsy in tuberous sclerosis complex | | Epilepsia refractaria en Complejo de Esclerosis Tuberosa | |
| E.1.1.1 | Medical condition in easily understood language | | Tuberosus Sclerosis Complex with epilepsy under diffcult control | | Esclerosis tuberosa con epilepsia de difícil control | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | evaluate changes in the number of seizures when administering complete cannabis extract, as a therapeutic active ingredient (API) in patients with epilepsy secondary to Tuberous Sclerosis Complex (TSC), refractory to treatment with antiepileptic drugs (FAEs) and/or other non-pharmacological treatments. | | Evaluar cambios en el número de crisis al administrar extracto completo de cannabis,como principio activo (API) terapéutico en pacientes con epilepsia secundaria a Complejo Esclerosis Tuberosa (CET), refractarios al tratamiento con fármacos antiepilépticos (FAEs) y/u otros tratamientos no farmacológicos. | |
| E.2.2 | Secondary objectives of the trial | - Assess the safety and tolerability of the compound during the study period
- Evaluate the improvement of the quality of life in control of epileptic crises, of the patient and consequently quality of life of relatives/caregivers.
- Evaluate the improvement at the cognitive-behavioral level of patients and disruptive behaviors, autism. | - Evaluar la seguridad y tolerabilidad del compuesto durante el periodo de estudio
- Evaluar la mejora de la calidad de vida en control de crisis epilépticas, del paciente y en consecuencia calidad de vida de familiares /cuidadores.
- Evaluar la mejoría a nivel cognitivo-conductual de los pacientes y conductas disruptivas, autismo. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | - Confirmed diagnosis of TSC (by clinical criteria and/or genetic study)
- Refractory epilepsy secondary to TSC, defined as epilepsy that does not respond successfully to traditional AEDs (2 or more), ketogenic diet, vagus nerve stimulator, and/or are not candidates for epilepsy surgery or persist with seizures after surgery surgical.
- The minimum seizure frequency is 4 or more per month with observable external signs (loss of consciousness or motor component)
- Stability in the dose of AEDs in the 4 weeks prior to the intervention with the oil enriched in CBD+THC, and ketogenic diet/programming of the device associated with the vagus nerve stimulator
- A maximum number of 3 concomitant drugs at the beginning of the clinical trial.
- Availability of caregivers to complete the "crisis diary" prior to inclusion in the study | -Diagnóstico confirmado de CET (por criterios clínicos y/o estudio genético)
-Epilepsia refractaria secundaria a CET, definida como aquella que no responde exitosamente a FAEs tradicionales (2 o más), dieta cetogénica, estimulador del nervio vago, y/o no sean candidatos a cirugía de la epilepsia o persistan con crisis posteriormente a la intervención quirúrgica.
-La frecuencia mínima de crisis es de 4 o más al mes con signos externos observables (pérdida de conciencia o componente motor)
-Estabilidad en la dosis de FAEs en las 4 semanas previas a la intervención con el aceite enriquecido en CBD+THC, y dieta cetogénica/programación del dispositivo asociado al estimulador del nervio vago sin cambios
-Un número máximo de 3 fármacos concomitantes al comienzo del ensayo clínico.
-Disponibilidad por parte de los cuidadores de completar el “diario de crisis” previo a la inclusión en el estudio | |
| E.4 | Principal exclusion criteria | - Patients with an unconfirmed diagnosis, receiving corticosteroids, who did not go through previous therapeutic alternatives or did not correctly adhere to AEDs before being included in the study
- Cardiac, renal, hepatic, pancreatic insufficiency, or hematological dysfunction with values above the normal limits of creatinine and urea; values 2 times the normal limit of serum transaminases, lipase and amylase; platelets <80,000/mm3, and white blood cell count <3,000/mm3.
- Severe uncontrolled medical condition such as: liver disease, cirrhosis, chronic hepatitis (hepatitis B or C), uncontrolled diabetes (defined as serum glucose >150 mg%), active infections (chronic or acute) or severe uncontrolled infections, bleeding assets.
- Patients whose families do not agree to comply with the requirements and visits of the study, or at the discretion of the treating physician present a high risk of non-compliance with the protocol.
- Allergy to any of the components of cannabis oil.
- Family history of schizophrenia or personal history of attempted suicide.
- Patients who changed the medication or dose of AEDs during the 30 days prior to the start of the study or DC/ENV | -Pacientes con diagnóstico no confirmado, que reciben corticoides, que no pasaron por las alternativas terapéuticas previas o no adhirieron correctamente a los FAEs antes de ser incluidos en el estudio
-Insuficiencia cardíaca, renal, hepática, pancreática, o disfunción hematológica con valores sobre los límites normales de creatinina y urea; valores 2 veces el límite normal de transaminasas, lipasa y amilasa sérica; plaquetas < 80000/mm3, y recuento de glóbulos blancos <3000/mm3.
-Condición médica severa no controlada como: enfermedad hepática, cirrosis, hepatitis crónica (hepatitis B o C), diabetes no controlada (definida como glucosa sérica >150 mg%), infecciones activas (crónicas o agudas) o infecciones severas no controladas, sangrados activos.
-Pacientes cuyas familias no accedan a cumplir con los requerimientos y visitas del estudio, o a criterio del médico tratante presenten alto riesgo de incumplimiento del protocolo.
-Alergia a alguno de los componentes del aceite de cannabis.
-Antecedentes familiares de esquizofrenia o antecedentes personales de intento de suicidio.
-Pacientes que cambiaron la medicación o dosis de FAEs durante los 30 días previos al inicio del estudio o dieta cetogenica o estimulador vagal
-Embarazo. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Comparison in the number of monthly seizures between the two groups and with the baseline period. | | Comparación en el número de crisis mensuales entre los dos grupos y con el periodo basal. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | reduction in the number of monthly seizures reported by parents compared to the standardized record provided prior to the start of the study for seizure frequency.
The crisis diary will be reviewed at each visit.
-Response rate: Responders will be considered those patients who achieve a reduction in the number of crises of at least 50%
-Proportion of patients free of seizures: defined as no seizures of any kind during the duration of the study or a period of time that doubles the baseline maximum interval between seizures (International League of Epilepsy, ILAE).
-Maximum interval between crises: obtained from the schedule documented in the crisis record for each period prior to each control.
-Effect on seizure type control: Focal with compromised state of consciousness, focal without compromised state of consciousness, focal secondarily generalized and epileptic spasms | reducción en el número de crisis mensuales reportadas por los padres respecto al registro estandarizado entregado previo al inicio del estudio para la frecuencia de crisis.
El diario de crisis será revisado en cada visita.
-Tasa de respuesta: se considerará respondedores a aquellos pacientes que alcancen una reducción en el número de crisis de al menos 50%
-Proporción de pacientes libres de crisis: definido como ninguna convulsión de ningún tipo durante la duración del estudio o un período de tiempo que duplique el intervalo máximo intercrisis basal (Liga Internacional de Epilepsia, ILAE).
-Intervalo máximo intercrisis: obtenido del horario documentado en el registro de crisis para cada período previo a cada control.
-Efecto en control del tipo de crisis: Focales con compromiso del estado de conciencia, focales sin compromiso del estado de conciencia, focales secundariamente generalizadas y espasmos epilépticos | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | at the beginning and the end | | Al comienzo y al final del estudio | |
| 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 | Yes |
| 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) | 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 2 |
| 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 | No |
| E.8.7 | Trial 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 | after taking the drug for 18/24 weeks.
If the expected effectiveness is demonstrated, the sponsor will administer the treatment until it is marketed. | tras la toma del medicamento durante 18/24 semanas.
si se ha demostrado la efectividad esperada, él sponsor administrará el tratamiento hasta la comercialización del mismo | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
