E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of stereotypical prolonged seizure |
Tratamiento de episodios de estereotipia prolongada |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076333 |
E.1.2 | Term | Prolonged seizure |
E.1.2 | System Organ Class | 100000004852 |
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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 |
Evaluation of the long-term safety and tolerability of Staccato alprazolam |
Evaluar la seguridad y tolerabilidad a largo plazo de Staccato® alprazolam |
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E.2.2 | Secondary objectives of the trial |
- Evaluation of the probability of success of repeated treatment with Staccato alprazolam (for seizures occurring within the first 6 months [up to a maximum of 10 treated seizures]) - Evaluation of the probability of success of repeated treatment with Staccato alprazolam with no recurrence of seizure(s) up to 2 hours (for seizures occurring within the first 6 months [up to a maximum of 10 treated seizures]) - Evaluation of the long-term pulmonary safety of Staccato alprazolam |
- Evaluar la probabilidad de éxito del tratamiento repetido con Staccato® alprazolam (en los episodios producidos en los 6 primeros meses [con un máximo de 10 episodios tratados]) - Evaluar la probabilidad de éxito del tratamiento repetido con Staccato® alprazolam sin recurrencia del episodio(s) en el plazo de 2 horas (en los episodios producidos en los 6 primeros meses [con un máximo de 10 episodios tratados]) - Evaluar la seguridad pulmonar a largo plazo de Staccato® alprazolam |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Participant must be ≥12 years of age at the time of signing informed consent (or giving assent, where required) - Participant must have a caregiver ≥18 years of age at the time of signing the informed consent; the caregiver(s) must be able to recognize and observe the participant - Participants with an established diagnosis of focal or generalized epilepsy or combined focal and generalized epilepsy with a documented history of stereotypical episodes of prolonged seizures that includes at least 1 of the following: a) Generalized seizure episodes starting with a flurry of absence seizures or myoclonic seizures with a minimum total duration of 5 minutes b) Episodes of a focal seizure with a minimum duration of 3 minutes c) Episodes of a focal seizure or myoclonic seizure for at least 90 seconds followed by a generalized/bilateral tonic-clonic seizure with a minimum total duration of 3 minutes - Prior to the Screening Visit, participant completed a study using Staccato alprazolam - Male and female participants: a) A male participant must agree to use contraception during the Treatment Period and for at least 7 days after investigational medicinal product (IMP) administration b) A female participant is eligible to participate if she is not pregnant, not breastfeeding, and: i) Not a woman of childbearing potential (WOCBP) OR ii) A WOCBP who agrees to follow the contraceptive guidance during the Treatment Period and for at least 30 days after IMP administration - Participant is capable of giving signed informed consent (or giving assent, where required). The informed consent form (ICF) or a specific assent form, where required, will be signed and dated by minors - The participant’s caregiver(s) must be capable of giving signed informed, which includes compliance with the requirements and restrictions listed in the ICF, the protocol, and the individualized participant management plan (iPMP) |
- El participante debe tener >=12 años de edad en el momento de firmar el consentimiento informado (o de dar su asentimiento, cuando proceda). - El participante debe tener un cuidador >=18 años de edad en el momento de firmar el ICF; el cuidador(es) debe ser capaz de reconocer y observar las crisis del participante. - Participante con diagnóstico establecido de epilepsia focal o generalizada o de epilepsia focal y generalizada combinada, con historia documentada de episodios de estereotipia prolongados que incluyen como mínimo 1 de lo siguiente: a) Episodios de crisis generalizadas que comienzan con un racimo de crisis de ausencia o de crisis mioclónicas con una duración total mínima de 5 minutos. b) Episodios de una crisis focal con una duración mínima de 3 minutos. c) Episodios de una crisis focal o mioclónica de como mínimo 90 segundos seguida por crisis tónico-clónica generalizada/bilateral con una duración total mínima de 3 minutos. - Antes de la visita de Selección, el participante ha completado un estudio con Staccato® alprazolam - Participantes de ambos sexos a) Si se trata de un participante masculino, deberá estar de acuerdo en seguir las recomendaciones acerca de anticoncepción durante el Periodo de Tratamiento y como mínimo los 7 días siguientes a la última administración del IMP. b) Las mujeres serán elegibles para participar si no están embarazadas o practicando la lactancia natural y: i) No se trata de una mujer potencialmente fértil (woman of childbearing potential, WOCBP) O ii) Se trata de una WOCBP que está de acuerdo en seguir las recomendaciones acerca de anticoncepción durante el Periodo de Tratamiento y como mínimo los 30 días siguientes a la última administración del IMP. - Participante que es capaz de firmar el ICF (o de dar su asentimiento, según proceda). Los menores firmarán y fecharán el ICF o el documento específico de asentimiento, según proceda. - Cuidador(es) del participante que es capaz de firmar el ICF, lo que incluye el cumplimiento de los requisitos y restricciones que se señalan en el ICF, el protocolo y el iPMP. |
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E.4 | Principal exclusion criteria |
- Participant has a history of convulsive status epilepticus in the 8 weeks prior to the Screening Visit - Participant has a history or presence of known nonepileptic seizures which cannot be distinguished from qualifying epileptic seizures - Participant has a clinically significant known airway hypersensitivity (eg, bronchospasm to known allergens, such as pollen, animals, or food) and/or acute respiratory signs/symptoms (eg, shortness of breath, wheezing on lung auscultation) - Participant has a clinically significant chronic pulmonary disorder (eg, asthma, chronic obstructive pulmonary disease, restrictive lung diseases [including idiopathic pulmonary fibrosis]) and/or recent history or presence of hemoptysis or pneumothorax - Participant has a condition for which oral alprazolam is contraindicated (eg, myasthenia gravis, severe respiratory insufficiency, and sleep apnea syndrome) - Participant is taking any drug that is a strong CYP3A4 inhibitor, including azole antifungal agents (ketoconazole and itraconazole) and nefazodone - Participant is taking any opioids (eg, fentanyl, oxycodone, morphine) or sedative hypnotics on a chronic basis - Participant is taking nonselective beta blockers (eg, propranolol, nadolol, and timolol) on a chronic basis - Participant has an FEV1 <80 % of predicted forced expiratory volume in 1 second (FEV1) as measured via spirometry at the Screening Visit - Participant has an oxygen saturation <95 % |
- Participante con antecedente de status epilepticus convulsivo en las 8 semanas previas a la Visita de Selección. - Participante con historia o presencia de crisis no epilépticas conocidas que no pueden diferenciarse de las crisis epilépticas cualificadoras. - Participante con hipersensibilidad conocida de las vías aéreas clínicamente importante (por ejemplo, broncoespasmo a alérgenos conocidos, como polen, animales o alimentos) y/o signos/síntomas respiratorios agudos (por ejemplo, disnea, ruidos torácicos en la auscultación pulmonar). - Participante que tiene un trastorno pulmonar crónico clínicamente importante (por ejemplo, asma, enfermedad pulmonar obstructiva crónica, enfermedad pulmonar restrictiva [incluida la fibrosis pulmonar idiopática]) y/o historia reciente o presencia de hemoptisis o neumotórax. - Participante que presenta un proceso para el que está contraindicado el alprazolam oral (por ejemplo, miastenia gravis, insuficiencia respiratoria severa y síndrome de apnea del sueño). - Participante que está en tratamiento con un medicamento que es un inhibidor potente de la isoenzima 3A4 del citocromo P450 (CYP), incluidos los azoles antifúngicos (ketoconazol e itraconazol) y la nefazodona - Participante que está en tratamiento crónico con opioides (por ejemplo, fentanilo, oxicodona, morfina) o hipnóticos sedantes. - Participante que está en tratamiento crónico con betabloqueantes no selectivos (por ejemplo, propranolol, nadolol y timolol). - Participante que presenta un volumen espiratorio forzado en un 1 segundo (forced expiratory volume in 1 second, FEV1) <80% del teórico en la espirometría de la Visita de Selección. - Participante con una saturación de oxígeno <95% |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Frequency of treatment-emergent adverse events (TEAEs) 2. Frequency of TEAEs leading to withdrawal from study 3. Frequency of serious TEAEs |
1. Frecuencia de acontecimientos adversos emergentes durante el tratamiento (treatment-emergent adverse events, TEAEs) 2. Frecuencia de TEAEs que resulten en el abandono del tratamiento 3. Frecuencia de TEAEs graves |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1&3: From Baseline up to the End of Study Visit (up to 48 months) |
1 y 3: desde la visita basal hasta la visita de fin del estudio (hasta 48 meses) |
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E.5.2 | Secondary end point(s) |
1. Treatment success after investigational medicinal product (IMP) administration for seizures occurring within the first 6 months 2. Treatment success after IMP administration with no recurrence after 2 hours for seizures occurring within first 6 months 3. Frequency of respiratory TEAEs |
1. Éxito del tratamiento tras la administración del IMP en los episodios producidos en los 6 primeros meses 2. Éxito del tratamiento tras la administración del IMP sin recurrencia del episodio(s) en el plazo de 2 horas en los episodios producidos en los 6 primeros meses 3. Frecuencia de TEAEs respiratorios |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1&2: From start of IMP treatment up to 6 months 3: From Baseline up to the End of Study Visit (up to 48 months) |
1 y 2: desde el inicio del tratamiento con IMP hasta los 6 meses 3: desde la visita basal hasta la visita de fin del estudio (hasta 48 meses) |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability |
Tolerabilidad |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
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 | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
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 |
Japan |
Ukraine |
United States |
Bulgaria |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
United Kingdom |
Czechia |
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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
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LVLS |
última visita del último paciente |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 21 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 20 |