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    EudraCT Number:2014-003961-49
    Sponsor's Protocol Code Number:P261-301
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-12-30
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-003961-49
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo Controlled Trial Examining the Safety and Efficacy of Midazolam Intranasal Spray (USL261) for the Treatment of Intermittent Bouts of Increased Seizure Activity in the Epilepsy Monitoring Unit (EMU)
    Ensayo aleatorizado, doble ciego, controlado con placebo para evaluar la eficacia y seguridad del spray intranasal de midazolam (USL261) en el tratamiento de series de crisis en la Unidad de Monitorización de Epilepsia (UME)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Trial to evaluate the efficacy, safety and tolerability of Midazolam Intranasal Spray compared with a placebo administered through the nose (intranasal) for the treatment of intermittent bouts of increased seizure in a site that monitors epilepsy.
    Ensayo Clínico para evaluar la eficacia, seguridad y tolerabilidad del spray intranasal de Midazolam comparado con placebo administrado por la nariz (intranasal) en el tratamiento de series de crisis en un centro que monitoriza la epilepsia.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberP261-301
    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 SponsorUpsher-Smith Laboratories, Inc.
    B.1.3.4CountryUnited States
    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 supportUpsher-Smith Laboratories, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharm-Olam International (Spain), S.L.U.
    B.5.2Functional name of contact pointDepartamento Asuntos Regulatorios
    B.5.3 Address:
    B.5.3.1Street AddressC/ Antracita, 7 - Planta 1 - Nave 6
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28045
    B.5.4Telephone number34911459110
    B.5.5Fax number34914342773
    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 No
    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.3.1Product nameIntranasal midazolam
    D.3.2Product code USL261
    D.3.4Pharmaceutical form Nasal spray, solution in single-dose container
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntranasal use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMIDAZOLAM
    D.3.9.1CAS number 59467-70-8
    D.3.9.2Current sponsor codeUSL261
    D.3.9.4EV Substance CodeSUB08950MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5.0
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboNasal spray, solution in single-dose container
    D.8.4Route of administration of the placeboIntranasal use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    E.1.1.1Medical condition in easily understood language
    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 17.1
    E.1.2Level LLT
    E.1.2Classification code 10015052
    E.1.2Term Epileptic seizure
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy, safety, and tolerability of USL261 compared with that of intranasal (IN) placebo for the treatment of intermittent bouts of increased seizure activity in the Epilepsy Monitoring Unit.
    Evaluar la eficacia, seguridad y tolerabilidad del USL261 en comparación con placebo intranasal (i.n.) en el tratamiento de series de crisis epilépticas en la Unidad de Monitorización de Epilepsia
    E.2.2Secondary objectives of the trial
    Not applicable
    No aplica
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A subject will be eligible for enrollment in the study if all of the following criteria apply:
    1.The subject or the subject's legally acceptable representative (LAR) has provided written informed consent, and subject has provided written assent where required by local law or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) policy
    2.Subject has been admitted to the institution's EMU for seizure characterization or pre-surgical evaluation, or such admission is planned within 28 days
    3.Subject body weight is > or = 40 kg to < or = 125 kg (inclusive)
    4.Subject is > or = 12 years of age at Screening
    5.Subject has an established diagnosis of partial or generalized epilepsy
    Un paciente será elegible para la inclusión en el ensayo si aplican todos los siguientes criterios:
    11. El paciente o el representante legal del paciente (RL) ha proporcionado su consentimiento informado por escrito y su asentimiento por escrito, en aquellos casos en que así lo requiera la legislación local o el Comité de Ética de Investigación Clínica (CEIC).
    2. El paciente ha ingresado en la UME del centro para la caracterización de las crisis o para una evaluación pre quirúrgica o, dicho ingreso está programado en los siguientes 28 días
    3. El peso corporal del paciente es > o = 40 kg y < o = 125 kg (inclusive).
    4. El paciente tiene > o = 12 años de edad en el momento de la selección.
    5. El paciente tiene un diagnóstico establecido de epilepsia parcial o generalizada.
    E.4Principal exclusion criteria
    1.Subject has a medical condition that could interfere with the absorption or pharmacokinetics of USL261
    2.Subject has history of status epilepticus in the 6 months prior to screening
    3.Subject has a progressive neurological disorder such as brain tumor, demyelinating disease, or degenerative central nervous system (CNS) disease that is likely to progress in the next 12 months
    4.Subject has a positive alcohol test or a positive urine drug screen (UDS) not associated with documented legitimate medical use. Individuals with cognitive disability that precludes the collection of a urine sample by conventional means are exempt from the screening UDS requirement provided that the subject is deemed unlikely to have been recently exposed to drugs of abuse based on the opinion of the investigator and the reason the urine could not be obtained is documented
    5.Subject has respiratory failure (or is at risk for respiratory failure) or other severe cardio-respiratory disease with New York Heart Association Class III or IV functional status, or requires supplemental oxygen
    6.Subject has acute narrow-angle glaucoma
    7.Subject (females only) has a positive pregnancy test during the Screening Phase or is currently pregnant or breastfeeding at time of Screening or time of admission to the EMU
    8.Subject has a prior history of any significant adverse reactions (including rash) to benzodiazepines or known allergies to midazolam or formulation components
    9.Subject requires concomitant treatment with any of the prohibited substances listed in this protocol (including strong CYP3A4 inhibitors or respiratory depressants), or cannot safely discontinue prohibited substances with sufficient washout prior to the Treatment Phase (See Appendix 1)
    10.Subject is receiving chronic benzodiazepine treatment (defined as an average of > or = 4 administrations per week) and cannot safely withdraw from such treatment within the washout period prior to the Treatment Phase. The management of safe withdrawal of benzodiazepine therapy is left to the discretion of the investigator. Benzodiazepines that are used for rescue therapy of seizures or for non-epilepsy indications are allowed provided they are typically used < or = 3 times in a 7-day period
    11.Subject has any clinically significant laboratory abnormality as determined by the investigator at Screening
    12.Subject has any clinically significant 12-lead electrocardiogram (ECG) findings as determined by the investigator at Screening
    13.Subject has any clinically significant abnormal vital sign values as determined by the investigator at Screening
    14.Subject is currently using an investigational drug or device or has used such within the 60 days prior to the Screening Phase. The use of experimental non-interventional devices such as seizure detection devices is not considered exclusionary.
    15.Subject has previously participated in a study of USL261
    16.Subject has any condition that may interfere with subject safety/safety monitoring, or preclude the safe administration of a benzodiazepine, or is not appropriate for the study for any other reason as determined by the investigator.
    1. Paciente que presenta una afección médica que podría interferir en la absorción o farmacocinética del USL261.
    2. Paciente con antecedentes de estado epiléptico en los 6 meses anteriores a la selección.
    3. Paciente que padece un trastorno neurológico progresivo, por ej., tumor cerebral, enfermedad desmielinizante o enfermedad degenerativa del sistema nervioso central (SNC), con probabilidad de progresión en los próximos 12 meses.
    4. Paciente que presenta un resultado positivo en la prueba de alcoholemia o en el análisis toxicológico en orina (ATO) no asociado a un uso médico lícito documentado. Las personas con discapacidad cognitiva que impida la obtención de una muestra de orina por medios convencionales están exentas del requisito relativo al ATO de la fase de selección siempre y cuando se considere improbable, a criterio del investigador, que el paciente haya estado expuesto recientemente a drogas y se documente el motivo por el cual no se ha podido obtener la muestra de orina.
    5. Paciente que presenta insuficiencia respiratoria (o riesgo de insuficiencia respiratoria) u otra enfermedad cardiorrespiratoria grave con un estado funcional Clase III o IV de la New York Heart Association, o que requiere oxígeno suplementario.
    6. Paciente que presenta glaucoma agudo de ángulo cerrado.
    7. Paciente (únicamente mujeres) que presenta un resultado positivo en la prueba de embarazo durante la fase de selección o que esté embarazada o dando el pecho en el momento de la selección o en el momento del ingreso en la UME.
    8. Paciente con antecedentes de reacciones adversas importantes (incluida erupción cutánea) a las benzodiacepinas o alergias conocidas al midazolam o a los excipientes.
    9. Paciente que requiere tratamiento concomitante con alguno de los fármacos prohibidos detallados en este protocolo (incluyendo inhibidores potentes del CYP3A4 o depresores respiratorios) o que no puede suspender dichos fármacos de forma segura durante un periodo de lavado suficiente antes de la fase de tratamiento (véase el Apéndice 1).
    10. Paciente que recibe un tratamiento crónico con benzodiacepinas (que se define como una media de > o = 4 administraciones por semana) y que no puede retirar de forma segura dicho tratamiento dentro del periodo de lavado previo a la fase de tratamiento. La retirada segura del tratamiento con benzodiacepinas se deja a criterio del investigador. Se permite el uso de benzodiacepinas para el tratamiento de rescate de crisis epilépticas o para indicaciones no relacionadas con la epilepsia siempre que habitualmente se administren < o = 3 veces en el transcurso de un periodo de 7 días.
    11. Paciente que presenta alguna alteración clínicamente significativa a criterio del investigador de los parámetros de laboratorio en la fase de selección.
    12. Paciente cuyo electrocardiograma de 12 derivaciones (ECG) presenta a criterio del investigador signos clínicamente significativos en la fase de selección.
    13. Paciente que presenta a criterio del investigador algún valor anormal clínicamente significativo en las constantes vitales en la fase de selección.
    14. Paciente que actualmente esté recibiendo un fármaco experimental o usando un dispositivo experimental o que lo haya hecho en los 60 días previos a la fase de selección. El uso de dispositivos experimentales no intervencionistas, como dispositivos para la detección de crisis, no constituye un motivo de exclusión.
    15. Paciente que anteriormente ha participado en un estudio con USL261.
    16. Paciente que presenta alguna afección que podría interferir en su seguridad o en la monitorización de la seguridad o impedir la administración segura de una benzodiacepina; o paciente que a criterio del investigador no es apto para el estudio por cualquier otro motivo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the difference between the USL261- and placebo-treated groups in the proportion of subjects that are seizure-free (no clinically observable seizures) during the Treatment Phase. The proportion of seizure-free subjects will be determined by the number of subjects who complete 6 hours of the Treatment Phase without a seizure. The difference in proportion of seizure-free subjects by treatments will be evaluated using two-sided standard Wald asymptotic 95% confidence intervals.
    El criterio de valoración principal de la eficacia es la diferencia entre el grupo tratado con USL261 y el grupo tratado con placebo en cuanto a la proporción de pacientes sin crisis epilépticas (ausencia de crisis clínicamente observables) durante la fase de tratamiento. La proporción de pacientes sin crisis se determinará a través del número de pacientes que hayan finalizado las 6 horas de la fase de tratamiento sin presentar ninguna crisis. La diferencia en la proporción de pacientes sin crisis entre tratamientos se evaluará utilizando intervalos de confianza asintóticos bilaterales estándar de Wald del 95%.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The proportion of seizure-free subjects will be determined by the number of subjects who complete 6 hours of the Treatment Phase without a seizure.
    La proporción de pacientes sin crisis se determinará a través del número de pacientes que hayan finalizado las 6 horas de la fase de tratamiento sin presentar ninguna crisis.
    E.5.2Secondary end point(s)
    Time to first seizure following treatment (TFSFT) - TFSFT will be defined as time from treatment with study drug to the onset of the next seizure or 6 hours, whichever comes first. Comparison of TFSFT between the USL261- and placebo-treated groups will be analyzed by a log-rank test, with right censoring for subjects who complete 6 hours without a seizure, and presented with Kaplan-Meier estimates of median and two-sided 95% Confidence Intervals for time to event. Those subjects who discontinue prior to 6 hours without a seizure will be analyzed at the time they discontinued.
    Tiempo hasta la primera crisis después del tratamiento (TPCDT): el TPCDT se definirá como el tiempo transcurrido desde el tratamiento con el fármaco del estudio hasta la aparición de la siguiente crisis o hasta las 6 horas, lo que suceda antes. La comparación del TPCDT entre el grupo tratado con USL261 y el grupo tratado con placebo se analizará mediante una prueba de orden logarítmico (log-rank test) con censura a la derecha para los pacientes que completen 6 horas sin crisis, y se presentará con estimaciones de Kaplan-Meier de la mediana e intervalos de confianza bilaterales del 95% para el tiempo hasta la aparición del evento. Aquellos pacientes que se retiren antes de las 6 horas sin haber presentado ninguna crisis serán analizados en el momento de su discontinuación.
    E.5.2.1Timepoint(s) of evaluation of this end point
    TFSFT will be defined as time from treatment with study drug to the onset of the next seizure or 6 hours, whichever comes first.
    El TPCDT se definirá como el tiempo transcurrido desde el tratamiento con el fármaco del estudio hasta la aparición de la siguiente crisis o hasta las 6 horas, lo que suceda antes.
    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 Yes
    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. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    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
    Czech Republic
    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
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    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: 10
    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) No
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2014-12-30. Yes
    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 No
    F.3.3.7Others Yes
    F. of other specific vulnerable populations
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 51
    F.4.2.2In the whole clinical trial 62
    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)
    Normal treatment of that condition
    Tratamiento normal para esta condición médica
    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 Decision2015-02-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-08-26
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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