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    Summary
    EudraCT Number:2018-000001-23
    Sponsor's Protocol Code Number:DroSpas-1
    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:2018-08-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-000001-23
    A.3Full title of the trial
    A phase III, multi-centre, randomised, double-blind, placebo-controlled, parallel-group clinical trial to investigate the efficacy and safety of BX-1 for the symptomatic relief of spasticity in patients with multiple sclerosis
    Ensayo clínico fase III, multicéntrico, aleatorizado, doble ciego, controlado con placebo, de grupos paralelos, para investigar la eficacia y seguridad de BX-1 para el alivio sintomático de la espasticidad en pacientes con esclerosis múltiple
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study to investigate the efficacy and safety of the test substance BX-1 (dronabinol) for the symptomatic relief of spasticity in patients with multiple sclerosis
    Estudio clínico para investigar la eficacia y seguridad de la sustancia BX-1 (dronabinol) para el alivio sintomático de la espasticidad en pacientes con esclerosis múltiple
    A.3.2Name or abbreviated title of the trial where available
    BX-1 in spasticity due to MS
    BX-1 para la espasticidad debida a la EM
    A.4.1Sponsor's protocol code numberDroSpas-1
    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 SponsorBionorica SE
    B.1.3.4CountryGermany
    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 supportBionorica SE
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBionorica SE
    B.5.2Functional name of contact pointClinical Operations R&D
    B.5.3 Address:
    B.5.3.1Street AddressKerschensteinerstr. 11-15
    B.5.3.2Town/ cityNeumarkt
    B.5.3.3Post code92318
    B.5.3.4CountryGermany
    B.5.4Telephone number+4991812317035
    B.5.5Fax number+49918123167035
    B.5.6E-maildrospas-1@bionorica.de
    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 nameDronabinol
    D.3.2Product code BX-1
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDronabinol
    D.3.9.1CAS number 1972-08-3
    D.3.9.2Current sponsor codeBX-1
    D.3.9.3Other descriptive nameDronabinol
    D.3.9.4EV Substance CodeSUB06407MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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 placeboOral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Symptomatic relief of spasticity in patients with multiple sclerosis
    Alivio sintomático de la espasticidad en pacientes con esclerosis múltiple
    E.1.1.1Medical condition in easily understood language
    Improvment of spasticity in patients with multiple sclerosis. Spasticity is a condition in which certain muscles are continuously contracted causing muscle stiffness.
    Mejora de la espasticidad en pacientes con esclerosis múltiple. La espasticidad es una condición en la cual ciertos músculos se contraen continuamente causando rigidez muscular.
    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 20.0
    E.1.2Level SOC
    E.1.2Classification code 10029205
    E.1.2Term Nervous system disorders
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the trial is to demonstrate superiority of BX-1 over placebo by comparison of proportions of NRS-S responders between the two treatment groups.
    El objetivo primario del ensayo es demostrar la superioridad de BX-1
    sobre placebo mediante la comparación de proporciones de respondedores según el NRS-S entre los dos grupos de tratamiento.
    E.2.2Secondary objectives of the trial
    To demonstrate improvement
    1) in spasticity as measured with Numerical Rating Scale for Spasticity
    2) in pain as measured with Numerical Rating Scale for Pain
    3) in spasm frequency and severity as measured with Penn Spasm Frequency Scale
    4) in walking ability as measured with Timed 25-Foot Walk Test
    5) of the physical and psychological impact of multiple sclerosis as measured with Multiple Sclerosis Impact Scale–29 version 2
    6) on quality of life as measured with Short-Form Health Survey of the Medical Outcomes Study Version 2
    7) in sleep quality as measured with Numerical Rating Scale for Sleep Quality
    8) in fatigue as measured with Numerical Rating Scale for Fatigue
    9) in patient’s status as measured with Patient´s Global Impression of Change Scale and Clinical Global Impression – Improvement Scale
    Safety objective is to evaluate the safety profile of BX-1 by assessing numbers of treatment emergent (serious) AEs, (serious) ARs, laboratory parameters, ECG and vital signs
    Demostrar mejoría
    1) de la espasticidad medida con Numerical Rating Scale for Spasticity
    2) del dolor medido con Numerical Rating Scale for Pain
    3) en la frecuencia y gravedad espasmódicas medidas con Penn Spasm Frequency Scale
    4) en la capacidad de andar medida con 25-Foot Walk Test
    5) en el impacto físico y psicológico de la esclerosis múltiple medido con Multiple Sclerosis Impact Scale–29 version 2
    6) en la calidad de vida medida con Short-Form Health Survey of the Medical Outcomes Study Version 2
    7) en la calidad del sueño medida con Nu-merical Rating Scale for Sleep Quality
    8) de la fatiga medida con Numerical Rating Scale for Fatigue
    9) en el estado de los pacientes medido con Patient´s Global Impression of Change Scale y Clinical Global Impression – Objetivo de Improvement Scale Safety: medir perfil de seguridad evaluando acont. adversos (AA)/reacciones adversas (RA) graves ocurridos durante el tratamiento, parámetros de laboratorio, ECG y constantes vitales.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients aged 18 to 65 years
    2. Presence of MS according to 2010 or 2017 revised McDonald criteria
    3. Patients with stable MS for at least 3 months before enrolment in the opinion of the treating physician
    4. Ongoing spasticity for at least 3 months before enrolment
    5. Spasticity in at least 2 lower limb muscles
    6. Expanded Disability Status Scale (EDSS) score ≥ 3.0 and ≤ 6.5
    7. Previous treatment with at least two different optimized oral MS anti-spasticity therapies before inclusion which must include at least baclofen and/or oral tizanidine at both treatment attempts which can be combined with other anti-spasticity drugs. Patients currently receiving an optimized treatment corresponding to the last treatment attempt with stable dosage for at least 30 days prior to Visit 0.
    Note: A treatment is optimized if, in the opinion of the investigator, it is the best efficient and the best tolerated dose in accordance with the available summary of product characteristics
    8. Female patients of non-childbearing potential or if of childbearing potential using highly effective contraceptive methods.
    For men: no specific contraception methods need to be used.
    9. Willingness to follow the study procedure for the whole duration of the trial and signed informed consent at screening prior to any trial-related procedure
    1. Pacientes de sexo masculino y femenino de entre 18 a 65 años
    2. Diagnóstico de EM de acuerdo con los criterios revisados de McDonald de 2010 o 2017
    3. Pacientes con EM estable durante al menos los 3 meses previos a la inclusión según la opinión del médico tratante
    4. Espasticidad activa durante al menos los 3 meses previos a la inclusión
    5. Espasticidad en al menos 2 músculos de las extremidades inferiores
    6. Puntuación en Expanded Disability Status Scale (escala expandida del estado de discapacidad) (EDSS) ≥3,0 y ≤6,5
    7. Tratamiento previo con al menos dos terapias diferentes anti-espásticas optimizadas por vía oral para la EM antes de la inclusión, que deben incluir al menos baclofeno y/o tizanidina oral en ambos intentos de tratamiento, y que se pueden combinar con otros medicamentos antiespásticos. Pacientes que reciben actualmente un tratamiento optimizado correspondiente con el último tratamiento probado con dosis estable durante al menos los 30 días anteriores a la Visita 0.
    Nota: Un tratamiento se considera optimizado si, en opinión del investigador, es la dosis más eficaz y mejor tolerada de acuerdo con la ficha técnica del producto disponible
    8. Mujeres no fértiles o, en caso de serlo, que utilicen métodos anticonceptivos eficaces.
    Para hombres: no es necesario utilizar métodos anticonceptivos específicos.
    9. Voluntad para seguir el procedimiento del estudio durante todo el desarrollo del ensayo y para firmar el consentimiento informado durante la selección, previamente a cualquier procedimiento relacionado con el ensayo.
    E.4Principal exclusion criteria
    1. Any present disease other than MS that could affect spasticity (e.g. traumatic brain injury, spinal cord injury, brain damage due to a lack of oxygen, stroke, encephalitis, meningitis)
    2. Intake of not permitted concomitant medication prior to screening and concomitant medication which should be unaltered prior to Visit 0 in an unstable dosage regimen (for details please refer to chapter concomitant/not permitted concomitant medication)
    3. Significant fixed tendon contractures
    4. History of epileptic seizures
    5. History of or existing relevant CNS disorder (other than MS)
    6. History of or existing relevant psychiatric disorders (e.g. schizophrenia, psychosis, manic disorders, severe depressive disorders, suicidal ideations, drug and/or alcohol abuse etc.)
    7. Patients with a positive drug abuse screening test, except for medications used to treat a medical condition and reported as such by the patient; all patients with a positive result for cannabis/THC
    8. History of or existing relevant cardiac diseases or pathological findings (e.g. chronic insufficiency NYHA III/IV, severe arrhythmia, unstable angina pectoris, myocardial infarction within the past 6 months, QT prolongation)
    9. Known HIV, and/or active Hepatitis B or C infection according to medical history
    10. History of or existing malignancy during the past 5 years before screening except history of basal cell carcinoma and melanoma in situ
    11.Significantly impaired renal function (creatinine clearance < 50 mL/min)
    12.Significantly impaired hepatic function (Alanine Aminotransferase > 3 times upper limit of normal or bilirubin > 2 times upper limit of normal, except Gilbert syndrome)
    13.Known allergic reactions to the active ingredients used or to constituents of the IMP
    14.Chronic or active infection requiring a systemic therapy
    15. Pregnancy, breastfeeding or planned pregnancy
    16.Any condition that interferes with the participation in the clinical trial at the discretion of the investigator
    17. Patients not able to follow study instructions, not able to follow the study assessments defined by the protocol, unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial
    18. Patients in custody by judicial or official order
    19. Patients who are members of the staff of the trial centre, staff of the sponsor or CRO, the investigator him/herself or close relatives of the investigator
    20. Parallel participation in another clinical trial, participation in another trial within less than 30 days or five half-lives of IMP (whatever is longer) to screening, or previous participation in this trial (except one time screening failures). A patient may be re-screened once, if any inclusion criterion is not met or any exclusion criterion is met during the first screening attempt.
    1. Cualquier otra enfermedad presente que no sea EM y que pueda afectar a la espasticidad (p. ej., lesión cerebral traumática, lesión de la columna vertebral, daño cerebral por falta de oxígeno, accidente cerebrovascular, encefalitis o meningitis)
    2. Ingesta de medicación concomitante no permitida antes de la selección, y medicación concomitante que no deba ser modificada a una posología inestable antes de la Visita 0 (para obtener más detalles, consulte el capítulo sobre medicación concomitante/concomitante no permitida)
    3. Contracturas de tendones fijas importantes
    4. Antecedentes de crisis epilépticas
    5. Antecedentes o existencia de trastornos del SNC relevantes (diferentes a la EM)
    6. Antecedentes o existencia de trastornos psiquiátricos relevantes (p. ej., esquizofrenia, psicosis, trastornos maníacos, trastornos depresivos graves, ideas de suicidio, alcoholismo y/o consumo de drogas, etc.)
    7. Pacientes que den positivo en una prueba detección de consumo de drogas, excepto para medicamentos que se utilizan para tra-tar una afección y comunicados como tal por el paciente; todos los pacientes con resultados positivos en cannabis/THC
    8. Antecedentes o existencia de enfermedades cardíacas o hallazgos patológicos relevantes (p. ej., insuficiencia crónica de clase III/IV según la NYHA, arritmia grave, angina de pecho inestable, infarto de miocardio en los últimos 6 meses, prolongación QT)
    9. Infección conocida de VIH y/o hepatitis B o C activa según la Historia Médica.
    10. Antecedentes o existencia de tumores malignos durante los últimos 5 años antes de la selección, excepto carcinoma de células basales y melanoma localizado
    11. Función renal alterada de forma significativa (aclaramiento de creatinina <50 ml/min)
    12. Función hepática alterada de forma significativa (alanina aminotransferasa >3 veces el límite superior normal o bilirrubina >2 veces el límite superior normal, excepto el síndrome de Gilbert)
    13. Reacciones alérgicas conocidas a los principios activos utilizados o componentes del PEI
    14. Infección activa o crónica que requiera terapia sistémica
    15. Embarazo, lactancia o embarazo planeado
    16. Cualquier afección que interfiera con la participación en el ensayo clínico a discreción del examinador
    17. Pacientes que no puedan seguir las instrucciones del estudio, que no puedan seguir los procedimientos del estudio definidos en el protocolo, que no puedan entender las instrucciones ver-bales y escritas, en concreto relativas a los riesgos e inconvenientes a los que se expondrán durante su participación en el ensayo clínico
    18. Pacientes bajo custodia judicial por orden oficial
    19. Pacientes que forman parte del personal del centro de ensayo, del personal del promotor o de la CRO, el propio investigador o investigadora o familiares cercanos de estos últimos
    20. Participación paralela en otro ensayo clínico, participación en otro ensayo clínico en un plazo inferior a 30 días o cinco semividas del PEI (lo que sea mayor) antes de la selección, o participación previa en este ensayo (excepto un único fallo de selección). Es posible volver a seleccionar a un paciente una vez, en caso de que no se cumpla alguno de los criterios de inclusión o se cumpla alguno de los criterios de exclusión durante el primer intento de selección.
    E.5 End points
    E.5.1Primary end point(s)
    Responder analysis: proportion of patients showing improvement in spasticity (change from baseline corresponding to the mean NRS-S score during 7 days prior to randomisation) of 18% or more in average NRS-S assessment at end of treatment (mean NRS-S score during 7 days prior to Visit 6).
    Análisis de respondedores: proporción de pacientes que muestran una mejora en la espasticidad (cambio desde el punto basal correspondiente a la puntuación media en NRS-S durante 7 días antes de la randomización) de al menos un 18 % en la valoración de la media NRS-S al final del tratamiento (puntuación NRS-S durante 7 días antes de la visita 6).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the trial
    Al final del ensayo
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    1.Responder analysis: proportion of patients showing improvement in spasticity (change from baseline) of 30% or more in average NRS-S assessment at end of treatment (Visit 6)
    2.Responder analysis: proportion of patients showing improvement in spasticity (change from baseline) of 50% or more in average NRS-S assessment at end of treatment (Visit 6)
    3.Time to response: time to reach first improvement in spasticity (change from baseline) of 18% or more, based on patient’s daily spasticity assessment on the NRS-S
    4.Time to response: time to reach first improvement in spasticity (change from baseline) of 30% or more, based on patient’s daily spasticity assessment on the NRS-S
    5.Weekly mean of the patient’s daily spasticity assessments on the NRS-S during Visit 0 - Visit 6
    6.Weekly mean of the patient’s daily pain assessments on the NRS-P during Visit 0 - Visit 6
    7.Responder analysis: proportion of patients showing improvement in pain (change from baseline) of 15% or more in average NRS-P assessment at end of treatment (Visit 6)
    8.Responder analysis: proportion of patients showing improvement in pain (change from baseline) of 30% or more in average NRS-P assessment at end of treatment (Visit 6)
    9.Time to response: time to reach first improvement in pain (change from baseline) of 15% or more, based on patient’s pain assessment on the NRS-P
    10. Time to response: time to reach first improvement in pain (change from baseline) of 30% or more, based on patient’s pain assessment on the NRS-P
    11. Weekly mean of the patient’s daily spasm frequency and severity assessments on the PSFS during Visit 0 - Visit 6
    12. Mean change from baseline of spasm frequency and severity assessments on the PSFS at end of treatment (Visit 6)
    13. Mean change from baseline of Timed 25-Foot Walk (T25-FW) at Visit 4 and Visit 6
    14. Responder analysis: proportion of patients showing improvement in TF25-FW (change from baseline) of 20% or more at Visit 6
    15. Mean change from baseline of the physical and psychological impact of multiple sclerosis assessed with the Multiple Sclerosis Impact Scale– 29 version 2 (MSIS-29 v2) at Visit 4 and Visit 6
    16. Mean change from baseline of quality of life measured with the Physical Functioning (PF), Role Limitations due to Physical Health (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Limitations due to Emotional Health (RE), and Mental Health (MH), the Physical Component Summary (PCS) and the Mental Component Summary (MCS) of SF-36 v2 at Visit 6
    17. Mean change from baseline of sleep quality measured with the NRS-SQ at Visit 3 - Visit 6
    18. Mean change from baseline of fatigue measured with the NRS-F at Visit 3 - Visit 6
    19. Overall patients’ status measured by Patient´s Global Impression of Change scale (PGIC) at Visit 5 and Visit 6
    20. Overall patients’ status measured by Clinical Global Impression – Improvement scale (CGI-I) at Visit 5 and Visit 6
    Safety endpoints:
    21. Nature (term) and frequency of treatment emergent adverse events (AEs), treatment emergent SAEs, adverse reactions (ARs) and SARs
    22. AEs leading to discontinuation
    23. Change from screening (Visit 0) in safety laboratory parameters (blood/urine) at end of treatment
    24. Change from screening (Visit 0) in vital signs at end of treatment
    25. Change from randomisation (Visit 2) in vital signs at end of treatment
    26. Change from screening (Visit 0) in physical examinations (including weight) at end of treatment
    27. Change from screening (Visit 0) in ECG at end of treatment
    1. Análisis de pacientes respondedores al tratamiento: proporción de pacientes que muestran mejoría en la espasticidad (cambio con respecto al valor de referencia) del 30 % o más de media en la evaluación de la NRS-S al final del tratamiento (Visita 6)
    2. Análisis de pacientes respondedores al tratamiento: proporción de pacientes que muestran mejoría de la espasticidad (cambio con respecto al valor de referencia) del 50 % o más de media en la evaluación de la NRS-S al final del tratamiento (Visita 6)
    3. Tiempo de respuesta: tiempo que transcurre hasta alcanzar la primera mejora de la espasticidad (cambio con respecto al valor de referencia) del 18 % o superior, de acuerdo con la evaluación de la espasticidad diaria del paciente en la NRS-S
    4. Tiempo de respuesta: tiempo que transcurre hasta alcanzar la primera mejora de la espasticidad (cambio con respecto al valor de referencia) del 30 % o superior, de acuerdo con la evaluación de la espasticidad diaria del paciente en la NRS-S
    5. Media semanal de las evaluaciones diarias de espasticidad del paciente en la NRS-S de la Visita 0 a la Visita 6
    6. Media semanal de las evaluaciones diarias de dolor del paciente en la NRS-P de la Visita 0 a la Visita 6
    7. Análisis de pacientes respondedores al tratamiento: proporción de pacientes que muestran una mejora del dolor (cambio con respecto al valor de referencia) del 15 % o más de media en la evaluación de la NRS-P al final del tratamiento (Visita 6)
    8. Análisis de pacientes respondedores al tratamiento: proporción de pacientes que muestran una mejora del dolor (cambio con respecto al valor de referencia) del 30 % o superior de media en la evaluación de la NRS-P al final del tratamiento (Visita 6)
    9. Tiempo de respuesta: tiempo que transcurre hasta alcanzar la primera mejora del dolor (cambio con respecto al valor de referencia) del 15 % o superior, de acuerdo con la evaluación diaria del dolor del paciente en la NRS-P
    10. Tiempo de respuesta: tiempo que transcurre hasta alcanzar la primera mejora del dolor (cambio con respecto al valor de referencia) del 30 % o superior, de acuerdo con la evaluación diaria del dolor del paciente en la NRS-P
    11. Media semanal de las evaluaciones diarias de la frecuencia y gravedad de los espasmos del paciente en la PSFS de la Visita 0 a la Visita 6
    12. Cambio medio con respecto al valor de referencia de las evaluaciones de la frecuencia y gravedad de los espasmos en la PSFS al final del tratamiento (Visita 6)
    13. Cambio medio con respecto al valor de referencia de la prueba Timed 25-Foot Walk (T25-FW) en las Visitas 4 y 6
    14. Análisis de pacientes respondedores al tratamiento: proporción de pacientes que muestran una mejora en la prueba TF25-FW (cambio con respecto al valor de referencia) del 20 % o su-perior en la Visita 6
    15. Cambio medio con respecto al valor de referencia del impacto físico y psicológico de la esclerosis múltiple evaluado con la versión 2 de la escala de impacto de la esclerosis múltiple 29 (MSIS-29 v2) en las Visitas 4 y 6
    16. Cambio medio con respecto al valor de referencia de la calidad de vida medida a través de la función física (FF), las limitaciones de rol por problemas físicos (RF), el dolor corporal (DC), la salud general (SG), la vitalidad (V), la función social (FS), las limitaciones de rol de origen emocional (RE) y la salud mental (SM) y el resumen del componente físico (CSF) y mental (CSM) del SF-36 v2 en la Visita 6
    17. Cambio medio con respecto al valor de referencia de la calidad del sueño medida con la NRS-SQ de la Visita 3 a la Visita 6
    18. Cambio medio con respecto al valor de referencia de la fatiga con la NRS-F de la Visita 3 a la Visita 6
    19. Estado general del paciente medido mediante la escala de impresión de cambio global del paciente (PGIC) en las Visitas 5 y 6
    20. Estado general del paciente medido mediante la escala de impresión/mejora clínica global (CGI-I) en las Visitas 5 y 6
    Criterios de evaluación de la seguridad:
    21. Naturaleza (término) y frecuencia de los acontecimientos adversos (AA) durante el tratamiento, AA graves (AAG) durante el tratamiento, reacciones adversas (RA) y RA graves (RAG)
    22. AA que derivan en la interrupción del tratamiento
    23. Cambio con respecto a la selección (Visita 0) en los parámetros de laboratorio de seguridad (sangre/orina) al final del tratamiento
    24. Cambio con respecto a la selección (Visita 0) en las constantes vitales al final del tratamiento
    25. Cambio con respecto a la aleatorización (Visita 2) en las constantes vitales al final del tratamiento
    26. Cambio con respecto a la selección (Visita 0) en las exploraciones físicas (incluido el peso) al final del tratamiento
    27. Cambio con respecto a la selección (Visita 0) en el ECG al final del tratamiento
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of the trial
    Al final del ensayo.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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.7.1.3.1Other 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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Patients are single-blind during the titration phase
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    Última visita del último sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 538
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 No
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 548
    F.4.2.2In the whole clinical trial 548
    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)
    After the end of the trial, the patients will be treated according to local standard practice. No further post-trial therapy will be offered by the sponsor.
    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 Decision2018-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-03-30
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