E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-remitting Multiple Sclerosis |
Esclerosis múltiple remitente recurrente. |
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E.1.1.1 | Medical condition in easily understood language |
Chronic inflammatory disease attacking the CNS |
Enfermedad inflamatoria crónica que ataca al SNC. |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
The primary objective is to demonstrate that ponesimod is not less effective than fingolimod in reducing relapses in pediatric participants with relapsing remitting multiple sclerosis (RRMS) if treatment is taken as directed through Week 108 |
El objetivo primario es demostrar que ponesimod no es menos eficaz que fingolimod en la reducción de las recaídas en pacientes pediátricos con esclerosis múltiple remitente recurrente (EMRR) si el tratamiento se toma según las indicaciones hasta la semana 108. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are: ●To assess the effect of ponesimod vs fingolimod on the annualized relapse rate (ARR) in pediatric participants with RRMS, as measured by the rate ratio of ponesimod to fingolimod ● To assess the effect of ponesimod on MS disability accumulation and magnetic resonance imaging (MRI) lesion accrual in comparison with fingolimod in pediatric participants with RRMS ●To evaluate the safety, tolerability, and pharmacodynamics (PD) of ponesimod in comparison with fingolimod in pediatric participants with RRMS ●To evaluate the pharmacokinetics(PK) of ponesimod in pediatric participants with RRMS ●To study the PK/PD relationship for key efficacy and safety outcomes in pediatric participants with RRMS treated with ponesimod |
Los objetivos secundarios son: ●Evaluar el efecto de ponesimod frente a fingolimod en la TRA en pacientes pediátricos con EMRR, determinado por el cociente de tasas de ponesimod frente a fingolimod. ●Evaluar el efecto de ponesimod en la acumulación de discapacidad de la EM y en la acumulación de lesiones por resonancia magnética (RM) en comparación con fingolimod en pacientes pediátricos con EMRR. •Evaluar la seguridad, tolerabilidad y farmacodinamia (FD) de ponesimod en comparación con fingolimod en pacientes pediátricos con EMRR. •Evaluar la farmacocinética (FC) de ponesimod en pacientes pediátricos con EMRR •Estudiar la relación FD/FC en cuanto a los resultados clave de eficacia y seguridad en pacientes pediátricos con EMRR tratados con ponesimod. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Open-Label PK sub-study will be conducted in parallel to the main study Objective: To determine if a maintenance dose of < 20 mg ponesimod in pediatric population with body weight <= 40 kg results in PK exposure and PD effects comparable to those achieved in adult participants with RMS |
Sub-estudio abierto de FC se realizará en pararalelo al estudio principal. Objetivo: Evaluar si la dosis de mantenimiento < de 20 mg en la población pediátrica con un peso corporal ≤40 kg da lugar a una exposición FC y a efectos FD comparables a los logrados en pacientes adultos con EMR. |
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E.3 | Principal inclusion criteria |
- A diagnosis of relapsing-remitting multiple sclerosis (RRMS) as defined by the 2017 revisions of the McDonald criteria. Central review of the diagnosis of pediatric multiple sclerosis (MS) will be required for all participants prior to Visit 3 (Day 1, randomization).
- Expanded Disability Status Scale (EDSS) score between 0 and 5.5 (inclusive).
- At least 1 MS relapse during the previous year or 2 MS relapses in the previous 2 years or evidence of gadolinium-enhancing (Gd+) lesions on magnetic resonance imaging (MRI) 6 months prior to Visit 3 (Day 1, Randomization), including MRI at Visit 2 (Baseline).
- Must be otherwise healthy per investigator clinical judgement on the basis of physical examination, medical history, vital signs, laboratory tests, and electrocardiogram (ECGs) at Visit 1 (Screening). Any documented abnormalities must be consistent with pediatric MS. This determination must be recorded in participant’s source documents and initiated by Principal investigator (PI).
- Participants with body weight or body surface area between 5th and 95th percentile for age and sex. Overweight participants greater than 95th percentile and underweight participants less than 5th percentile may participate following medical clearance.
Refer protocol for all inclusion criteria. |
- Un diagnóstico de esclerosis múltiple remitente-recurrente (EMRR) según la definición de las revisiones de 2017 de los criterios de McDonald. Se requerirá una revisión central del diagnóstico de esclerosis múltiple (EM) pediátrica para todos los participantes antes de la Visita 3 (Día 1, aleatorización). - Puntuación de la Escala de Estado de Discapacidad Expandida (EDSS) entre 0 y 5,5 (inclusive). - Al menos 1 recaída de la EM durante el año anterior o 2 recaídas de la EM en los 2 años anteriores o evidencia de lesiones con realce de gadolinio (Gd+) en las imágenes de resonancia magnética (IRM) 6 meses antes de la Visita 3 (Día 1, Aleatorización), incluyendo la IRM en la Visita 2 (Inicio). - Deben estar sanos, según el criterio clínico del investigador, teniendo como base la exploración física, la historia clínica, los signos vitales, las pruebas de laboratorio y el electrocardiograma (ECG) en la visita 1 (selección). Cualquier anormalidad documentada debe ser consistente con la EM pediátrica. Esta determinación debe registrarse en los documentos fuente del participante y ser iniciada por el investigador principal (IP). - Participantes con peso o superficie corporal entre el 5º y el 95º percentil para la edad y el sexo. Los participantes con sobrepeso superior al percentil 95 y los participantes con peso inferior al percentil 5 pueden participar tras recibir la autorización médica.
Consulte el protocolo para conocer todos los criterios de inclusión. |
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E.4 | Principal exclusion criteria |
- Presenting with a diagnosis of MS with progressive course from onset (that is, primary progressive MS or progressive relapsing MS).
- Widespread and symmetric white matter alterations in the baseline MRI suggestive of other demyelinating disorders (example, metabolic disorders, mitochondrial disorders).
- Tested positive for aquaporin 4 (AQP4) or anti-myelin oligodendrocyte glycoprotein (MOG) antibodies at Visit 1 (Screening).
- Pregnant (defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin laboratory test), or breastfeeding, or planning to become pregnant while enrolled in this study.
- Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (example, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
Refer protocol for all exclusion criteria. |
- Presentar un diagnóstico de EM con curso progresivo desde el inicio (es decir, EM primaria progresiva o EM progresiva recidivante). - Alteraciones generalizadas y simétricas de la sustancia blanca en la RM de base que sugieren otros trastornos desmielinizantes (por ejemplo, trastornos metabólicos, trastornos mitocondriales). - Prueba positiva para la acuaporina 4 (AQP4) o anticuerpos contra la glicoproteína oligodendrocítica de mielina (MOG) en la visita 1 (selección). - Embarazada (definido como el estado de una mujer después de la concepción y hasta la terminación de la gestación, confirmado por una prueba de laboratorio de gonadotropina coriónica humana positiva), o en período de lactancia, o que planea quedar embarazada mientras está participando en este estudio. - Cualquier condición por la cual, en opinión del investigador, la participación no sea conveniente para el participante (por ejemplo, comprometiendo su bienestar) o que pudiera impedir, limitar o confundir las evaluaciones especificadas en el protocolo.
Consulte el protocolo para conocer todos los criterios de exclusión. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time from randomization to first confirmed relapse |
Tiempo desde la aleatorización hasta la primera recaída confirmada. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Randomization to Week 108 |
Desde la aleatorización hasta la semana 108. |
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E.5.2 | Secondary end point(s) |
a. ARR, defined as the number of confirmed relapses per participant year b. Time to 12- and 24-week confirmed disability accumulation as measured by Expanded Disability Status Scale (EDSS) score c. Annualized rate of new/newly enlarging T2 lesions d. Adverse events (AEs), including AEs of special interest (AESI) e. Electrocardiogram (ECG) parameters, including heart rate (HR), intervals for PR, QRS, QT, and QTcF f. Pulmonary function test (PFT), including forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC) g. Blood pressure h. Laboratory values, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin i. Change in body weight/height j. Suicidality assessment using the Columbia-Suicide Severity Rating Scale (C-SSRS) k. Peripheral blood lymphocyte counts l. Population PK parameters |
a. TRA, definida como el número de recaídas confirmadas por paciente-año. b. Tiempo hasta la acumulación de discapacidad confirmada a las 12 y 24 semanas según lo determinado por la puntuación de la Escala Ampliada del Estado de Discapacidad (EDSS). c. Tasa anualizada de lesiones en T2 nuevas/aumentadas. d. Acontecimientos adversos (AA), incluidos AA de especial interés (AAEI). e. Parámetros del electrocardiograma (ECG), incluidos la frecuencia cardíaca, los intervalos de PR, QRS, QT y QTcF. f. Prueba de función pulmonar (PFP), incluidos el volumen espiratorio forzado en 1 segundo (VEM1) y la capacidad vital forzada (CVF). g. Presión arterial. h. Valores analíticos, incluidas la alanina aminotransferasa (ALT), la aspartato aminotransferasa (AST) y la bilirrubina. i. Cambio en el peso corporal/estatura. j. Evaluación de tendencias suicidas con la Escala Columbia para Evaluar el Riesgo de Suicidio (C-SSRS). k. Recuentos de linfocitos en sangre periférica. l. Parámetros FC poblacionales. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At timepoints as specified within the protocol |
En los tiempos especificados en el protocolo. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 |
Biomarker evaluation, Tolerability, analysis of MRI parameters, cognitive function, fatigue and Health-related quality of life |
Evaluación de biomarcadores, tolerabilidad, análisis de parámetros de RMN, función cognitiva, fatiga y calidad de vida relacionada con la salud. |
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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 | 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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Doble simulación. |
Double-dummy |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
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 |
Argentina |
Australia |
Brazil |
Canada |
Israel |
Peru |
Puerto Rico |
Taiwan |
United States |
Austria |
Estonia |
Finland |
France |
Poland |
Sweden |
Bulgaria |
Spain |
Switzerland |
Czechia |
Germany |
Greece |
Italy |
Belgium |
Croatia |
Hungary |
Portugal |
Slovakia |
Turkey |
United Kingdom |
Serbia |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 | 2 |