E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Secondary progressive multiple sclerosis |
Esclerosis Múltiple Secundaria Progresiva |
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E.1.1.1 | Medical condition in easily understood language |
Secondary progressive multiple sclerosis |
Esclerosis Múltiple Secundaria Progresiva |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063400 |
E.1.2 | Term | Secondary progressive 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 |
Primary objective: To demonstrate the efficacy of Siponimod (BAF312) relative to placebo in delaying the time to 3-month confirmed disability progression in patients with secondary progressive multiple sclerosis (SPMS) as measured by expanded disability status scale (EDSS) |
El objetivo principal es demostrar la eficacia de BAF312 respecto al placebo para retrasar el tiempo hasta la progresión de la discapacidad confirmada a 3 meses en pacientes con EMSP medida mediante la EDSS. |
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E.2.2 | Secondary objectives of the trial |
First key secondary objective: To demonstrate the efficacy of Siponimod relative to placebo in delaying the time to 3-month confirmed worsening of at least 20% from Baseline in the timed 25-foot walk test (T25W) Second key secondary objective: To demonstrate the efficacy of Siponimod relative to placebo in reducing the increase in T2 lesion volume from Baseline to the end of the study
For further secondary objectives please see protocol |
El primer objetivo secundario clave es demostrar la eficacia de BAF312 respecto al placebo para retrasar el tiempo hasta un empeoramiento confirmado a 3 meses de al menos un 20% respecto a la Visita basal en la marcha cronometrada de 7,62 metros (25 pies) (T25W). El segundo objetivo secundario clave es demostrar la eficacia de BAF312 respecto al placebo para reducir el aumento en el volumen de lesiones en T2 desde la Visita basal hasta el final del estudio. |
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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 |
1. Exploratory blood and CSF biomarker sub-study (2012-7-12, Version 00) - Characterization of changes in biomarker levels in the CSF and peripheral blood during study course 2. Exploratory cognitive sub-study (2012-7-12, Version 00) - Exploration of cognitive impairment in SPMS patients - Investigation of relationship between cognitive test performance and certain brain imaging findings 3. Exploratory optical coherence tomography (OCT) sub-study (2012-7-12, Version 00) -Exploration of the utility of retinal layer thickness as a marker of axonal degeneration and disability progression in SPMS 4. Magnetic resonance imaging (MRI) sub-study (2012-07-12, Version 00) -Exploration of the use of MRI techniques that may provide additional information about the extent and nature of structural damage due to demyelination or axonal loss, in patients with SPMS treated with Siponimod and placebo, respectively -In addition to the conventional MRI, MTR (magnetization transfer ratio) and high resolution structural imaging will be implemented at centers meeting pre-specified technical requirements to evaluate structural integrity of the brain lesions visible on conventional MRI and in the normal appearing brain tissue as well as the grey matter volume of the patients participating in the CBAF312A2304 study 5. Exploratory fluorescence-activated cell sorting (FACS) sub-study (2012-07-12, Version 00) -Investigation of the influence of pre-treatment peripheral lymphocyte composition on the on-treatment absolute lymphocyte count (ALC) -Increase understanding of the effect of Siponimod on different lymphocyte subpopulations, follow their longitudinal changes on treatment and relate these changes to the clinical and MR outcomes |
1. Subestudio de biomarcadores exploratorios en sangre y en LCR. (2012-7-12, Version 00) - Caracterizar los cambios en la concentración de biomarcadores en LCR y en sangre periférica durante el estudio. 2. Subestudio exploratorio cognitivo. (2012-7-12, Version 00) - Explorar el deterioro cognitivo en pacientes con EMSP e investigar la relación entre la ejecución de la prueba cognitiva y ciertos hallazgos de imagen cerebral. 3. Subestudio exploratorio de OCT. (2012-7-12, Version 00) - Explorar la utilidad del grosor de las capas retinianas como marcador de degeneración axónica y progresión de la incapacidad en la EMSP 4. Subestudio de RM. (2012-07-12, Version 00) -Explorar el empleo de las técnicas de RM que pueden proporcionar información adicional sobre la extensión y la naturaleza del daño estructural debido a desmielinización o a pérdida axónica, en pacientes con EMSP tratados con BAF312 y placebo, respectivamente. Además de la RM convencional, se implementará el MTR y las pruebas de imagen estructural de alta resolución en centros que cumplan los requisitos técnicos pre-especificados para evaluar la integridad estructural de las lesiones cerebrales visibles en la RM convencional y en el tejido cerebral de aspecto normal así como el volumen de sustancia gris en los pacientes que participan en el estudio CBAF312A2304. 5. Subestudio exploratorio FACS. (2012-07-12, Version 00) - Investigar la influencia de la composición de linfocitos periféricos pre-tratamiento sobre el ALC durante el tratamiento y obtener una mejor comprensión del efecto de BAF312 en las diferentes subpoblaciones de linfocitos, seguir sus cambios longitudinales sobre el tratamiento y relacionar estos cambios con los resultados clínicos y de RM. |
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E.3 | Principal inclusion criteria |
Prior history of relapsing remitting MS
Secondary progressive multiple sclerosis (SPMS) defined as progressive increase of disability in at least 6 months
EDSS score of 3.0 to 6.5
No relapse or corticosteroid treatment within 3 months
Other protocol-defined inclusion criteria may apply |
-Antecedentes previos de EM remitente recurrente (EMRR) de acuerdo con los criterios revisados de McDonald 2010 (Polman et al. 2011) -Curso secundariamente progresivo de la EM (EMSP), definido como un aumento progresivo de la discapacidad de al menos 6 meses de duración - Estado de discapacidad en la Selección con una puntuación EDSS de 3,0 a 6,5 (ambas inclusive) - Ninguna evidencia de recidiva o tratamiento con corticoesteroides en los 3 meses previos a la aleatorización
Ver apartado criterios de inclusión del protocolo para el resto de criterios. |
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E.4 | Principal exclusion criteria |
Women of child bearing potential must use reliable forms of contraception.
Diagnosis of Macular edema during screening period
Any medically unstable condition determined by investigator
Unable to undergo MRI scans
Hypersensitivity to any study drugs or drugs of similar class
Other protocol-defined inclusion criteria may apply |
-Mujeres embarazadas o en período de lactancia deben utilizar métodos anticonceptivos altamente eficaces. -Diagnóstico de edema macular durante la fase de prealeatorización -Pacientes con alguna enfermedad inestable, según lo determine el investigador -Pacientes que no puedan ser sometidos a exploraciones con RM -Antecedentes de hipersensibilidad a cualquiera de las medicaciones del estudio o a fármacos de clases químicas similares Ver apartado criterios de exclusión del protocolo para el resto de criterios. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The delay in time to 3-month confirmed disability progression by Siponimod (BAF312) relative to placebo as measured by expanded disability status scale (EDSS)
Confirmed disability is defined as an increase of score of 1 point in patients with baseline score of 3.0-5.0 and 0.5 point increase with baseline score of 5.5 to 6.5. |
Eficacia de BAF312 respecto al placebo para retrasar el tiempo hasta la progresión de la discapacidad confirmada a 3 meses medida mediante la EDSS.
La progresión de la discapacidad se define como un incremento en 1 punto en pacientes con una puntuación basal entre 3.0 y 5.0 y un incremento de 0,5 puntos en pacientes con una puntuación basal entre 5.5 y 6.5. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
baseline, every three months |
basal, cada 3 meses |
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E.5.2 | Secondary end point(s) |
The first key secondary endpoint is the delay in time to 3-month confirmed worsening of at least 20% from Baseline in the timed 25-foot walk test (T25W) by Siponimod (BAF312) compared to placebo.
The second key secondary endpoint is the efficacy of Siponimod (BAF312) relative to placebo in reducing the increase in T2 lesion volume from Baseline to the end of the study. |
El primer objetivo secundario clave es demostrar la eficacia de BAF312 respecto al placebo para retrasar el tiempo hasta un empeoramiento confirmado a 3 meses de al menos un 20% respecto a la Visita basal en la marcha cronometrada de 7,62 metros (25 pies) (T25W). El segundo objetivo secundario clave es demostrar la eficacia de BAF312 respecto al placebo para reducir el aumento en el volumen de lesiones en T2 desde la Visita basal hasta el final del estudio. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.) baseline, every three months 2.) baseline, every year |
1.) Basal, cada 3 meses 2.) basal, cada año |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | Yes |
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 | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 173 |
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 |
Austria |
Belgium |
Bulgaria |
Canada |
Czech Republic |
Egypt |
Estonia |
France |
Germany |
Greece |
Hungary |
Ireland |
Israel |
Italy |
Latvia |
Lithuania |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
Slovakia |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
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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 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 | 0 |
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 | 0 |