E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple Sclerosis |
Esclerosis Multiple |
|
E.1.1.1 | Medical condition in easily understood language |
Multiple Sclerosis |
Esclerosis Multiple |
|
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 | PT |
E.1.2 | Classification code | 10067063 |
E.1.2 | Term | Progressive relapsing multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
|
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 |
To evaluate the efficacy and safety of BIIB033 used as add-on therapy to DMTs in subjects with relapsing multiple sclerosis (RMS). |
Evaluar la eficacia y la seguridad de BIIB033 como tratamiento adicional a los tratamientos antinflamatorios modificadores de la enfermedad (TME) en sujetos con esclerosis múltiple recurrente (EMR) |
|
E.2.2 | Secondary objectives of the trial |
Evaluate effects of BIIB033 versus placebo on additional measures of disability improvement - Proportion of subjects with 12-week confirmed improvement in at least 1 of following assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND - Proportion of subjects with 12-week confirmed improvement in at least 1 of the following assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced Auditory Serial Addition Test (PASAT-3) - Proportion of subjects with 12-week confirmed improvement in at least 1 of following assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and without confirmed worsening in any of 4 assessments during 72 weeks of study - Proportion of subjects with 12-week confirmed improvement in at least 1 of the following assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit Modalities Test (SDMT) - Proportion of subjects with 12-week confirmed improvement in at least 1 of following assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% thresholds for T25FW and 9HPT) |
Evaluar los efectos de BIIB033 con placebo en medidas adicionales de mejoría de la discapacidad -Prop. sujetos con mejoría confirmada durante 12 semanas al menos una de las siguientes evaluaciones: EDSS,T25FW,9HPT-D o 9HPT-ND -Prop.de sujetos con mejoría confirmada durante 12 semanas al menos una de las siguientes evaluaciones: EDSS, 25FW, HPT-D,9HPT-ND o en la prueba de la adición auditiva consecutiva ritmada de 3 seg (PASAT-3) -Prop. de sujetos con mejoría confirmada durante 12 semanas en al menos una de las siguientes evaluaciones: EDSS, T25FW, 9HPT-D o 9HPT-ND, y sin empeoramiento confirmado en ninguna de las 4 evaluaciones durante las 72 semanas del ensayo -Prop. de sujetos con mejoría confirmada durante 12 semanas al menos una de las siguientes evaluaciones:EDSS,T25FW,9HPT-D,9HPT-ND, y la prueba de modalidades de símbolos y dígitos(SDMT) -Prop. de sujetos con mejoría confirmada durante 12 semanas al menos una de las siguientes evaluaciones: EDSS, T25FW, 9HPT-D o 9HPT-ND |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria: -Baseline Expanded Disability Status Scale (EDSS) of 2.0 to 6.0, have a diagnosis of relapsing-remitting multiple sclerosis (RRMS) per the 2010 McDonald’s criteria or onset of secondary progressive multiple sclerosis (SPMS) per the Lublin and Reingold criteria, and should have experienced their first MS symptom(s) within the previous 20 years. -Subjects must have experienced at least 1 of the following within 24 months prior to Day 1/Baseline: a clinical relapse (but not within 24 weeks prior to Day 1/Baseline), gadolinium-enhancing lesions on brain or spinal cord magnetic resonance imaging (MRI), or new T2 lesion(s) on brain or spinal cord MRI. -Subjects must be on a stable dose of a protocolspecified anti-inflammatory disease-modifying therapies (DMT) (IFNβ [Avonex, Plegridy, Betaferon/Betaseron, or Rebif], dimethyl fumarate (DMF) [Tecfidera], or natalizumab [Tysabri]) for at least 24 weeks prior to enrollment. -In addition, subjects must have met protocol-defined MRI characteristics consistent with the presence of demyelination and relatively well-preserved tissue integrity. For enrollment, subjects must meet the following MRI criteria on the Screening/Baseline brain MRI: magnetization transfer ratio (MTR) in T2 lesions ≤-0.17 normalized MTR unit and diffusion tensor imaging (DTI) – radial diffusivity in T2 lesions ≤0.98 × 10-3 mm2/s |
-Puntuación inicial de la Escala ampliada del estado de discapacidad (Expanded Disability Status Scale, EDSS) de 2,0 a 6,0, presentar un diagnóstico de esclerosis múltiple recidivante-remitente (EMRR) según los criterios de McDonald de 2010 o inicio de esclerosis múltiple progresiva secundaria (EMPS) según los criterios de Lublin y Reingold, y haber experimentado sus primeros síntomas de EM en los 20 años anteriores. -Los pacientes tienen que haber experimentado al menos 1 de las siguientes situaciones en los 24 meses anteriores al día 1/inicio: una recidiva clínica (pero no en las 24 semanas anteriores al día 1/inicio), lesiones realzadas por gadolinio en la resonancia magnética (RM) cerebral o de la médula espinal, o lesiones nuevas en T2 en la RM cerebral o de la médula espinal. -Los pacientes deben estar recibiendo una dosis estable de uno de los tratamientos modificadores de la enfermedad (TME) antiinflamatorios especificados en el protocolo (IFNβ [Avonex, Plegridy, Betaferon/Betaseron o Rebif], dimetilfumarato (DMF) [Tecfidera] o natalizumab [Tysabri]) durante al menos 24 semanas antes de la inscripción. -Además, los sujetos deben haber cumplido las características de la RM definidas por el protocolo, consistentes en presencia de desmielinización e integridad tisular relativamente bien conservada. Para la inscripción, los pacientes deben cumplir los siguientes criterios de la RM en la RM cerebral de la selección/inicio: índice de transferencia de magnetización (RTM) en lesiones en T2 ≤-0,17 unidad de RTM normalizada e imágenes de tensor de difusión (ITD) – difusividad radial en lesiones en T2 ≤0,98 × 10-3 mm2/s |
|
E.4 | Principal exclusion criteria |
Key Exclusion Criteria -Primary progressive MS -An MS relapse that has occurred within 24 weeks prior to Day 1/Baseline or the subject has not stabilized from a previous relapse at the time of Screening. -Treatment with any chemotherapeutic agents (e.g., mitoxantrone, cyclophosphamide, cladribine), celldepleting monoclonal antibodies (mAbs) (e.g., rituximab, ocrelizumab, alemtuzumab), total lymphoid irradiation, T-cell or T-cell receptor vaccination, or teriflunomide within 1 year prior to Day 1/Baseline. -Treatment with other anti-inflammatory DMTs (e.g., GA, fingolimod, daclizumab) or plasmapheresis within 24 weeks prior to Day1/Baseline. -Treatment with Botox for limb spasticity within 24 weeks before Day 1/Baseline. -Contraindications to MRI, for example, presence of pacemakers or other implanted metal devices (excluding dental braces), an allergy to gadolinium renal impairment, or claustrophobia that cannot be medically managed. -History of human immunodeficiency virus or other immunodeficient conditions. -History of malignancy; however, subjects with a history of excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas are eligible to participate in this study. |
-EM progresiva primaria -Una recidiva de EM que se haya producido en las 24 semanas anteriores al día 1/inicio o el paciente no se ha estabilizado después de una recidiva anterior en el momento de la selección. -Tratamiento con cualquier agente quimioterápico (p. ej., mitoxantrona, ciclofosfamida, cladribina), anticuerpos monoclonales (mAb) reductores de células (p. ej., rituximab, ocrelizumab, alemtuzumab), irradiación linfoide total, vacunación con linfocitos T o receptores de linfocitos T, o teriflunomida en el plazo de 1 año antes del día 1/inicio. -Tratamiento con otros TME antiinflamatorios (p. ej., GA, fingolimod, daclizumab) o plasmaféresis en las 24 semanas anteriores al día 1/inicio. -Tratamiento con toxina botulínica para la espasticidad de las extremidades en las 24 semanas anteriores al día 1/inicio. -Contraindicaciones para la RM, por ejemplo, presencia de marcapasos u otros dispositivos metálicos implantados (excepto ortodoncias), alergia al gadolinio, insuficiencia renal o claustrofobia que no pueda controlarse médicamente. -Antecedentes de virus de la inmunodeficiencia humana u otras afecciones inmunodeficientes. -Antecedentes de neoplasia maligna; sin embargo, los pacientes con antecedentes de carcinoma basocelular extirpado o tratado, o menos de 3 carcinomas epidermoides serán aptos para participar en este estudio. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Score Overall Response Score is a multicomponent score based on 4 components: Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test in the dominant hand (9HPT-D), and 9HPT in the nondominant hand (9HPTND). It assesses overall changes in disability over time. Overall Score ranges from +4 to -4. At each visit, each component is given a score relative to baseline: -1 if threshold is met for worsening, 0 if no changes meet threshold criteria, or +1 if threshold is met for improvement. The thresholds for T25FW and 9HPT are defined by a 15% change from baseline (≥15% decrease from baseline for improvement and ≥15% increase from baseline for worsening). For EDSS, improvement is defined as a ≥1.0-point decrease in EDSS from a baseline score of ≤6.0, and worsening is defined as a ≥1-point increase from a baseline score of ≤5.5 or a ≥0.5-point increase from a baseline score equal to 6.0. |
La puntuación de la respuesta global es una puntuación de múltiples componentes, que se basa en 4 componentes: Escala ampliada del estado de discapacidad (EDSS), 25 pasos cronometrados (Timed 25-Foot Walk, T25FW), prueba de los 9 agujeros en la mano dominante (9-Hole Peg Test in the dominant hand, 9HPT-D) y prueba de los 9 agujeros en la mano no dominante (9-Hole Peg Test in the nondominant hand, 9HPT-ND). Evalúa los cambios globales de la discapacidad en el tiempo. La puntuación global oscila entre +4 y -4. En cada visita, se puntúa cada componente en relación al inicio: -1 si se alcanza el umbral de empeoramiento, 0 si ningún cambio cumple los criterios del umbral o +1 si se alcanza el umbral de mejoría. Los umbrales para T25FW y 9HPT se definen por un cambio del 15 % respecto al valor inicial (una disminución ≥ 15 % respecto al inicio para mejoría y un aumento ≥ 15 % respecto al inicio para empeoramiento). Para la EDSS, la mejoría se define como una disminución ≥1,0 punto en la EDSS respecto a una puntuación inicial ≤6,0, y el empeoramiento se define como un aumento ≥1 punto respecto a una puntuación inicial ≤5,5 o un aumento ≥0,5 puntos respecto a una puntuación inicial igual a 6,0. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessed every 12 weeks from Baseline to Week 72 |
Evaluado cada 12 semanas desde el inicio hasta la semana 72 |
|
E.5.2 | Secondary end point(s) |
- Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND - Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, or 3-Second Paced Auditory Serial Addition Test (PASAT-3) - Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND, and without confirmed worsening in any of the 4 assessments during the 72 weeks of the study - Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, 9HPT-ND, and Symbol Digit Modalities Test (SDMT) - Percentage of Participants with 12-week Confirmed Improvement in at least 1 of the Following Assessments: EDSS, T25FW, 9HPT-D, or 9HPT-ND (20% thresholds for T25FW and 9HPT) |
- Porcentaje de participantes con mejora confirmada a las 12 semanas en al menos 1 de las siguientes evaluaciones: EDSS, T25FW, 9HPT-D o 9HPT-ND - Porcentaje de participantes con mejora confirmada a las 12 semanas en al menos 1 de las siguientes evaluaciones: EDSS, T25FW, 9HPT-D, 9HPT-ND o en la prueba de la adición auditiva consecutiva ritmada de 3 segundos (3-Second Paced Auditory Serial Addition Test, PASAT-3) - Porcentaje de participantes con mejora confirmada a las 12 semanas en al menos 1 de las siguientes evaluaciones: EDSS, T25FW, 9HPT-D o 9HPT-ND, y sin empeoramiento confirmado en ninguna de las 4 evaluaciones durante las 72 semanas del estudio - Porcentaje de participantes con mejora confirmada a las 12 semanas en al menos 1 de las siguientes evaluaciones: EDSS, T25FW, 9HPT-D, 9HPT-ND y prueba de modalidades de símbolos y dígitos (Symbol Digit Modalities Test, SDMT) - Porcentaje de participantes con mejora confirmada a las 12 semanas en al menos 1 de las siguientes evaluaciones: EDSS, T25FW, 9HPT-D o 9HPT-ND (umbrales del 20 % para T25FW y 9HPT) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessed every 12 weeks from Baseline to Week 72 |
Evaluado cada 12 semanas desde el inicio hasta la semana 72 |
|
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 | No |
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 | Yes |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 84 |
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 |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
|
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
|
LVLS |
Ultima visita ultimo paciente |
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |