E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing remitting multiple sclerosis |
Esclerosis múltiple remitente |
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E.1.1.1 | Medical condition in easily understood language |
Relapsing-remitting multiple sclerosis, is a chronic inflammatory disease that affects the central nervous system |
La esclerosis múltiple remitente-recurrente es una enfermedad inflamatoria que afecta al Sistema nervioso central. |
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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 | 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 |
To assess the efficacy, safety and tolerability of a daily dose of 0.6 mg and 1.2 mg of laquinimod as compared to placebo in subjects with relapsing remitting multiple sclerosis (RRMS). |
Estudio para evaluar la eficacia, seguridad y tolerabilidad de una dosis diaria de 0.6 mg y 1.2 mg de laquinimod comparada con placebo en pacientes con esclerosis múltiple remitente-recurrente. |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
No aplica. |
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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 |
Ancillary-studies (sub-studies) are included in the main study protocol LAQ-MS-305, dated 15 August 2012 (final version)
GENETIC MARKERS SUB-STUDY to investigate possible associations between genetic polymorphisms and response to laquinimod
IMMUNOLOGICAL SUB-STUDY to evaluate the immunological response to treatment with laquinimod and further investigation of the potential mechanism of action
MTR MRI SUB-SUDY to evaluate change in whole brain average Magnetization Transfer (MTR) to be used as an exploratory endpoint
CERVICAL CORD MRI SUB-SUDY to evaluate the percent change in cervical cord volume to be used as an exploratory endpoint |
En el protocolo del estudio principal LAQ-MS-305 de fecha 15 de Agosto de 2012: se incluyen estudios auxiliares:
- SUB-ESTUDIO DE MARCADORES GENETICOS para investigar las posibles asociaciones entre los polimorfismos. genéticos y la respuesta al laquinomd.
- SUB-ESTUDIO INMUNOLÓGICO para evaluar la respuesta inmunológica al tratamiento con laquinomid e investigación mas a fondo del posible mecanismo de acción.
-RTM RM SUB-SUDY para evaluar el cambio en el histograma de Transferencia de la Magnetización (RTM). Se utilizará como variable exploratoria.
- SUB-ESTUDIO MEDULA CERVICARL MR. utilizará como variable exploratoria el cambio porcentual del volumen de la médula cervica. |
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E.3 | Principal inclusion criteria |
1. Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria, with relapse onset disease or a relapsing-remitting disease course. 2. Subjects must be ambulatory with Kurtzke EDSS score of 0-5.5 in both screening and randomization visits. 3.Subjects must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)] or adrenocorticotrophic hormone (ACTH), 60 days prior to randomization. 4. Subjects must have experienced at least one documented relapse in the 12 months prior to randomization. 5. Subjects must be between 18 and 55 years of age at screening, inclusive. 6. Subjects must have disease duration of at least 6 months, but not more than 12 years (from the first symptom) prior to randomization. 7. Women of child-bearing potential must practice an acceptable method of birth control until 30 days after the last dose of treatment was administered. 8. Subjects must be able to sign and date a written informed consent prior to entering the study. 9. Subjects must be willing and able to comply with the protocol requirements for the duration of the study. |
1.Los sujetos deben tener un diagnóstico confirmado y documentado de EM definida por los criterios revisados de McDonald, con una recidiva como inicio de la enfermedad o evolución remitente-recurrente de la enfermedad. 2.Los sujetos deben tener capacidad de deambulación con una puntuación en la EDSS de Kurtzke de 0-5,5 tanto en la visita de selección como en la de aleatorización. 3.Los sujetos deben tener un estado neurológico estable, sin recidivas y sin tratamiento con corticosteroides [intravenoso (IV), intramuscular (IM) y/o por vía oral (PO)] ni hormona adrenocorticotropa (ACTH), 60 días antes de la aleatorización. 4.Los sujetos deben haber experimentado al menos una recidiva documentada en los 12 meses previos a la aleatorización. 5.Los sujetos deben tener entre 18 y 55 años en la selección, ambos inclusive. 6.Los sujetos deben tener una duración de la enfermedad de al menos 6 meses, pero no más de 12 años (desde el primer síntoma) antes de la aleatorización. 7.Las mujeres con capacidad fértil deben utilizar un método anticonceptivo aceptable hasta 30 días después de la administración de la última dosis del tratamiento [los métodos anticonceptivos considerados como aceptables en este estudio son: esterilización quirúrgica, dispositivos intrauterinos anticonceptivos orales, parches anticonceptivos, anticonceptivos inyectables de acción prolongada o métodos de doble barrera (preservativo o diafragma con espermicida)]. 8.Los sujetos deben ser capaces de firmar y fechar un consentimiento informado por escrito antes de ser incluidos en el estudio. 9.Los sujetos deben estar dispuestos y ser capaces de cumplir con los requisitos del protocolo durante todo el estudio. |
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E.4 | Principal exclusion criteria |
1. Subjects with progressive forms of MS. 2. Subjects with Neuromyelitis Optica (NMO). 3. Use of experimental or investigational drugs (including dimethyl fumarate and Teriflunomide)and/or participation in drug clinical studies within 6 months prior to randomization. 4. Use of immunosuppressive agents, including fingolimod (Gilenya®) or cytotoxic agents, including Cyclophosphamide within 6 months prior to randomization. 5. Use of either of the following within 2 years prior to randomization: natalizumab (Tysabri®), rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab. 6. Previous treatment with glatiramer acetate (Copaxone®) Interferon-? (either 1a or 1b) or intravenous immunoglobulin (IVIG) within 2 months prior to randomization. 7. Chronic (more than 30 consecutive days) systemic (IV, IM or PO) corticosteroid treatment within 2 months prior to randomization. 8. Previous use of Mitoxantrone (Novantrone®), Cladribine, or alemtuzumab (CAMPATH-1H). 9. Previous use of laquinimod. 10. Previous total body irradiation or total lymphoid irradiation. 11. Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation. 12. Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to randomization. 13. Use of inducers of CYP3A4 within 2 weeks prior to randomization. 14. Pregnancy or breastfeeding. 15. Serum levels ?3xULN of either ALT or AST at screening. 16. Serum direct bilirubin which is ?2xULN at screening. 17. Subjects with a clinically significant or unstable medical or surgical condition or any other condition that cannot be well-controlled by the allowed medications permitted in the study protocol that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests MRI or chest X-ray. 18. A known history of sensitivity to gadolinium (Gd). 19. GFR ? 60 mL/min at the screening visit. 20. Inability to successfully undergo MRI scanning. 21. Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI) within 3 months prior to randomization. 22. Known hypersensitivity that would preclude administration of laquinimod capsule, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate. |
1.Sujetos con formas progresivas de EM. 2.Sujetos con neuromielitis óptica (NMO). 3.Utilización de fármacos experimentales o en investigación (incluyendo dimetil fumarato y teriflunomida) y/o participación en estudios clínicos con fármacos en los 6 meses anteriores a la aleatorización. 4.Utilización de inmunosupresores, incluyendo fingolimod (Gilenya®) o fármacos citotóxicos, incluyendo ciclofosfamida, en los 6 meses anteriores a la aleatorización. 5.Utilización de alguno de los siguientes fármacos en los 2 años anteriores a la aleatorización: natalizumab (Tysabri®), rituximab, ocrelizumab, atacicept, belimumab u ofatumumab. 6.Tratamiento previo con glatiramer acetato (Copaxone®), interferón-? (1a o 1b) o inmunoglobulinas intravenosas (IGIV) en los 2 meses anteriores a la aleatorización. 7.Tratamiento sistémico (IV, IM o PO) crónico (más de 30 días consecutivos) con corticosteroides en los 2 meses anteriores a la aleatorización. 8.Utilización previa de mitoxantrona (Novantrone®), cladribina o alemtuzumab (CAMPATH-1H). 9.Utilización previa de laquinimod. 10.Irradiación corporal total o irradiación linfoide total previas. 11.Tratamiento previo con células madre, trasplante autólogo de médula ósea o trasplante alogénico de médula ósea. 12.Utilización de inhibidores moderados/potentes de CYP3A4 en las 2 semanas anteriores a la aleatorización. 13.Utilización de inductores de CYP3A4 en las 2 semanas anteriores a la aleatorización. 14.Embarazo o lactancia materna. 15.Niveles séricos de ALT o AST ?3xLSN en la selección. 16.Bilirrubina directa sérica ?2xLSN en la selección. 17.Sujetos con un trastorno médico o quirúrgico inestable o clínicamente significativo o cualquier otro trastorno que no puede controlarse bien con las medicaciones permitidas en el protocolo del estudio y que impediría la participación segura y completa en el estudio, de acuerdo con la historia clínica, las exploraciones físicas, los ECG, los análisis de laboratorio, las RMN o las radiografías de tórax. 18.Antecedentes conocidos de sensibilidad a gadolinio (Gd). 19.TFG ? 60 ml/min en la visita de selección. 20.Incapacidad para someterse de forma satisfactoria a una RMN. 21.Sujetos sometidos a tratamiento endovascular por Insuficiencia Venosa Cerebroespinal Crónica (IVCEC) en los 3 meses anteriores a la aleatorización. 22.Hipersensibilidad conocida a fármacos que impediría la administración de las cápsulas de laquinimod, como hipersensibilidad a: manitol, meglumina o estearil fumarato sódico |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to Confirmed Disease Progression (CDP) during Period 1. CDP is defined as an increase in EDSS of > and = 1 point from baseline for subjects with baseline EDSS of < and = 5.0, or an increase in EDSS of > and = 0.5 points from baseline for subjects with baseline EDSS of 5.5. Analysis will be performed at the completion of Period 1. |
Tiempo hasta la Progresión Confirmada de la Enfermedad (PCE) durante el Periodo 1. La PCE se define como un aumento de > and= 1 punto con respecto al valor basal en la EDSS en los sujetos con una EDSS basal de ?5,0, o un aumento de > and =0,5 puntos con respecto al valor basal en la EDSS en los sujetos con una EDSS basal de 5,5. El análisis se realizará a la finalización del Periodo 1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation will be performed at months -1 (screening), 0 (baseline) and every 3 months thereafter and until completion visit of Period 1 |
La evaluación se hará en el mes - 1 ( Seleccion), 0 (Basal) y cada 3 meses pposteriorment hasta la finalización del Periodo 1. |
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E.5.2 | Secondary end point(s) |
-Brain atrophy as defined by the percent change in brain volume from baseline to month 15
-The time to first confirmed relapse during Period 1. |
- Atrofia cerebral determinada mediante el Cambio Porcentual del Volumen Cerebral (CPVC) desde el momento basal hasta el mes 15. - Tiempo hasta la primera recidiva confirmada durante el periodo 1. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
In terms of brain atrophy:
evaulation at baseline and at month 15
In terms relapse evaluation:
Evaluation will be done at each timepoint during the study once any symptoms suggestive of a relapse appear / are reported by any subject. |
- Atrofia cerebral: Evaluación en basal y en el mes 15.
- Evaluacion de recidiva: Se realizará durante el estudi cada vez que el paciente informe sobre cualquier sintoma sugestivo de recidiva. |
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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 | No |
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 | 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) | 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 | 3 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
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 |
Albania |
Belarus |
Bosnia and Herzegovina |
Canada |
Chile |
Croatia |
Georgia |
Israel |
Kazakhstan |
Korea, Democratic People's Republic of |
Macedonia, the former Yugoslav Republic of |
Mexico |
Moldova, Republic of |
Montenegro |
Puerto Rico |
Russian Federation |
Serbia |
South Africa |
Ukraine |
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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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |