E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Active rheumatoid arthritis |
Artritis reumatoide activa. |
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E.1.1.1 | Medical condition in easily understood language |
Rheumatoid Arthritis due to overactive immune system |
Artritis reumatoide activa. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
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 | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue 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 determine the effects of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment as measured by ACR20 response. -To determine the safety and tolerability of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment. |
-Comparar los efectos de 100 mg 2 v/d de MK-8457 y un placebo durante 12 semanas de tratamiento, medidos por la respuesta ACR20. -Comparar la seguridad y la tolerabilidad de 100 mg 2 v/d de MK-8457 y el placebo durante 12 semanas de tratamiento. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by ACR20 at Week 24; DAS28CRP change from baseline at Week 12; and ACR50 at Week 12.
- Base Study: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by change from baseline in DAS28CRP at Week 24; ACR50 at Week 24; and HAQ change from baseline at Weeks 12 and 24.
Safety Extension: To assess the safety and tolerability of MK-8457 during the safety extension period through Week 100. |
Objetivo secundario clave: Comparar los efectos de 100 mg 2 v/d de MK-8457 y del placebo, determinados mediante la ACR20 en la semana 24; el cambio de la DAS28PCR respecto a la basal en la semana 12, y la ACR50 en la semana 12. Estudio base: Comparar los efectos de 100 mg 2 v/d de MK-8457 y del placebo, determinados por el cambio de la DAS28PCR respecto a la basal en la semana 24; la ACR50 en la semana 24, y el cambio del HAQ respecto al basal en las semanas 12 y 24. Extensión de seguridad: Valorar la seguridad y la tolerabilidad de MK-8457 durante el período de extensión de seguridad hasta la semana 100. |
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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 |
CI Version 00_ Genetic and future samples( 28/06/2012) |
CI Versión 00_ Genético y Muestras Futuras (28/06/2012) |
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E.3 | Principal inclusion criteria |
-Subject must be > or = to 18 years of age on the day of signing the informed consent. -Subject has a diagnosis of RA for at least 6 months prior to screening. -Subject has active RA as defined by the presence of 6 swollen joints (of 66 joint count) AND 6 tender joints (of 68 joint count) at screening (Visit 1) and baseline (Visit 2). -Subject has a C-reactive protein (CRP) blood level > 0.9 mg/dL from the central reference laboratory at screening. -Subject is anti-cyclic citrullinated antibody positive and/or rheumatoid factor positive at screening. -Subject is ACR functional Class I, II, or III. -Subject must have received MTX for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening (15-25 mg/wk for regions outside of Asia, and 6-25 mg/week for Asia). The subject's dose of weekly MTX must remain stable through week 24 of the study. -Subject must have either failed treatment with 1 or 2 anti-TNF alpha therapies or was intolerant to anti-TNF alpha therapy prior to screening. For subjects who have failed therapy, the treatment with anti-TNF therapies must have been for at least 3 months. Note: The inadequate response or intolerance to anti-TNF therapy will be defined by the Investigator's assessment and will be recorded. Typically, an inadequate response is based on clinical reasons (e.g., no improvement or worsening of RA). Lack of access to the medication or financial reasons are not considered an inadequate response
(Read the rest in the protocol) |
-El sujeto deberá tener ?18 años de edad en el día en que firme el consentimiento informado. -El sujeto tiene un diagnóstico de AR desde al menos 6 meses antes de la selección -El sujeto sufre AR activa, definida por la presencia de ?6 articulaciones hinchadas (de un total de 66) Y ?6 articulaciones dolorosas (de un total de 68) en la selección (visita 1) y el momento basal (visita 2). -El sujeto tiene una concentración en sangre de proteína C reactiva (PCR) >0,9 mg/dl según el laboratorio de referencia central en la selección -El sujeto da positivo en la prueba para anticuerpos antiproteína citrulinada (ACPA) o la del factor reumatoide o ambas en la selección -El sujeto muestra una clase funcional I, II o III de la ARA -El sujeto deberá haber recibido MTX durante un mínimo de 3 meses antes de la selección con una dosis semanal estable regionalmente adecuada durante al menos 4 semanas antes de la selección (15-25 mg/semana en regiones fuera de Asia y 6-25 mg/semana en Asia). La dosis semanal de MTX del sujeto deberá permanecer estable hasta la semana 24 del estudio. -El sujeto deberá no haber respondido al tratamiento con 1 ó 2 tratamientos anti-TNF-alpha o mostró intolerancia al tratamiento anti-TNF-alpha antes de la selección. En el caso de los sujetos en quienes haya fracasado el tratamiento, el tratamiento con fármacos anti-TNF-alpha deberá haber durado al menos 3 meses. -Nota: La respuesta insuficiente o la intolerancia al tratamiento anti-TNF la definirá la valoración del investigador y se registrará. Normalmente, una respuesta insuficiente se basa en motivos clínicos (p. ej., ausencia de mejoría o empeoramiento de la AR). La falta de acceso a la medicación o los motivos económicos no se consideran respuesta insuficiente.
Leer el resto en el protocolo. |
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E.4 | Principal exclusion criteria |
-Subject has inflammatory disease other than RA, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease. -Previous exposure to fostamatinib or other splenic tyrosine kinase (SYK) inhibitors. -Previous exposure to any biological agents other than anti-TNF therapeutic agents, including but not limited to abatacept, tocilizumab, rituximab or other biological agents used for the treatment of RA. -Subject has received any treatment (listed in the table below) more recently than the indicated washout period prior to randomization. Washout Period for Medications Prior to Randomization Medications, Supplements, and Other Substances Washout Period Prior to Randomization Anti-TNF-alpha Therapies: Adalimumab-8 weeks Certolizumab-8 weeks Etanercept-4 weeks Golimumab-8 weeks Infliximab- 8 weeks Cyclosporine, corticosteroids¹ (parenteral, intra-articular), azathioprine, sulfasalazine, hydroxychloroquine--4 weeks Leflunomide² -8 weeks unless subject undergoes standard cholestyramine or activated charcoal washout in which case 4 weeks washout is required. Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents 3 months -Live vaccinations 1 month Investigational medications -30 days or 5 half lives of the investigational agent whichever is longer Bacille Calmette-Guerin (BCG) -vaccination 1 month 1 Subjects will be allowed to take stable doses of oral corticosteroids as specified in inclusion criterion #10; i.e., subjects must be on a stable dose of ?10 mg prednisone per day (or equivalent) for at least 2 weeks prior to first administration of study medications. 2 Subjects may be allowed to use leflunomide instead of methotrexate on or after Week 24 of study treatment. |
-El sujeto sufre una enfermedad inflamatoria distinta a la AR incluidas, entre otras, la artritis psoriásica, la espondilitis anquilosante, el lupus eritematoso diseminado o la enfermedad de Lyme. -Exposición previa al fostamatinib o a otros inhibidores de la tirosina cinasa esplénicos (SYK). -Exposición previa a cualquier fármaco biológico distinto de los fármacos anti-TNF incluidos, entre otros, abatacept, tocilizumab, rituximab u otros fármacos biológicos utilizados para el tratamiento de la AR. El sujeto ha recibido cualquiera de los tratamientos enumerados en la tabla 2-1 sin que haya transcurrido el período de lavado indicado antes de la aleatorización. Período de lavado de la medicación antes de la aleatorización:
Tratamientos anti-TNF: Adalimumab -8 semanas Certolizumab-8 semanas Etanercept-4 semanas Golimumab-8 semanas Infliximab-8 semanas Ciclosporina, corticosteroides¹ (parenterales, intraarticulares), azatioprina, sulfasalazina, hidroxicloroquina-4 semanas Leflunomida2-8 semanas a menos que el sujeto se someta a lavado habitual de colestiramina o carbón activado, caso en el que se precisan 4 semanas de lavado. Fármacos citotóxicos como el clorambucilo, la ciclofosfamida, la mostaza nitrogenada u otros agentes alquilantes-3 meses Vacunas de microorganismos vivos-1 mes Medicamentos en investigación-30 días o 5 semividas del fármaco en investigación, lo que sea más prolongado. Vacuna de bacilo de Calmette-Guérin (BCG)- 1 mes 1 Se permitirá que los sujetos tomen dosis estables de corticosteroides orales según se especifica en el criterio de inclusión 10; es decir, los sujetos deberán haber recibido una dosis estable de ?10 mg de prednisona al día (o su equivalente) durante al menos 2 semanas antes de la primera administración de las medicaciones del estudio. 2 Puede permitirse a los sujetos utilizar leflunomida en lugar de metotrexato en o después de la semana 24 de tratamiento del estudio.
Leer el resto en el protocolo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
-The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12. The primary safety endpoints are: -Percentage of subjects with adverse experiences; -Change from baseline in laboratory parameters; -Change from baseline in vital signs parameters; -Change in blood pressure from predose to 1 hour, 2 hours and 3 hours after the morning study drug dose at Week 2 and Week 12; and -Average change in blood pressure from predose in the 3 hours time period after am study drug dose at Week 2 and Week 12 |
-El Criterio de valoración de la eficacia principal es la proporción de sujetos que logran una respuesta ACR20 en la semana 12 Criterios de valoración de la seguridad principales:
-Porcentaje de sujetos con acontecimientos adversos -Cambio de los parámetros analíticos respecto al momento basal en cada punto temporal especificado en el procedimiento del estudio -Cambio de las constantes vitales respecto al momento basal en cada punto temporal especificado en el procedimiento del estudio -Cambio de la presión arterial desde antes de la administración hasta 1 hora, 2 horas y 3 horas después de la dosis del fármaco del estudio en las semanas 2 y 12 -Cambio medio de la presión arterial respecto a antes de la administración en el período de 3 horas después de la dosis del fármaco del estudio en las semanas 2 y 12 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints are:
-Proportion of subjects achieving ACR20 response at Week 24; -Change from baseline in DAS28CRP at Week 12; and -Proportion of subjects achieving ACR50 response at Week 12.
Other secondary efficacy endpoints that will be evaluated include: -Change from baseline in DAS28CRP at Week 24; -Proportion of subjects achieving ACR50 response at Week 24; and -?Change from baseline in HAQ at Weeks 12 and 24. Safety endpoints will also be evaluated through Week 100 of the safety extension. |
Criterios de valoración de la eficacia secundarios clave -Proporción de sujetos que logran una respuesta ACR20 en la semana 24 -Cambio de la DAS28CRP en la semana 12 respecto a la basal -Proporción de sujetos que logran una respuesta ACR50 en la semana 12
Criterios de valoración de la eficacia secundarios -Cambio de la DAS28CRP en la semana 24 respecto a la basal -Proporción de sujetos que logran una respuesta ACR50 en la semana 24 -Cambio del HAQ en las semanas 12 y 24 respecto al basal
Los criterios de valoración de la seguridad serán también evaluados en la semana 100 de la extensión de seguridad. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 12 and 24 |
Semana 12 y 24 |
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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 | Yes |
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) | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Brazil |
Colombia |
Denmark |
France |
Greece |
Hungary |
Italy |
New Zealand |
Peru |
Poland |
South Africa |
Spain |
Sweden |
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 (Post-Study Visit is the scheduled last visit for patients.) |
LPLV |
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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |