E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Systemic Juvenile Idiopathic Arthritis (sJIA) |
Artritis idiopática juvenil sistémica (AIJs) |
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E.1.1.1 | Medical condition in easily understood language |
Systemic juvenile idiopathic arthritis (sJIA) is a condition which causes persistant joint pain, swelling, stiffness, fever and rash in children, with onset prior to 16 years of age. |
La artritis idiopática juvenil sistémica (AIJs) es una enfermedad que causa afectación articular persistente, inflamación, rigidez, fiebre y erupciones en niños y se manifiesta antes de los 16 años. |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059176 |
E.1.2 | Term | Juvenile idiopathic 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 evaluate the pharmacokinetics of Tocilizumab (TCZ) over 12 weeks in patients less than 2 years of age with sJIA. |
Evaluar la FC de Tocilizumab (TCZ) durante 12 semanas en pacientes con AIJs menores de 2 años |
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E.2.2 | Secondary objectives of the trial |
To evaluate safety of TCZ over 12 weeks in combination with stable ongoing therapy. To evaluate PD and appropriate efficacy of TCZ over 12 weeks in combination with stable ongoing therapy. |
Evaluar la seguridad de TCZ durante 12 semanas en combinación con el tratamiento estable actual. Evaluar la FD y determinar si la eficacia de TCZ es apropiada en combinación con el tratamiento estable actual, durante 12 semanas. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age less than 24 months at baseline - Fulfills International League of Associations for Rheumatology classification criteria for sJIA - Duration of sJIA lasting at least 1 month since onset of sJIA symptoms - Presence of active disease as determined by the presence of >=2 active joints at screening and baseline, with at least 14 consecutive days of temperature recordings to identify presence or absence of fever (>=38°C) during screening and baseline; or >=2 active joints at screening and baseline, with a fever >=38°C for at least 5 consecutive days during screening and baseline; under these circumstances a patient does not need to complete a full 14 days of temperature diary entries to meet this inclusion criteria - Not currently receiving corticosteroids (CS) OR if taking oral CS, receiving prednisone or equivalent at a stable dose of <=1 milligrams per kilograms per day (mg/kg/day); and the dose remained stable for at least 2 weeks prior to baseline - Not currently receiving methotrexate (MTX) OR if taking MTX, the dose has remained stable or has been discontinued for at least 4 weeks prior to baseline - Not currently receiving non-steroidal anti-inflammatory drug (NSAID) OR if taking NSAID, the dose has remained stable or has been discontinued for at least 2 weeks prior to baseline - Never treated with biologics except anakinra which has been discontinued >=1 week prior to the baseline visit |
- Tener menos de 24 meses de edad en el momento de la visita basal - Cumplir los criterios de la International League of Associations for Rheumatology (clasificación ILAR) para la artritis idiopática juvenil sistémica - AIJs de un mes de duración, como mínimo, desde el comienzo de los síntomas - Presencia de enfermedad activa, determinada por la presencia ? 2 articulaciones activas en los períodos de selección y basal, con registros de la temperatura durante al menos 14 días consecutivos para detectar la presencia o ausencia de fiebre (? 38?C ) durante dichos períodos o ?2 articulaciones activas en los períodos de selección y basal, con fiebre ?38?C durante al menos 5 días consecutivos en dichos períodos; en estas circunstancias, para que se cumpla este criterio de inclusión no es necesario rellenar los apartados correspondientes del diario de temperatura durante los 14 días. - No estar recibiendo CS actualmente o en caso de que estén tomando CS por vía oral recibiendo una dosis estable de ? 1 mg/kg/día de prednisona o un CS equivalente y la dosis se debe haber mantenido estable como mínimo durante las 2 semanas previas a la visita basal. - No estar recibiendo metotrexato (MTX) o en caso de que lo estén tomando, la dosis se debe haber mantenido estable o bien se debe haber suspendido su administración como mínimo 4 semanas antes de la visita basal. - No estar recibiendo AINEs o en caso de que los estén tomando, la dosis se debe haber mantenido estable o bien se debe haber suspendido su administración como mínimo 2 semanas antes de la visita basal. - No haber sido tratados previamente con agentes biológicos, a excepción de anakinra siempre que se haya suspendido su administración ?1 semana antes de la visita basal. |
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E.4 | Principal exclusion criteria |
- Any other auto-immune, rheumatic disease or overlap syndrome other than sJIA - Any significant concurrent medical or surgical condition which would jeopardize the patient?s safety or ability to complete the trial or planned surgery during the study (myringotomy surgery does not exclude patient) - Evidence of serious uncontrolled concomitant diseases including but not limited to the nervous system, renal, hepatic, or endocrine systems - Asthma for which the patient has required the use of oral or parenteral corticosteroids for >=2 weeks within 6 months prior to the baseline visit - Any active acute, subacute, chronic or recurrent bacterial, viral, or systemic fungal infection including but not limited to: acute or chronic renal / bladder infections; acute or chronic pulmonary infections - History of atypical tuberculosis (TB) and active TB requiring treatment at any point prior to screening visit and positive TB test result at screen, unless treated with anti-tuberculosis therapy for at least 4 weeks prior to receiving study medication and chest radiograph is negative for active tuberculosis - Any major episode of infection requiring hospitalization or treatment during screening or treatment with intravenous antibiotics completing within 4 weeks of the screening visit or oral antibiotics completing within 2 weeks of the screening visit - History of reactivation or new onset of a systemic infection such as herpes zoster or Epstein Barr virus within 2 months of the screening visit - Significant cardiac or pulmonary disease - History or concurrent serious gastrointestinal disorders such as ulcer or inflammatory bowel disease, ulcerative colitis or other symptomatic lower gastrointestinal conditions, including ulcer and perforation; - History of or current cancer or lymphoma - History of macrophage activation syndrome within 1 month prior to the screening visit - Administration of intravenous immunoglobulin within 4 weeks prior to the baseline visit - Previous treatment with any cell depleting therapies, including investigational agents (e.g. anti-CD19 and anti-CD20) - Prior stem cell transplant at any time - Live or attenuated vaccines within 4 weeks prior to the baseline visit, or intending to receive while on study medication or 8 weeks following the last dose of study medication |
- Presentar otras enfermedades autoinmunes, reumáticas o síndrome de superposición, que sean distintas de AIJs. - Cualquier condición médica o quirúrgica concurrente significativa que podría comprometer la seguridad del paciente o su capacidad para completar el estudio. - Evidencia de enfermedades concomitantes graves no controladas incluyendo, pero no limitadas únicamente, a los sistemas nervioso, renal, hepático o endocrino. - Asma que haya requerido el uso de corticosteroides orales o parenterales durante ? 2 semanas, en los 6 meses previos a la visita basal. - Cualquier infección fúngica sistémica, viral o bacteriana, recurrente o crónica, aguda o subaguda activa, incluyendo las siguientes, aunque no exclusivamente: Infecciones renales/de vejiga agudas o crónicas; infecciones pulmonares agudas o crónicas. - Resultado positivo en la prueba de TB en la visita de selección, a menos que el paciente haya recibido tratamiento antituberculoso durante al menos las 4 semanas anteriores a la administración de la medicación del estudio y la radiografía de tórax sea negativa para tuberculosis activa. - Cualquier episodio importante de infección que requiera hospitalización o tratamiento durante el período de selección, o tratamiento con antibióticos IV que haya terminado en las 4 semanas anteriores a la visita de selección o con antibióticos orales que haya finalizado en las 2 semanas previas a dicha visita. - Antecedentes de reactivación o comienzo nuevo de una infección sistémica, tal como herpes zoster o virus de Epstein Barr en los 2 meses previos a la visita de selección. - Enfermedad cardiaca o pulmonar significativa. - Trastornos gastrointestinales graves previos o concomitantes, tales como úlcera o enfermedad intestinal inflamatoria, colitis ulcerosa u otras afecciones sintomáticas del tracto gastrointestinal inferior, incluyendo úlceras y perforaciones. - Antecedentes o presencia de cáncer o linfoma. - Antecedentes de SAM en el mes anterior a la visita de selección. - Administración de inmunoglobulina intravenosa en las 4 semanas previas a la visita basal. - Tratamiento previo con cualquier terapia de depleción celular, incluyendo agentes en investigación (p. ej. anti-CD19 y anti-CD20). - Trasplante previo de células madre en cualquier momento. - Administración de vacunas de microorganismos vivos o atenuadas en las 4 semanas previas a la visita basal o intención de administrar dichas vacunas durante el tratamiento con la medicación del estudio u 8 semanas después de administrar la última dosis de la medicación del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetic: Serum TCZ concentration assessed by area under the serum concentration-time profile (AUC[2weeks]), maximum concentration observed (Cmax), and minimum concentration under steady-state conditions within a dosing interval (Cmin) |
Farmacocinéticos: Concentración de suero TCZ evaluada por área bajo el perfil de concentración-tiempo (AUC[2 semanas]), la concentración máxima observada (Cmax) y la concentración mínima en condiciones de estado estable dentro de un intervalo de dosificación (Cmin). |
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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) |
1. Safety: Adverse events 2. Safety: Clinical laboratory results 3. Safety: Physical examination including vital signs |
1. Seguridad: Acontecimientos adversos 2. Seguridad: Resultados de laboratorio clínico 3. Seguridad: Examen físico incluyendo signos vitales |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 18 weeks 2-3. Up to 21 weeks |
1. Hasta 18 semanas 2-3. Hasta 21 semanas |
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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 | 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 | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety and pharmadynamics |
Seguridad y Farmacodinámica |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 |
Belgium |
France |
Germany |
Hungary |
Italy |
Poland |
Russian Federation |
Spain |
United Kingdom |
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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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The end of the study will occur when the last participating patient completes the final follow-up visit. |
El estudio terminará en la fecha en la que tenga lugar la última visita de seguimiento del último paciente participante. |
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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 | 2 |
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 | 4 |
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 | 23 |