E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Macrophage activation syndrome / Secondary hemophagocytic lymphohistiocytosis (MAS/sHLH) in patients with Systemic Juvenile Idiopathic Arthritis (sJIA) |
Síndrome de activación de macrofagos / linfohistiocitosis hemofagocítica secundaria (MAS/sHLH) en pacientes con artritis idiopática juvenile sistesmica (sJIA) |
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E.1.1.1 | Medical condition in easily understood language |
A rare, life-threatening condition, characterized by uncontrolled hyper-inflammation on the background of a rheumatologic disease. |
Una afeccion rara y potencialmente mortal, caracterizada por una hiperinflamacion incontrolada en el fondo de una enfermedad reumatologica. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053867 |
E.1.2 | Term | Macrophage activation syndrome |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To describe the pharmacokinetic profile of NI-0501 in sJIA patients with MAS •To confirm the proposed dosing regimen of NI-0501 •To evaluate the safety and tolerability profile of intravenous administrations of NI-0501 •To preliminary assess the efficacy of NI-0501 •To assess the levels of relevant biomarkers •To assess the immunogenicity of NI-0501 |
•Describir el perfil de farmacocinética (FC) de NI-0501 en pacientes con AIJiS con SAM. •Confirmar la pauta posológica propuesta de NI-0501. •Evaluar el perfil de seguridad y tolerabilidad de administraciones intravenosas de NI-0501. •Evaluar de forma preliminar la eficacia de NI-0501. •Evaluar los niveles de biomarcadores relevantes. •Evaluar la inmunogenicidad de NI-0501. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Patients of both genders, aged <18 years •Confirmed sJIA or high presumption of sJIA. •Diagnosis of active MAS confirmed by the treating rheumatologist •Patient presenting an inadequate response to high dose i.v. glucocorticoid treatment •Informed consent provided by the patient (as required by local law), or by the patient’s legally authorized representative(s) with the assent of patients who are legally capable of providing it, as applicable. |
•Pacientes de ambos sexos con una edad < 18 años. •AIJiS confirmada o sospecha elevada de AIJiS. •Diagnóstico de SAM activo confirmado por el reumatólogo responsable del tratamiento. •Paciente que presenta una respuesta inadecuada al tratamiento i.v. con glucocorticoides a dosis elevadas. inicio del tratamiento i.v. con glucocorticoides a dosis elevadas. •Consentimiento informado proporcionado por el paciente (según se requiera según la normativa local) o por el(los) representante(s) legal(es) del paciente con el asentimiento de los pacientes que estén legalmente capacitados para otorgarlo, según proceda. |
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E.4 | Principal exclusion criteria |
•Diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease. •Patients treated with Tocilizumab, Canakinumab or TNF inhibitors within 5 times of their defined half-life. •Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania infections. •Clinical suspicion of latent tuberculosis. •Positive serology for HIV antibodies. •Presence of malignancy. •Receipt of a BCG vaccine within 12 weeks prior to screening. •Receipt of live or attenuated live vaccines (other than BCG) within 6 weeks prior to screening. |
•Diagnóstico de sospecha o confirmación de HLH primario o HLH debido a una enfermedad neoplásica. •Pacientes tratados con tocilizumab, canakinumab o inhibidores del FNT durante un plazo correspondiente a 5 veces su semivida definida. •Infecciones por micobacterias activas (típicas y atípicas), Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter y Leishmania . •Sospecha clínica de tuberculosis latente. •Serología positiva para anticuerpos frente al VIH. •Presencia de neoplasia maligna. •Haber recibido una vacuna de BCG en las 12 semanas anteriores a la selección. •Haber recibido vacunas vivas o vivas atenuadas (diferentes de BCG) en las 6 semanas anteriores a la selección. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability: •Incidence, severity, causality and outcomes of AEs (serious and non-serious), with particular attention being paid to infections. •Evolution of laboratory parameters, in particular CBC, LFTs, inflammatory markers (ferritin and CRP) and coagulation parameters. •Number of patients withdrawn from the study due to safety reasons.
Pharmacokinetics and pharmacodynamics: •PK profile of NI-0501. •Levels of circulating free IFNγ at predose, and total IFNγ after initiation of NI-0501. •Levels of the main IFNγ-induced chemokines and other potential disease biomarkers. •Levels (if any) of circulating antibodies against NI-0501 to determine immunogenicity. |
La seguridad y la tolerabilidad : •Incidencia, gravedad, relación causal y resultado de los AA (graves y no graves), prestando especial atención a las infecciones. •Evolución de los parámetros analíticos, especialmente el hemograma completo, las PFH, los marcadores inflamatorios (ferritina y PCR) y los parámetros de coagulación. •Número de pacientes retirados por motivos de seguridad. Farmacocineticos y Farmacodinámicos: • Perfil PK de NI-0501 •Niveles de IFNγ libre circulante antes de la dosis y de IFNγ total tras el cominezo con NI-0501 •Niveles (en caso de que haya) de anticuerpos circulantes contra NI-0501 para determinar la inmunogenicidad. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At multiple timepoints over 8 weeks |
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E.5.2 | Secondary end point(s) |
Efficacy: •Number of patients achieving MAS remission by Week 8 after initiation of NI-0501 treatment. •Time to MAS remission. •Number of patients for whom at any time during the study glucocorticoids can be tapered i) to the same (or lower) dose being administered before the occurrence of MAS ((in those patients who are already treated for sJIA) or ii) by 50% (or less) of the dose administered at NI-0501 treatment start (in those patients who present with MAS at sJIA onset). •Time to glucocorticoids tapering (as above described). •Survival time. •Number of patients withdrawn from the study due to lack of efficacy. |
Eficacia: •Número de pacientes que alcanzan remisión del SAM en la semana 8 después del comienzo del tratamiento con NI-0501. •Tiempo hasta la remisión del SAM. •Número de pacientes en los que pueden reducirse progresivamente los glucocorticoides en cualquier momento durante el estudio i) hasta la misma dosis (o inferior) que se administraba antes de la aparición del SAM (en aquellos pacientes que ya reciben tratamiento para el AIJiS) o ii) hasta el 50 % (o menos) de la dosis administrada al inicio del tratamiento con NI-0501 (en aquellos pacientes que presentan SAM al inicio de la AIJiS). •Tiempo hasta la reducción de la dosis de glucocorticoides (tal como se ha definido anteriormente). •Tiempo de supervivencia. •Número de pacientes retirados del estudio por falta de eficacia. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At multiple timepoints over 8 weeks |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |