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) |
Sindrome da attivazione macrofagica / linfoistiocitosi emofagocitica secondaria (MAS/sHLH) in pazienti con Artrite giovanile idiopatica sistemica (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. |
Malattia rara, pericolosa per la vita, caratterizzata da una infiammazione intensa incontrollata, che si sviluppa nel contesto di una malattia reumatica |
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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 | 19.1 |
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 |
•Descrivere il profilo famacocinetico di NI-0501
•Confermare il regime terapeutico proposto per NI-0501
•Valutare il profilo di sicurezza e tollerabilità di somministrazioni endovenose (e.v.) di NI-0501
•Valutare preliminarmente l’efficacia di NI-0501
•Valutare i livelli di rilevanti biomarcatori
•Valutare l’immunogenicita’ di NI-0501 |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
Non applicabile |
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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 |
•Pazienti di entrambi i sessi di eta’ <18 anni
•Diagnosi di sJIA, precedentemente confermata o altamente probabile.
•Diagnosi di MAS attiva, confermata dal reumatologo curante
•Risposta inadeguata a terapia e.v. con corticosteroidi ad alto dosaggio
•Consenso informato firmato dal paziente (secondo legislazione locale), o dal/dai suo/suoi tutore/i legale, unitamente all’assenso del paziente che sia legalmente in grado di fornirlo, se applicabile |
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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. |
•Diagnosi, confermata o sospetta, di HLH primaria o di HLH secondaria ad una patologia neoplastica.
•Trattamento con Tocilizumab, Canakinumab, inibitori del TNF nel periodo temporale di 5 volte la loro emivita.
•Infezioni micobatteriche attive (tipiche ed atipiche), infezioni attive da Histoplasma Capsulatum, Shigella, Salmonella, Campylobacter e Leishmania.
•Sospetto clinico di tubercolosi latente
•Serologia positiva agli anticorpi anti-HIV.
•Patologie neoplastiche maligne
•Vaccinazione antitubercolare (bacillo di Calmette e Guérin, BCG) nelle 12 settimane antecedenti la visita di screening.
•Vaccinazione per mezzo di agenti vivi o attenuati (diversi dal BCG) nelle 6 settimane prima della visita di screening |
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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.
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Sicurezza e tollerabilita’:
•Incidenza, severita’, causalita’ ed esito degli eventi avversi (AEs, seri e non-seri) con attenzione particolare alle infezioni.
•Evoluzione dei valori di laboratorio, in particolare emocromo completo, test di funzionalita’ epatica, markers infiammatori (ferritina e PCR) e parametri di coagulazione
•Numero di pazienti ritirati dallo studio per ragioni di sicurezza.
Farmacocinetica e Farmacodinamica:
•Profilo farmacocinetico di NI-0501.
•Livelli di IFNγ circolante libero predose, ed IFNγ totale dopo somministratzione di NI-0501.
•Livelli delle principali chemochine indotte dall’ IFNγ e di altri potenziali biomarcatori della malattia.
•Livelli (se presenti) di anticorpi anti-NI-0501 al fine di determinarne l’immunogenicita’. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At multiple timepoints over 8 weeks |
A diversi tempi di osservazione nelle 8 settimane dello studio |
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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.
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Efficacia:
•Numero di pazienti nei quali verra’ raggiunta la remissione della MAS entro la settimana 8 dall’inizio del trattamento con NI-0501.
•Tempo al raggiungimento della remissione della MAS.
•Numero di pazienti per i quali, in qualunque momento dello studio, sia possibile ridurre la dose di glucocorticoidi i) alla stessa dose (o inferiore) somministrata prima dell’insorgenza della MAS (nei pazienti gia’ in terapia per la sJIA) oppure ii) di almeno il 50% rispetto alla dose somministrata all’inizio del trattamento con NI-0501 (nei pazienti in cui la MAS rappresenta la prima manifestazione della sJIA).
•Tempo alla riduzione della dose di glucocorticoidi (come descritto sopra).
•Analisi di sopravvivenza.
•Numero di pazienti che escono dallo studio per mancanza di efficacia
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At multiple timepoints over 8 weeks |
A diversi tempi di osservazione nelle 8 settimane dello studio |
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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
| 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 | 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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LVLS |
Ultima visita dell’ultimo paziente |
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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 |