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) |
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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. |
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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 pharmacokinetics (PK) profile of NI-0501 in sJIA patients with MAS. • To confirm the proposed dosing regimen of NI-0501 in sJIA patients with MAS. • To evaluate the safety and tolerability profile of intravenous (i.v.) administrations of NI-0501 in sJIA patients with MAS. • To preliminary assess the efficacy of NI-0501 in sJIA patients with MAS. • To assess the levels of relevant biomarkers, such as IFNγ and main IFNγ-induced chemokines (CXCL9, CXCL10). • To assess other potential disease biomarkers (e.g. sCD25, sCD163, IL-10, IL-6, IL-18, TNF CXCL11). • To assess the immunogenicity of NI-0501 in sJIA patients with MAS.
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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 from birth to <18 years • Confirmed sJIA or high presumption of sJIA • Diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the followings: Febrile patient presenting with: - Ferritin > 684 ng/mL and any two of - Platelet count ≤ 181 x10^9/L - AST levels > 48 U/L - Triglycerides > 156 mg/dL - Fibrinogen levels ≤ 360 mg/dL. • Patient presenting an inadequate response to high dose i.v. glucocorticoid treatment administered for at least 3 days as per local standard of care (including but not limited to pulses of 30 mg/kg methylprednisolone (mPDN) on 3 consecutive days). High i.v. glucocorticoid dose should not be lower than 2 mg/kg/ day of mPDN equivalent in 2 divided doses, up to a total of 60 mg/day. In case of rapid worsening of the patient’s condition and/or lab parameters, inclusion may occur within less than 3 days from starting high dose i.v. glucocorticoids. • 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. • Having received guidance on contraception for both male and female patients sexually active and having reached puberty: Females of child-bearing potential require use of highly effective contraceptive measures (failure rate of less than 1% per year) from screening until 6 months after receiving last dose of the study drug. Highly effective contraceptive measures include: o Sexual abstinence o Hormonal contraceptives: combination or progesterone only o Intrauterine methods: intrauterine devices or systems o Bilateral tubal occlusion o Vasectomised partner Males with partners(s) of child-bearing potential must agree to take appropriate precautions (such as sexual abstinence, barrier contraception, vasectomy) to avoid fathering a child from screening until 6 months after receiving last dose of the study drug.
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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. • Patients who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, CNS, liver or renal function that in the opinion of the Investigator may significantly affect likelihood to respond to treatment and/or assessment of NI-0501 safety. • History of hypersensitivity or allergy to any component of the study drug. • 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. • Pregnant or lactating female patients.
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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 (CXCL9, CXCL10) •Correlation between chemokine levels (CXCL9, CXCL10) and levels of free NI-0501, free IFNγ (pre-dose) and total IFNγ (exploratory analysis). • Correlation of chemokine and total IFNγ levels, and laboratory parameters of MAS severity, e.g. ferritin, platelet count, LFTs (exploratory analysis). • Levels of other potential disease biomarkers (e.g. sCD25, sCD163, IL-10, IL-6, IL-18, TNFCXCL11). • Levels (if any) of circulating antibodies against NI-0501 to determine immunogenicity (ADA). In particular, based on: • levels of circulating NI-0501 • levels of total IFNγ • levels of main IFNγ–induced chemokines (namely CXCL9 and CXCL10) a PK/PD modelling will be used to confirm that the proposed dose regimen is adequate in relation to the IFNγ production in this patient population.
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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.
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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 | 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 |
Canada |
France |
Italy |
Netherlands |
Spain |
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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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 |