A study to investigate a new medication, NI-0501, in children with the disease systemic Juvenile Idiopathic Arthritis (sJIA) developing Macrophage Activation Syndrome/secondary Hemophagocytic Lymphohistiocytosis (MAS/sHLH)

• Register: EUCTR
• Last refreshed on: 18 August 2020
• Main ID: EUCTR2016-004223-23-FR
• Date of registration: 13/02/2017
• Prospective Registration: Yes
• Primary sponsor: Novimmune SA
• Public title: A study to investigate a new medication, NI-0501, in children with the disease systemic Juvenile Idiopathic Arthritis (sJIA) developing Macrophage Activation Syndrome/secondary Hemophagocytic Lymphohistiocytosis (MAS/sHLH)
• Scientific title: A pilot, open-label, single arm, multicenter study to evaluate safety, tolerability, pharmacokinetics and efficacy of intravenous administrations of NI-0501, an anti-interferon gamma (anti-IFN?) monoclonal antibody, in patients with systemic Juvenile Idiopathic Arthritis (sJIA) developing Macrophage Activation Syndrome/secondary HLH (MAS/sHLH)
• Target sample size: 10
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004223-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, France, Italy, Netherlands, Spain, United Kingdom, United States

Contacts

• Name: Clinical Science
• Affiliation: Novimmune SA

• Name: Clinical Science
• Affiliation: Novimmune SA

Key inclusion & exclusion criteria

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.

Are the trial subjects under 18? yes
Number of subjects for this age range: 10
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Macrophage activation syndrome / Secondary hemophagocytic lymphohistiocytosis (MAS/sHLH) in patients with Systemic Juvenile Idiopathic Arthritis (sJIA)
MedDRA version: 20.0 Level: LLT Classification code 10053867 Term: Macrophage activation syndrome System Organ Class: 100000004851

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Name: Emapalumab
Product Code: NI-0501
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: EMAPALUMAB
Current Sponsor code: NI-0501
Other descriptive name: Fully human anti-interferon gamma monoclonal antibody
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: At multiple timepoints over 8 weeks

Main Objective: • 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 IFN? and main IFN?-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.

Secondary Objective: Not applicable

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 IFN? at predose, and total IFN? after initiation of NI-0501.
•Levels of the main IFN?-induced chemokines and (CXCL9, CXCL10)
•Correlation between chemokine levels (CXCL9, CXCL10) and levels of free NI-0501, free IFN? (pre-dose) and total IFN? (exploratory analysis).
• Correlation of chemokine and total IFN? 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, TNF???CXCL11).
• 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 IFN?
• levels of main IFN?–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 IFN? production in this patient population.

Secondary Outcome(s)

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.

Timepoint(s) of evaluation of this end point: At multiple timepoints over 8 weeks

Secondary ID(s)

2016-004223-23-IT

NI-0501-06

Source(s) of Monetary Support

Novimmune SA