Evaluate Efficacy, Safety and Tolerability, PK and PD of Emapalumab in Children and Adults With MAS in Still's or SLE

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability and efficacy of emapalumab in children and adults with macrophage activation syndrome (sHLH/MAS) in Still's disease (including systemic juvenile idiopathic arthritis and adult onset Still's disease) or with sHLH/MAS in systemic lupus erythematous, resenting an inadequate response to high dose glucocorticoid treatment.

Detailed Description
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Study NI-0501-14 is a two-cohort trial that enrolls subjects who are diagnosed with sHLH/MAS (MAS being a form of secondary HLH) and who are presenting an inadequate response to high doses of GCs. These subjects will be enrolled in 2 cohorts as per their background disease. The cohorts are defined as follows: Cohort 1: MAS in the context of sJIA and AOSD. Cohort 2: MAS in the context of pediatric and adult SLE. The study has the objectives to investigate the efficacy, safety and tolerability, for 8 weeks, and PK and PD, QoL and immunogenicity in these 2 cohorts for up to 1 year after last dose of of emapalumab. Macrophage Activation Syndrome (MAS) Secondary Hemophagocytic Lymphohistiocytosis (sHLH) systemic Juvenile Idiopathic Arthritis (sJIA) Adult-onset Still's Disease (AOSD) Systemic Lupus Erythematosus (SLE)

Official Title
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A Two-cohort, Open-label, Single Arm, Multicenter Study to Evaluate Efficacy, Safety and Tolerability, PK and PD, of Emapalumab in Children and Adults With MAS in Still's Disease or With MAS in Systemic Lupus Erythematous

Conditions
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Macrophage Activation Syndrome, Secondary Hemophagocytic Lymphohistiocytosis, Still Disease, Systemic Lupus Erythematosus, SJIA, AOSD, MAS

Intervention / Treatment
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* Drug: Emapalumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Run-in phase in all cohorts Informed consent provided by the subject or by the subject s' legally authorized representative(s) with the assent of subjects who are legally capable of providing it, as required by local law. Male and female subjects aged between 6 months and 80 years of age at the time of diagnosis of MAS. MAS defined as per the criteria defined below for each cohort and requiring treatment with GCs. Interventional phase in all cohorts Informed consent provided by the subject or by the subject's legally authorized representative(s) with the assent of subjects who are legally capable of providing it, as as required by local law. Male and female subjects aged between 6 months and 80 years of age at the time of diagnosis of active MAS. Subjects who have shown an inadequate response to high dose intravenous (i.v.) GCs administered for at least 3 days according to local standard clinical practice, including but not limited to pulses of 30 mg/kg PDN on 3 consecutive days. High i.v. GCs dose is recommended not to be lower than 2 mg/kg/ day PDN equivalent (or at least 60 mg/day in pediatric subjects of 30 kg or more, and at least 1g/day in adult MAS subjects). In case of rapid worsening of the subject's condition and/or laboratory parameters, as per Investigator judgment, inclusion may occur within less than 3 days from starting high dose GCs. Diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the followings: a. Febrile subjects presenting with ferritin > 684 ng/mL. b. and any 2 of: i. Platelet count ≤ 181 x109/L ii. AST-level > 48 U/L iii. Triglycerides > 156 mg/dL iv. Fibrinogen level ≤ 360 mg/dL Female subjects of child-bearing potential willing to use highly effective methods of contraception from study drug initiation to 6 months after the last dose of study drug. Specific inclusion criteria to Cohort 1 and Cohort 2 Cohort 1: Confirmed sJIA diagnosis. For subjects presenting with MAS in the context of the onset of sJIA, high presumption of sJIA will suffice for eligibility. Confirmed diagnosis of AOSD as per Yamaguchi criteria. Cohort 2: Confirmed diagnosis of SLE as per SLICC'12 criteria. Exclusion criteria Primary HLH documented by either the presence of a known causative genetic mutation or abnormal perforin expression and CD107a degranulation assay as described with primary hemophagocytic lymphohistiocytosis or by the presence of family history. Confirmed malignancy. Note: subjects with a suspected malignancy should have mononuclear cells typed by flow cytometry and/or tissue biopsy, as applicable, to rule out malignancy. Treatment with canakinumab, JAK inhibitors, TNF inhibitors and tocilizumab at the time of emapalumab initiation. Ongoing treatment with anakinra at a dose above 4 mg/kg at time of emapalumab initiation. Subjects treated with etoposide for MAS in the last 1 month. Clinically active mycobacteria (typical and atypical), Histoplasma Capsulatum, or Salmonella infections. Evidence of leishmania infections. Evidence of latent tuberculosis. History of hypersensitivity or allergy to any component of the study drug. Receipt of a Bacillus Calmette-Guerin (BCG) vaccine within 12 weeks prior to screening. Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to screening. Pregnancy or lactating female subjects.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 2 cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (sJIA and AOSD) and Cohort 2 (SLE)<br>MAS in the context of systemic juvenile idiopathic arthritis and adult onset Still's disease (sJIA and AOSD) or SLE | Drug: Emapalumab<br>* Emapalumab iv infusion<br>* Other names: ATC code: L04AA39 (WHO);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with complete response (CR) at Week 8 after first administration of emapalumab | Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm. Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm. Clinical signs will be considered as resolved if VAS is below or equal to 1/10. And Normalization of laboratory parameters relevant to MAS, as follows: WBC above LLN platelet count above LLN LDH below 1.5 ULN ALT below 1.5 ULN AST below 1.5 ULN fibrinogen higher than 100 mg/dL ferritin levels decreased by at least 80 % from values at screening or baseline (whichever is higher) or below 2000 ng/ml, whichever is low | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GCs tapering to a dose below 50% of prednisolone (PDN) equivalent at the time of emapalumab start or to the same (or lower) dose being administered before the occurrence of MAS whichever occurs first | GC tapering as per investigator discretion | At any time in the study, up to 1 year | 
| GCs tapering to ≤1mg/kg/day of PDN equivalent at any time during the study. | GC tapering as per investigator discretion | At any time in the study, up to 1 year | 
| Time to achieve GCs tapering as defined above. | GC tapering as per investigator discretion | At any time in the study, up to 1 year | 
| Time to first Complete Remission | Time to CR | At any time in the study, up to 1 year | 
| Proportion of subjects with overall response as defined by CR or PR | Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm. | At any time in the study, up to 1 year | 
| Time to first overall response as defined by CR or PR | CR defined as below: Resolution of clinical signs and symptoms present at baseline: The MAS clinical activity will be measured on a visual analog scale (VAS) 10 cm. | At any time in the study, up to 1 year | 
| MAS recurrence at anytime after achievement of CR | Time to MAS recurrence after CR | At any time after CR, up to 1 year | 
| Withdrawal from the study due to lack of response as per Investigator decision | Time to withdrawal | At any time in the study, up to 1 year | 
| Survival time | Time to Survival | At any time in the study, up to 1 year |