A Repeated Dose-finding Study of Sarilumab in Children and Adolescents With Systemic Juvenile Idiopathic Arthritis (SKYPS)

Study Overview
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Brief Summary
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Primary Objective: To describe the pharmacokinetic (PK) profile of sarilumab in patients aged 1-17 years with Systemic Juvenile Idiopathic Arthritis (sJIA) in order to identify the dose and regimen for adequate treatment of this population. Secondary Objective: To describe the pharmacodynamics (PD) profile, the efficacy, and the long term safety of sarilumab in patients with sJIA.

Detailed Description
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The total study duration per patient will be 166 weeks that will consist of a 4- week screening, a 12-week core treatment phase, a 144-week extension phase, and a 6-week post-treatment follow-up.

Official Title
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An Open-label, Sequential, Ascending, Repeated Dose-finding Study of Sarilumab, Administered With Subcutaneous (SC) Injection, in Children and Adolescents, Aged 1 to 17 Years, With Systemic Juvenile Idiopathic Arthritis (sJIA), Followed by an Extension Phase

Conditions
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Juvenile Idiopathic Arthritis

Intervention / Treatment
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* Drug: Sarilumab SAR153191 (REGN88)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Male and female patients aged ≥1 and ≤17 years (or country specified age requirement, 12-17 years for Russia) at the time of the screening visit. Diagnosis of systemic JIA subtype according to the International Associations against Rheumatism (ILAR) 2001 Juvenile Idiopathic Arthritis (JIA) Classification Criteria with the following features: 5 active joints at screening or 2 active joints at screening with systemic JIA fever >37.5 0C in the 3 days preceding baseline or for at least 3 out of any 7 consecutive days during screening despite glucocorticoids at a dose stable for at least 3 days. Patient with an inadequate response to current treatment and considered as a candidate for a biologic disease modifying anti rheumatic drug (DMARD) as per investigator's judgment. Exclusion criteria: Body weight <10 kg or >60 kg for patients enrolled in the ascending dose cohorts, then body weight <10 kg for patients subsequently enrolled at the selected dose. Uncontrolled severe systemic symptoms and/or Macrophage Activation Syndrome (MAS) within 6 months prior to screening. History of or ongoing interstitial lung disease, pulmonary hypertension, pulmonary alveolar proteinosis. If nonsteroidal anti-inflammatory drugs (NSAIDs) (including cyclo oxygenase-2 inhibitors [COX-2]) taken, dose stable for less than 2 weeks prior to the baseline visit and/or dosing prescribed outside of approved label. If non-biologic DMARD taken, dose stable for less than 6 weeks prior to the baseline visit or at a dose exceeding the recommended dose as per local labeling. If oral glucocorticoid taken, dose exceeding equivalent prednisone dose 1 mg/kg/day (or 60 mg/day) within 3 days prior to baseline. Use of parenteral or intra-articular glucocorticoid injection within 4 weeks prior to baseline. Prior treatment with anti-interleukin 6 (IL-6) or IL-6 receptor (IL-6R) antagonist therapies, including but not limited to tocilizumab or sarilumab. Treatment with any biologic treatment for sJIA within 5 half-lives prior to the first dose of sarilumab (the required off treatment periods and procedures may vary according to local requirements). Treatment with a Janus kinase inhibitor within 4 weeks prior to the first dose of sarilumab; and treatment with growth hormone within 4 weeks prior to the first dose of sarilumab (the required off treatment periods and procedures may vary according to local requirements). Treatment with any investigational biologic or non-biologic product within 8 weeks or 5 half-lives prior to baseline, whichever is longer. Exclusion related to tuberculosis. Exclusion criteria related to past or current infection other than tuberculosis. Any live, attenuated vaccine within 4 weeks prior to the baseline visit, such as varicella-zoster, oral polio, rubella vaccines. Killed or inactive vaccine may be permitted based on the Investigator's judgment. Exclusion related to history of a systemic hypersensitivity reaction to any biologic drug and known hypersensitivity to any constituent of the product. Laboratory abnormalities at the screening visit (identified by the central laboratory). Severe cardiac disease due to sJIA. Pregnant or breast-feeding female adolescent patients. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sarilumab<br>Participants will receive one of two ascending doses (or an additional intermediate dose based on available data) of sarilumab by subcutaneous (SC) injection based on body weight. All the participants will receive the selected dose once the selected dose is identified. Sarilumab will be given during 12-week core treatment phase followed by a 144- week extension treatment phase. | Drug: Sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form: Solution Route of administration: Subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK parameter: maximum serum concentration observed (Cmax) |  | Up to Week 12 | 
| Assessment of PK parameter: Area under the serum concentration versus time curve calculated using the trapezoidal method during a dose interval (AUC0-t) |  | Up to Week 12 | 
| Assessment of PK parameter: Concentration observed before treatment administration during repeated dosing (Ctrough) |  | Up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events |  | Core treatment phase: Up to Week 12. Extension phase: Up to Week 162 | 
| Number of patients with local site reactions |  | Core treatment phase: Up to Week 12. Extension phase: Up to Week 156 | 
| Juvenile Idiopathic Arthritis ACR30/50/70/90/100 (in the absence of fever) response rate |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in JIA ACR component: Physician's global assessment of disease activity |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in JIA ACR Component: Patient / parent assessment of overall well-being |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in JIA ACR Component: Childhood Health Assessment Questionnaire (CHAQ) - Disability Index |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in JIA ACR Component: Number of joints with active arthritis |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in JIA ACR Component: Number of joints with limitation of motion |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in JIA ACR Component: High sensitivity C-reactive protein (hs-CRP) |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in JIA ACR Component: fever |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Change from baseline in Juvenile Arthritis Disease Activity Score-27 (JADAS) |  | Core treatment phase: Up to Week 12. Extension phase: At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Changes in glucocorticoid use |  | Core treatment phase: Up to Week 12. Extension phase: Up to Week 156 | 
| Changes in IL-6 associated biomarkers: IL6 |  | Up to Week 12 | 
| Changes in IL-6 associated biomarkers: sIL-6R |  | Up to Week 12 | 
| Proportion of patients receiving glucocorticoids by dose category (glucocorticoid equivalent prednisone dose ≥0.5 mg/kg, ≥0.2 mg/kg and <0.5 mg/kg, <0.2 mg/kg) |  | At weeks 24, 48, and every 24 weeks up to Week 156 | 
| Proportion of patients free of glucocorticoids and without JIA flare |  | At weeks 24, 48, and every 24 weeks up to Week 156 |