An Open-label, Ascending, Repeated Dose-finding Study of Sarilumab in Children and Adolescents With Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA)

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 2-17 years with Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) in order to identify the dose and regimen for adequate treatment of this population Secondary Objective: To describe the pharmacodynamic (PD) profile, the efficacy and the long-term safety of sarilumab in patients with pcJIA.

Detailed Description
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For approximately 72 patients enrolled in the dose-finding and second portions, 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. For approximately 28 patients enrolled in the third portion, the total study duration per patient will be 106 weeks that will consist of a 4- week screening, a 12-week core treatment phase, a 84-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 2 to 17 Years, With Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) Followed by an Extension Phase

Conditions
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Juvenile Idiopathic Arthritis

Intervention / Treatment
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* Drug: Sarilumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Male and female patients aged ≥2 and ≤17 years (or country specified age requirement) at the time of the screening visit. Diagnosis of rheumatoid factor-negative or rheumatoid factor positive polyarticular Juvenile Idiopathic Arthritis (JIA) subtype or oligoarticular extended JIA subtype according to the International League of Associations for Rheumatology (ILAR) 2001 Juvenile Idiopathic Arthritis Classification Criteria with at least 5 active joints as per American College of Rheumatology (ACR) definition for active arthritis at Screening Patient with an inadequate response to current treatment and considered as a candidate for a biologic disease modifying antirheumatic drug (DMARD) as per investigator's judgment Exclusion criteria: Body weight <10 kg or >60 kg for patients enrolled in the 3 ascending dose cohorts, then body weight <10 kg for patients subsequently enrolled at the selected dose-regimen. If nonsteroidal anti-inflammatory drugs (NSAIDs) [including cyclo oxygenase-2 inhibitors (COX-2)] taken, dose stable for <2 weeks prior to the baseline visit and/or dosing prescribed outside of approved label. If non-biologic DMARD taken, dose stable for <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 0.5 mg/kg/day (or 30 mg/day) within 2 weeks 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 pcJIA within 5 half-lives prior to the first dose of sarilumab. 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. Lipid lowering drug stable for less than 6 weeks prior to screening. Exclusion related to tuberculosis (TB). 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). 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: 2 Years
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 three ascending dose regimens of sarilumab by subcutaneous (SC) injection based on body weight. All the participants will receive the selected dose regimen once this is identified. Sarilumab will be given during 12-week core treatment phase followed by an extension treatment phase (144 weeks for approximately 72 patients enrolled in dose-finding and second portions and 84 weeks for approximately 28 patients enrolled in third portion) | Drug: Sarilumab<br>* Pharmaceutical form:Solution Route of administration: Subcutaneous<br>* Other names: SAR153191 (REGN88);|

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(W) 12. Extension phase: Up to end of study (W162 for dose-finding and second portions or W102 for third portion) | 
| Number of patients with local site reactions |  | Core treatment phase: Up to Week 12. Extension phase: Up to end of treatment (W156 for dose-finding and second portions or W96 for third portion) | 
| Juvenile Idiopathic Arthritis (JIA ACR) 30/50/70/90/100 response rate |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change from baseline in JIA ACR Component: Physician's global assessment of disease activity |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change from baseline in JIA ACR Component: Patient / parent assessment of overall well-being |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change from baseline in JIA ACR Component: Childhood Health Assessment Questionnaire (CHAQ) - Disability Index |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change from baseline in JIA ACR Component: Number of joints with active arthritis |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change from baseline in JIA ACR Component: Number of joints with limitation of motion |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change from baseline in JIA ACR Component: High sensitivity C-reactive protein (hs-CRP) |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change from baseline in Juvenile Arthritis Disease Activity Score-27 (JADAS) |  | Core treatment phase: Up to Week 12. Extension phase: up to W156 for dose-finding and second portions or W96 for third portion | 
| Change in IL-6 associated biomarkers: IL6 |  | Up to Week 12 | 
| Change in IL-6 associated biomarkers: sIL-6R |  | Up to Week 12 |