A Study of Anakinra in Japanese Patients With Still's Disease (SJIA and AOSD)

Study Overview
=================
Brief Summary
-----------------
A study to demonstrate efficacy and safety of anakinra in pediatric and adult Japanese patients with Still's disease (Systemic juvenile idiopathic arthritis [SJIA] and Adult-onset Still's disease [AOSD]).

Detailed Description
-----------------
The study consists of a 2-Week, randomized, double-blind, placebo-controlled period, followed by a 52-Week open-label phase treatment with anakinra. After the last dose of anakinra at Week 54, the safety will be evaluated at a Safety Follow-up visit i.e., at Week 58. The primary endpoint will be evaluated at Week 2 visit. Patients will be randomly assigned to either anakinra or placebo for a period of 2 weeks.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 3 Efficacy and Safety Study of Subcutaneous Anakinra in Japanese Patients With Still's Disease (SJIA and AOSD)

Conditions
-----------------
Still's Disease, Juvenile Onset, Still's Disease, Adult-Onset

Intervention / Treatment
-----------------
* Drug: Anakinra
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female patients, 8 months of age or older with a body weight ≥ 10 kg Diagnosis of Still's disease If < 16 years of age at disease onset, the diagnosis is madeaccording to adapted ILAR criteria i.e., CARRA criteria for SJIA. If ≥ 16 years of age at disease onset, the diagnosis is made according to Yamaguchi criteria for AOSD. Active disease confirmed by the following three signs and symptoms. a. Active arthritis in ≥ 1 joint. b. CRP > 30 mg/L. c. At least one fever episode (≥ 38.0 degree Celsius) attributable to the disease within one week before enrollment. The result of tuberculosis test within 8 weeks prior to enrollment is negative. Exclusion Criteria: Previous or current treatment with anakinra, or any other Interleukin-1 (IL-1) inhibitor except for canakinumab. Previous treatment with canakinumab is allowed if canakinumab was discontinued for reasons other than lack of efficacy and after a washout period of minimum 130 days. Patients who have discontinued canakinumab because of insufficient effect or refractory disease are not allowed to be enrolled in the study. Use of the following therapies prior to enrollment. Narcotic analgesics within 24 hours prior to enrollment. Diaminodiphenyl sulfone within 1 week prior to enrollment or etanercept within 2 weeks prior to enrollment. Intraarticular, intramuscular, or intravenous administration of glucocorticoids within 72h(3 days) prior to enrollment, or intravenous immunoglobulin within 4 weeks prior to enrollment. Intravenous immunoglobulins with proven Still's disease modifying effect, leflunomide, infliximab, or adalimumab within 8 weeks prior to enrollment. Thalidomide within 72h(3 days) prior to enrollment, cyclosporine within 5 weeks prior to enrollment, mycophenolate mofetil within 1 week prior to enrollment, 6-mercaptopurine within 48h(2 days) prior to enrollment, azathioprine within 72h(3 days) prior to enrollment, cyclophosphamide within 96h(4 days) prior to enrollment, chlorambucil (not approved inJapan) within 48h(2 days) prior to enrollment, or any other immunosuppressants within 12 weeks prior to enrollment. Tocilizumab within 4 weeks prior to enrollment or any other immunomodulatory medications within 4 half-lives prior to enrollment. Rituximab within 13 weeks prior to enrollment. Canakinumab within 130 days prior to enrollment Live vaccines within 4 weeks prior to enrollment. Known presence or suspicion of active, chronic, or recurrent bacterial, fungal, or viral infections, including but not limited to tuberculosis, HIV infection, Covid-19 infection, or hepatitis B or C infection at baseline. Patients with acute or chronic HBV. Clinical evidence of liver disease or liver injury as indicated by presence of abnormal liver tests. Presence of severe chronic kidney disease (CKD) grades 4 and 5. Presence of neutropenia (absolute neutrophil count [ANC] < 1.5 x 10^9/L). Presence of thrombocytopenia (platelets count < 100 x 10^9/L). Presence or suspicion of MAS at baseline. History or diagnosis of MAS within the last 4 weeks prior to enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 8 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anakinra<br>100 mg/day or 2 mg/kg/day of subcutaneous anakinra for those with a body weight ≥50 kg or <50 kg, respectively. | Drug: Anakinra<br>* sub cutaneous daily injection<br>* Other names: Kineret;|
| Placebo Comparator: Placebo<br>Corresponding volume to 100 mg/day or 2 mg/kg/day | Drug: Placebo<br>* sub cutaneous daily injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| An improvement of ≥ 30% from baseline in physician global assessment of disease activity (visual analogue scale [VAS]). | ACR30 response with absence of fever attributable to the disease during the 7 days | Week 2 | 
| An improvement of ≥ 30% from baseline in patient/parent global assessment of overall well-being (VAS). | ACR30 response with absence of fever attributable to the disease during the 7 days | Week 2 | 
| An improvement of ≥ 30% from baseline in number of joints with active arthritis. | ACR30 response with absence of fever attributable to the disease during the 7 days | Week 2 | 
| An improvement of ≥ 30% from baseline in number of joints with limitation of motion. | ACR30 response with absence of fever attributable to the disease during the 7 days | Week 2 | 
| An improvement of ≥ 30% from baseline in assessment of physical function: Child health assessment questionnaire (CHAQ)/Stanford health assessment questionnaire (SHAQ). | ACR30 response with absence of fever attributable to the disease during the 7 days | Week 2 | 
| An improvement of ≥ 30% from baseline in C-reactive protein (CRP) (mg/L). | ACR30 response with absence of fever attributable to the disease during the 7 days | Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the number/proportion of patients reporting problems by dimension of EQ-5D-Y Proxy (4-7 years). | To evaluate and compare the health status between anakinra treated patients and patients treated with placebo. | Week 2 | 
| Change in the number/proportion of patients reporting problems by dimension of EQ-5D-Y (8-15 years). | To evaluate and compare the health status between anakinra treated patients and patients treated with placebo. | Week 2 | 
| Change in the number/proportion of patients reporting problems by dimension of EQ-5D-3L (≥ 16 years). | To evaluate and compare the health status between anakinra treated patients and patients treated with placebo. | Week 2 | 
| Absence of fever during the 7 days preceding the visit. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Absence of rash during the 7 days preceding the visit. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| ACR30 response with absence of fever during the 7 days preceding the visit. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| ACR50 response with absence of fever during the 7 days preceding the visit. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| ACR70 response with absence of fever during the 7 days preceding the visit. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| ACR90 response with absence of fever during the 7 days preceding the visit. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in physician global assessment of disease activity (VAS). | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in patient/parent global assessment of overall well-being (VAS). | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in patient/parent global assessment of disease related pain (VAS). | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in swelling joints count. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in tender joints count. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in CRP. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in ferritin. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in haemoglobin. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in platelets count. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Change in white blood cells count. | To evaluate efficacy of anakinra in Still's disease. | Week 4 to Week 54 | 
| Occurrence of inactive disease. | Proportion of patients who reach inactive disease.Inactive disease is defined as no joints with active arthritis, no fever, no rash, serositis, no hepatosplenomegaly, no generalized lymphadenopathy attributable to Still's disease, CRP level within normal limits, physician's global assessment of disease activity score below 10 mm on a 100 mm VAS, and a documented morning stiffness ≤15 min. | Week 8 to Week 54 | 
| Change in the number/proportion of patients reporting problems by dimension of EQ-5D-Y Proxy (4-7 years). | To evaluate the health status in anakinra treated patients with Still's disease. | Week 4 to Week 54 | 
| Change in the number/proportion of patients reporting problems by dimension of EQ-5D-Y (8-15 years). | To evaluate the health status in anakinra treated patients with Still's disease. | Week 4 to Week 54 | 
| Change in the number/proportion of patients reporting problems by dimension of EQ-5D-3L(≥ 16 years). | To evaluate the health status in anakinra treated patients with Still's disease. | Week 4 to Week 54 | 
| ACR30 response with absence of fever during the 7 days preceding the study visits over time. | To evaluate sustained efficacy of anakinra in patients responding to study drug. | Week 2 to Week 54 | 
| To evaluate the occurrence of study drug discontinuation in anakinra treated patients with Still's disease. | Time to study drug discontinuation due to lack of efficacy or progressive disease. Time to study drug discontinuation due to any reason. Number of patients discontinuing study treatment. | Day 1 to Week 54 | 
| Time of initiation of glucocorticoids tapering. | To evaluate glucocorticoids tapering in anakinra treated patients with Still's disease. | Week 2 to Week 54 | 
| Percentage decrease of glucocorticoids dose for patients tapering their glucocorticoids dose. | To evaluate glucocorticoids tapering in anakinra treated patients with Still's disease. | Week 2 to Week 54 | 
| Discontinuation of glucocorticoids. | To evaluate glucocorticoids tapering in anakinra treated patients with Still's disease. | Week 2 to Week 54 | 
| - Occurrence of adverse events (AEs) (serious adverse events [SAEs] and non-SAEs). | To evaluate the safety of anakinra in patients with Still ́s disease. | Baseline to Week 58 | 
| Occurrence of deaths | To evaluate the safety of anakinra in patients with Still ́s disease. | Baseline to Week 58 | 
| Occurrence of AEs leading to study drug discontinuation at all study visits. | To evaluate the safety of anakinra in patients with Still ́s disease. | Baseline to Week 58 | 
| Occurrence of vital signs changes from baseline, including blood pressure, heart rate, and body weight at all study visits up to Week 58 visit. Changes of height in patients younger than 19 years old. | To evaluate the safety of anakinra in patients with Still ́s disease. | Baseline to Week 58 | 
| Occurrence of laboratory safety assessments changes over time. | To evaluate the safety of anakinra in patients with Still ́s disease. | Baseline to Week 58 | 
| Occurrence of abnormal laboratory values. | To evaluate the safety of anakinra in patients with Still ́s disease. | Baseline to Week 58 | 
| To evaluate immunogenicity of anakinra in patients with Still's disease. | Occurrence of ADAs, NAbs, cross-reactivity, and titer levels of ADAs and NAbs Occurrence and titer levels of ADAs in relation to AEs Occurrence and titer levels of ADAs, NAbs cross-reactivityin relation to ACR30 response and CRP levels | Baseline, Weeks 2, 4, 12, 34, 54 and 58 | 
| To evaluate the pharmacokinetic of anakinra in patients with Still's disease | Anakinra serum concentrations | Baseline, Weeks 1 and 2 | 
| Change in CRP. | To demonstrate the efficacy of anakinra compared to placebo in reducing inflammation in Still's disease. | Week 2 | 
| Change in ferritin. | To demonstrate the efficacy of anakinra compared to placebo in reducing inflammation in Still's disease. | Week 2 | 
| Change in haemoglobin. | To demonstrate the efficacy of anakinra compared to placebo in reducing inflammation in Still's disease. | Week 2 | 
| Change in platelets count. | To demonstrate the efficacy of anakinra compared to placebo in reducing inflammation in Still's disease. | Week 2 | 
| Change in white blood cells count. | To demonstrate the efficacy of anakinra compared to placebo in reducing inflammation in Still's disease. | Week 2 | 
| Absence of fever during the 24 hours preceding the evaluation visit at Week 1. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Absence of rash during the 24 hours preceding the evaluation visit at Week 1. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| ACR30 response with absence of fever during the 24 hours preceding the evaluation visit at Week 1. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| ACR50 response with absence of fever during the 24 hours preceding the evaluation visit at Week 1. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| ACR70 response with absence of fever during the 24 hours preceding the evaluation visit at Week 1. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in physician global assessment of disease activity, measured on a VAS from no pain (0 mm) to very severe (100 mm). | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in patient/parent global assessment of overall well-being, measured on a VAS from no pain (0 mm) to very severe (100 mm). | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in patient/parent global assessment of disease related pain, measured on a VAS from no pain (0 mm) to very severe (100 mm). | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in swelling joints count. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in tender joints count. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in CRP. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in ferritin. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in haemoglobin. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in platelets count. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 | 
| Change in white blood cells count. | To demonstrate early onset of efficacy of anakinra compared to placebo in Still's disease. | Week 1 |