Study of Efficacy and Safety of Canakinumab in Japanese Patients With AOSD

Study Overview
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Brief Summary
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This is a phase III study designed to provide efficacy and safety data for canakinumab administered for at least 48 weeks as subcutaneous (s.c.) injection every 4 weeks (q4wk) in Japanese patients with Adult Onset Still's Disease (AOSD). Interim analysis (IA) data at Week 28 and 48 from this study supports a registration submission of canakinumab in the indication of Adult still's disease (ASD) in Japan.

Official Title
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An Open-label, Single-arm, Active-treatment Study to Evaluate Efficacy and Safety of Canakinumab (ACZ885) Administered for at Least 48 Weeks in Japanese Patients With Adult Onset Still's Disease (AOSD)

Conditions
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Adult Onset Still's Disease

Intervention / Treatment
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* Biological: Canakinumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Parent's or legal guardian's written informed consent and child's assent, if appropriate, are required before any assessment is performed for participants < 20 years of age Japanese male and female participants aged ≥ 16 years Confirmed diagnosis of AOSD as per Yamaguchi criteria (Yamaguchi M, 1992) with an onset of disease ≥ 16 years of age. Yamaguchi criteria requires at least five criteria, including two major criteria and no exclusion criteria Active disease at the time of baseline defined as follows Fever (body temperature > 38°C) due to AOSD for at least 1 day within 1 week before baseline At least 2 active joints (tender or swollen) CRP ≥ 10 mg/L Exclusion Criteria: Pregnant or nursing (lactating) female participants, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ mL) at screening visit. History of significant hypersensitivity to study drug or to biologics. History/evidence of active macrophage activation syndrome or disseminated intravascular coagulation prior to 6 months of enrollment. With underlying metabolic, renal, hepatic, infectious or gastrointestinal conditions which in the opinion of the investigator compromises the articipant and/ or places the participant at unacceptable risk for participation in an immunomodulatory therapy. With active or recurrent bacterial, fungal or viral infection at the time of enrollment, including participants with evidence of Human Immunodeficiency Virus (HIV) infection, Hepatitis B and Hepatitis C infection. Participants with absolute neutrophil count < 1500/mm3 at screening.

Ages Eligible for Study
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Minimum Age: 16 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: Canakinumab<br>All participants receive canakinumab (ACZ885) as open-label study medication. Participants are administered canakinumab 4 mg/kg every 4 weeks. The maximal total single dose of canakinumab allowed is 300 mg. | Biological: Canakinumab<br>* Provide as 150 mg/1 mL solution for subcutaneous injection and administer 4mg/kg every 4 weeks.<br>* Other names: ACZ885;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who achieve adapted American College of Rheumatology (ACR) 30 response at Week 8 | Adapted ACR30 response is defined as 30% reduction between baseline and post-baseline values in at least 3 of the 5 response variables 1 to 5 and no intermittent fever in the preceding week (variable 6), with no more than one of variables 1-5 worsening by more than 30%: Physicians global assessment of disease activity Participant's assessment of disease activity (PtGA) Functional ability assessed using Health Assessment Questionnaire (HAQ) Number of active joints (68 joints evaluated for pain/tenderness and 66 for swelling) Laboratory measure of inflammation: CRP (mg/L) Absence of intermittent fever in the preceding week | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who are able to taper corticosteroids based on success criteria at Week 28. | To evaluate ability of canakinumab to taper corticosteroids based on success criteria starting from Week 8 to Week 28 | Week 28 | 
| Proportion of participants who achieved adapted ACR 30/50/70/90/100 response criteria at Day 15 and all subsequent visits. | The adapted ACR 50, 70, 90 and 100 criteria will be used as additional efficacy assessments, i.e., an improvement ≥ 50%, ≥ 70%, ≥ 90%, or = 100% in at least 3 of 5 response variables and no intermittent fever in the preceding week (variable 6) with no more than one variable of 1-5 worsening by more than 30%. | Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144, End of Study(EOS)(up to Week 152) | 
| Change from baseline in Systemic Feature Score (total score and each components) at Day 15 and all subsequent visits. | Systemic feature score consists of 5 clinical and 5 laboratory assessments. Clinical features include fever, rash, lymphadenopathy, hepatosplenomegaly and serositis. Laboratory features include erythrocyte sedimentation rate, C reactive protein, leucocyte count, hemoglobin level and platelet count. Each clinical and laboratory feature will be assigned a score of 1 (present) or 0 (absent): | Baseline, Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144, EOS(up to Week 152) | 
| Absolute change from baseline in the component of adapted ACR at Day 15 and all subsequent visits: Physician's global assessment of disease activity | The physician will rate the participant's current condition on a 0-100 mm Visual Analog Scale (VAS), ranging from no disease activity (0 mm) to very severe disease activity (100 mm). | Baseline, Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144, EOS(up to Week 152) | 
| Absolute change from baseline in the component of adapted ACR at Day 15 and all subsequent visits: Patient's global assessment of disease activity | The participant's assessment of disease activity will be assessed on the VAS. The VAS scale ranges from 0-100 mm, from no pain/very well (0 mm) to very severe pain/very poor (100 mm). | Baseline, Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144, EOS(up to Week 152) | 
| Absolute change from baseline in the component of adapted ACR at Day 15 and all subsequent visits: Health Assessment Questionnaire | The health assessment questionnaire, HAQ©, will be used to assess physical ability and functional status of participants as well as quality of life. The disability dimension consists of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing, arising, eating, walking, hygiene, reach, grip and usual activities. Participants choose from four response categories, ranging from 'without any difficulty' to 'unable to do'. | Baseline, Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144, EOS(up to Week 152) | 
| Absolute change from baseline in the component of adapted ACR at Day 15 and all subsequent visits: Tender and swollen joint counts | Active joints are defined as joints with swelling or pain/tenderness. 68 joints will be assessed for tenderness and 66 joints for swelling. | Baseline, Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144, EOS(up to Week 152) | 
| Absolute change from baseline in the component of adapted ACR at all visits: C-Reactive Protein(CRP) | CRP values were standardized to a normal range of 0 to 10 mg/L. | Baseline, Days 3, 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, EOS(up to Week 152) | 
| Absolute change from baseline in the component of adapted ACR at all visits: Fever assessment | The absence or presence of intermittent fever due to AOSD (oral, rectal, or axillary body temperature > 38°C only for several hours during the day) will be assessed. | Baseline, Days 3, 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, EOS(up to Week 152) | 
| Change from baseline of corticosteroid dose at all visits after Week 8. | To evaluate ability of canakinumab to taper corticosteroids dose over time after Week 8 | Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, EOS(up to Week 152) | 
| Presence of rash (typical/atypical) at all visits during study. | The absence or presence of skin rash will be assessed based on physical exam findings including whether it is typical or atypical. | Baseline, Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, EOS(up to Week 152) | 
| Change from baseline in DAS28-CRP at Day 15 and all subsequent visits. | DAS28-CRP is a composite index, validated for RA patients and takes into account the following items: Tender joint count (number of tender joints; 0-28); swollen joint count (number of swollen joints; 0-28); C-reactive protein (mg/l) and Global Health (Patient's Global Assessment of Disease Activity; from 0=best to 100=worst). Thus, given the reliability, validity, and ability of DAS28 to discriminate the severity of joint involvement, this index has been used in other rheumatic diseases characterized by RA-like poly-articular involvement. Of note, a DAS28 score > 5.1 implies active disease, ≤3.2 low disease activity, and <2.6 remission. Moderate/high disease activity is defined as a DAS28 higher than 3.2. | Baseline, Day 15, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, 72, 84, 96, 108, 120, 132, 144, EOS(up to Week 152) | 
| Canakinumab concentrations over time | To evaluate the pharmacokinetics (PK) of canakinumab | Baseline, Days 3, 15, Weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 | 
| Total IL-1β (sum of IL-1β free and bound to canakinumab) level s over time | To evaluate the pharmacodynamic (PD) of canakinumab | Baseline, Days 3, 15, Weeks 4, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 | 
| Anti-canakinumab antibody identification and titer | To assess the immunogenicity of canakinumab | Baseline, Weeks 24, 48, 72, 96, 120 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Canakinumab, AOSD, IL-1β, Japanese participants