An Open-label Extension Study of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis and Active Systemic Manifestations Manifestations and Response Characterization Study in Canakinumab Treatment-naïve Patients With Active SJIA With and Without Fever.

An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participants or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs or SAEs were defined as AEs or SAEs that were suspected to be related to study treatment as per investigator.

Immunogenicity assessment included determination of anti-canakinumab (ACZ885) antibodies in serum samples using BIAcore system.

Local injection site tolerability was assessed on the injection site. Each participant was classified into one of the following four categories: 1. no tolerability reactions at any time during the study, 2. mild reaction observed on at least one occasion but no moderate or severe reactions. 3. moderate reaction observed on at least one occasion but no severe reaction. 4. severe reaction observed on at least one occasion.

Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 1-100 millimeter (mm) visual analog scale (VAS); 2. Participants Global Assessment on a 1-100 mm VAS; 3. Functional ability; 4. Joints count with active arthritis; 5. Joints count with limitation of motion; 6. Laboratory measure of C-reactive protein (CRP) and 7. Absence of intermittent fever due to severe juvenile idiopathic arthritis (SJIA) during the preceding week. Response was defined as more than or equal to (≥) 30%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature less than or equal to (≤) 38 °C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.

Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 3. Functional ability; 4. Joints count with active arthritis; 5. Joints count with limitation of motion; 6. Laboratory measure of CRP and 7. Absence of intermittent fever due to SJIA during the preceding week. Response was defined as ≥ 30%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature ≤ 38 °C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.

Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 3. Functional ability; 4. Joints count with active arthritis; 5. Joints count with limitation of motion; 6. Laboratory measure of CRP and 7. Absence of intermittent fever due to SJIA during the preceding week. Response was defined as ≥ 30%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature ≤ 38 °C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.

Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 3. Functional ability; 4. Joints count with active arthritis; 5. Joints count with limitation of motion; 6. Laboratory measure of -CRP and 7. Absence of intermittent fever due to SJIA during the preceding week. Response was defined as ≥ 30%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever (i.e. body temperature ≤ 38°C) in the preceding week (variable 7) and with no more than one variable 1 to 6, worsening by more than 30%.

Adapted ACR Paediatric 30/50/70/90 or 100 was assessed based on following 7 variables: 1.Physician's Global Assessment on a 0-100 mm VAS; 2. Participants Global Assessment on a 0-100 mm VAS; 3. Functional ability; 4. Joints count with active arthritis; 5. Joints count with limitation of motion; 6. Laboratory measure of CRP and 7. Absence of intermittent fever due to SJIA during the preceding week. Response was defined as ≥ 30%/50%/70%/90% or 100% improvement in at least 3 of the response variables 1 to 6, no intermittent fever in the preceding week (variable 7) and with no more than one variable 1 to 6 worsening by more than 30%. For minimum adapted ACR paediatric scores, the last measurement recorded from the participant's previous study was considered baseline for the current study.

Steroid tapering with oral steroids was allowed if the participant achieved an adapted ACR Paediatric 50 response and had no fever. A participant was considered to have tapered steroids successfully, if the steroid dose was reduced from baseline and the participant did not flare and maintained a minimum adapted ACR Paediatric 30 at the last measurement. A participant was considered to have unsuccessfully tapered steroids if the steroid dose was reduced during the study but dose at last assessment was equal to or greater than dose at baseline or; if steroid dose was reduced but the participant did not maintain a minimum adapted ACR Paediatric 30 at the last measurement.

The canakinumab dose could be reduced from 4 mg/kg to 2 mg/kg in participants who were steroid-free, if requested by the treating physician and agreed by the sponsor. For treatment naive participants , dose reduction was allowed after the participant had received 6 months treatment with canakinumab.

Clinical remission was defined as at least 6 months of inactive disease or at least 12 months of inactive disease on medication during the extension period. Participants with inactive disease for at least 6 months, but had loss of inactive disease before 12 months were also determined.

The CHAQ was used to assess physical ability, overall well- being and pain intensity experienced by participants. The CHAQ (disability and well-being) dimension consisted of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and other "activities". Participants were graded for the response in four categories, ranging from 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty) and 3 (unable to do). Participant's pain intensity was assessed by parents and adult participants (18-20 years old) on a VAS scale of 0-100 mm (0 mm: no pain to 100: very severe pain). Change from baseline was calculated by using the formula = (post baseline value - baseline value). For both scales, lower scores indicate increased functional ability.

The Child Health Questionnaire - Parent Form (CHQ-PF50) instrument was used to measure HRQoL aged 5 to 18 years from a parent's perspective. This 14 concept questionnaire measured physical and psychosocial health of the participants on following points: physical functioning, role/social emotional, role/social behavior, role/social physical, bodily pain, general behavior, mental health, self-esteem, general health perception, change in health, parental impact - emotional, parental impact - time, family activities, and family cohesion. Total score ranged from 1-100. Increase in score represented improvement in overall well being of participants. Change from baseline was calculated by using the formula = (post baseline value - baseline value).

EQ-5D HRQoL tool was used for participants above 12 years and EQ-5D proxy for 8-11 years. EQ-5D index scores range from -0.11 (worst possible health, worse than dead), to 0 (dead) to 1 (perfect health). Utility based EQ-5D questionnaire provides generic measure of health for clinical and economic appraisal based on 2 parts: EQ-5D descriptive system - 5 dimensions each with 3 levels (1:no, 2:moderate, 3:severe problem) on: mobility (1=0, 2=0.069, 3=0.314), self-care (1=0, 2=0.104, 3=0.214), usual activities (1=0, 2=0.036, 3=0.094), pain/discomfort (1=0, 2=0, 3=0.386) and anxiety/depression (1=0, 2=0.071, 3=0.2). EQ-5D Total score= 1-0.081-(score of level 2 in present)-0.269 (if at least one of level 3 presents). EQ-5D total score: 1=high quality of life; -0.59 worst quality of life; and EQ-VAS - record participant's self-rated health on vertical, visual analog scale as '100=Best and 0=Worst imaginable health state'.

Positive change from baseline score indicated improved health status.

Sleep patterns in children and adolescents aged between 11 and 15 years were determined using PDSS instrument to evaluate whether canakinumab helps in reducing sleepiness in children with SJIA. Participants were assessed on 8 items of PDSS, on a scale of 0 to 4 (0 - never, 1 - seldom, 2- sometimes, 3 - frequently and 4 - always). The sum of all the items was reported as total score with a range of 0-32. Change from baseline was calculated by using the formula = (post baseline value - baseline value). A positive change from baseline score indicated improvement.

Growth velocity parameter height percentile was determined. Percentile was based on the growth charts smoothed percentile curve released by Centers for Disease control and prevention (CDC) in 2000, by sex and age.

Inactive disease was defined as no joints with active arthritis; no fever (body temperature ≤ 38 degree Celsius); no rheumatoid rash, serositis, splenomegaly, hepatomegaly, or generalized lymphadenopathy attributable to SJIA; normal CRP, and a rating of no disease activity on the Physician's Global Assessment of disease activity (with a best possible score ≤10 mm on the VAS).

Growth velocity parameter weight percentile was determined. Percentile was based on the growth charts smoothed percentile curve released by Centers for Disease control and prevention (CDC) in 2000, by sex and age.

Growth velocity parameter BMI percentile was determined. Percentile was based on the growth charts smoothed percentile curve released by Centers for Disease control and prevention (CDC) in 2000, by sex and age.