An open-label canakinumab (ACZ885) dose reduction or dose interval prolongation efficacy and safety study in patients with Systemic Juvenile Idiopathic Arthritis (SJIA)

Systemic Juvenile Idiopathic Arthritis (SJIA) is a unique subset of Juvenile
Idiopathic Arthritis (JIA) that occurs in children 16 years of age and younger,
and accounts for approximately 4 - 17 % of JIA). The peak age of disease onset
lies between 18 months and 2 years, but SJIA may occur in children of any age
and, rarely, in young adults too.

Canakinumab, as a potent neutralizer of IL-1*, is expected to treat the
underlying structural features of arthritis (inflammation, bone and cartilage
degradation), as well as providing relief of the symptoms in at least a subset
of patients with these forms of arthritis.

To date, four clinical studies (CACZ885A2203, CACZ885G2305, CACZ885G2301, and
CACZ885G2301E1) have been performed by Novartis to evaluate canakinumab as a
potential therapeutic agent to treat patients with SJIA. In study
CACZ8852301E1, an ongoing extension study with the primary purpose to capture
long term safety data, patients with adequate response were allowed to reduce
their dose to 2mg/kg every 4 weeks at the request of the investigator and with
agreement from Novartis.
At the time of an interim analysis of 18 August 2012, 26 patients received at
least three consecutive 2 mg/kg doses. All 26 patients had an ACR100 throughout
the time the reduced dose was given and none of these patients had discontinued
from the study due to unsatisfactory therapeutic response. Although limited,
this data strongly suggest that canakinumab dose reduction can be achieved in
patients with adequate response.

Primary:
To evaluate if the proportion of patients in clinical remission on canakinumab
4mg/kg (+/- concomitant NSAID only) who are able to
remain on a reduced canakinumab dose (2mg/kg every 4 weeks) or prolonged
canakinumab dose interval (4mg/kg every 8 weeks) for at
least 24 consecutive weeks is at least 40% in either treatment arm (Part II).
Secondary:
To assess the long-term safety and tolerability of canakinumab (Part I and II).

This two-part, open-label study evaluates the long-term efficacy, safety and
tolerability of canakinumab in SJIA patients.

In part 1, patients are treated with canakinumab 4 mg/kg every 4 weeks.
If SJIA in remission for at least 24 subsecutive weeks, the canacunimab dose
will be reduced (part 2): As follows:
* In Group 1, the dosage canakinumab reduces, but still the injections
administered every 4 weeks. First, the dosage is lowered to 2 mg per kg of body
weight. If the SJIA ,24 weeks later, is still in remission, the dosage is
further reduced to 1 mg per kg of body weight. If the SJIA, 24 weeks later, is
still in remission, treatment with canakunimab is discontinued. These patients
continue to participate in the study.
* In group 2, the injections can be administered less frequently but the dose
of canakinumab per injection will remain the same (4 mg per kg of body weight).
First the injections administered every 8 weeks. If the SJIA, 24 weeks later,
is still in remission, the injections to be administered every 12 weeks. If the
SJIA, 24 weeks later, is still in remission, treatment with canakinumab is
discontinued. These patients continue to participate in the study.
* The SJIA can become active again during the reduction or discontinuation of
canakinumab. In this case, canakinumab treatment is restarted (original
schedule of 4 mg per kg body weight every 4 weeks).
* We want to collect information of 80 patients for who the dose of canakinumab
is reduced. If this number 80 is reached, the remaining patients will be
treated with canakinumab 4 mg per kg every 4 weeks till end of the study.
* Patients who are not in remission, canakinumab treatment of 4 mg per kg every
4 weeks remains until the end of the study.
It is expected that duration study will be approximately 2 to 4 years.

Subcutaneous injections canakunimab 4 mg / kg every 4 weeks, the dosage will be
redused when clinical remission for at least 24 weeks.

Burden:
Study duration 2-4 years. 28-56 visit of 1-2 hours.
Physical examination, including weight, pulse, blood pressure, bodytemperature:
each visit
Length: Annual
CHAQ questionnaire: each visit
Diary: daily reporting during the treatment phase
Determining the stage of puberty: 1st half a year twice, then every 48 weeks
Assessment activity / flashing SJIA: each visit
ECG: 2x
Skin Test: 1x (QF), only Cohort 2.
Blood collection: up to 54 times (10 ml each time).

Optional sub studies (additional blood collection):
Biomarkers: max 30 x (8.5 ml each time). If body weight <14kg then no blood is
collected. Weight between 14 and 26 kg less blood is collected(max 3 ml each
time).
Blood collection in the event of vaccination: 3 x

Risk:
Risk of side effects study medication.