A randomized, double-blind, placebo controlled, withdrawal study of flare prevention of canakinumab (ACZ885) in patients with Systemic Juvenile Idiopathic Arthritis (SJIA) and active systemic manifestations

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 (Ravelli and Martini 2007). The
peak age of disease onset lies between 18 months and 2 years (Symmons, et al
1996), but SJIA may occur in children of any age and, rarely, in young adults
too (Woo 2006).
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.
Preliminary data from the phase II ongoing trial indicate that 13/22 patients
(59%) responded to canakinumab achieving at least an adapted ACR pediatric 50
after 15 days. In 4 cases inactive disease status was reached (no joints with
active arthritis, no fever, normal CRP and no disease activity according to
physician*s assessment).

Based upon the encouraging preliminary results from POC/phase II, Novartis
believes that it has a responsibility to evaluate canakinumab as a safe and
efficacious treatment option for children with SJIA.

The primary objectives of this study are:
Part II: to demonstrate that the time to flare in Part II is higher with
canakinumab than with placebo.
Part I: to assess if canakinumab allows tapering of steroids as per protocol in
at least 25% of the
patients.
Secondary objectives of this study are:
Part II:
* To evaluate the maintenance of efficacy (length of time that patients
continuously maintain or
improve their adapted ACR Pediatric 30/ 50/ 70/ 90/ 100 criteria reached at
entry into Part II)
of canakinumab as compared to placebo
Part I:
* To evaluate number of patients who have reached a steroid dose * 0.2 mg/kg at
end of Part
Ic
* To evaluate the level of steroid tapering achieved at the end of Part Ic
* To evaluate the efficacy (percentage of patients who meet the adapted ACR
Pediatric 30/ 50/
70/ 90/ 100 criteria) of canakinumab in Part I
* To evaluate the efficacy of canakinumab based percentage of
patients who have body temperature * 38°C) at Day 3 in Part Ia
* To evaluate time to adapted ACR Pediatric 50 criteria and normal C-Reactive
Protein (CRP
<10 mg/L) during Part I
* To evaluate time to adapted ACR Pediatric 70 criteria and normal CRP (<10
mg/L) during
Part I
Parts I and II:
* To evaluate the change in disability over time by use of the cross culturally
adapted and
validated version of the Child Health Assessment Questionnaire (CHAQ©)
* To evaluate the change in Health-Related Quality of Life (HRQoL) over time by
use of the
cross culturally adapted and validated version Child Health Questionnaire (CHQ)
* To evaluate the safety, tolerability and immunogenicity of canakinumab
* To evaluate the pharmacokinetics (PK) / pharmacodynamic (PD) of canakinumab
Exploratory objectives of this study are:
Part II:
* To explore the time to inactive disease
* To explore the percentage of patients who will meet the definition of
inactive disease on
medication as defined by Wallace, Ruperto, and Giannini (2004)
* To explore the progression of joint erosions in the affected hand and/or
wrist by x-ray in a
subset of volunteer patients
Parts I and II:
* To explore the change in HRQoL over time by use of the EuroQoL Five Dimension
Questionnaire (EQ-5D) (for patients * 12 years of age) or EQ-5D proxy (for
patients 8 - 11
years of age)
* To explore the impact of treatment with canakinumab on sleepiness in children
over time by
use of the Pediatric Daytime Sleepiness Scale (PDSS)
* To explore the impact of treatment with canakinumab on growth velocity
* To explore the impact of treatment with canakinumab on physical development
in children,
and adolescents from ages 6 * 20 by use of the Tanner stages scale
* To explore the protein, mRNA and DNA biomarkers (e.g. HLA-DQA1) in order to
identify
retrospectively responder/non-responder patients

Study design:
This is a two-part study with an open-label, single-arm active treatment in
Part I followed by a
randomized, double-blind, placebo controlled, event-driven withdrawal design in
Part II.
No interim analysis is planned.
Part I (Open-label treatment period):
Part I is an open-label, active treatment period to identify
canakinumab-treated patients who meet the
adapted ACR Pediatric 30 criteria at Day 15 and to allow for these patients to
taper their steroid dose.
The maximum duration of Part I will be 32 weeks, corresponding to maximum 8
injections of
canakinumab. Part I is separated into 4 subparts Ia to Id. While subparts Ia
and Ib aim to induce and
maintain an at least adapted ACR Pediatric 30 response without steroid
tapering, subpart Ic aims to
reduce steroid dose to the lowest possible dose prior to the potentially long
duration of Part II and to
evaluate steroid tapering in responders. Subpart Id is designed to stabilize
patients on an achieved
steroid dose before entering the withdrawal Part II.
An Interactive Voice Response System (IVRS) will be used in Part I to identify
the treatment to be
prepared and administered.
Part Ia
Once patient eligibility is confirmed at screening, patients will enter Part Ia
and receive the first
subcutaneous (s.c.) injection of canakinumab (4 mg/ kg) on Day 1. The duration
for Part Ia is 4 weeks.
Rule for rolling over patients from study CACZ885G2305 and CACZ885A2203 into
Part Ia:
* Placebo patients who did not clinically improve with study treatment, as per
investigator*s
discretion, between Day 3 and Day 15 during the study CAZ885G2305 will be
allowed to roll
over into study CACZ885G2301: They will start their participation in study
CACZ885G2301 at
Day 1, i.e. no screening visit will be required for those patients.
* Placebo patients who did not meet the adapted ACR Pediatric 30 criteria at
Day 15 in study
CAZ885G2305 will be allowed to roll over into study CACZ885G2301: They will
start their
participation in study CACZ885G2301 at Day 1, i.e. no screening visit will be
required for
those patients.
* Placebo-treated patients who achieves a minimum adapted ACR Pediatric 30
response at
Day 15 but clinically deteriorates between Day 15 and Day 29 during study
CACZ885G2305
and intervention is deemed necessary by the investigator will be allowed to
roll over into study
CACZ885G2301: They will start their participation in study CACZ885G2301 at Day
1, i.e. no
screening visit will be required for those patients.
* Patients from the study CACZ885A2203 will enter the CACZ885G2301 study when
they
would receive the next dose of canakinumab in protocol CACZ885A2203. They will
need to
be screened prior to entry.
Steroids will be maintained stable for the full duration of Part Ia. No
tapering of steroids is allowed in
Part Ia.
At Day 1, Physician*s Global Assessment of disease activity on a 0-100 mm VAS,
CHAQ©, CHQPF50
©, EQ-5D, PDSS, number of joints with active arthritis using the ACR
definition, number of joints
with limitation of motion, laboratory measure of inflammation: CRP (mg/L) and
assessment of
intermittent fever due to SJIA (oral or rectal body temperature > 38°C only for
several hours during the
day) during the preceding week will be assessed.
All patients with an affected hand and/or wrist who consent at baseline (Day 1)
(volunteer patients) will
be subjected to an articular x-ray. The x-ray film will be sent to a Clinical
Research Organization
(CRO) for confirmation of the quality. Assessment of the x-ray film will be
performed by an
independent x-ray reading committee.
At Day 3 clinical response will be assessed as per Physician*s Global
Assessment of disease activity,
number of joints with active arthritis, number of joints with limitation of
motion, CRP, and body
temperature.
At Day 15, clinical response will be assessed as per adapted ACR Pediatric 30
criteria, i.e.
improvement from baseline of at least 30% in at least three of the six response
variables and no
intermittent fever (i.e. body temperature * 38°C) in the preceding week, with
no more than one of the
remaining variables worsening more than 30% (see Section 7.4.1).
Patients who meet the adapted ACR Pediatric 30 criteria at Day 15 will continue
in the study.
Patients who do not meet the adapted ACR Pediatric 30 criteria at Day 15 will
be discontinued from
the study, will complete Visit 5 (Day 29) assessments, and will be treated as
per standard local
medical practice but will be followed-up for safety for 2 months after the last
injection.
Patients who do not maintain a minimum adapted ACR Pediatric 30 response
between Day 15 and
Day 29 during Part Ia will complete Visit 5 (Day 29) assessments, be withdrawn
from Part Ia, and may
enter the extension study CACZ885G2301E1. Physician and family have the option
to continue
treatment with canakinumab if it is thought to be beneficial to the patient.
At Day 29, clinical response as per adapted ACR Pediatric criteria will be
assessed.
During Part Ia, efficacy, safety and tolerability assessments will be performed
at all visits.
Any patient who discontinues Part Ia and does not enroll into the extension
study CACZ885G2301E1
will be followed up for safety for 2 months after the last injection.
Part Ib
Patients completing Ia will enter Part Ib on Day 29 if they continue to meet at
least adapted ACR
Pediatric 30 criteria. The duration for Part Ib is 4 weeks.
Rule for rolling over patients from study CACZ885G2305 into Part Ib:
* Canakinumab patients who completed CACZ885G2305 and continue to meet at least
adapted
ACR Pediatric 30 criteria will be allowed to roll over into study CACZ885G2301:
They will start
their participation in study CACZ885G2301 at Day 29, i.e. no screening visit
and no Part Ia visits
at Days 1, 3, and 15 will be required for those patients.
Steroids will continue to be maintained stable for the full duration of Part
Ib. No tapering of steroids is
allowed in Part Ib.
At Day 29, all patients will receive an injection of study drug (canakinumab)
and clinical response will
be assessed as per adapted ACR Pediatric criteria.
At Day 57, clinical response will be assessed as per adapted ACR Pediatric
criteria.
Patients who do not maintain a minimum adapted ACR Pediatric 30 response
between Day 29 and
Day 57 during Part Ib will be withdrawn from Part Ib, will complete Visit 6
(Day 57) assessments and
may enter the extension study CACZ885G2301E1 at the physician*s and family*s
discretion.
During Part Ib, efficacy, safety and tolerability assessments will be performed
at Day 29 and Day 57.
Part Ic (Steroid tapering)
Patients completing Ib on Day 57 will continue into Part Ic if they meet at
least an adapted ACR
Pediatric 30 criteria. Corticosteroid use is encouraged to be tapered down to
the lowest possible dose
during Part Ic prior to entry into the potentially long duration of Part II.
The maximum duration of Part Ic
is 20 weeks. The objective of Part Ic is to evaluate canakinumab*s ability to
allow patients to taper
down their steroid dose.
Patients who are unable to reduce their steroid dose to the predefined minimum
dose in order to
qualify for Part Id and Part II by Day 197 (End of Part Ic) will be
discontinued from the study, complete
End of Part Ic assessments and may enter the extension study CACZ885G2301E1.

Patients who are able to taper off of steroids prior to completing the maximum
20 weeks duration of
Part Ic and still maintain a minimum adapted ACR Pediatric response of 50 or
higher should complete
their end of Part Ic assessments (Visit 11) at their next dosing visit and
continue into Part Id.

During Part Ic patient will return to study site every 4 weeks to receive the
next injection of
canakinumab and clinical response will be assessed as per adapted ACR Pediatric
criteria. Efficacy,
safety and tolerability assessments will be performed at all dosing visits.
Part Id
Patients will enter Part Id at the time of their next canakinumab dose after
they have completed Part Ic
successfully. Patients who are steroid free at study entry should enter
directly into Part Id after
completing Part Ib without entering and completing Part Ic. The duration of
Part Id is 4 weeks.
Patient will receive their next dose of canakinumab upon entry into Part Id and
clinical response as per
adapted ACR Pediatric criteria will be assessed. Efficacy, safety and
tolerability assessments will be
performed at the dosing visit.
Any patients on steroid will need to maintain stable dose for the full duration
of Part Id. No tapering of
steroids is allowed in Part Id.
Patients who do not maintain a minimum adapted ACR Pediatric 30 response during
Part Id will be
withdrawn from Part Id, will complete End of Part Id assessments and may enter
the extension study
CACZ885G2301E1 at the investigator*s and family*s discretion.
The purpose of Part Id is to ensure that all patients have been treated with
canakinumab for at least 12
weeks before entering Part II and that patients who have tapered and are still
on steroids are on stable
steroid dose for at least 4 weeks before entering Part II.
Part II (Withdrawal period)
In Part II, the sustained efficacy of canakinumab will be assessed in a
double-blind, randomized,
placebo-controlled, event-driven design with respect to the incidence of
patients who flare.
The study will be stopped when the required number of 37 flares has occurred.
Patients who
discontinue the study while in Part II will be counted as flares unless they
discontinued because of
inactive disease for at least 24 weeks in Part II.
At start of Part II visit, patients who have sustained response to treatment
with canakinumab according
to the adapted ACR Pediatric 30 criteria and have achieved a stable oral
prednisone (or equivalent)
dose of * 0.5 mg/kg at the end of Part I will be randomized to either
canakinumab or placebo in a ratio
of 1:1 and will receive an s.c. injection of study drug (canakinumab 4 mg/ kg
or placebo).
Randomization will be stratified by prednisone (or equivalent) dose at the end
of Part I (two strata: *
0.4 mg/kg, > 0.4 mg/kg) and degree of adapted ACR Pediatric response reached at
the end of Part Id
(two strata: > adapted ACR Pediatric 50 criteria met (e.g. 70/90/100), *
adapted ACR Pediatric 50
criteria met (e.g. 30/50)).
Steroids will be maintained stable for the first 24 weeks participation in the
double-blind Part II. No
tapering of steroids is allowed during this first 24 weeks.

Patients who are on * 0.2 mg/kg oral prednisone (or equivalent) in Part II must
continue to maintain
their steroid dose after the first 24 weeks in Part II until study completion
(i.e. no steroid tapering is
allowed for the full duration of Part II).
Patients who entered Part II with an oral prednisone (or equivalent) dose > 0.2
mg/kg and * 0.5 mg/kg,
and who do not flare after at least 24 weeks participation in Part II may
restart tapering their steroid.
During Part II patient will return to study site every 4 weeks to receive the
next injection of study drug
(canakinumab or placebo) and clinical response will be assessed as per adapted
ACR Pediatric
criteria. During Part II, efficacy, safety and tolerability assessments will be
performed at all dosing
visits.
It is estimated that approximately 15 volunteer patients with an affected hand
and/or wrist and who
consented at baseline (volunteer patients) will be subjected to an articular
x-ray of both (left and right)
hands and wrists at End of Part II visit provided there is already a baseline
x-ray available.
All patients who flare at any time during Part II, regardless if due to steroid
tapering, will be withdrawn
from Part II, complete End of Part II assessments, and may enroll into the
extension study
CACZ885G2301E1 at the investigator*s and family*s discretion.
Patients who maintained a status of inactive disease for at least 24 weeks
during Part II may be
discontinued from the trial and will not be considered as having flared in the
primary analysis. These
patients may enter the extension study CACZ885G2301E1 (e.g. to taper their
steroid).
Premature Patient Withdrawal (PPW) will occur when patients discontinue from
the study at any time.
Patients will complete the study when the required number of 37 flares has
occurred during Part II.
At the End of Study, an open-label extension study of at least 2 year duration
is planned to allow
patients to continue treatment with canakinumab until the product has been
launched or until patients
have reached clinical remission and canakinumab can be discontinued (whichever
occur first).
Novartis intends to launch the product worldwide. In case a launch in a country
is for whatever reason
not possible, a compassionate use or maintenance protocol will be provided by
Novartis. In case
Novartis decides due to an emerging unfavourable benefit/risk profile or are
asked by Health
Authorities to stop the development of canakinumab the compassionate use or
maintenance protocol
program cannot be pursued.

Investigational and reference therapy:
Patients will be dosed every 4 weeks:
* Part I: a single dose of canakinumab (4 mg/kg)
* Part II: canakinumab (4 mg/kg) or placebo in a 1:1 ratio
The maximal total single dose of canakinumab allowed is 300 mg.
Note: Any patient who requires a dose greater than 150 mg (patients > 37.5 kg)
will require two s.c. injections.

Risks and inconveniences
Risks are possible side effects of the study medicine or another medicine.
Risks are also possible side effects that result from taking blood. If you were
taking medication that made your symptoms of SJIA better or go away completely
and you had to stop this medication to take part in the study, stopping this
medication may cause these symptoms to come back. Your study doctor will
discuss this more with you. The tests done at each visit are standard medical
tests, however they may cause some discomfort. For example you will be asked to
give some blood, which can also make you feel a bit faint or sick. It can also
be uncomfortable and cause bruising. Rarely, a small blood clot or infection
could occur at the site where the blood was taken, but this does not happen
very often at all. When you have your blood pressure taken, the blood pressure
cuff may feel a little tight and might cause a small bruise on your arm. When
you are given a dose of canakinumab or placebo this will be injected just under
the skin and may cause light pain, redness, bruising or itching. The testing to
see if you already have tuberculosis may cause some swelling and hardness at
the injection site. You will also be asked to have an ECG. This is a test of
your heart which does not hurt. However the skin may become a little itchy and
red where the sticky pads are placed. There is no radiation used during the ECG
procedure. If you need a chest x-ray you will be given a very small amount of
radiation. This can carry very small risks but the dose of radiation in a chest
x-ray is very low.
The sonography is a painless test to have a picture of your liver and spleen.
If your joints are inflamed, the assessment of your joints by your doctor may
cause slight pain.

Side effects of study drug, canakinumab:
The study drug may involve risks that are currently unknown. Twenty clinical
studies with canakinumab have been started; approximately 700 patients
(including 43 children 4 years and above) have been treated with canakinumab
(as of
December 2008 with several studies currently ongoing). Canakinumab was well
tolerated. Canakinumab treatment discontinuations were rare. The maximum
average duration patients have been on canakinumab is currently 2 1/2 years.
In clinical trials, infections, mainly of the upper airways and in some
instances serious, have been reported more frequently with patients taking
canakinumab than with placebo (sugar pill). No unusual or opportunistic
infections were reported and all infections that were
reported responded normally to standard therapy. The risk for the development
of cancer with medications that inhibit the protein Interleukin-1,
including canakinumab, is unknown, but can not be excluded entirely. A
temporary spinning sensation (vertigo) has been reported in some patients soon
after they begin canakinumab therapy. It usually did not require treatment and
resolved without problem
or interruption of their canakinumab treatment. There were serious events (or
bad events). A *serious adverse event* is a side effect that may
be life-threatening or may require a study participant to be hospitalized for a
time, it may or may not be related to a study drug.
Preliminary findings from an ongoing study with 23 SJIA patients show that the
most common adverse events were upper respiratory tract infections. There were
17 serious adverse events where the patients were hospitalized. Eleven of these
events were due to
other underlying medical history of the patients (irritated stomach (twice)
,hip arthritis, bleeding rectal skin lesion, abdominal pain from constipation
with rectal bleeding, suspected pericarditis, worsening of SJIA (twice), pain
and fear, tendonitis and
blood in the urine). Six of these events were infections leading to
hospitalization (acute
tonsillitis, severe sore throat, flu-like viral illness, stomach virus with
mild bleeding abnormality, hepatitis and severe nail infection).. All of these
events resolved while continuing canakinumab treatment.
Serious events occurring more than once and suspected to be related to
canakinumab iIn all
previous and ongoing studies of approximately 670 patients who do not have
SJIA: vertigo (dizziness) (twice), nausea (twice) and vomiting (twice).
Mild skin inflammations at the injection site were reported by a few patients.

Allergic reactions
Sometimes people have allergic reactions to drugs. Most allergic reactions to
drugs like canakinumab occurred within 2 hours after dose administration.
Serious allergic reaction which may include low blood pressure, trouble
breathing, seizures and death may occur. However, most reactions seen were mild
to moderate. Some things that can happen during an
allergic reaction are: a rash, itching, having a hard time breathing, wheezing
when you breathe, sudden drop in blood pressure, swelling around the mouth,
throat or eyes, fast pulse, fever, sweating, and chills. There is a risk that a
rare or previously unknown side effect will occur.

Other treatments
You do not have to be in this study to receive treatment for your SJIA. You may
receive the standard therapy for SJIA which may include corticosteroids.

Benefits of treatment
You may receive no direct benefit from being in this study. However, your
taking part may help patients get better care in the future.