The purpose of this open-label phase III extension study is to collect additional long term safety and efficacy data on canakinumab in the treatment of SJIA from patients who qualify to roll-over into this study from the CACZ885G2305 and…
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Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Study Objectives:
* To assess the long-term safety, tolerability, and immunogenicity of
canakinumab
* To assess efficacy at an exploratory level by investigating disease control
defined by
maintenance of at least an adapted ACR pediatric 30
* To perform biomarker analyses to explore the characteristics of response to
canakinumab
treatment
* To introduce Juvenile Arthritis Disease Activity Score (JADAS) and Disease
Activity Score
(DAS) as exploratory assessments of efficacy
* To assess response to canakinumab treatment based on adapted pediatric ACR30
criteria in
patients who report previous Anakinra, tocilizumab or other biologic treatment
Secondary outcome
Safety and efficacy will be evaluated with regards to:
* Percentage of patients who meet the adapted pediatric ACR 30/50/70/90/100
* Number of patients who are able to taper steroids
* Number of patients who reached steroid free regimen
* Number of steroid free patients who are able to reduce the canakinumab dose
to 2 mg/kg every four weeks
* Percentage of patients who will meet the definition of inactive disease on
medication and possible clinical remission on medication as defined by Wallace,
Ruperto and Giannini (2004)
* Change in disability over time by use of the cross culturally adapted and
validated version of the CHAQ©
* Change in Health-Related Quality of Life (HRQoL) over time by use of the
cross culturally adapted and validated version Child Health Questionnaire (CHQ)
* Change in HRQoL over time by use of EQ-5D (for patients * 12 years of age) or
EQ-5D proxy (for patients 8 - 11 years of age)
* The impact of treatment with canakinumab on sleepiness in children over time
by use of the Pediatric Daytime Sleepiness Scale (PDSS)
* Progression of joint erosions in the affected hand and wrist by x-ray in a
subset of volunteer patients
* Impact of treatment with canakinumab on growth velocity over time
* Impact of treatment with canakinumab on physical development in children, and
adolescents
from ages 6 * 20 by use of the Tanner stages scale over time
* Change over time in JADAS and DAS
* Progression of joint erosions in the affected hand and wrist by x-ray in a
subset of volunteer
patients
Applicable to previous canakinumab treatment-naïve patients only (Cohort 2):
* Percentage of patients, who reported previous Anakinra, tocilizumab or other
biological treatment,
who meet the adapted ACR 30/50/70/90/100
Background summary
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.
Study objective
The purpose of this open-label phase III extension study is to collect
additional long term safety and efficacy data on canakinumab in the treatment
of SJIA from patients who qualify to roll-over into this study from the
CACZ885G2305 and CACZ885G2301 protocols. Also canakinumab-naive patients with
active SJIA will be enrolled.
Study design
This open-label extension study collects long-term safety and efficacy data
from patients who were responsive to canakinumab in studies CACZ885G2305 and/or
CACZ885G2301, or canakinumab-naive patients with active SJIA.
During this open-label, active treatment study all patients will be treated
with canakinumab 4 mg/kg or 2 mg/kg s.c. every 4 weeks up until study end
unless discontinuation occurs. Dosing visits and safety assessments will occur
every 4 weeks. Efficacy will be assessed every 12 weeks, with the exception of
CRP, which will be measured every four weeks.
Efficacy will be assessed every 12 weeks, with the exception of CRP, which will
be measured
every four weeks. Efficacy will also be assessed at each visit when patient is
tapering
corticosteroid, reducing canakinumab dose, or investigator is concerned
regarding possible
loss of response.
All patients who do not maintain adapted ACR Pediatric 30 response or
clinically deteriorate
during this study and intervention is deemed necessary by the investigator will
be
discontinued unless their loss of the adapted ACR Pediatric 30 response is
considered a
consequence of steroid tapering or the reduction of the canakinumab dose.
Rules for steroid tapering and canakinumab tapering can be found in the final
protocol (v 5 19-jan-2010)
If patients are discontinued, they will be treated as per local standard
medical practice but will
be followed-up for safety for 2 months after the last injection.
The extension study will run for a set time period, meaning all patients
regardless of when they enter
the extension will have a last visit date during December 2012, unless
discontinuation occurs prior to
this date.
Depending on local regulatory requirements access to canakinumab will be made
available to patients
via, but not limited to, an Expanded Access program until the product is
launched. Novartis will provide
the drug free of cost. Countries will ensure that, in compliance with local
regulations, a simplified
access program is set up using the product monograph as a reference. Patients
from countries in
whom canakinumab is not yet approved, individual arrangement in these countries
for continuous care
of patients with canakinumab will be sought that may include, but not limited
to, a local patient need or
compassionate use program.
Intervention
Patients will be dosed every 4 weeks with 4 mg/kg or 2 mg/kg of s.c.
canakinumab up until October 2012 or until premature patient withdrawal (PPW).
On average, patients will be followed for up to 2 years following their
participation in the CACZ885G2305 or CACZ885G2301 studies. This is dependent
on when last patient last visit occurs for study CACZ885G2301; because the
studies run concurrently not all patients who enter the extension study will be
able to receive 96 weeks of treatment.
Patients who are still receiving corticosteroid therapy (oral prednisone or
equivalent) may taper their dose during this study. Guidelines for steroid
tapering for patients who flared early in CACZ885G2305 or CACZ885G2301 between
days 15 and 29 will be introduced.
For patients who are steroid naïve, steroid free, or who have completely
tapered their corticosteroids, there is the option of decreasing the
canakinumab dose to 2 mg/kg every 4 weeks.
The maximal total single dose of canakinumab allowed is 300 mg, which is
administered as two s.c. 150 mg injections.
Novartis will supply investigational drug (active canakinumab) in individual 6
mL glass vials each containing either 150 mg canakinumab (to be used in
patients being on canakinumab 2 mg/kg with * 15 kg BW, and all patients on
canakinumab 4 mg/kg), 25 mg canakinumab (to be used in patients being on
canakinumab 2 mg/kg with < 15 kg BW).
Study burden and risks
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. 37 clinical
studies with canakinumab have been started; approximately 3330 patients
(including 319 children 2 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.
There were serious events (or bad events). A *serious adverse event* is a side
effect that may be life-threatening or may requires the 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
8 serious adverse events where the patients were hospitalized. Five of these
events were due to other underlying medical history of the patients (irritated
stomach with bleeding ulcer, suspected
pericarditis, worsening of SJIA, pain and fear, and blood in the urine). Three
of these events were infections leading to hospitalization (acute tonsillitis,
severe sore throat and severe nail infection. All of these events resolved
while continuing canakinumab treatment. In all previous and ongoing studies of
approximately 670 patients without SJIA taking
canakinumab serious events occurring more than once and suspected to be related
to canakinumab were included: vertigo (dizziness) (twice), nausea (twice) and
vomiting (twice). You will be promptly informed should any further risks about
the study drug become known.
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.
It is unknown if canakinumab and other similar medications change the risk or
frequency of MAS. Cases of MAS, some fatal, have been reported in SJIA patients
treated with canakinumab and similar medications. The number of MAS cases
reported in SJIA studies of canakinumab has been within the range of expected
number of cases.
Cancer
The impact of canakinumab treatment on risk of cancer is not known. However,
treatment with immunosuppressant drugs like canakinumab may result in an
increase in the risk of cancer.
White blood cell count
Canakinumab treated patients may experience low white blood cell count. White
blood cells are infection fighting cells in the blood stream.
Platelet count in blood
Canakinumab treated patients may experience low platelet count in blood.
Platelets in blood take part in blood clotting.
Immunizations
Some vaccines should not be taken during the study It has been recommended that
live and live attenuated vaccines
should not be taken by patients participating in this study. These include BCG
(type of tuberculosis vaccine), Ty21a (a Salmonella typhi vaccine), Measles,
Mumps, Rubella, Oral Polio, Influenza, Yellow fever, Varicella, Vaccinia, and
Rotavirus.
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.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
Inclusion * Cohort 1
1. Parent*s or legal guardian*s written informed consent and child*s assent, if appropriate, or
patient*s informed consent for * 18 years of age before any study related activity is
performed
2. The following patients are eligible to participate in the open label extension study
(CACZ885G2301E1):
* Patients from study CACZ885G2305 or CACZ885G2301 who achieved an adapted
ACR pediatric 30 response 15 days after their initial dose of canakinumab but
clinically deteriorated as defined by a minimum ACR Pediatric 30 response not being
maintained after Day 15 and intervention is deemed necessary by the investigator.
* Patients in study CACZ885G2301 who are not eligible to enter Part II (withdrawal
part) because they were not able to meet the corticosteroid entry criteria of 0.5 mg/kg
oral prednisone (or equivalent) or were not able to taper their steroids by at least 0.3
mg/kg (please refer to CACZ885G2301 protocol for detailed rules)
* Responder patients in Part I or Part II who were maintaining their minimum ACR
pediatric 30 response or had not flared when CACZ885G2301 was stopped.
* CACZ885G2301 patients who were responders in Part I (achieved and maintained a
minimum adapted ACR pediatric 30) but experienced a flare in Part II.
Inclusion criteria * Cohort 2:
1. Parent*s or legal guardian*s written informed consent and child*s assent, if appropriate, or
patient*s informed consent for * 18 years of age before any study related activity is
performed.
2. Male and female patients aged * 2 to < 20 years at the time of the screening visit
3. Confirmed diagnosis of SJIA as per ILAR definition that must have occurred at least 2
months prior to enrollment with an onset of disease < 16 years of age:
* Arthritis in one or more joints with or preceded by fever of at least 2 weeks duration
that is documented to be daily/ quotidian for at least 3 days and accompanied by one
or more of the following:
* Evanescent nonfixed erythematous rash,
* Generalized lymph node enlargement,
* Hepatomegaly and/ or splenomegaly,
* Serositis
4. Active systemic disease at the time of enrollment (baseline visit) defined as having 2 or
more of the followings:
* Documented spiking, intermittent fever (body temperature > 38°C) for at least 1
day during the screening period and within 1 week before first canakinumab dose
* At least 2 joints with active arthritis (using ACR definition of active joint)
* C-reactive protein (CRP) > 30 mg/L (normal range < 10 mg/L)
* Rash
* Serositis
* Lymphadenopathy
* Hepatosplenomegaly
5. Patient*s willingness to discontinue anakinra, rilonacept, tocilizumab or other
experimental drug under close monitoring (Please refer to Cohort 2 exclusion criteria #3
for washout period)
6. No concomitant use of second line agents such as disease-modifying and/or
immunosuppressive drugs will be allowed with the exception of:
* Stable dose of methotrexate (maximum of 20 mg/ m2/ week) for at least 1 week prior
to the baseline visit, and folic/folinic acid supplementation (according to standard
medical practice of the center)
* Stable dose of no more than one non-steroidal anti-inflammatory drug (NSAID) for at
least 1 week prior to the baseline visit
* Stable dose of steroid treatment * 1.0 mg/kg/day (maximum 60 mg/day for children
over 60 kg) in 1-2 doses per day of oral prednisone (or equivalent) for at least 3 days
prior to baseline (Day 1)
7. Negative Purified Protein Derivative (PPD) test (< 5 mm induration) or negative
QuantiFERON test at screening or within 1 month prior to the screening visit, according to
the national guidelines. Patients with a positive PPD test (* 5 mm induration) at screening
may be enrolled only if they have either a negative chest x-ray or a negative
QuantiFERON test (QFT-TB G In-Tube). If the patient has a history of Bacillus Calmette-
Guérin (BCG) vaccination, then a QuantiFERON test should be performed in place of a
PPD test
Exclusion criteria
1. Pregnant or nursing (lactating) female patients, where pregnancy is defined as the state of
a female after conception and until the termination of gestation, confirmed by a positive
urine pregnancy test at screening visit
2. Female patients having reached sexual maturity (e.g. Tanner Stage 2 or above), i.e. being
physiologically capable of becoming pregnant UNLESS they are:
* female patients whose career, lifestyle, or sexual orientation precludes intercourse
with a male partner and/or
* using an acceptable method of contraception with a failure rate (Pearl Index (PI)) < 1.
Reliable contraception should be maintained throughout the study and for 3 months
after study drug discontinuation.
3. History hypersensitivity to study drug or to biologics.
4. With active or recurrent bacterial, fungal or viral infection at the time of enrollment,
including patients with evidence of Human Immunodeficiency Virus (HIV) infection,
Hepatitis B and Hepatitis C infection.
5. Risk factors for tuberculosis (TB) such as:
* History of any of the following: residence in a congregate setting (e.g. jail or prison,
homeless shelter, or chronic care facility), substance abuse (e.g. injection or
noninjection); health-care workers with unprotected exposure to patients who are at
high risk of TB or patients with TB disease before the identification and correct
airborne precautions of the patient, or
* Close contact (i.e. share the same air space in a household or other enclosed
environment for a prolonged period (days or weeks, not minutes or hours)) with a
person with active pulmonary TB disease within the last year
6. With underlying metabolic, renal, hepatic, infectious or gastrointestinal conditions which
in the opinion of the investigator immunocompromises the patient and/ or places the
patient at unacceptable risk for participation in an immunodulatory therapy. In particular,
clinical evidence or history of multiple sclerosis or other demyelinating diseases, or
Felty*s syndrome
7. With neutropenia (absolute neutrophil count < 1500/mm3) at screening
8. With significant medical conditions, which in the opinion of the Investigator will exclude
the patient from the study (can be discussed on a case by case basis with Novartis)
9. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin), treated or untreated, within the past 5 years, regardless of whether there is
evidence of local recurrence or metastases
10. Live vaccinations within 3 months prior to the start of the study. Killed or inactivated
vaccines may be permitted according to the investigator*s discretion.
11. Donation or loss of blood (amount depending on age and weight, 10-20% or more of
volume, see Appendix 3 within 8 weeks prior to first dosing, or longer if required by local
regulation.
12. Familial and social conditions rendering regular medical assessment not possible
13. History of drug or alcohol abuse within the 12 months prior to dosing.
Additional exclusion criteria for Cohort 2:
1. Presence of moderate to severe impaired renal function as indicated by clinically
significantly abnormal creatinine (* 1.5 x upper normal limit (ULN)) or urea values or
abnormal urinary constituents (e.g., albuminuria) at screening. Evidence of urinary
obstruction or difficulty in voiding at screening.;2. Clinical evidence of liver disease or liver injury as indicated by abnormal liver
function tests at screening such as AST, ALT, GGT, alkaline phosphatase, or serum
bilirubin (must not exceed twice the upper limit value of the normal range for age).
3. Use of the following therapies:
* Anakinra within 24 hours prior to Baseline visit
* Rilonacept within 1 week prior to Baseline visit
* Tocilizumab within 3 weeks prior to Baseline visit
* Etanercept within 4 weeks prior to Baseline visit
* Adalimumab within 8 weeks prior to the Baseline visit
* Infliximab within 12 weeks prior to the Baseline visit
* Rituximab within 26 weeks prior to the Baseline visit
* Leflunomide within 4 weeks prior to the Baseline visit. Documentation of a
completion of a full cholestyramine elimination treatment after most recent
leflunomide use will be required.
* Thalidomide within 4 weeks prior to the Baseline visit
* Cyclosporine within 4 weeks prior to the Baseline visit
* Intravenous immunoglobulin (i.v. Ig) within 8 weeks prior to the Baseline visit
* 6-Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil within 12 weeks
prior to the Baseline visit
* Dapsone, mycophenolate mofetil within 3 weeks prior to the Baseline visit
* Corticosteroids (oral prednisone (or equivalent)) > 1.0 mg/kg/day (or greater than the
maximum of 60 mg/day for children over 60 kg) for at least 3 days prior to the
Baseline visit
* Intra-articular, peri-articular, or intramuscular corticosteroid injections within 4 weeks
prior to the Baseline visit
* Any other investigational biologics (with the exception of the ones mentioned above
or canakinumab (previous participation in studies CACZ885A2203, CACZ885G2301
or CACZ885G2305)) within 8 weeks prior to the Baseline visit
* Any other investigational drugs, other than investigational biologic treatment, within
30 days (or 3 months for investigational monoclonal antibodies) or 5 half-lives prior to
the Baseline visit, whichever is longer
Wash-out period may be longer according to local requirements.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-008008-42-NL |
| CCMO | NL28260.041.09 |