To describe the pharmacokinetic (PK) profile and effectiveness of sarilumab in patients with sJIA in order to identifythe dose and regimen for continued development in this population.
ID
Source
Brief title
Condition
- Immune system disorders congenital
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Assessment of PK parameter: maximum serum concentration observed (Cmax)
Assessment of PK parameter: Area under the serum concentration versus time
curve calculated using the trapezoidal
method during a dose interval (AUCO-t)
Assessment of PK parameter: Concentration observed before treatment
administration during repeated dosing (Ctrough)
Secondary outcome
Number of patients witha dverse events
Number of patients with local site reactions
Juvenile ldiopathic Arthritis (JIA) American College of Rheumatology 30 (ACR30)
response rate
Change from baseline in individual JIA ACR components
Changes in IL-6 associated biomarkers
Background summary
Interleukin 6 (IL-6) is a key cytokine involved in the pathogenesis of
rheumatoid arthritis (RA) and JIA causing
inflammation and joint destruction. The relevance of elevated IL-6 levels to
disease mechanisms of systemic JIA (RF- and
RF+ has been well documented in the medical-scientific literature. inhibition
of IL-6 signaling through blockade of the
IL-6 receptor (IL-6R) was first demonstrated to be effective in sJIA by
tocilizumab, an intravenously administered,
humanized monoclonal antibody (mAb) to the IL-6R. In the sJIA studies that led
to the approval of tocilizumab in this
indication, the safety profile of tocilizumab appeared to be similar to that of
the adult RA population.
Sarilumab is a recombinant human monoclonal antibody blocking the IL-6 receptor.
Sarilumab may become an effective and safe therapeutic option for patients
suffering from sJIA. Th is study will evaluate
the efficacy, safety and PK, PO profiles of different doses of sarilumab
administered to patients with sJIA.
Study objective
To describe the pharmacokinetic (PK) profile and effectiveness of sarilumab in
patients with sJIA in order to identify
the dose and regimen for continued development in this population.
Study design
An Open-label, Ascending, Repeated Dose-finding Study in children aged 1 to 18
years old with sJIA.
Children are classified in weight groups (10 to 30 kg and 30 to 60 kg), en the
heaviest group will start first with the lowest
sarilumab dose for a period of 12 weeks. After 6 weeks the cohort is evaluated
by the DMC and a second cohort will be
opened if the DMC has no objections. Sarilumab is administered every 2 weeks or
weekly by subcutaneous injections.
After 12 weeks the patients are offered an extension part of 144 weeks, in case
there are no safety issues or benefit issues.
The dose of the core study part is maintained.
Intervention
Participants will receive one of three ascending doses of sarilumab trough
subcutaneous injection based on body weight
-Group A (above 30 kg and below 60 kg) or;
-Group B { below 30 kg and above 10 kg)] weekly or biweekly injections
Study burden and risks
Based on the safety profile of tocilizumab (an approved IL-6 receptor
inhibitor) and other biological DMARDs, potential
important risks to be considered with sarilumab administration are tuberculosis
and clinically significant opportunistic
infections, complications of diverticulitis/gastrointestinal perforations,
anaphylaxis, clinical consequences of
immunogenicity, clinical consequences of thrombocytopenia, malignancy, and
demyelinating disorders. In addition,
clinical consequences of laboratory abnormalities which may occur due to
sarilumab administration (eg, serious infection
secondary to neutropenia) are considered an important potential risk.
Based on the experience to date from the sarilumab clinical development
program, the potential important risks
associated with sarilumab administration are non-opportunistic infections,
neutropenia, elevation in lipids, elevation in
liver transaminase, and injection site reactions (ie, erythema, pain).
From the results ofthe completed studies within the sarilumab RA development
program in adult patients, the two
selected doses of sarilumab for the phase 3 program appear to be efficacious
and have an acceptable safety profile and
may serve as an appropriate reference for the further evaluation of sarilumab
in pediatrie patients with polyarticular
course juvenile idiopathic arthritis (sJIA).
Kampenringweg 45E
Gouda 2803PE
NL
Kampenringweg 45E
Gouda 2803PE
NL
Listed location countries
Age
Inclusion criteria
1) Male and female patients aged >=1 and <=17 years at the time of the screening visit.
2) Diagnosis of systemic Juvenile Idiopathic Arthritis (JIA) subtype according to the International League of Associations for Rheumatology (ILAR) 2001 Juvenile Idiopathic Arthritis Classification Criteria with the following features at screening: ->=5 active joints at screening or; ->=2 active joints at screening with systemic JIA fever bigger as 37.5 °C in the 3 days preceding baseline or for at least 3 out of any 7 consecutive days during screening despite glucocorticoids at a stable dose for at least 3 days.
3) Patients with an inadequate response to current treatment and considered as a candidate for a biologic disease-modifying anti-rheumatic drug (DMARD) as per Investigator*s judgment.
Exclusion criteria
-Body weight below 10 kg or more than 60 kg.
-Uncontrolled severe systemic symptoms and/or Macrophage Activation Syndrome within 6 months prior to screening.
-If nonsteroidal anti-inflammatory drugs [NSAIDs, including cyclo-oxygenase-2 inhibitors (COX-2)] taken, dose stable for less than 2 weeks prior to the baseline visit and/or dosing prescribed outside of approved label.
-If non-biologic DMARD taken, dose stable for less than 6 weeks prior to the baseline visit or at a dose exceeding the recommended dose as per local labeling.-If oral glucocorticoid taken, dose exceeding equivalent prednisone dose 1 mg/kg/day (or 60 mg/day) within 3 days prior to baseline.
-Use of parenteral intra-articular injection of glucocorticoid within 4 weeks prior baseline.
-Lipid-lowering drug stable for less than 6 weeks prior to screening.
-Prior treatment with anti-interleukin 6 (IL-6) or IL-6 receptor (IL-6R) antagonist therapies, including but not limited to tocilizumab or sarilumab.
-Treatment with any biologic treatment for sJIA within 5 half-lives prior to the first dose of sarilumab.
-Treatment with a Janus kinase inhibitor within 4 weeks prior to the first dose of sarilumab.
-Treatment with any Investigational biologic or non-biologic product within 8 weeks or 5 half-lives prior to baseline, whichever is longer.
-Exclusion related to tuberculosis (TB)
-Exclusion criteria related to past or current infection other than tuberculosis.
-Any live, attenuated vaccine within 4 weeks prior to the baseline, such as varicella-zoster, oral polio, rubella vaccines. Killed or inactive vaccine may be permitted based on the Investigators judgment.
-Severe cardiac disease due to sJIA.
-History of or ongoing interstitial lung disease, pulmonary hypertension, pulmonary alveolar proteinosis.
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 | EUCTR2015-004000-35-NL |
| CCMO | NL59322.041.16 |
| Other | U1111-1177-3584 |