To describe the pharmacokinetic (PK) profile and effectiveness of sarilumab in patients with pcJIA 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 (AUC0-t)
Assessment of PK parameter: Concentration observed before treatment
administration during repeated dosing (Ctrough)
Secondary outcome
Number of patients with adverse events
Number of patients with local site reactions
Juvenile Idiopathic 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 polyarticular
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 pcJIA by tocilizumab, an intravenously
administered, humanized monoclonal antibody (mAb) to the IL-6R. In the pcJIA
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, that can be administered via subcutaneous injections in stead of IV.
Sarilumab may become an effective and safe therapeutic option for patients
suffering from pcJIA. In previous trials in adults with rheumatoid arthritis a
significant decease in inflammation was observed. This study will evaluate the
efficacy, safety and PK, PD profiles of different doses of sarilumab
administered to juvenile patients with pcJIA.
Study objective
To describe the pharmacokinetic (PK) profile and effectiveness of sarilumab in
patients with pcJIA 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 2 to 18
years old with pc JIA.
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 is 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
subcutaeous injection based on body weight [Group A (>=30 kg and <=60 kg) or
Group B (<30 kg and >=10 kg)] weekly or biweekly.
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 of the 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
pediatric patients with polyarticular course juvenile idiopathic arthritis
(pcJIA).
Kampenringweg 45 E
Gouda 2803PE
NL
Kampenringweg 45 E
Gouda 2803PE
NL
Listed location countries
Age
Inclusion criteria
Patients need to fulfill all inclusion criteria mentioned below:;1) -Male and female patients aged >=2 and <=17 years at the time of the screening visit.;2) -Diagnosis of rheumatoid factor-negative or rheumatoid factor positive polyarticular Juvenile Idiopathic Arhtritis (JIA) subtype or oligoarticular extended JIA subtype according to the International League of Associations for Rheumatology (ILAR) 2001 Juvenile Idiopathic Arthritis Classification Criteria with at least 5 active joints as per American College of Rheumatology (ACR) definition for *active arthritis* at screening.;3) -Patient with an inadequate response to current treatment and considered as a candidate for a biologic disease-modifying antirheumatic drug (DMARD) as per Investigator*s judgment.
Exclusion criteria
-Body weight <10 kg or >60 kg.
-If non-steroidal anti-inflammatory drugs 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 0.5 mg/kg/day (or 30 mg/day) within 2 weeks prior to baseline.
-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 DMARD 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 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;-Wheelchair-bound or bed ridden
- Diagnosis of JIA subtypes except polyarticular RF positive (RF+) or RF negative (RF ) JIA or extended oJIA
-Use of parenteral or intra-articular glucocorticoid injection within 4 weeks prior to Baseline
-Lipid-lowering drug stable for less than 6 weeks prior to screening.
-Exclusion related to tuberculosis (TB)
-Prior or current history of malignancy
-Prior or current history of other significant concomitant illness(es) that, according to the investigator*s judgment, would adversely affect the patient*s participation in the study.
-Patient with nonhealed/healing skin ulcers
-Surgery within 4 weeks prior to the screening visit or planned surgery during the course of the study.
- History of a systemic hypersensitivity reaction, other than localized injection site reaction, to any biologic drug and known hypersensitivity to any constituent of the product
-History of inflammatory bowel disease, severe diverticulitis, or previous gastrointestinal perforation whatever the cause
-Uncontrolled diabetes mellitus, defined as glycosylated hemoglobin (HbA1c) >=9% at the Screening visit
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 | EUCTR2015-003999-79-NL |
| CCMO | NL57013.041.16 |