A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 3 Efficacy and Safety Study of 2 Dose Levels of Subcutaneous Anakinra (Kineret®) in Patients With Still's Disease (SJIA and AOSD)
Trial Snapshot
- Phase
- Phase 3
- Status
- Terminated
- Sponsor
- Enrollment
- 13
- Locations
- 39
- Primary Endpoint
- Proportion of ACR30 Responders With Absence of Fever Attributable to the Disease During the 7 Days Preceding Week 2.
Study Overview
Brief Summary
The aim of this study is to demonstrate the efficacy and to evaluate the safety, pharmacokinetics (PK) and immunogenicity of anakinra in patients with newly diagnosed Still's disease, including SJIA (Systemic juvenile idiopathic arthritis) and AOSD (Adult-onset Still's disease).
Detailed Description
The study consists of a 12-week, randomized, double-blind, placebo controlled period with two dose levels of anakinra and a 4-week safety follow-up after last dose of investigational medicinal product (IMP). The primary endpoint will be evaluated at Week 2. Sustained efficacy and time to study drug discontinuation will be evaluated during the full study period.
A screening visit is optional and may be done to identify patients that could be suitable for the study. During the study 6 visits and 2 telephone contacts are scheduled i.e., Day 1 (baseline visit), Day 4Tel, Week 1, Week 2, Week 4, Week 8, Week 12 and Week 16Tel (End of Study).
Patients will be randomly assigned to study drug, after they meet all of the inclusion criteria and none of the exclusion criteria. Patients will receive treatment for 12 weeks, either anakinra or placebo. Patients will be randomized to anakinra in a dose of either 2 or 4 mg/kg/day, with a maximum dose of 100 or 200 mg once daily, respectively. Patients will be randomized to placebo with corresponding volumes for each of the two anakinra dose levels.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Signed informed consent.
- •Male and female patients with a body weight ≥ 10 kg.
- •Diagnosis of Still's disease.
- •If currently on glucocorticoid treatment, a stable dose for at least 1 week prior to randomization.
- •If currently on methotrexate treatment, a stable dose for at least 8 weeks prior to randomization.
- •Active disease.
- •Female patients of childbearing potential must use an effective method of contraception during the study (abstinence being a possible option) as well as present a negative pregnancy test prior to randomization.
- •Negative interferon-gamma release assay or Purified protein derivative ( PPD) test within 2 months prior to randomization. If not available, a test should be performed at day of randomization.
Exclusion Criteria
- •Diagnosis of Still's disease more than 6 months prior to randomization.
- •Previous randomization into this study.
- •Participation in another concurrent clinical interventional study within 30 days of randomization.
- •Treatment with an investigational drug within 5 half-lives prior to randomization.
- •Previous or current treatment with anakinra, canakinumab or any other IL-1 inhibitor.
- •Use of the following therapies prior to randomization:
- •Narcotic analgesics within 24 hours prior to randomization.
- •Dapsone or etanercept within 3 weeks prior to randomization.
- •Intraarticular, intramuscular or intravenous administration of glucocorticoids or intravenous immunoglobulin (Ig) within 4 weeks prior to randomization.
- •Intravenous Ig with proven Still's disease modifying effect, leflunomide, infliximab or adalimumab within 8 weeks prior to randomization.
- •Thalidomide, cyclosporine, mycophenolate mofetil, 6-mercaptopurine, azathioprine, cyclophosphamide, chlorambucil or any other immunosuppressant within 12 weeks prior to randomization.
- •Tocilizumab within 12 weeks prior to randomization or any other immunomodulatory medication within 4 half-lives prior to randomization
- •Rituximab within 26 weeks prior to randomization.
- •Live vaccines within 1 month prior to randomization.
- •Known presence or suspicion of active, chronic or recurrent bacterial, fungal or viral infections, including tuberculosis, HIV infection or hepatitis B or C infection.
- •Clinical evidence of liver disease or liver injury.
- •Presence of severe renal function impairment.
- •Presence of neutropenia.
- •Presence or suspicion of MAS at baseline.
- •A diagnosis of MAS within the last 2 months prior to randomization.
- •History of malignancy within 5 years.
- •Known hypersensitivity to E coli-derived proteins, or any components of Kineret® (anakinra).
- •Pregnant or lactating women.
- •Foreseeable inability to cooperate with given instructions or study procedures.
- •Presence of any medical or psychological condition or laboratory result that in the opinion of the investigator can interfere with the patient's ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with IMP.
Arms & Interventions
anakinra
2 mg/kg/day (max 100 mg/day) or 4 mg/kg/day (max 200 mg/day)
Intervention: anakinra (Biological)
Placebo
Corresponding volume to anakinra 2 mg/kg/day or 4 mg/kg/day
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Proportion of ACR30 Responders With Absence of Fever Attributable to the Disease During the 7 Days Preceding Week 2.
Time Frame: Week 2
ACR30 response is defined as an improvement of ≥ 30% from baseline in at least 3 of any 6 variables listed below. Also no more than 1 of the 6 variables may worsen by \>30% from baseline. (ACR: American College of Rheumatology) 1. Physician global assessment of disease activity - Assessed on a Visual Analogue Scale (VAS) from no disease activity (0 mm) to very severe disease activity (100 mm). 2. Patient/parent global assessment of overall well-being - Assessed on a VAS from very well (0 mm) to very poor (100 mm). 3. Number of joints with active arthritis. 4. Number of joints with limitation of motion. 5. Assessment of physical function - Patient Reported Outcome instruments : Childhood Health Assessment Questionnaire (CHAQ) /Stanford Health Assessment Questionnaire (SHAQ). 6. C-Reactive Protein (CRP) (mg/L).
Secondary Outcomes
- Proportion of Patients With at Least One Serious Adverse Event Including Death.(From Informed consent to Week 16)
- Proportion of Patients With Antidrug Antibodies (ADA) Against Anakinra.(Week 2)
- Anakinra Serum Pre-dose Concentrations.(Week 2)
- Anakinra Serum Pharmacokinetic Parameters: Cmax,(Week 12)
- Anakinra Serum Pharmacokinetic Parameters, Tmax and T½(Week 12)
- Anakinra Serum Pharmacokinetic Parameter: AUC 0-24 h(Week 12)
- Number of Days Off School or Work Due to Still's Disease.(Week 2)
- Percentage Decrease of the Glucocorticoid Dose From Baseline.(From Day 1 to Week12)
- Time to Study Drug Discontinuation for Any Reason.(From Day 1 to Week12)
- Proportion of ACR50 Responders With Absence of Fever During 7 Days Preceding Week 2.(Week 2)
- Proportion of ACR90 Responders With Absence of Fever During 7 Days Preceding Week 2.(Week 2)
- Proportion of Patients Who Have Initiated Tapering of Glucocorticoids.(From Week 2 to Week12)
- Proportion of Patients That Have Decreased the Glucocorticoid Dose With at Least 50% From Baseline.(From Week 2 to Week12)
- Proportion of Patients With Macrophage Activation Syndrome (MAS).(From Day 1 to Week 16)
- Proportion of Patients With Neutralizing Antibodies.(Week 2)
- Proportion of ACR50 Responders With Absence of Fever During 24 Hours Preceding Week 1.(Week 1)
- Proportion of ACR90 Responders With Absence of Fever During 24 Hours Preceding Week 1.(Week 1)
- Proportion of ACR70 Responders With Absence of Fever During 7 Days Preceding Week 2.(Week 2)
- Proportion of Responders in Physician Global Assessment of Disease Activity.(Week 2)
- Proportion of Responders in Patient/Parent Global Assessment of Overall Well-being.(Week 2)
- Proportion of Responders in Assessment of Physical Function (CHAQ/SHAQ).(Week 2)
- Proportion of Patients With Sustained ACR30, ACR50, ACR70 and ACR90 Response in Relation to Glucocorticoid Tapering.(Week 2, Week 4, Week 8 and Week 12)
- Change From Baseline in Hemoglobin (Hb). Results at Week 2 Reported Here.(Week 2)
- Change From Baseline in Platelet Count.(Week 2)
- Change From Baseline in Ferritin.(Week 2)
- Time to Study Drug Discontinuation Due to Lack of Efficacy or Progressive Disease.(From Day 1 to Week12)
- Proportion of ACR70 Responders With Absence of Fever During 24 Hours Preceding Week 1.(Week 1)
- Change From Baseline in Patient/Parent Global Assessment of Overall Well-being at Week 1.(Day 1 and Week 1)
- Proportion of ACR30 Responders With Absence of Fever During 24 Hours Preceding Week 1.(Week 1)
- Proportion of Responders in Number of Joints With Active Arthritis.(Week 2)
- Proportion of Responders in Number of Joints With Limitation of Motion.(Week 2)
- Proportion of Responders in CRP (mg/L).(Week 2)
- Proportion of Patients With Absence of Fever During the 7 Days Preceding Week 2.(Week 2)
- Proportion of Patients With Absence of Fever During the 24 Hours Preceding Week 1.(Week 1)
- Change From Baseline in Physician Global Assessment of Disease Activity at Week 1.(Day 1 and Week 1)
- Change From Baseline in CRP.(Week 2)
- Proportion of Patients With Sustained ACR30, ACR50, ACR70 and ACR90 Response.(Week 12)
- Proportion of Patients With Absence of Rash.(Week 2)
- Change From Baseline in Patient/Parent Global Assessment of Disease Related Pain.(Week 2)
- Change From Baseline in IL-18.(Week 2)
- Change From Baseline in Serum Calprotectin.(Week 2)
- Change From Baseline in Neopterin.(Week 2)
- Proportion of Patients With at Least One Adverse Event.(From Day 1 to Week 16)
- Anakinra Serum Pharmacokinetic Parameter: CL/F(Week 12)
- Anakinra Serum Pharmacokinetic Parameter: Vd/F(Week 12)
- Change From Baseline in JADAS27.(Week 2)
- Proportion of Patients With Inactive Disease.(Week 12)
- Change From Baseline in IL-6.(Week 2)