Clinical trial NCT03265132: A Study to Evaluate Efficacy and Safety of Anakinra in the Treatment of Still's Disease (SJIA and AOSD)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Still's Disease, Adult-Onset
Still's Disease, Juvenile-Onset
Keywords: Interleukin 1 receptor antagonist
IL-1 receptor antagonist
Kineret
anakinra
Adult-Onset Still's Disease
Systemic Juvenile Idiopathic Arthritis
Lead sponsor: Swedish Orphan Biovitrum
Sponsor class: INDUSTRY
First posted: 2017-08-29
Enrollment: 13
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Signed informed consent.
2. Male and female patients with a body weight ≥ 10 kg.
3. Diagnosis of Still's disease.
4. If currently on glucocorticoid treatment, a stable dose for at least 1 week prior to randomization.
5. If currently on methotrexate treatment, a stable dose for at least 8 weeks prior to randomization.
6. Active disease.
7. 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.
8. 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:

1. Diagnosis of Still's disease more than 6 months prior to randomization.
2. Previous randomization into this study.
3. Participation in another concurrent clinical interventional study within 30 days of randomization.
4. Treatment with an investigational drug within 5 half-lives prior to randomization.
5. Previous or current treatment with anakinra, canakinumab or any other IL-1 inhibitor.
6. 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.
7. Live vaccines within 1 month prior to randomization.
8. Known presence or suspicion of active, chronic or recurrent bacterial, fungal or viral infections, including tuberculosis, HIV infection or hepatitis B or C infection.
9. Clinical evidence of liver disease or liver injury.
10. Presence of severe renal function impairment.
11. Presence of neutropenia.
12. Presence or suspicion of MAS at baseline.
13. A diagnosis of MAS within the last 2 months prior to randomization.
14. History of malignancy within 5 years.
15. Known hypersensitivity to E coli-derived proteins, or any components of Kineret® (anakinra).
16. Pregnant or lactating women.
17. Foreseeable inability to cooperate with given instructions or study procedures.
18. 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.

Primary outcomes:
measure: Proportion of ACR30 Responders With Absence of Fever Attributable to the Disease During the 7 Days Preceding Week 2.
timeFrame: Week 2
Secondary outcomes:
measure: Proportion of ACR30 Responders With Absence of Fever During 24 Hours Preceding Week 1.
timeFrame: Week 1
measure: Proportion of ACR50 Responders With Absence of Fever During 24 Hours Preceding Week 1.
timeFrame: Week 1
measure: Proportion of ACR70 Responders With Absence of Fever During 24 Hours Preceding Week 1.
timeFrame: Week 1
measure: Proportion of ACR90 Responders With Absence of Fever During 24 Hours Preceding Week 1.
timeFrame: Week 1
measure: Proportion of ACR50 Responders With Absence of Fever During 7 Days Preceding Week 2.
timeFrame: Week 2
measure: Proportion of ACR70 Responders With Absence of Fever During 7 Days Preceding Week 2.
timeFrame: Week 2
measure: Proportion of ACR90 Responders With Absence of Fever During 7 Days Preceding Week 2.
timeFrame: Week 2
measure: Proportion of Responders in Physician Global Assessment of Disease Activity.
timeFrame: Week 2
measure: Proportion of Responders in Patient/Parent Global Assessment of Overall Well-being.
timeFrame: Week 2
measure: Proportion of Responders in Number of Joints With Active Arthritis.
timeFrame: Week 2
measure: Proportion of Responders in Number of Joints With Limitation of Motion.
timeFrame: Week 2
measure: Proportion of Responders in Assessment of Physical Function (CHAQ/SHAQ).
timeFrame: Week 2
measure: Proportion of Responders in CRP (mg/L).
timeFrame: Week 2
measure: Proportion of Patients With Absence of Fever During the 7 Days Preceding Week 2.
timeFrame: Week 2
measure: Proportion of Patients With Absence of Fever During the 24 Hours Preceding Week 1.
timeFrame: Week 1
measure: Change From Baseline in Physician Global Assessment of Disease Activity at Week 1.
timeFrame: Day 1 and Week 1
measure: Change From Baseline in Patient/Parent Global Assessment of Overall Well-being at Week 1.
timeFrame: Day 1 and Week 1
measure: Change From Baseline in CRP.
timeFrame: Day 1 and Week 1
measure: Proportion of Patients With Sustained ACR30, ACR50, ACR70 and ACR90 Response.
timeFrame: Week 12
measure: Proportion of Patients With Sustained ACR30, ACR50, ACR70 and ACR90 Response in Relation to Glucocorticoid Tapering.
timeFrame: Week 2, Week 4, Week 8 and Week 12
measure: Proportion of Patients With Absence of Rash.
timeFrame: Week 2
measure: Change From Baseline in CRP.
timeFrame: Week 2
measure: Change From Baseline in Hemoglobin (Hb). Results at Week 2 Reported Here.
timeFrame: Week 2
measure: Change From Baseline in Platelet Count.
timeFrame: Week 2
measure: Change From Baseline in Ferritin.
timeFrame: Week 2
measure: Change From Baseline in Patient/Parent Global Assessment of Disease Related Pain.
timeFrame: Week 2
measure: Time to Study Drug Discontinuation for Any Reason.
timeFrame: From Day 1 to Week12
measure: Time to Study Drug Discontinuation Due to Lack of Efficacy or Progressive Disease.
timeFrame: From Day 1 to Week12
measure: Proportion of Patients Who Have Initiated Tapering of Glucocorticoids.
timeFrame: From Week 2 to Week12
measure: Proportion of Patients That Have Decreased the Glucocorticoid Dose With at Least 50% From Baseline.
timeFrame: From Week 2 to Week12
measure: Percentage Decrease of the Glucocorticoid Dose From Baseline.
timeFrame: From Day 1 to Week12
measure: Proportion of Patients With at Least One Adverse Event.
timeFrame: From Day 1 to Week 16
measure: Proportion of Patients With at Least One Serious Adverse Event Including Death.
timeFrame: From Informed consent to Week 16
measure: Proportion of Patients With Macrophage Activation Syndrome (MAS).
timeFrame: From Day 1 to Week 16
measure: Proportion of Patients With Antidrug Antibodies (ADA) Against Anakinra.
timeFrame: Week 2
measure: Proportion of Patients With Neutralizing Antibodies.
timeFrame: Week 2
measure: Anakinra Serum Pre-dose Concentrations.
timeFrame: Week 2
measure: Anakinra Serum Pharmacokinetic Parameters: Cmax,
timeFrame: Week 12
measure: Anakinra Serum Pharmacokinetic Parameters, Tmax and T½
timeFrame: Week 12
measure: Anakinra Serum Pharmacokinetic Parameter: AUC 0-24 h
timeFrame: Week 12
measure: Anakinra Serum Pharmacokinetic Parameter: CL/F
timeFrame: Week 12
measure: Anakinra Serum Pharmacokinetic Parameter: Vd/F
timeFrame: Week 12
measure: Change From Baseline in JADAS27.
timeFrame: Week 2
measure: Number of Days Off School or Work Due to Still's Disease.
timeFrame: Week 2
measure: Proportion of Patients With Inactive Disease.
timeFrame: Week 12
measure: Change From Baseline in IL-6.
timeFrame: Week 2
measure: Change From Baseline in IL-18.
timeFrame: Week 2
measure: Change From Baseline in Serum Calprotectin.
timeFrame: Week 2
measure: Change From Baseline in Neopterin.
timeFrame: Week 2
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Beverly Hills
country: United States
facility: Attune Health
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital & Health Center
state: California
city: Aurora
country: United States
facility: The Children's Hospital Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics
state: Kansas
city: Louisville
country: United States
facility: University of Louisville School of Medicine Research Foundation
state: Kentucky
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Eagan
country: United States
facility: Saint Paul Rheumatology
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Summit
country: United States
facility: Institute for Rheumatic and Autoimmune Diseases
state: New Jersey
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Hospitals
state: North Carolina
city: Durham
country: United States
facility: Duke Children's Hospital and Health Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Brenner Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: MetroHealth System
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Nashville
country: United States
facility: Monroe Carell Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: Baylor Research Institute
state: Texas
city: Dallas
country: United States
facility: Univ of TX Southwestern Medical Center Dallas - Texas Scottish Rite Hospital for Children
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospitals and Clinics
state: Utah
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: University of Calgary - Alberta Children's Hospital
city: Calgary
country: Canada
facility: University of Calgary
city: Toronto
country: Canada
facility: The Hospital for Sick Children
Study officials:
affiliation: Swedish Orphan Biovitrum
name: Sven Ohlman, MD PhD
role: STUDY_DIRECTOR
References: