A Study to Evaluate Efficacy and Safety of Anakinra in the Treatment of Still's Disease (SJIA and AOSD) (anaSTILLs)

• ClinicalTrials.gov Identifier: NCT03265132
• Recruitment Status: Terminated
• First Posted: August 29, 2017
• Results First Posted: April 28, 2020
• Last Update Posted: June 30, 2021
• Sponsor: Swedish Orphan Biovitrum
• Information provided by (Responsible Party): Swedish Orphan Biovitrum

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Still's Disease, Adult-Onset; Still's Disease, Juvenile-Onset	Biological: anakinra; Drug: Placebo	Phase 3

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 (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: September 26, 2017
• Actual Primary Completion Date: February 13, 2019
• Actual Study Completion Date: May 23, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: anakinra; 2 mg/kg/day (max 100 mg/day) or 4 mg/kg/day (max 200 mg/day)	Biological: anakinra; sub cutaneous injection; Other Name: Kineret
Placebo Comparator: Placebo; Corresponding volume to anakinra 2 mg/kg/day or 4 mg/kg/day	Drug: Placebo; sub cutaneous injection

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. Proportion of ACR30 Responders With Absence of Fever During 24 Hours Preceding Week 1. [ Time Frame: Week 1 ]
   ACR30 response is defined as an improvement of ≥ 30% from baseline in at least 3 of any 6 variables listed in the description of the primary outcome measure. Also no more than 1 of the 6 variables may worsen by >30% from baseline.
2. Proportion of ACR50 Responders With Absence of Fever During 24 Hours Preceding Week 1. [ Time Frame: Week 1 ]
   ACR50 response is defined as an improvement of ≥ 50% from baseline in at least 3 of any 6 variables listed in the description of the primary outcome measure. Also no more than 1 of the 6 variables may worsen by >30% from baseline.
3. Proportion of ACR70 Responders With Absence of Fever During 24 Hours Preceding Week 1. [ Time Frame: Week 1 ]
   ACR70 response is defined as an improvement of ≥ 70% from baseline in at least 3 of any 6 variables listed in the description of the primary outcome measure. Also no more than 1 of the 6 variables may worsen by >30% from baseline.
4. Proportion of ACR90 Responders With Absence of Fever During 24 Hours Preceding Week 1. [ Time Frame: Week 1 ]
   ACR90 response is defined as an improvement of ≥ 90% from baseline in at least 3 of any 6 variables listed in the description of the primary outcome measure. Also no more than 1 of the 6 variables may worsen by >30% from baseline.
5. Proportion of ACR50 Responders With Absence of Fever During 7 Days Preceding Week 2. [ Time Frame: Week 2 ]
   ACR50 response is defined as an improvement of ≥ 50% from baseline in at least 3 of any 6 variables listed in the description of the primary outcome measure. Also no more than 1 of the 6 variables may worsen by >30% from baseline.
6. Proportion of ACR70 Responders With Absence of Fever During 7 Days Preceding Week 2. [ Time Frame: Week 2 ]
   ACR70 response is defined as an improvement of ≥ 70% from baseline in at least 3 of any 6 variables listed in the description of the primary outcome. Also no more than 1 of the 6 variables may worsen by >30% from baseline.
7. Proportion of ACR90 Responders With Absence of Fever During 7 Days Preceding Week 2. [ Time Frame: Week 2 ]
   ACR90 response is defined as an improvement of ≥ 90% from baseline in at least 3 of any 6 variables listed in the description of the primary outcome . Also no more than 1 of the 6 variables may worsen by >30% from baseline.
8. Proportion of Responders in Physician Global Assessment of Disease Activity. [ Time Frame: Week 2 ]
   Assessed on a VAS from no disease activity (0 mm) to very severe disease activity (100 mm). Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline. Only improvement of ≥90% at Week 2 reported here.
9. Proportion of Responders in Patient/Parent Global Assessment of Overall Well-being. [ Time Frame: Week 2 ]
   Assessed on a VAS from very well (0 mm) to very poor. (100 mm). Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.Only improvement of ≥90% at Week 2 reported here.
10. Proportion of Responders in Number of Joints With Active Arthritis. [ Time Frame: Week 2 ]
    Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.Only improvement of ≥90% at Week 2 reported here.
11. Proportion of Responders in Number of Joints With Limitation of Motion. [ Time Frame: Week 2 ]
    Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.Only improvement of ≥90% at Week 2 reported here.
12. Proportion of Responders in Assessment of Physical Function (CHAQ/SHAQ). [ Time Frame: Week 2 ]
    Childhood Health Assessment Questionnaire (CHAQ) and Stanford Health Assessment Questionnaire (SHAQ) assess physical and functional status (see Clinical protocol section 6.5.4.1.5). Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline. Only improvement of ≥90% at Week 2 reported here.
13. Proportion of Responders in CRP (mg/L). [ Time Frame: Week 2 ]
    Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline. Only improvement of ≥90% at Week 2 reported here.
14. Proportion of Patients With Absence of Fever During the 7 Days Preceding Week 2. [ Time Frame: Week 2 ]
    Proportion of patients with absence of fever during the 7 days preceding Week 2.
15. Proportion of Patients With Absence of Fever During the 24 Hours Preceding Week 1. [ Time Frame: Week 1 ]
    Absence of fever during the 24 hours preceding week 1.
16. Change From Baseline in Physician Global Assessment of Disease Activity at Week 1. [ Time Frame: Day 1 and Week 1 ]
    Change from baseline in Physician global assessment of disease activity measured on a VAS 0 (very well)-100 (very poor) at Week 1.
17. Change From Baseline in Patient/Parent Global Assessment of Overall Well-being at Week 1. [ Time Frame: Day 1 and Week 1 ]
    Change from baseline in patient/parent global assessment of overall well-being measured on a VAS 0 (very well)-100 (very poor) at Week 1.
18. Change From Baseline in CRP. [ Time Frame: Day 1 and Week 1 ]
    Change from baseline in C-Reactive Protein (CRP). CRP is measured in mg/L.
19. Proportion of Patients With Sustained ACR30, ACR50, ACR70 and ACR90 Response. [ Time Frame: Week 12 ]
    Proportion of patients that still meet the corresponding week 2 response with absence of fever in the preceding 7 days. Only the strictest criteria, ACR90, is reported here.
20. Proportion of Patients With Sustained ACR30, ACR50, ACR70 and ACR90 Response in Relation to Glucocorticoid Tapering. [ Time Frame: Week 2, Week 4, Week 8 and Week 12 ]
    Please note no patients were treated with any systemic glucocorticoids at randomization. Hence no results available.
21. Proportion of Patients With Absence of Rash. [ Time Frame: Week 2 ]
    Absence of rash is evaluated 24 hours preceding Week 1 and 7 days preceding Week 2, Week 4, Week 8 and Week 12. Only data at Week 2 reported here.
22. Change From Baseline in CRP. [ Time Frame: Week 2 ]
    Change from baseline in CRP. Results at Week 2 reported here.
23. Change From Baseline in Hemoglobin (Hb). Results at Week 2 Reported Here. [ Time Frame: Week 2 ]
    Change from baseline in Hemoglobin (Hb). Results at Week 2 reported here.
24. Change From Baseline in Platelet Count. [ Time Frame: Week 2 ]
    Change from baseline in platelet count. Results at Week 2 reported here.
25. Change From Baseline in Ferritin. [ Time Frame: Week 2 ]
    Change from baseline in ferritin. Results at Week 2 reported here.
26. Change From Baseline in Patient/Parent Global Assessment of Disease Related Pain. [ Time Frame: Week 2 ]
    Assessed on a VAS from no pain (0 mm) to very severe pain (100 mm).
27. Time to Study Drug Discontinuation for Any Reason. [ Time Frame: From Day 1 to Week12 ]
    Time to study drug discontinuation was analyzed using Kaplan-Meier curves. Number of patients with premature study drug discontinuation for any reason is reported here.
28. Time to Study Drug Discontinuation Due to Lack of Efficacy or Progressive Disease. [ Time Frame: From Day 1 to Week12 ]
    Proportion of study drug discontinuation due to lack of efficacy or progressive disease was analyzed using Kaplan-Meier curves. Number of patients discontinuing study drug due to lack of efficacy or progressive disease is reported here.
29. Proportion of Patients Who Have Initiated Tapering of Glucocorticoids. [ Time Frame: From Week 2 to Week12 ]
    Please note no patients were treated with any systemic glucocorticoids at randomization. Hence no results available
30. Proportion of Patients That Have Decreased the Glucocorticoid Dose With at Least 50% From Baseline. [ Time Frame: From Week 2 to Week12 ]
    Please note no patients were treated with any systemic glucocorticoids at randomization. Hence no results available
31. Percentage Decrease of the Glucocorticoid Dose From Baseline. [ Time Frame: From Day 1 to Week12 ]
    Please note no patients were treated with any systemic glucocorticoids at randomization. Hence no results available
32. Proportion of Patients With at Least One Adverse Event. [ Time Frame: From Day 1 to Week 16 ]
    All adverse events collected from start of study treatment up to 28 days after stopping study treatment.
33. Proportion of Patients With at Least One Serious Adverse Event Including Death. [ Time Frame: From Informed consent to Week 16 ]
    Serious adverse events (SAEs) will be collected from informed consent up to 28 days after stopping study treatment.
34. Proportion of Patients With Macrophage Activation Syndrome (MAS). [ Time Frame: From Day 1 to Week 16 ]
    Proportion of patients with Macrophage Activation Syndrome (MAS).
35. Proportion of Patients With Antidrug Antibodies (ADA) Against Anakinra. [ Time Frame: Week 2 ]
    Proportion of patients with antidrug antibodies (ADA) against anakinra.
36. Proportion of Patients With Neutralizing Antibodies. [ Time Frame: Week 2 ]
    Confirmed ADA positive samples will be analyzed for the presence of neutralizing antibodies.
37. Anakinra Serum Pre-dose Concentrations. [ Time Frame: Week 2 ]
    Week 2 reported here.
38. Anakinra Serum Pharmacokinetic Parameters: Cmax, [ Time Frame: Week 12 ]
    PK parameters only available for 2 patients.
39. Anakinra Serum Pharmacokinetic Parameters, Tmax and T½ [ Time Frame: Week 12 ]
    PK parameters only available for 2 patients
40. Anakinra Serum Pharmacokinetic Parameter: AUC 0-24 h [ Time Frame: Week 12 ]
    PK parameters only available for 2 patients
41. Anakinra Serum Pharmacokinetic Parameter: CL/F [ Time Frame: Week 12 ]
    Pharmacokinetic parameters only available for 2 patients
42. Anakinra Serum Pharmacokinetic Parameter: Vd/F [ Time Frame: Week 12 ]
    PK parameters only available for 2 patients
43. Change From Baseline in JADAS27. [ Time Frame: Week 2 ]

    Juvenile Arthritis Disease Activity Score (JADAS) includes 4 measures: physician global assessment of disease activity, patient or parent global assessment of overall well-being, 27 active joint count, and CRP. The JADAS27 includes the 27 joints. JADAS27 is calculated as the sum of its four components, physician global assessment of disease activity converted to cm from the VAS (0=no activity, 10=maximum activity); patient global assessment of well-being converted to cm from the VAS (0=very well, 10=very poor); active joint count (0-27); and CRP. Prior to calculation CRP is truncated to a 0 - 10 scale according to the following formula: (CRP (mg/l) -10)/10. Before calculation, CRP values <10 mg/l are converted to 10 and CRP values >110 mg/l are converted to 110. The JADAS27 tool yields a global score of 0-57.

    Only results from Week 2 reported here.

44. Number of Days Off School or Work Due to Still's Disease. [ Time Frame: Week 2 ]
    Number of days off school or work due to Still's disease week 1-2.
45. Proportion of Patients With Inactive Disease. [ Time Frame: Week 12 ]
    Inactive disease is a composite of the following parameters: no joints with active arthritis, no fever, no rash, no serositis, no splenomegaly, no generalized lymphadenopathy attributable to Still's disease, CRP level within normal limits, physician's global assessment of disease activity score below 10 mm on a 100 mm VAS and a documented morning stiffness ≤15 minutes.
46. Change From Baseline in IL-6. [ Time Frame: Week 2 ]
    Only results from Week 2 reported here.
47. Change From Baseline in IL-18. [ Time Frame: Week 2 ]
    Only results from Week 2 reported here
48. Change From Baseline in Serum Calprotectin. [ Time Frame: Week 2 ]
    Change from baseline in serum calprotectin. Only results from Week 2 reported here
49. Change From Baseline in Neopterin. [ Time Frame: Week 2 ]
    Only results from Week 2 reported here

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama Birmingham

Birmingham, Alabama, United States, 35294

United States, California

Attune Health

Beverly Hills, California, United States, 90211

Rady Children's Hospital & Health Center

San Diego, California, United States, 92123

United States, Colorado

The Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Florida

University of Florida

Gainesville, Florida, United States, 32611

University of Miami

Miami, Florida, United States, 33124

Nicklaus Children's Hospital

Miami, Florida, United States, 33155

United States, Iowa

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States, 52242

United States, Kansas

Children's Mercy Hospital and Clinics

Kansas City, Kansas, United States, 67208

United States, Kentucky

University of Louisville School of Medicine Research Foundation

Louisville, Kentucky, United States, 40202

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02115

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

Saint Paul Rheumatology

Eagan, Minnesota, United States, 55121

University of Minnesota

Minneapolis, Minnesota, United States, 55454

United States, Missouri

Saint Louis University

Saint Louis, Missouri, United States, 63104

United States, New Jersey

Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

Institute for Rheumatic and Autoimmune Diseases

Summit, New Jersey, United States, 07901

United States, New York

Hospital for Special Surgery

New York, New York, United States, 10021

Columbia University Medical Center

New York, New York, United States, 10032

United States, North Carolina

UNC Hospitals

Chapel Hill, North Carolina, United States, 27514

Duke Children's Hospital and Health Center

Durham, North Carolina, United States, 27710

Wake Forest Baptist Brenner Medical Center

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

MetroHealth System

Cleveland, Ohio, United States, 44109

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Pennsylvania

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

Monroe Carell Jr. Children's Hospital at Vanderbilt

Nashville, Tennessee, United States, 37232

United States, Texas

Baylor Research Institute

Dallas, Texas, United States, 75204

Univ of TX Southwestern Medical Center Dallas - Texas Scottish Rite Hospital for Children

Dallas, Texas, United States, 75219

Texas Children's Hospital

Houston, Texas, United States, 77030

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States, 78229

United States, Utah

University of Utah Hospitals and Clinics

Salt Lake City, Utah, United States, 84113

United States, Vermont

University of Vermont Medical Center

Burlington, Vermont, United States, 05401

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

United States, Washington

University of Washington

Seattle, Washington, United States, 98195

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Canada

University of Calgary - Alberta Children's Hospital

Calgary, Canada

University of Calgary

Calgary, Canada

The Hospital for Sick Children

Toronto, Canada

Sponsors and Collaborators

Swedish Orphan Biovitrum

Investigators

• Study Director: Sven Ohlman, MD PhD; Swedish Orphan Biovitrum

  Study Documents (Full-Text)

Documents provided by Swedish Orphan Biovitrum:

Study Protocol  [PDF] July 3, 2018

Statistical Analysis Plan  [PDF] July 24, 2019

More Information

• Responsible Party: Swedish Orphan Biovitrum
• ClinicalTrials.gov Identifier: NCT03265132
• Other Study ID Numbers: Sobi.ANAKIN-301
• First Posted: August 29, 2017
• Results First Posted: April 28, 2020
• Last Update Posted: June 30, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Swedish Orphan Biovitrum:

Interleukin 1 receptor antagonist; IL-1 receptor antagonist; Kineret; anakinra; Adult-Onset Still's Disease; Systemic Juvenile Idiopathic Arthritis

Additional relevant MeSH terms:

Arthritis, Juvenile; Still's Disease, Adult-Onset; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Arthritis, Rheumatoid; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents