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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03265132
Recruitment Status : Terminated (Meeting enrolment target (81 pat) will not be feasible within reasonable time.)
First Posted : August 29, 2017
Results First Posted : February 28, 2020
Last Update Posted : April 28, 2020
Sponsor:
Information provided by (Responsible Party):
Swedish Orphan Biovitrum

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.

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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


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03265132


Locations
Show Show 39 study locations
Sponsors and Collaborators
Swedish Orphan Biovitrum
Investigators
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Study Director: Sven Ohlman, MD PhD Swedish Orphan Biovitrum
  Study Documents (Full-Text)

Documents provided by Swedish Orphan Biovitrum:
Statistical Analysis Plan  [PDF] July 24, 2019
Study Protocol  [PDF] July 3, 2018

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Responsible Party: Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier: NCT03265132    
Other Study ID Numbers: Sobi.ANAKIN-301
First Posted: August 29, 2017    Key Record Dates
Results First Posted: February 28, 2020
Last Update Posted: April 28, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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