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

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ClinicalTrials.gov Identifier: NCT03265132
Recruitment Status : Recruiting
First Posted : August 29, 2017
Last Update Posted : October 31, 2018
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 early termination 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 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
Estimated Primary Completion Date : September 15, 2019
Estimated Study Completion Date : December 31, 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 movement.
    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: Day 1, Week 1 and 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.

  9. Proportion of responders in Patient/parent global assessment of overall well-being. [ Time Frame: Day 1, Week 1 and 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.

  10. Proportion of responders in Number of joints with active arthritis. [ Time Frame: Day 1, Week 1 and Week 2 ]
    Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.

  11. Proportion of responders in Number of joints with limitation of movement. [ Time Frame: Day 1, Week 1 and Week 2 ]
    Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.

  12. Proportion of responders in Assessment of physical function (CHAQ/SHAQ). [ Time Frame: Day 1, Week 1 and Week 2 ]
    Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.

  13. Proportion of responders in CRP (mg/L). [ Time Frame: Day 1, Week 1 and Week 2 ]
    Response is defined as an improvement of ≥ 30%, 50%, 70% and 90% from baseline.

  14. Proportion of patients with absence of fever during the 7 days preceding Week 2. [ Time Frame: Week 2 ]
  15. Proportion of patients with absence of fever during the 24 hours preceding week 1. [ Time Frame: Week 1 ]
  16. Change from baseline in Physician global assessment of disease activity at Week 1. [ Time Frame: Day 1 and 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 ]
  18. Change from baseline in CRP. [ Time Frame: Day 1 and Week 1 ]
  19. Proportion of patients with sustained ACR30, ACR50, ACR70 and ACR90 response. [ Time Frame: Week 2, Week 4, Week 8 and Week 12 ]
    Proportion of patients that still meet the corresponding week 2 response of ACR, with absence of fever in the preceding 7 days.

  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 ]
    Proportion of patients that still meet the corresponding week 2 response of ACR, with absence of fever in the preceding 7 days, despite glucocorticoid tapering.

  21. Proportion of patients with ACR30, ACR50, ACR70 and ACR90 response. [ Time Frame: Week 4, Week 8 and Week 12 ]
  22. Proportion of patients with absence of rash. [ Time Frame: Week 1, Week 2, Week 4, Week 8 and Week 12 ]
    Absence of rash is evaluated 24 hours preceding Week 1 and 7 days preceding Week 2, Week 4, Week 8 and Week 12.

  23. Change from baseline in CRP. [ Time Frame: Day 1, Week 1, Week 2, Week 4, Week 8 and Week 12 ]
  24. Change from baseline in Hemoglobin (Hb). [ Time Frame: Day 1, Week 1, Week 2, Week 4, Week 8 and Week 12 ]
  25. Change from baseline in platelet count. [ Time Frame: Day 1, Week 1, Week 2, Week 4, Week 8 and Week 12 ]
  26. Change from baseline in ferritin. [ Time Frame: Day 1, Week 1, Week 2, Week 4, Week 8 and Week 12 ]
  27. Change from baseline in patient/parent global assessment of disease related pain. [ Time Frame: Day 1, Week 1, Week 2, Week 4, Week 8 and Week 12 ]
    Assessed on a VAS from no pain (0 mm) to very severe pain (100 mm).

  28. Time to early termination. [ Time Frame: From Day 1 to Week12 ]
    Early termination is defined as an escape or withdrawal due to any reason.

  29. Time to early termination due to lack of efficacy or progressive disease. [ Time Frame: From Day 1 to Week12 ]
    Early termination is defined as an escape or withdrawal due to lack of efficacy or progressive disease.

  30. Proportion of patients who have initiated tapering of glucocorticoids. [ Time Frame: From Week 2 to Week12 ]
  31. Proportion of patients that have decreased the glucocorticoid dose with at least 50% from baseline. [ Time Frame: From Week 2 to Week12 ]
  32. Percentage decrease of the glucocorticoid dose from baseline. [ Time Frame: From Day 1 to Week12 ]
  33. Proportion of patients with at least one adverse event. [ Time Frame: From Day 1 to Week 16 ]
    All adverse events to be recorded Day 1 until Week 16.

  34. 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 until Week 16.

  35. Proportion of patients with Macrophage Activation Syndrome (MAS). [ Time Frame: From Day 1 to Week 16 ]
  36. Proportion of patients with antidrug antibodies (ADA) against anakinra. [ Time Frame: Week 1, Week 2, Week 4, Week 8 and Week 12 ]
  37. Proportion of patients with neutralizing antibodies. [ Time Frame: Week 1, Week 2, Week 4, Week 8 and Week 12 ]
    Confirmed ADA positive samples will be analyzed for the presence of neutralizing antibodies.

  38. Anakinra serum pre-dose concentrations. [ Time Frame: Week 1, Week 2, Week 4, Week 8 and Week 12 ]
  39. Anakinra serum pharmacokinetic parameters, Cmax, tmax, AUClast, AUC0-24h, Vd/F, t½, CL/F. [ Time Frame: Week 12 ]
  40. Number of days off school or work due to Still's disease. [ Time Frame: Week 1, Week 2, Week 4, Week 8 and Week 12 ]
  41. 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.

  42. Change from baseline in JADAS27. [ Time Frame: Week 2 and Week 12 ]
    The JADAS27 includes 4 measures: physician global assessment of disease activity, patient or parent global assessment of overall well-being, 27 active joint count, and CRP.

  43. Change from baseline in IL-6. [ Time Frame: Day 1, Week 1, Week 2, Week 12 ]
  44. Change from baseline in IL-18. [ Time Frame: Day 1, Week 1, Week 2, Week 12 ]
  45. Change from baseline in serum calprotectin. [ Time Frame: Day 1, Week 1, Week 2 and Week 12 ]
  46. Change from baseline in neopterin. [ Time Frame: Day 1, Week 1, Week 2 and Week 12 ]


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.


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.
    • Tocilizumab, dapsone or mycophenolate mofetil within 3 weeks prior to randomization.
    • Etanercept, leflunomide, thalidomide, or cyclosporine or intraarticular, intramuscular or intravenous administration of glucocorticoids within 4 weeks prior to randomization.
    • Intravenous immunoglobulin (i.v. Ig) or adalimumab within 8 weeks prior to randomization.
    • Infliximab, 6-mercaptopurine, azathioprine, cyclophosphamide or chlorambucil within 12 weeks 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. Current signs and symptoms of MAS as judged by the investigator.
  13. A diagnosis of MAS within the last 2 months prior to randomization.
  14. History of malignancy.
  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


Contacts
Contact: Bent Winding, MD +46 8 697 2000 anaSTILLs@sobi.com
Contact: Anna Olsson +46 8 697 2000 anaSTILLs@sobi.com

  Show 37 Study Locations
Sponsors and Collaborators
Swedish Orphan Biovitrum
Investigators
Study Director: Bent Winding, MD Swedish Orphan Biovitrum

Responsible Party: Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier: NCT03265132     History of Changes
Other Study ID Numbers: Sobi.ANAKIN-301
First Posted: August 29, 2017    Key Record Dates
Last Update Posted: October 31, 2018
Last Verified: September 2018
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