Business decision

The purpose of this study is to evaluate the efficacy and safety of anakinra in Chinese patients with Systemic Juvenile Idiopathic Arthritis (SJIA) and Adult-Onset Still's Disease (AOSD).The study consists of up to four weeks screening, to see if a patient is suitable to the study, 48 weeks of treatment with anakinra and 4 weeks safety follow up after last dose of anakinra. In total 60 patients(expected allocation is 30 SJIA and 30 AOSD), male or female patients, 8 months of age or older with a body weight ≥ 10 kg, will be enrolled to the study.

This is a prospective, open-label, multicenter, efficacy and safety study of anakinra in Chinese patients with Still's disease (SJIA and AOSD). The study consists of a 48-Week treatment period with anakinra followed by a 4-Week period to evaluate safety of anakinra after the last dose of IMP. The study is divided into three parts: screening, treatment period, and safety follow-up, and will be performed in China.

The study will recruit a total of 60 patients (expected allocation is 30 SJIA and 30 AOSD).

The patient will enter screening after informed consent is obtained and will undergo screening assessments to confirm eligibility. Duration of the screening period will be kept as short as possible and should not exceed 4 weeks.

Patients will be assigned to study drug after they have met all of the inclusion criteria and none of the exclusion criteria. Patients will receive treatment with anakinra for 48 weeks.

After the last dose of anakinra at Week 48, the safety will continue to be evaluated at a Safety Follow-up visit i.e., at Week 52.

14 visits and 1 telephone contact are scheduled during the study as follows: Screening visit (Visit 0), Day 1 (Baseline visit), Day 4Tel, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48 (last dose of anakinra), and Week 52 (end of study).

All patients included in the study will be carefully monitored by the investigator. Patients can withdraw from the study drug at any time for any reason. If a patient permanently discontinues study drug, at any time during the study prior to week 48, a Study Drug Discontinuation visit should be performed, if possible before standard of care treatment is initiated. If clinically not feasible, the Study Drug Discontinuation visit should be performed as soon as possible.

4 weeks after discontinuation of study drug, a subsequent Safety Follow-up visit will be performed, according to the assessments described for the Week 52 visit, after which the patient will be withdrawn from the study.

Inclusion Criteria:

1. Informed consent form signed by the patient or a legal guardian representative.

2. Male or female patients, 8 months of age or older with a body weight ≥ 10 kg.

3. Diagnosis of Still's disease.

4. Criteria for diagnosis of Still's disease:

   1. If < 16 years of age at disease onset, the diagnosis is made according to international league for associations of rheumatology (ILAR) criteria for SJIA.
   2. If ≥ 16 years of age at disease onset, the diagnosis is made according to Yamaguchi criteria for AOSD.

5. Active disease confirmed by the following three signs and symptoms:

   1. Active arthritis in ≥ 1 joint.
   2. CRP > 30 mg/L.
   3. At least one fever episode attributable to the disease within one week before enrollment.

   Definition of fever: Body temperature ≥ 38.0 °C attributable to the disease

6. Background treatment with stable dose of ≤ 1 mg/kg/d (Max 60 mg/d) of oral prednisolone or equivalent for at least 3 days prior to enrollment is permitted.

7. If currently on methotrexate (MTX) treatment, the dose must be stable for at least 4 weeks prior to enrollment. Maximum dose allowed is 20 mg/m2/week. If the patient discontinued MTX prior to enrollment, the discontinuation is required to be at least 4 weeks prior to enrollment.

8. Female patients of childbearing potential and male patient with female partner of childbearing potential must use an effective method of contraception during the study (abstinence being a possible option). A negative pregnancy test prior to enrollment is also required.

9. In case of use of oral contraception, women should have been stable on the same brand (or generic equivalent) for a minimum of 3 months before taking study treatment.

10. Negative tuberculosis screening confirmed at the Screening visit by the Mantoux Tuberculin skin test (TST) using purified protein derivative (PPD), or by Interferon-Gamma-Release Assays (IGRAs) e.g., QuantiFERON® TB Gold Plus (QFT-Plus) or T¬Spot-® (TB Test) within 8 weeks prior to enrollment. Negative results must be complemented by the medical history, physical examination, and Chest X-Ray. Patients presenting positive TST or IGRA, with or without active or clinical suspicion of latent tuberculosis, are not eligible to enter the study.

Previously vaccinated for Tuberculosis patients: IGRA positive patients are not eligible to enter the Study; TST positive patients with an induration of 15 mm and more are also not eligible to enter the study, TST positive patients (with an induration less than 15 mm) are also not eligible to enter the study, unless an IGRA test is subsequently performed and provides a negative result.

Exclusion Criteria:

1. Previous enrollment to this study

2. Participation in another clinical interventional study 30 days prior to enrollment.

3. Treatment with an investigational drug within 5 half-lives prior to enrollment.

4. Previous or current treatment with anakinra, or any other IL-1 inhibitor, except for canakinumab. Previous treatment with canakinumab is allowed if canakinumab was discontinued for reasons other than lack of efficacy and after a washout period of minimum 130 days (Refer to Exclusion Criteria 5). Patients who have discontinued canakinumab because of insufficient effect, refractory disease or toxicities are not allowed to be enrolled in the study.

5. Use of the following therapies prior to enrollment:

   • Narcotic analgesics within 24 hours prior to enrollment.
   • Dapsone within 1 week prior to enrollment or etanercept within 2 weeks prior to enrollment.
   • Intraarticular, intramuscular, or intravenous administration of glucocorticoids within 72h (3 days) prior to enrollment, or intravenous immunoglobulin within 4 weeks prior to enrollment.
   • Leflunomide, infliximab or adalimumab within 8 weeks prior to enrollment.
   • Thalidomide within 72h (3 days) prior to enrollment, cyclosporine within 5 weeks prior to enrollment, tacrolimus hydrate within 2 weeks prior to enrollment, mycophenolate mofetil within 1 week prior to enrollment, 6-mercaptopurine within 48h (2 days) prior to enrollment, azathioprine within 72h (3 days) prior to enrollment, cyclophosphamide within 96h (4 days) prior to enrollment, chlorambucil within 48h (2 days) prior to enrollment, Janus kinase (JAK) inhibitors within 5 half-lives prior to enrollment, or any other immunosuppressant within 12 weeks prior to enrollment.
   • Tocilizumab within 4 weeks prior to enrollment or any other immunomodulatory medication within 5 half-lives prior to enrollment.
   • Rituximab within 26 weeks prior to enrollment.
   • Canakinumab within 130 days prior to enrollment.

6. Live vaccines within 4 weeks prior to enrollment.

7. Known presence or suspicion of active, chronic or recurrent bacterial, fungal or viral infections, including but not limited to tuberculosis, human immunodeficiency virus (HIV) infection, coronavirus disease (Covid-19) infection, hepatitis B or C infection at baseline.

8. Clinical evidence of liver disease or liver injury as indicated by presence of abnormal liver tests:

   1. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN), or
   2. AST or ALT > 3 x ULN and elevated bilirubin > 2 x ULN.

9. Presence of severe chronic kidney disease (CKD) stages 4 and 5 (estimated creatinine clearance < 30 mL/min/1.73m2).

10. Presence of neutropenia (ANC < 1.5 x 109/L).

11. Presence of thrombocytopenia (platelets count < 100 x 109/L).

12. Presence or suspicion of macrophage activation syndrome (MAS) at baseline.

13. A diagnosis of macrophage activation syndrome (MAS) within the last 2 months prior to enrollment.

14. History of malignancy within 5 years prior to enrollment. Exceptions are basal cell skin cancer, carcinoma-in-situ of the cervix, or low-risk prostate cancer after curative therapy.

15. Known hypersensitivity to E. Coli-derived proteins, or any components of anakinra.

16. Pregnant or lactating women.

17. Foreseeable inability to cooperate with given instructions or study procedures.

18. Presence of any medical, 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 make the patient not appropriate for inclusion to the study and treatment with IMP.