臨床研究等提出・公開システム

A randomized, double-blind, placebo-controlled, multicenter, phase 3 efficacy and safety study of subcutaneous anakinra in Japanese patients with Still's disease (SJIA and AOSD)

Sobi.ANAKIN-303

15

Core phase: In terms of demographics, of the 15 patients included, 2 were male and 13 were female. The age at disease onset was less than 16 years (SJIA) in 5 patients (33.3%) and 16 years and older (AOSD) in 10 patients (66.7%). The anakinra arm included more SJIA patients (4 patients) than the placebo arm (1 patient). The median weight was 48.50 kg (range: 10.3 to 94.4 kg) in the anakinra arm and 53.30 kg (range: 12.5 to 89.2 kg) in the placebo arm. Eight patients (53.3%) were treated with glucocorticoids at inclusion, which comprised 4 patients (50.0%) in the anakinra arm and 4 patients (57.1%) in the placebo arm. Extension phase: The single patient who entered the extension phase was a 66-year-old woman with adult-onset Still's disease (AOSD)

Core phase: A total of 15 patients were randomized to study treatment and received study drug. During the RDB period, 8 patients received anakinra and 7 patients received placebo. Two patients in the placebo arm discontinued the RDB period due to withdrawal by the patient and rescue criteria met (1 patient each). Fourteen patients, including the patient who met rescue criteria in the RDB period, started the open-label treatment period. Five patients discontinued the study during the open-label treatment period due to AEs (3 patients) and lack of efficacy (2 patients). Of the 9 patients who completed the open-label treatment period in the core phase, 1 patient entered the extension phase. Eight patients entered the Safety Follow-up and completed the study without entering the extension phase. Extension phase: One patient entered the extension phase and completed the extension phase of the study.

Core phase: AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA).All 15 patients (100.0%) experienced at least 1 TEAE during the core phase. Most TEAE preferred terms were assessed as not related to study drug by the investigator, except injection site reactions. All injection site reactions were assessed as related to study drug by the investigators. Core phase: TEAEs reported in more than 1 patient during the core phase were injection site reaction (11 patients, 73.3%), COVID-19 and insomnia (4 patients, 26.7% each), nasopharyngitis, Still's disease and asteatosis (3 patients, 20.0% each), and vomiting, gastroenteritis, influenza, paronychia, dyslipidaemia, steroid diabetes and miliaria (2 patients, 13.3% each). There was no fatal TEAE during the core phase. There were 7 serious TEAEs in 6 patients during the core phase, 6 events in 5 patients during the open-label treatment period and 1 event in 1 patient during safety follow-up. There were 3 TEAEs (2 events of relapse of Still's disease and 1 event of haemophagocytic lymphohistiocytosis) leading to study drug withdrawal during the core phase. There was no adverse event of special interest (AESI) of drug reaction with eosinophilia and systemic symptoms (DRESS) or pulmonary events during the core phase. Extension phase: The patient experienced 1 TEAE of spinal osteoarthritis during the extension phase, which was non-serious, mild, and not related to the study drug. No serious TEAE, AESI, or TEAE leading to study drug withdrawal was reported during the extension phase.

Core phase: The primary endpoint was American College of Rheumatology (ACR) 30 response at Week 2 visit with absence of fever attributable to the disease during the 7 days preceding Week 2 visit. The primary endpoint was analyzed using a Fisher's exact test. Anakinra demonstrated superiority to placebo in achieving the primary endpoint. A total of 7 patients (87.5%) in the anakinra arm and 1 patient (14.3%) in the placebo arm achieved ACR30 response with absence of fever at Week 2. The treatment difference was 73.2% (90% CI: 29.3, 94.8) and the corresponding p-value was 0.009, confirming the statistically significant difference when comparing the anakinra arm to the placebo arm. Anakinra demonstrated superiority over placebo in terms of absence of fever, absence of rash, ACR50 and ACR70 responses with absence of fever at Week 2. Anakinra had a rapid onset of action, with superiority over placebo observed as early as Week 1 in ACR30 response. In addition, the efficacy of anakinra persisted through Week 54 for most patients, including the patients initially randomized to the placebo arm who switched to anakinra treatment at Week 2. Extension phase: The patient had a sustained response in ACR30 with absence of fever at Week 54, 67, and 80 visits. The patient achieved inactive disease at both Week 67 and 80 visits.

Anakinra demonstrated clinically meaningful and statistically significant superiority to placebo for the primary endpoint of ACR30 response with absence of fever at Week 2. Safety results were in line with the known safety and tolerability profile of anakinra and no new or notable safety concern was reported. Extension phase findings in 1 Japanese patient were consistent with the core phase, with sustained efficacy through Week 84 and no new safety concerns.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031220222

Takeshi KUROSAWA

CMIC Co., Ltd.

1-1-1, Minato-ku, Shibaura, Tokyo

ClinicalTrialInformation@cmic.co.jp

CMIC Co., Ltd

CMIC Co., Ltd.

1-1-1, Minato-ku, Shibaura, Tokyo

+81-3-6779-8000

ClinicalTrialInformation@cmic.co.jp

Complete

July. 01, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Male and female patients, 8 months of age or older with a body weight >_10 kg
2. Diagnosis of Still's disease.
3. If < 16 years of age at disease onset, the diagnosis is made according to adapted ILAR criteria i.e., CARRA criteria for SJIA. If >_ 16 years of age at disease onset, the diagnosis is made according to Yamaguchi criteria for AOSD.
4. Active disease confirmed by the following three signs and symptoms. a. Active arthritis in >_ 1 joint. b. CRP > 30 mg/L. c. At least one fever episode (>_ 38.0 degree Celsius) attributable to the disease within one week before enrollment.
5. The result of tuberculosis test within 8 weeks prior to enrollment is negative.

1. Previous or current treatment with anakinra, or any other Interleukin-1 (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 5h). Patients who have discontinued canakinumab because of insufficient effect or refractory disease are not allowed to be enrolled in the study.
2. Use of the following therapies prior to enrollment. a. Narcotic analgesics within 24 hours prior to enrollment. b. Diaminodiphenyl sulfone within 1 week prior to enrollment or etanercept within 2 weeks prior to enrollment. c. Intraarticular, intramuscular, or intravenous administration of glucocorticoids within 72h (3 days) prior to enrollment, or intravenous immunoglobulin within 4 weeks prior to enrollment. d. Intravenous immunoglobulin with proven Still's disease modifying effect, leflunomide, infliximab, or adalimumab within 8 weeks prior to enrollment. e. Thalidomide within 72h (3 days) prior to enrollment, cyclosporine within 5 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) week prior to enrollment, cyclophosphamide within 96h (4 days) prior to enrollment, chlorambucil (not approved in Japan) within 48h (2 days) prior to enrollment, or any other immunosuppressant within 12 weeks prior to enrollment. f. Tocilizumab within 4 weeks prior to enrollment or any other immunomodulatory medication within 4 half-lives prior to enrollment. g. Rituximab within 13 weeks prior to enrollment. h. Canakinumab within 130 days prior to enrollment.
3. Live vaccines within 4 weeks prior to enrollment.
4. Known presence or suspicion of active, chronic, or recurrent bacterial, fungal, or viral infections, including but not limited to tuberculosis, HIV infection, Covid-19 infection, or hepatitis B or C infection at baseline. Patients with acute or chronic HBV (i.e., with positive HBsAg, except if a documented history of vaccination), or at risk of HBV reactivation (i.e., with negative HBsAg AND positive anti-HBc) will be excluded.
5. Clinical evidence of liver disease or liver injury as indicated by presence of abnormal liver tests. a. AST or ALT > 5 x upper limit of normal (ULN), or b. AST or ALT > 3 x ULN accompanied by elevated bilirubin > 2 x ULN.
6. Presence of severe chronic kidney disease (CKD) grades 4 and 5 (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2).
7. Presence of neutropenia (absolute neutrophil count [ANC] < 1.5 x 10^9/L).
8. Presence of thrombocytopenia (platelets count < 100 x 10^9/L).
9. Presence or suspicion of MAS at baseline.
10. History or diagnosis of MAS within the last 4 weeks prior to enrollment.

Both

Systemic juvenile idiopathic arthritis(SJIA)., adult-onset Still's disease (AOSD)

- Pediatric and adult patients weighing >_ 50kg:Anakinra 100mg/day
- Pediatric and adult patients weighing < 50 kg:should be dosed by body weight with a starting dose of 2mg/kg/day of anakinra (with a maximum of 100mg/day)

ACR30 response at Week 2 with absence of fever attributable to the disease during the 7 days preceding Week 2 visit.

+81-44-977-8111

June. 15, 2022

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