A multicenter randomized investigator-initiated clinical study to evaluate efficacy and safety of Anakinra in combination with Intravenous Immunoglobulin (IVIG) therapy in patients with Kawasaki Disease refractory to IVIG therapy

JRCT ID: jRCT2031240646

Registered date:30/01/2025

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Kawasaki Disease
• Date of first enrollment: 02/01/2025
• Target sample size: 70
• Study type: Interventional

Intervention(s)

A total of 70 patients will be randomized in a 1:1 ratio; 35 patients and 35 patients to IVIG monotherapy and anakinra in combination with IVIG therapy groups, respectively. IVIG is administered at a dose of 2g/kg by intravenous infusion to all patients. Anakinra is administered once a day by subcutaneous injection at the following dose. The administration is continued for up to 14 days (14 times) every 24 hours until the criteria for discontinuing Anakinra administration are met.
<patients who are at least 8 months old and weigh at least 10 kg>
Start with 2 mg/kg/day (once a day). From the second dose onwards, increase the dose by 2 mg/kg/day, if the axillary temperature is 37.5 degrees Celsius or higher at 24 hours after each dose. Dose may be increased up to a maximum of 6 mg/kg/day.
<patients who are less than 8 months old or weigh less than 10 kg>
Start with 2 mg/kg/day (once a day). From the second dose onwards, increase the dose by 2 mg/kg/day, if the axillary temperature is 37.5 degrees Celsius or higher at 24 hours after administration. The dose may be increased by 2 mg/kg every 24 hours up to a maximum of 8 mg/kg/day.

Outcome(s)

• Primary Outcome: Antipyretic rate within 48 hours after administration of the investigational product

Secondary Outcome

(1) Antipyretic rate within 48 hours after administration of maximum dosage of the investigational product
(2) Percentage of Coronary Lesion complication from the day of the first administration to Day 56
(3 )Coronary Z-score
(4) Antipyretic rate within 24 and 72 hours after administration of the investigational product
(5) Acute treatment efficacy rate
(6) Duration of fever after administration of the investigational product
(7) Presence of major acute symptoms
(8) Changes in white blood cell count, neutrophil count, platelet count, albumin, and CRP value
(9) Administration of rescue therapy
(10) Recurrence rate

Key inclusion & exclusion criteria

• Age minimum: >= 3month old
• Age maximum: <= 10age old
• Gender: Both

Include criteria

<Provisional registration>
Patients who meet all the following inclusion criteria are eligible for enrolment:
(1) Patients who have been diagnosed with Kawasaki Disease (limited to the newly onset) based on the Japanese Diagnostic Guidelines (6th Revised Edition) on the Diagnosis of Kawasaki Disease prepared by the Research Team on Refractory Vasculitis of the MHLW who exhibit five or more of the six major symptoms of Kawasaki Disease, including fiver.
(2) Patients with Kawasaki Disease diagnosed within the 7th day of illness (the day of onset of fever is defined as the first day of illness). However, if initial treatment with IVIG (limited to a single dose) has already been administered, up to the 9th day of illness is allowed.
(3) Patients aged 3 months or older and 10 years or younger at the time of enrollment. However, patients who are less than 8 months old or weigh less than 10 kg , enrollment in this trial will begin after safety has been confirmed in 10 patients aged 8 months or older and weighing 10 kg or more.
(4) Patients whose parent(s)/legal guardian have given written consent to participate in this clinical trial.

<Definitive Registration>
Patients who meet all the following inclusion criteria are eligible for enrolment:
(1) Patients who are considered refractory to IVIG therapy after the initial IVIG monotherapy (single dose only).
1) Patients with axillary temperature of 37.5 degrees Celsius or higher at 48 hours after the start of the initial IVIG monotherapy.
2) Patients who develop a recurrent fever of 37.5 degrees Celsius or higher after the fever is resolved by the initial IVIG monotherapy.
(2) Patients with axillary temperature of 37.5 degrees Celsius or higher at the time of enrollment.
(3) Patients who can start administering investigational product by the 9th day illness (the day of onset of fever is defined as the first day of illness).
(4) Patients who can, in principle, be hospitalized for clinical trial evaluation and observation from the start of administration of the investigational product up to 56th day. If the investigator confirms the acute-phase inflammation of Kawasaki Disease has subsided (major symptoms of Kawasaki Disease have disappeared and CRP has negative negative) and determines that hospitalization for observation is no longer necessary, the patient may be discharged and evaluation and observation will be permitted on an outpatient basis.

Exclude criteria

<Provisional registration>
Patients who meet any one of the following exclusion criteria will be excluded from the study.
(1) Patients with abnormal findings in the coronary arteries detected by cardiac ultrasound within 48 hours prior to provisional registration. However, only increased brightness will not be excluded.
(2) Patients who have received IVIG treatment two or more times for the treatment of Kawasaki Disease.
(3) Patients who have received prednisolone, cyclosporin A, steroid pulse therapy, or urinastatin for the treatment of Kawasaki Disease. Treatment with antiplatelet and anticoagulants such as aspirin, as described in the "Guideline for the Treatment of Acute Stage of Kawasaki Disease 2020" is allowed.
(4) Patients who received 1 mg/kg or more of corticosteroids in prednisolone equivalents within 4 weeks prior to provisional registration.
(5) Patients with a history of severe infections (active hepatitis, pneumonia, pyelonephritis, etc.) requiring hospitalization within 6 months prior to provisional registration.
(6) Patients with a history of opportunistic infections (cytomegalovirus infection, systemic fungal infection, Pneumocystis pneumonia, atypical mycobacterial infection, etc.) within 6 months prior to provisional registration.
(7) Patients diagnosed with active tuberculosis.
(8) Patients with a history of tuberculosis or suspected of having tuberculosis.
(9) Patients diagnosed with active hepatitis B or active hepatitis C or patients confirmed to be hepatitis B virus carriers.
(10) Patients confirmed to be infected with HIV.
(11) Patients with a history of multisystem inflammatory syndrome in children (MIS-C).
(12) Patients diagnosed with chronic infections (chronic renal infection, chronic
respiratory infection with bronchiectasis, chronic sinusitis, etc.).
(13) Patients diagnosed with severe chronic kidney disease (grade 4 or 5).
(14) Patients diagnosed with or suspected of having lymphoproliferative disease or splenomegaly, or patients with a history of lymphoproliferative disease.
(15) Patients diagnosed to have malignant tumors or patients who have had a malignant tumor within 5 years prior to provisional registration.
(16) Patients diagnosed with serious diseases such as chromosomal abnormalities, congenital heart disease, immunodeficiency, autoimmune disease, or autoinflammatory disease.
(17) Patients who are hypersensitivity to E. coli, anakinra, or anakinra-containing products.
(18) Patients who are otherwise deemed by the investigator (M.D.) to be ineligible for this clinical trial.

<Definitive registration>
Patients who meet any one of the following exclusion criteria will be excluded from the study.
(1) Patients with abnormal findings in the coronary arteries detected by cardiac ultrasound at the time of Definitive registration. However, only increased brightness will not be excluded.
(2) Patients who meet any one of the following criteria at the time of Definitive registration.
1) WBC count: < 3500 x 10^6 /L
2) Neutrophils: < 1500 x 10^6 /L
3) Lymph count: < 500 x 10^6 /L
4) Platelet count: < 10 x 10^4 /uL
5) HBs antigen or HBs antibody*: positive
6) HCV antibody: positive
7) HIV antibody: positive
8) AST or ALT: >= 500IU/L
* Patients with an evident history of HB vaccination will not be excluded even if HBs antibody is positive.
(3) Patients who meet any of the exclusion criteria at the time of provisional enrollment during the observation period.
(4) Patients who are otherwise deemed by the investigator (M.D.) to be ineligible for this clinical trial.

Related Information

• Primary Sponsor: Mori Masaaki