Efficacy and Safety of Immunoglobulin Plus Firsekibart in Patients With Kawasaki Disease

This is a two-center, open-label, randomized controlled exploratory clinical trial in China. The investigators will enroll KD pediatric patients within 10 days of illness onset. Participants will be randomly assigned in a 1:2 ratio to the experimental group (receiving 3 mg/kg Firsekibart plus 2 g/kg IVIG and 30 mg/kg aspirin) or the control group (receiving 2 g/kg IVIG and 30 mg/kg aspirin). Baseline characteristics of each participant will be collected, including sex, age at onset, height, body weight, subtype of KD, fever days before initial IVIG, echocardiographic findings at enrolment, and a series of pre-IVIG laboratory tests. Two-dimensional echocardiography will be performed at admission, 2 weeks, 1 month, 3 months, and 6 months after illness onset to assess the coronary artery lesions. This study aims to determine the therapeutic potential of standard therapy combined with Firsekibart in the acute phase of KD for reducing the incidence of coronary artery lesions (CAL) , decreasing IVIG resistance, and improving inflammation control.

• IVIG (Drug), also known as Intravenous Immunoglobulins, Human: IVIG 2g/kg once, given over 8 to 12 hours, with the maximum dose of 60g.
• Aspirin (Drug), also known as Acetylsalicylic acid: Aspirin 30 mg/kg in oral per day (given in 3 divided doses), then 3 to 5 mg/kg per day when fever subsides for 3 days and CRP is normal. Aspirin will be continued for at least 6 weeks after onset of illness.
• Firsekibart (Drug), also known as Interleukin (IL)-1β receptor antagonist: Firsekibart 3 mg/kg by a single subcutaneous injection prior to IVIG infusion. After a 30-minute observation period confirming the absence of adverse reactions, the IVIG infusion is initiated.

Primary outcomes

• Occurrence of coronary artery lesions (CAL) at one month of illness [from admission to 1 month of illness onset]: Two-dimensional echocardiography will be performed to evaluate CAL at 1 month of illness. Measurements for each patient include the diameter of the left main coronary artery (LMCA), the left anterior descending artery (LAD), the left circumflex coronary artery (LCX), and the proximal and middle segments of the right coronary artery (RCA). Z score of each coronary artery will be calculated (Journal of the American Society of Echocardiography, 2011, 24(1).). CAL is defined as z≥2.5 of any coronary artery of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.
• Occurrence of the need for rescue therapy [from admission to discharge (about 2 weeks of illness onset)]: Temperature will be measured every 6 hours a day during hospitalization. Participants who have recurrent or persistent fever (temperature ≥38°C) after 36 hours of completion of initial IVIG infusion will be given rescue therapy.

Secondary outcomes

• Duration of fever (hours) after initiation of initial IVIG infusion [from initiation of the initial IVIG infusion to the first recorded afebrile status (up to 60 hours after the infusion of IVIG)]: Temperature will be measured every 6 hours a day during hospitalization. Participants with temperature <37.5℃ for more than 24 hours are considered afebrile. Record the time of the initiation of IVIG infusion and the time of the body temperature first becoming normal.
• Change in serum C-reactive protein (CRP) concentration [from admission to 1 month of illness onset]: Serum CRP levels will be measured at three time points: at enrolment, 72 hours after completion of the initial IVIG infusion, and 1 month of illness onset.
• Change in Serum Amyloid A (SAA) concentration [from admission to 1 month of illness onset]: SAA levels will be measured at three time points: at enrolment, 72 hours after completion of the initial IVIG infusion, and 1 month of illness onset.
• Change in serum interleukin (IL)-1β concentration [from admission to 72 hours after completion of the initial IVIG infusion]: Serum IL-1β levels will be measured at two time points: at enrolment, 72 hours after completion of the initial IVIG infusion.
• Occurrence of coronary artery lesions (CAL) at 2 weeks of illness [from admission to 2 weeks of illness onset]: Two-dimensional echocardiography will be performed to evaluate CAL at 2 weeks of illness. The measurement of each patient included the diameter of the left main coronary artery (LMCA), the left anterior descending artery (LAD), the left circumflex coronary artery (LCX), and the proximal and middle segments of the right coronary artery (RCA). Z score of each coronary artery will be calculated (Journal of the American Society of Echocardiography, 2011, 24(1).). CAL is defined as z≥2.5 of any coronary artery of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.
• Occurrence of coronary artery lesions (CAL) at 3 months of illness [from admission to 3 months of illness onset]: Two-dimensional echocardiography will be performed to evaluate CAL at 3 months of illness. Measurements for each patient include the diameter of the left main coronary artery (LMCA), the left anterior descending artery (LAD), the left circumflex coronary artery (LCX), and the proximal and middle segments of the right coronary artery (RCA). Z score of each coronary artery will be calculated (Journal of the American Society of Echocardiography, 2011, 24(1).). CAL is defined as z≥2.5 of any coronary artery of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.
• Occurrence of medium-to-giant coronary artery aneurysms (CAAs) [from admission to 6 months of illness onset]: This is a repeatedly measured binary variable. CAL classification is based on the maximum Z score according to the 2024 American Heart Association guideline. Medium CAAs is defined as a maximum Z score ≥5 to <10, and all internal diameters <8 mm; large or giant CAAs defined as a maximum Z score ≥10, or any internal diameter ≥8 mm.
• Changes in z scores of LAD [from admission to 6 months of illness onset]: This is a repeated measurement. The internal diameter of LAD will be measured by echocardiography at five time points: at enrolment, at 2 weeks, 1 month, 3 months and 6 months of illness. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1).).
• Changes in z scores of LMCA [from admission to 6 months of illness onset]: This is a repeated measurement. The internal diameter of LMCA will be measured by echocardiography at five time points: at enrolment, at 2 weeks, 1 month, 3 months and 6 months of illness. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1).).
• Changes in z scores of LCX [from admission to 6 months of illness onset]: This is a repeated measurement. The internal diameter of LCX will be measured by echocardiography at five time points: at enrolment, at 2 weeks, 1 month, 3 months and 6 months of illness. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1).).
• Changes in z scores of the proximal segment of RCA [from admission to 6 months of illness onset]: This is a repeated measurement. The internal diameter of the proximal segment of RCA will be measured by echocardiography at five time points: at enrolment, at 2 weeks, 1 month, 3 months and 6 months of illness. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1).).
• Changes in z scores of the middle segment of RCA [from admission to 6 months of illness onset]: This is a repeated measurement. The internal diameter of the middle segment of RCA will be measured by echocardiography at five time points: at enrolment, at 2 weeks, 1 month, 3 months and 6 months of illness. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1).).
• Occurrence of CAL regression [from admission to 6 months of illness onset]: CAL regression is defined as Z score <2.5 in any coronary artery (LMCA, LAD, LCX, and the proximal and middle segments of the RCA), with no stenotic or occlusive lesions present.The internal diameter of the coronary artery will be measured by echocardiography at five time points: at enrolment, at 2 weeks, 1 month, 3 months and 6 months after illness onset. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1).).
• Occurrence of CAL progression [from admission to 6 months of illness onset]: CAL progression is defined as an increment in the Z score >1 from admission in any coronary artery (LMCA, LAD, LCX, proximal and middle segments of RCA) at any given time point within 6 months of illness onset. The outcome will be assessed in all participants and those with CAL at baseline.
• Occurrence of adverse events [from admission to 6 months of illness onset]: This is a composite outcome, including (a) clinical adverse events (death, severe infection, allergic reactions, heart failure, and thrombosis); (b) laboratory abnormalities (neutropenia, defined as <1.5×10⁹/L; thrombocytopenia, defined as <100×10⁹/L; newly developed ALT abnormality after medication, or further elevation of abnormal baseline ALT); (c) infectious events (occurrence of bacterial/viral infections); and (d) injection-site allergic reactions (redness and swelling at the injection site, rash, and anaphylactic shock) , etc.

Sex: All, ages: 29 Days to 17 Years

Inclusion Criteria:

1. Meeting diagnostic criteria for Kawasaki disease (KD) released by American Heart Association (AHA) in 2024
2. Diagnosed before the tenth day of illness (with the first day of illness defined as the first day of fever)
3. Not treated with IVIG yet
4. Age >28 days，<18 years

Exclusion Criteria:

1. Receiving steroids or other immunosuppressive agents in the previous 30 days;
2. With a previous history of KD;
3. Afebrile before enrolment;
4. Contraindications for subcutaneous injection, including severe local skin infection, ulceration, etc;
5. Known hypersensitivity to immunoglobulins, Firsekibart, or any of the excipients;
6. With suspected infectious diseases, such as sepsis, septic meningitis, peritonitis, bacterial pneumonia, varicella, and influenza;
7. With serious immune diseases, such as immunodeficiency, or chromosomal abnormalities;
8. With severe hepatic dysfunction (ALT > 3 times the upper limit of normal) prior to treatment
9. Unwillingness to provide written informed consent;
10. Unlikely to complete at least 3 months of follow-up;
11. Any other conditions deemed unsuitable for enrolment by investigators.

• Fang Liu, MD, Study director, Children's Hospital of Fudan University