Efficacy of Immunoglobulin Plus Prednisolone in Reducing Coronary Artery Lesion in Patients With Kawasaki Disease

Study Overview
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Brief Summary
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This study evaluates the efficacy of the addition of prednisolone to conventional initial treatment (intravenous immunoglobulin [IVIG] plus aspirin) in reducing coronary artery lesion in children with Kawasaki disease (KD) .

Detailed Description
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This is a multicenter, open-label, blind-endpoints, randomized controlled trial at more than 10 hospitals in China. The investigators enrolled KD children diagnosed within 10 days of onset. Participants will be randomly assigned in a 1:1 ratio to the control group (receiving 2g/kg IVIG and 30 mg/kg aspirin) or the intervention group (receiving 2 g/kg IVIG, 30 mg/kg aspirin and additional 2 mg/kg prednisolone). Baseline characteristics of each participant will be collected, including sex, age of 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, 6 months，and 12 months after onset of KD to assess the coronary artery lesions.

Official Title
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Efficacy of Immunoglobulin Plus Prednisolone in Reducing Coronary Artery Lesion in Patients With Kawasaki Disease: A Multicentre Randomised Controlled Trial

Conditions
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Kawasaki Disease

Intervention / Treatment
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* Drug: IVIG
* Drug: Aspirin
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meeting diagnostic criteria for Kawasaki disease (KD) released by American Heart Association (AHA) in 2017 Diagnosed before the tenth day of illness (with the first day of illness defined as the first day of fever) Not treated with IVIG yet Age ≥1 month Exclusion Criteria: Z score of any coronary artery before initial treatment ≥10 Receiving steroids or other immunosuppressive agents in the previous 30 days With a previous history of KD Afebrile before enrolment With suspected infectious diseases including sepsis, septic meningitis, peritonitis, bacterial pneumonia, varicella and influenza With serious immune diseases such as immunodeficiency or chromosomal abnormalities

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: the standard group<br>IVIG 2g/kg once, given within 12 to 24 hours; 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 C-reactive protein (CRP) is normal. Aspirin will be continued for at least 6 weeks after onset of illness. | Drug: IVIG<br>* IVIG at a single dose of 2 g/kg, with the maximum dose of 60g<br>* Other names: Intravenous Immunoglobulins, Human;Drug: Aspirin<br>* 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 C-reactive protein (CRP) is normal. Aspirin will be continued for at least 6 weeks after onset of illness.<br>* Other names: Acetylsalicylic acid;|
| Experimental: the standard+prednisolone group<br>IVIG 2g/kg once, given within 12 to 24 hours; 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. Intravenous methylprednisolone 1.6 mg/kg per day (given in 2 divided doses) for 3 days, then changed to oral prednisolone 2 mg/kg when fever subsides for 3 days . If CRP is normal, the oral dose will be reduced every 5 days from 2 mg/kg to 1 mg/kg to 0.5 mg/kg (tapered over 15 days). Then prednisolone will be discontinued. | Drug: IVIG<br>* IVIG at a single dose of 2 g/kg, with the maximum dose of 60g<br>* Other names: Intravenous Immunoglobulins, Human;Drug: Aspirin<br>* 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 C-reactive protein (CRP) is normal. Aspirin will be continued for at least 6 weeks after onset of illness.<br>* Other names: Acetylsalicylic acid;Drug: Prednisolone<br>* Intravenous methylprednisolone 1.6 mg/kg per day (given in 2 divided doses, with the maximum dose 60mg of prednisolone ) for 3 days, then changed to oral prednisolone 2 mg/kg when fever subsides for 3 days. If CRP is normal, the oral dose will be reduced every 5 days from 2 mg/kg to 1 mg/kg to 0.5 mg/kg (tapered over 15 days). Then prednisolone will be discontinued.<br>* Other names: STEROLONE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of coronary artery lesions(CAL) at one month of illness | Two-dimensional echocardiography will be performed to evaluate CAL at 1 month 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≥2of any coronary artery of LMCA, LAD, LCX, and the proximal and middle segment of the RCA. | at one month of illness | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of the need for additional treatment | Axillary temperature (or rectal temperature) will be measured every 6 hours a day during hospitalization. Participants who have recurrent or persistent fever (axillary temperature ≥37.5°C or rectal temperature ≥38°C) after 36 hours of completion of initial IVIG infusion will be given additional treatment. | from admission to discharge (about 2 weeks of illness) | 
| Duration of fever (hours) after initiation of initial IVIG infusion | Axillary temperature (or rectal temperature) will be measured every 6 hours a day during hospitalization. Participants with an axillary temperature <37.5℃ (or rectal temperature <38℃) 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. | from initiation of initial IVIG infusion to the first record of being afebrile(defined as an axillary temperature <37.5 for more than 24 hours) | 
| Changes in z scores of LMCA throughout the study period | This is a repeated measurement. The internal diameter of LMCA will be measured by echocardiography at six time points: at enrolment, at 2 weeks, 1 month, 3 months, 6 months and 12 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).）. | from admission to 12 months of illness | 
| Changes in z scores of LAD throughout the study period | This is a repeated measurement. The internal diameter of LAD will be measured by echocardiography at six time points: at enrolment, at 2 weeks, 1 month, 3 months, 6 months and 12 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).）. | from admission to 12 months of illness | 
| Changes in z scores of LCX throughout the study period | This is a repeated measurement. The internal diameter of LCX will be measured by echocardiography at six time points: at enrolment, at 2 weeks, 1 month, 3 months, 6 months and 12 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).）. | from admission to 12 months of illness | 
| Changes in z scores of the proximal segment of RCA throughout the study period | This is a repeated measurement. The internal diameter of the proximal segment of RCA will be measured by echocardiography at six time points: at enrolment, at 2 weeks, 1 month, 3 months, 6 months and 12 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).）. | from admission to 12 months of illness | 
| Changes in z scores of the middle segment of RCA throughout the study period | This is a repeated measurement. The internal diameter of the middle segment of RCA will be measured by echocardiography at six time points: at enrolment, at 2 weeks, 1 month, 3 months, 6 months and 12 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).）. | from admission to 12 months of illness | 
| Change in serum C-reactive protein (CRP) concentration | CRP level is measured before initial IVIG infusion and 72 hours after completion of initial IVIG infusion. | from admission to 72 hours after completion of initial IVIG infusion | 
| Number of patients with serious adverse events | This is a composite outcome, including death, hypertension, severe infection, allergic reactions, heart failure, thrombosis, etc. | from admission to 3 months of illness | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kawasaki disease, prednisolone, coronary artery lesion