Efficacy of Immunoglobulin Plus Infliximab for the Early Regression of Coronary Artery Lesion in Kawasaki Disease

Efficacy of Primary Treatment With Immunoglobulin Plus Infliximab for the Early Regression of Coronary Artery Lesion in Kawasaki Disease: a Multicenter, Open-label, Blinded-end Randomized Controlled Study.

This study evaluates the efficacy of the addition of infliximab to conventional initial treatment (intravenous immunoglobulin [IVIG] plus aspirin) in early regression of coronary artery lesion in patients with Kawasaki disease (KD).

Study Overview

• Status: Withdrawn
• Conditions: Kawasaki Disease
• Intervention / Treatment: Drug: IVIG; Drug: Aspirin; Drug: Infliximab

Detailed Description

This is a multicenter, open-label, blind-end, randomized controlled trial at 5 hospitals in Shanghai, China. The KD children diagnosed within 14 days of onset according to the diagnostic criteria for KD released by American Heart Association (AHA) in 2017 will be considered for participants in the trial. The patients meeting eligibility criteria will be randomly assigned in a 1:1 ratio to the control group (receiving 2 g/kg*1 IVIG and 30 mg/kg/d aspirin) or intervention group (receiving 2 g/kg*1 IVIG, 30 mg/kg/d aspirin and additional 5 mg/kg*1 infliximab) based on the randomly block design (block sizes 4). Baseline characteristics of each participant will be collected, including sex, age of onset, height, body weight, subtype of KD, fever days before initial IVIG, other clinical manifestations, echocardiographic findings at enrolment, and a series of pre-IVIG laboratory tests. Two-dimensional echocardiography will be performed at least 7 timepoints: at admission, 2 weeks, 1 month, 3 months, 6 months, 9 months and 12 months after onset of KD to assess the coronary artery lesions.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 200127
    • Shanghai Children's Medical Center
  • Shanghai, China, 201102
    • Children's Hospital of Fudan University
  • Shanghai, China, 200072
    • Shanghai 10th People's Hospital
  • Shanghai, China, 200062
    • Shanghai Children's Hospital
  • Shanghai, China, 200092
    • Xinhua Hospital, Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 14 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meeting diagnostic criteria for KD released by American Heart Association (AHA) in 2017, including complete KD (also sometimes referred to as typical or classic KD) and incomplete KD ((also sometimes referred to as atypical KD);
• Diagnosed within 14 days of illness (including the 14th day, considering the first day of illness as the first day of fever);
• Not treated with IVIG or other treatments for KD yet;
• Z score of any coronary artery of LMCA, LAD, LCX, the proximal and middle segment of RCA ≥ 2 calculated based on the height, weight and coronary artery diameter measured by echocardiography;
• Aged between one month and 14 years.

Exclusion Criteria:

• Receiving steroids or other immunosuppressive agents in the previous 30 days;
• With a previous history of KD;
• Afebrile and all the inflammation indicators (including white blood cell count, CRP, and erythrocyte sedimentation) become normal before enrolment;
• With suspected infectious diseases including tuberculosis, sepsis, septic meningitis, peritonitis, bacterial pneumonia, varicella, influenza, EBV infection, etc;
• With serious immune diseases such as immunodeficiency or chromosomal abnormalities;
• Unable to be followed up for at least 1 year.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: the standard group; IVIG 2 g/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 72 hours and C-reactive protein (CRP) is normal. Aspirin will be continued for at least 6 weeks after onset of illness.	Drug: IVIG; IVIG at a single dose of 2 g/kg; Other Names: Intravenous Immunoglobulins, Human; Drug: Aspirin; 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 72 hours and C-reactive protein (CRP) is normal. Aspirin will be continued for at least 6 weeks after onset of illness.; Other Names: Acetylsalicylic acid
Experimental: the standard + infliximab group; IVIG 2 g/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 72 hours and C-reactive protein (CRP) is normal. Aspirin will be continued for at least 6 weeks after onset of illness.; Intravenous infliximab at single dose of 5 mg/kg, given more than 2 hours.	Drug: IVIG; IVIG at a single dose of 2 g/kg; Other Names: Intravenous Immunoglobulins, Human; Drug: Aspirin; 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 72 hours and C-reactive protein (CRP) is normal. Aspirin will be continued for at least 6 weeks after onset of illness.; Other Names: Acetylsalicylic acid; Drug: Infliximab; Intravenous infliximab at single dose of 5 mg/kg, given more than 2 hours.; Other Names: Remicade

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of the regression of coronary artery lesion (CAL) at one month of illness	The regression of CAL is defined as z < 2 of all coronary arteries of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.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):60-74).	at one month of illness

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of the need for additional treatment	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, including a second dose of IVIG (2 g/kg), or a high dose of methylprednisolone (10 to 30 mg/kg per day), or other immunosuppressive agents such as ciclosporin and cyclophosphamide, or a combination with two or more drugs, or even more aggressive treatment such as plasmapheresis, depending on patients'condition and physicians' experience. Axillary temperature (or rectal temperature) will be measured every 6 hours a day during hospitalization.	from admission to discharge (about 2 weeks of illness)
z scores of LMCA throughout the study period	This is a repeated measurement. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1): 60-74.). The internal diameter of LMCA will be measured by echocardiography at least seven time points: at enrollment, at 2 weeks, 1 month, 3 months, 6 months, 9 months and 12 months of illness.	from admission to 12 months of illness
z scores of LAD throughout the study period	This is a repeated measurement. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1): 60-74.). The internal diameter of LAD will be measured by echocardiography at least seven time points: at enrollment, at 2 weeks, 1 month, 3 months, 6 months, 9 months and 12 months of illness.	from admission to 12 months of illness
z scores of LCX throughout the study period	This is a repeated measurement. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1): 60-74.). The internal diameter of LCX will be measured by echocardiography at least seven time points: at enrollment, at 2 weeks, 1 month, 3 months, 6 months, 9 months and 12 months of illness.	from admission to 12 months of illness
z scores of the proximal segment of RCA throughout the study period	This is a repeated measurement. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1): 60-74.). The internal diameter of the proximal segment of RCA will be measured by echocardiography at least seven time points: at enrollment, at 2 weeks, 1 month, 3 months, 6 months, 9 months and 12 months of illness.	from admission to 12 months of illness
z scores of the middle segment of RCA throughout the study period	This is a repeated measurement. Z score will be calculated based on the height, weight and coronary artery diameter (Journal of the American Society of Echocardiography, 2011, 24(1): 60-74.). The internal diameter of the middle segment of RCA will be measured by echocardiography at least seven time points: at enrollment, at 2 weeks, 1 month, 3 months, 6 months, 9 months and 12 months of illness.	from admission to 12 months of illness
Duration of fever (hours) after initiation of initial IVIG infusion	Participants with an axillary temperature <37.5℃ (or rectal temperature <38℃) for more than 24 hours are considered afebrile. Axillary temperature (or rectal temperature) will be measured every 6 hours a day during hospitalization. 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)
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.Change would be described by difference.	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 (defined as the blood pressure (BP) ≥90th percentile for age and height or ≥ 120/80 mmHg in the children younger than 13, and ≥ 120/80 mmHg in children ≥ 13 years), severe infection (such as septicopyemia, pulmonary infection and urinary system infection), allergic reactions, heart failure, thrombosis, etc.	from admission to 12 months of illness
Percentage of the regression of coronary artery lesion (CAL) at 3 months of illness	The regression of CAL is defined as the z < 2 of all coronary arteries of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.	at 3 months of illness
Percentage of the regression of coronary artery lesion (CAL) at 6 months of illness	The regression of CAL is defined as the z < 2 of all coronary arteries of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.	at 6 months of illness
Percentage of the regression of coronary artery lesion (CAL) at 9 months of illness	The regression of CAL is defined as the z < 2 of all coronary arteries of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.	at 9 months of illness
Percentage of the regression of coronary artery lesion (CAL) at 12 months of illness	The regression of CAL is defined as the z < 2 of all coronary arteries of LMCA, LAD, LCX, and the proximal and middle segment of the RCA.	at 12 months of illness

Collaborators and Investigators

• Sponsor: Children's Hospital of Fudan University
• Collaborators: Shanghai 10th People's Hospital; Shanghai Children's Hospital; Shanghai Children's Medical Center; Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
• Investigators: Study Director: Guoying Huang, MD., Children's Hospital of Fudan University

Publications and helpful links

General Publications

• Dallaire F, Dahdah N. New equations and a critical appraisal of coronary artery Z scores in healthy children. J Am Soc Echocardiogr. 2011 Jan;24(1):60-74. doi: 10.1016/j.echo.2010.10.004. Epub 2010 Nov 13.

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2020
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: August 27, 2020
• First Submitted That Met QC Criteria: August 28, 2020
• First Posted (Actual): September 2, 2020

Study Record Updates

• Last Update Posted (Actual): March 12, 2021
• Last Update Submitted That Met QC Criteria: March 10, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: infliximab; Kawasaki disease; coronary artery lesion
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Lymphatic Diseases; Vasculitis; Skin Diseases, Vascular; Mucocutaneous Lymph Node Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Aspirin; Immunoglobulins; Immunoglobulins, Intravenous; Infliximab; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: KD-4-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No