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

Primary Purpose

Kawasaki Disease

Status
Withdrawn
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
IVIG
Aspirin
Infliximab
Sponsored by
Children's Hospital of Fudan University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kawasaki Disease focused on measuring Kawasaki disease, infliximab, coronary artery lesion

Eligibility Criteria

1 Month - 14 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Shanghai Children's Hospital
  • Shanghai 10th People's Hospital
  • Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
  • Shanghai Children's Medical Center
  • Children's Hospital of Fudan University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

the standard group

the standard + infliximab group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
August 27, 2020
Last Updated
March 10, 2021
Sponsor
Children's Hospital of Fudan University
Collaborators
Shanghai Children's Hospital, Shanghai Children's Medical Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 10th People's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04535518
Brief Title
Efficacy of Immunoglobulin Plus Infliximab for the Early Regression of Coronary Artery Lesion in Kawasaki Disease
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Withdrawn
Why Stopped
lack of funding
Study Start Date
October 2020 (Anticipated)
Primary Completion Date
September 2022 (Anticipated)
Study Completion Date
September 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital of Fudan University
Collaborators
Shanghai Children's Hospital, Shanghai Children's Medical Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 10th People's Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kawasaki Disease
Keywords
Kawasaki disease, infliximab, coronary artery lesion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Masking Description
Participants and physicians will not be masked to the assignment. Pediatric cardiologists who assess coronary artery lesions (CAL) by echocardiography will be masked to the allocation.
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
the standard group
Arm Type
Active Comparator
Arm Description
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.
Arm Title
the standard + infliximab group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
IVIG
Other Intervention Name(s)
Intravenous Immunoglobulins, Human
Intervention Description
IVIG at a single dose of 2 g/kg
Intervention Type
Drug
Intervention Name(s)
Aspirin
Other Intervention Name(s)
Acetylsalicylic acid
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Infliximab
Other Intervention Name(s)
Remicade
Intervention Description
Intravenous infliximab at single dose of 5 mg/kg, given more than 2 hours.
Primary Outcome Measure Information:
Title
Percentage of the regression of coronary artery lesion (CAL) at one month of illness
Description
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).
Time Frame
at one month of illness
Secondary Outcome Measure Information:
Title
Percentage of the need for additional treatment
Description
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.
Time Frame
from admission to discharge (about 2 weeks of illness)
Title
z scores of LMCA throughout the study period
Description
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.
Time Frame
from admission to 12 months of illness
Title
z scores of LAD throughout the study period
Description
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.
Time Frame
from admission to 12 months of illness
Title
z scores of LCX throughout the study period
Description
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.
Time Frame
from admission to 12 months of illness
Title
z scores of the proximal segment of RCA throughout the study period
Description
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.
Time Frame
from admission to 12 months of illness
Title
z scores of the middle segment of RCA throughout the study period
Description
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.
Time Frame
from admission to 12 months of illness
Title
Duration of fever (hours) after initiation of initial IVIG infusion
Description
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.
Time Frame
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)
Title
Change in serum C-reactive protein (CRP) concentration
Description
CRP level is measured before initial IVIG infusion and 72 hours after completion of initial IVIG infusion.Change would be described by difference.
Time Frame
from admission to 72 hours after completion of initial IVIG infusion
Title
Number of patients with serious adverse events
Description
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.
Time Frame
from admission to 12 months of illness
Title
Percentage of the regression of coronary artery lesion (CAL) at 3 months of illness
Description
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.
Time Frame
at 3 months of illness
Title
Percentage of the regression of coronary artery lesion (CAL) at 6 months of illness
Description
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.
Time Frame
at 6 months of illness
Title
Percentage of the regression of coronary artery lesion (CAL) at 9 months of illness
Description
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.
Time Frame
at 9 months of illness
Title
Percentage of the regression of coronary artery lesion (CAL) at 12 months of illness
Description
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.
Time Frame
at 12 months of illness

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
14 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guoying Huang, MD.
Organizational Affiliation
Children's Hospital of Fudan University
Official's Role
Study Director
Facility Information:
Facility Name
Shanghai Children's Hospital
City
Shanghai
ZIP/Postal Code
200062
Country
China
Facility Name
Shanghai 10th People's Hospital
City
Shanghai
ZIP/Postal Code
200072
Country
China
Facility Name
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
City
Shanghai
ZIP/Postal Code
200092
Country
China
Facility Name
Shanghai Children's Medical Center
City
Shanghai
ZIP/Postal Code
200127
Country
China
Facility Name
Children's Hospital of Fudan University
City
Shanghai
ZIP/Postal Code
201102
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
21074965
Citation
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.
Results Reference
background

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

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