KIDCARE (Kawasaki Disease Comparative Effectiveness Trial) (KIDCARE)

Kawasaki disease (KD) is a self-limited illness that affects the heart blood vessels (coronary arteries) of infants and children and is now the most common cause of acquired heart disease in children. A mixture of proteins from human blood (Intravenous immunoglobulin, IVIG) is a treatment that reduces the rate of the major complication of the disease: a bulging of the wall of the coronary arteries called an aneurysm. However, 10-20% of children are resistant to this treatment and the fever returns. These children have the highest rates of aneurysm formation and thus should be treated aggressively. Unfortunately, there are no guidelines for the best secondary treatment for these resistant patients because the problem has never been adequately studied. Most physicians choose either a second infusion of IVIG or an engineered antibody called infliximab that inactivates a molecule that promotes inflammation. This trial will randomize (assign by chance like the flip of a coin) IVIG-resistant patients to receive either a second IVIG infusion or infliximab and the response to treatment will be compared to learn which treatment stops the fever the fastest. In addition, parents and caregivers will provide observations about their child's response to the different treatments.

Study Overview

• Status: Completed
• Conditions: Mucocutaneous Lymph Node Syndrome
• Intervention / Treatment: Drug: IVIG; Drug: Infliximab

Detailed Description

This is a 3-year (2.75-years of enrollment), Phase III, two-arm, randomized, multi-center, superiority treatment study to compare infliximab to a second intravenous immunoglobulin (IVIG) infusion for treatment of persistent or recrudescent fever in children with KD who fail to become afebrile after the first IVIG infusion.

1. Specific aim 1 will test the hypothesis that infliximab will be superior to a second intravenous immunoglobulin (IVIG) infusion for treatment of persistent or recrudescent fever in children with KD who fail to become afebrile after the first IVIG infusion (resistant KD). Cessation of fever (<38°C rectally or orally) within 24h of initiation of study treatment infusion will be the primary outcome measure.
2. Specific aim 2 will test the hypothesis that infliximab treatment will result in more rapid resolution of inflammation compared to second IVIG as measured by the change in white blood cell count (WBC), absolute neutrophil count (ANC), and high-sensitivity C-reactive protein (hsCRP) concentration between baseline and 24 hours and 2 weeks following study treatment.
3. Specific aim 3 will test the hypothesis that infliximab treatment will result in a reduction from baseline in coronary artery Zworst score of ≥ 0.05 standard deviation units as compared to second IVIG at 2 weeks following study treatment measured by echocardiography.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • UAB Children's of Alabama
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Long Beach, California, United States, 90806
      • Memorial Care
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA
    • Los Angeles, California, United States, 90502
      • Harbor-UCLA Medical Center
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital-Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94920
      • UCSF Benioff Children's Hospital-San Francisco
    • West Hollywood, California, United States, 94305
      • Cedar-Sinai Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Comer Children's Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Children's Health Indiana University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Kansas Ciry
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • Valhalla, New York, United States, 10595
      • Maria Fareri Children's Hospital
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • University of South Dakota Sanford School of Medicine
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center of Dallas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Care University of Utah
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Children's

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eligible subjects will be as follows:

  1. 4 weeks to 17 years of age,
  2. fulfill the American Heart Association case definition for complete or incomplete KD,
  3. have had fever (T ≥38°C) for 3 to 10 days prior to initial IVIG treatment,
  4. have fever (T ≥38°C orally or rectally) between 36 hours and 7 days after end of the first IVIG infusion without other likely cause

Exclusion Criteria:

1. Patient treated with infliximab or steroids for present illness (pts who received oral steroids as outpatients prior to KD diagnosis but who otherwise qualify for the study will not be excluded)
2. Known prior infection with tuberculosis, coccidiomycosis, or histoplasmosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: IVIG; Patient will be randomly assigned to receive a second IVIG infusion: 2 g/kg IV over 8-10 hours single infusion	Drug: IVIG; Subjects randomized to this arm will receive IVIG 2g/kg over 10-12 hours; Other Names: Intravenous immunoglobulin
Active Comparator: Infliximab; Patient will be randomly assigned to receive Infliximab 10 mg/kg IV over 2 hours	Drug: Infliximab; Subjects randomized to this arm will receive infliximab 10 mg/kg over 2 hours; Other Names: Remicade

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Cessation of Fever Within 24h of Initiation of Study Treatment With no Fever Recurrence Within Next 7 Days.	A fever will be considered ≥38°C rectally or orally and ≥ 37.5°C axillary. Cessation of fever within 24h of initiation of study treatment with no fever recurrence within next 7 days.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in White Blood Cell Count (WBC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment.	Change in white blood cell count (WBC), between baseline and 24 hours and 2 weeks following study treatment.	24h
Change in Zworst Score Between Baseline and 2-week (± 4 Days) Echocardiograms	Zworst score is defined as the largest internal diameter of either the right coronary or left anterior descending arteries normalized for body surface area and expressed as standard deviation units from the mean. A Z-score >= 2.5 is considered a aneurysm according to the American Heart Association criteria.	2 weeks
Total Number of Fever Days (24 Hour Period With a T≥38.0°C) From Enrollment	Determine the number of days a participant had a fever once the participant has been enrolled into the study.	7 days
Duration of Hospitalization	How long a participant was hospitalized for.	2 weeks
Number of Participants With IVIG and Infliximab Infusion Reactions and Complications	Determine any complications and/or reactions to each treatment.	7 days
Change in Absolute Neutrophil Count (ANC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment.	Change in absolute neutrophil count (ANC) between baseline and 24 hours and 2 weeks following study treatment.	24h
Change in C-reactive Protein (CRP, mg/dL) Concentration Between Baseline and 24 Hours and 2 Weeks Following Study Treatment.	Change in C-reactive protein (CRP, mg/dL) concentration between baseline and 24 hours and 2 weeks following study treatment.	24h

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: Patient-Centered Outcomes Research Institute
• Investigators: Principal Investigator: Jane C Burns, MD, UCSD

Publications and helpful links

General Publications

• Burns JC, Roberts SC, Tremoulet AH, He F, Printz BF, Ashouri N, Jain SS, Michalik DE, Sharma K, Truong DT, Wood JB, Kim KK, Jain S; KIDCARE Multicenter Study Group. Infliximab versus second intravenous immunoglobulin for treatment of resistant Kawasaki disease in the USA (KIDCARE): a randomised, multicentre comparative effectiveness trial. Lancet Child Adolesc Health. 2021 Dec;5(12):852-861. doi: 10.1016/S2352-4642(21)00270-4. Epub 2021 Oct 27. Erratum In: Lancet Child Adolesc Health. 2022 Feb;6(2):e5.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2017
• Primary Completion (Actual): August 31, 2020
• Study Completion (Actual): November 2, 2020

Study Registration Dates

• First Submitted: January 17, 2017
• First Submitted That Met QC Criteria: February 21, 2017
• First Posted (Actual): February 27, 2017

Study Record Updates

• Last Update Posted (Actual): December 3, 2021
• Last Update Submitted That Met QC Criteria: November 5, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Kawasaki disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Lymphatic Diseases; Vasculitis; Skin Diseases, Vascular; Mucocutaneous Lymph Node Syndrome; Physiological Effects of Drugs; Antirheumatic Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Immunoglobulins; Immunoglobulins, Intravenous; Infliximab; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: UCSD 170064

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes