Kawasaki Disease
Conditions
Keywords
Kawasaki disease, Infliximab, Remicade, Pediatrics
Brief summary
The purpose of this study is to determine whether the addition of infliximab to standard primary therapy of intravenous immunoglobulin (IVIG) and high dose aspirin will reduce resistance to therapy in acute Kawasaki disease (KD).
Detailed description
KD, an orphan disease of low prevalence in U.S. children, causes significant long term cardiac sequelae in a subset of patients. KD patients that are resistant to therapy are more likely to develop coronary artery abnormalities. This phase III placebo-controlled, multicenter, randomized clinical trial of infliximab plus standard therapy vs. placebo plus standard therapy in acute KD will determine if the addition of infliximab to primary therapy can reduce the percentage of children resistant to therapy.
Interventions
DRUGPlacebo
Placebo (same volume as active drug)
DRUGInfliximab
5 mg/kg IV over 2 hours once
Sponsors
Nationwide Children's Hospital
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Weeks to 17 Years
Healthy volunteers
No
Inclusion criteria
1. All eligible subjects, or legal representative, must provide written informed consent/assent, prior to initiation of any study procedure. 2. Eligible subjects will be infants and children, 4 weeks to 17 years old, who have had fever for 3 to 15 days (illness day 1 = first day of fever ≥ 38.3° C) 3. Patients who meet one of the following sets of criteria will be eligible for enrollment (adapted from AHA guidelines: Newburger et al. 2004): * Case definition for complete KD: Fever (≥ 38.3°C) for ≥ 3 days and 4/5 standard clinical criteria (Table 1) * Case definition for incomplete KD: Fever ≥ 5 days and 2-3 clinical criteria plus either C-reactive protein (CRP) ≥ 3.0 mg/dL or ESR ≥40 mm/hr AND ≥ 3 supplemental laboratory criteria: albumin ≤ 3.0 g/dl, anemia for age, ALT ≥ 45, platelet count ≥ 450,000/mm3, white blood cell count ≥ 15,000/mm3, or urinalysis with ≥10 white blood cells/hpf. * Case definition for incomplete KD with echocardiogram data: Fever ≥ 5 days and \<4/5 clinical criteria plus abnormal echocardiogram with z score of LAD or RCA ≥ 2.5 4. Females of childbearing potential and males must be using adequate contraception (abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) throughout the trial. 5. All eligible subjects must have a chest radiograph within one week prior to first infusion of study drug with no evidence of tuberculosis or other infection.
Exclusion criteria
1. Have been receiving corticosteroids (i.e. via any route) at doses \> 1 mg/kg prednisone equivalent daily. 2. History of tuberculosis (TB) or TB exposure. 3. Have received a BCG vaccination within the past 6 months. 4. History of histoplasmosis or coccidioidomycosis 5. Have received anakinra (Kineret®), etanercept (Enbrel®), or adalimumab (Humira®) within 1 month prior to first study drug administration. 6. Have any chronic disease, except asthma, atopic dermatitis or controlled seizure disorder. 7. Have documented history of current active Hepatitis B or a history of Hepatitis C infection. 8. Have a documented history of human immunodeficiency virus (HIV) infection. 9. Have received a transplanted organ (with the exception of a corneal transplant performed \> 3 months prior to the first study drug administration). 10. Have a known malignancy or history of malignancy within the 5-year period prior to first study drug administration (with the exception of basal cell or squamous cell carcinoma of the skin that has been completely excised without evidence of recurrence). 11. Have a history of prior lymphoproliferative disease including lymphoma. 12. Have multiple sclerosis or other central demyelinating disorder. 13. Have received any previous treatment with infliximab or other monoclonal antibodies 14. Have used any investigational drug within 1 month prior to first study drug administration or within 5 half-lives of the investigational agent, whichever is longer. 15. Are participating in another investigative trial, involving investigational agents, during participation in this trial. 16. Have a history of substance abuse (drug or alcohol) within the previous 3 years. 17. Are pregnant, nursing, or planning pregnancy (both men and women) during the trial or within the 6-month period thereafter. 18. Have a known allergy to murine proteins or other chimeric proteins. 19. Patients with ischemic congestive heart failure, defined by ECG changes, elevated Troponin 1 and CPK-MB consistent with myocardial ischemia. 20. Have an abnormal chest radiograph 21. Afebrile for ≥ 48 hours
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Number of Subjects in Each Arm That Have Persistent or Recrudescent Fever 24 Hours After Completion of the Intravenous Immunoglobulin (IVIG) Infusion | 10 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Days of Fever Following Therapy During Study Period (up to 6 Weeks) | up to 6 weeks | — |
| Change in C-reactive Protein (CRP) From Baseline at 24 Hours After Completion of Intravenous Immunoglobulin (IVIG) by Study Arm. | 24 hours | — |
| Change From Baseline in Left Anterior Descending Coronary Artery Outcomes at Week 2 by Treatment Arm | 2 weeks | left anterior descending coronary artery Z-score; a Z score is the coronary artery adjusted for body surface area |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Infliximab Arm 98 recieved infliximab plus IVIG
Infliximab: 5 mg/kg IV over 2 hours once | 98 |
| Placebo Arm 98 received Placebo plus IVIG
Placebo: Placebo (same volume as active drug) | 98 |
| Total | 196 |
Baseline characteristics
| Characteristic | Total | Infliximab Arm | Placebo Arm |
|---|---|---|---|
| Age, Continuous | 2.9 years | 3.0 years | 2.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 121 Participants | 57 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 75 Participants | 41 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 10 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 10 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 32 Participants | 15 Participants | 17 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 120 Participants | 61 Participants | 59 Participants |
| Region of Enrollment United States | 196 participants | 98 participants | 98 participants |
| Sex: Female, Male Female | 75 Participants | 38 Participants | 37 Participants |
| Sex: Female, Male Male | 121 Participants | 60 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 49 / 98 | 61 / 98 |
| serious Total, serious adverse events | 22 / 98 | 17 / 98 |
Outcome results
Primary
The Number of Subjects in Each Arm That Have Persistent or Recrudescent Fever 24 Hours After Completion of the Intravenous Immunoglobulin (IVIG) Infusion
Time frame: 10 weeks
Population: 1 subject in the placebo group was removed from the modified ITT analysis (this subject was removed from the study prior to receiving the placebo)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab | The Number of Subjects in Each Arm That Have Persistent or Recrudescent Fever 24 Hours After Completion of the Intravenous Immunoglobulin (IVIG) Infusion | 11 participants |
| Placebo | The Number of Subjects in Each Arm That Have Persistent or Recrudescent Fever 24 Hours After Completion of the Intravenous Immunoglobulin (IVIG) Infusion | 11 participants |
Secondary
Change From Baseline in Left Anterior Descending Coronary Artery Outcomes at Week 2 by Treatment Arm
left anterior descending coronary artery Z-score; a Z score is the coronary artery adjusted for body surface area
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infliximab | Change From Baseline in Left Anterior Descending Coronary Artery Outcomes at Week 2 by Treatment Arm | -0.605 Z-score |
| Placebo | Change From Baseline in Left Anterior Descending Coronary Artery Outcomes at Week 2 by Treatment Arm | -0.313 Z-score |
Secondary
Change in C-reactive Protein (CRP) From Baseline at 24 Hours After Completion of Intravenous Immunoglobulin (IVIG) by Study Arm.
Time frame: 24 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Infliximab | Change in C-reactive Protein (CRP) From Baseline at 24 Hours After Completion of Intravenous Immunoglobulin (IVIG) by Study Arm. | -6.6 mg/dL |
| Placebo | Change in C-reactive Protein (CRP) From Baseline at 24 Hours After Completion of Intravenous Immunoglobulin (IVIG) by Study Arm. | -3.6 mg/dL |
Secondary
Number of Days of Fever Following Therapy During Study Period (up to 6 Weeks)
Time frame: up to 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Infliximab | Number of Days of Fever Following Therapy During Study Period (up to 6 Weeks) | 1 days |
| Placebo | Number of Days of Fever Following Therapy During Study Period (up to 6 Weeks) | 2 days |