Infliximab Plus Intravenous Immunoglobulin for the Primary Treatment of Kawasaki Disease

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.

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 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