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Infliximab Plus Intravenous Immunoglobulin for the Primary Treatment of Kawasaki Disease

Information source: University of California, San Diego
Information obtained from ClinicalTrials.gov on December 08, 2011
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Kawasaki Disease

Intervention: Infliximab (Drug); Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: University of California, San Diego

Official(s) and/or principal investigator(s):
Jane C Burns, M.D., Principal Investigator, Affiliation: University of California, San Diego
Adriana H. Tremoulet, M.D., Study Director, Affiliation: University of California, San Diego
Octavio Ramilo, M.D., Study Director, Affiliation: University of Texas

Overall contact:
Adriana H Tremoulet, M.D., Phone: 858-246-0012, Email: atremoulet@ucsd.edu

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).

Clinical Details

Official title: Infliximab (Remicade) Plus Intravenous Immunoglobulin (IVIG) for the Primary Treatment of Patients With Acute Kawasaki Disease

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: The percentage of KD patients that have persistent or recrudescent fever 24 hours after completion of the IVIG infusion

Secondary outcome:

Number of days of fever following therapy

z hemoglobin adjusted for age

Markers of inflammation including C-reactive protein, platelet count, white blood cell count, absolute neutrophil count, and percent bands

Days of fever

The larger of the z scores (normalized for body surface area) of the internal diameter of the right and left anterior descending coronary arteries at follow up

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.

Eligibility

Minimum age: N/A. Maximum age: 17 Years. Gender(s): Both.

Criteria:

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

Locations and Contacts

Adriana H Tremoulet, M.D., Phone: 858-246-0012, Email: atremoulet@ucsd.edu

University of California, San Diego, La Jolla, California 92093, United States; Recruiting
Adriana H. Tremoulet, M.D., Phone: 858-246-0012, Email: atremoulet@ucsd.edu
Joan Pancheri, R.N., Phone: 858-966-6264, Email: jpancheri@rchsd.org
Jane C. Burns, M.D., Principal Investigator
Adriana H. Tremoulet, M.D., Sub-Investigator

Nationwide Children's Hospital, Columbus, Ohio, United States; Recruiting
Octavio Ramilo, M.D., Email: octavio.ramilo@nationwidechildrens.org
Preeti Jaggi, MD, Email: preeti.jaggi@nationwidechildrens.org
Octavio Ramilo, M.D., Principal Investigator
Preeti Jaggi, M.D., Sub-Investigator

Additional Information

Kawasaki Disease Research Center at UCSD

Related publications:

Burns JC, Best BM, Mejias A, Mahony L, Fixler DE, Jafri HS, Melish ME, Jackson MA, Asmar BI, Lang DJ, Connor JD, Capparelli EV, Keen ML, Mamun K, Keenan GF, Ramilo O. Infliximab Treatment of Intravenous Immunoglobulin-Resistant Kawasaki Disease. J Pediatr. 2008 Jul 29; [Epub ahead of print]

Tremoulet AH, Best BM, Song S, Wang S, Corinaldesi E, Eichenfield JR, Martin DD, Newburger JW, Burns JC. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr. 2008 Jul;153(1):117-21. Epub 2008 Mar 4.

Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, Atz AM, Li JS, Takahashi M, Baker AL, Colan SD, Mitchell PD, Klein GL, Sundel RP; Pediatric Heart Network Investigators. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med. 2007 Feb 15;356(7):663-75.

Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004 Dec;114(6):1708-33. Erratum in: Pediatrics. 2005 Apr;115(4):1118.

Burns JC, Mason WH, Hauger SB, Janai H, Bastian JF, Wohrley JD, Balfour I, Shen CA, Michel ED, Shulman ST, Melish ME. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr. 2005 May;146(5):662-7.

Starting date: March 2009
Last updated: April 7, 2011

Page last updated: December 08, 2011

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