Infliximab Plus Intravenous Immunoglobulin for the Primary Treatment of Kawasaki Disease

Kawasaki Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00760435
• Other study ID #: 1R01FD003514-01
• Status: Completed
• Phase: Phase 3
• First received: September 25, 2008
• Last updated: November 12, 2014
• Start date: March 2009
• Est. completion date: October 2012

Study information

• Verified date: November 2014
• Source: University of California, San Diego
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 196
• Est. completion date: October 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 17 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Kawasaki Disease
• Mucocutaneous Lymph Node Syndrome

Intervention

Drug:
• Infliximab
5 mg/kg IV over 2 hours once
• Placebo
Placebo (same volume as active drug)

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of California, San Diego	La Jolla	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Diego	Nationwide Children's Hospital

Country where clinical trial is conducted

United States, 

References & Publications (5)

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 Dec;153(6):833-8. doi: 10.1016/j.jpeds.2008.06.011. Epub 2008 Jul 30. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. doi: 10.1016/j.jpeds.2007.12.021. Epub 2008 Mar 4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Number of Days of Fever Following Therapy During Study Period (up to 6 Weeks)		up to 6 weeks	No
Secondary	Change in C-reactive Protein (CRP) From Baseline at 24 Hours After Completion of Intravenous Immunoglobulin (IVIG) by Study Arm.		24 hours	No
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	2 weeks	No