Clinical trial NCT00760435: Infliximab Plus Intravenous Immunoglobulin for the Primary Treatment of Kawasaki Disease
Official title: Infliximab (Remicade®) Plus Intravenous Immunoglobulin (IVIG) for the Primary Treatment of Patients With Acute Kawasaki Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Kawasaki Disease
Keywords: Kawasaki disease
Infliximab
Remicade
Pediatrics
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Nationwide Children's Hospital
First posted: 2008-09-26
Enrollment: 196
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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

Primary outcomes:
measure: The Number of Subjects in Each Arm That Have Persistent or Recrudescent Fever 24 Hours After Completion of the Intravenous Immunoglobulin (IVIG) Infusion
timeFrame: 10 weeks
Secondary outcomes:
measure: Number of Days of Fever Following Therapy During Study Period (up to 6 Weeks)
timeFrame: up to 6 weeks
measure: Change in C-reactive Protein (CRP) From Baseline at 24 Hours After Completion of Intravenous Immunoglobulin (IVIG) by Study Arm.
timeFrame: 24 hours
measure: Change From Baseline in Left Anterior Descending Coronary Artery Outcomes at Week 2 by Treatment Arm
timeFrame: 2 weeks
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
Study officials:
affiliation: University of California, San Diego
name: Jane C Burns, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Adriana H. Tremoulet, M.D.
role: STUDY_DIRECTOR
affiliation: University of Texas
name: Octavio Ramilo, M.D.
role: STUDY_DIRECTOR
References:
citation: 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.
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.
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. doi: 10.1056/NEJMoa061235.
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. doi: 10.1542/peds.2004-2182.
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. doi: 10.1016/j.jpeds.2004.12.022.
citation: Tremoulet AH, Jain S, Jaggi P, Jimenez-Fernandez S, Pancheri JM, Sun X, Kanegaye JT, Kovalchin JP, Printz BF, Ramilo O, Burns JC. Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet. 2014 May 17;383(9930):1731-8. doi: 10.1016/S0140-6736(13)62298-9. Epub 2014 Feb 24.
citation: Burns JC, Song Y, Bujold M, Shimizu C, Kanegaye JT, Tremoulet AH, Franco A. Immune-monitoring in Kawasaki disease patients treated with infliximab and intravenous immunoglobulin. Clin Exp Immunol. 2013 Dec;174(3):337-44. doi: 10.1111/cei.12182.
citation: Kanegaye JT, Van Cott E, Tremoulet AH, Salgado A, Shimizu C, Kruk P, Hauschildt J, Sun X, Jain S, Burns JC. Lymph-node-first presentation of Kawasaki disease compared with bacterial cervical adenitis and typical Kawasaki disease. J Pediatr. 2013 Jun;162(6):1259-63, 1263.e1-2. doi: 10.1016/j.jpeds.2012.11.064. Epub 2013 Jan 7.