Infliximab Plus Intravenous Immunoglobulin for the Primary Treatment of Kawasaki Disease

NCT00760435 | Completed Phase 3 Results DMC

• 1 other identifier: 1R01FD003514-01
• Study Type: interventional
• Target: 196
• Locations: 1 country
• Sites: 2

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).

Conditions

Kawasaki Disease

Keywords

Kawasaki disease; Infliximab; Remicade; Pediatrics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• 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

Study Arms (2)

1

EXPERIMENTAL

Infliximab plus Intravenous immunoglobulin (IVIG)

Drug: Infliximab

2

PLACEBO COMPARATOR

Placebo plus IVIG

Drug: Placebo

Interventions

Infliximab DRUG

5 mg/kg IV over 2 hours once

Also known as: Remicade

1

Placebo DRUG

Placebo (same volume as active drug)

2

Eligibility Criteria

• Age: 4 Weeks - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• All eligible subjects, or legal representative, must provide written informed consent/assent, prior to initiation of any study procedure.
• 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)
• 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
• 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.
• 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.

You may not qualify if:

• Have been receiving corticosteroids (i.e. via any route) at doses \> 1 mg/kg prednisone equivalent daily.
• History of tuberculosis (TB) or TB exposure.
• Have received a BCG vaccination within the past 6 months.
• History of histoplasmosis or coccidioidomycosis
• Have received anakinra (Kineret®), etanercept (Enbrel®), or adalimumab (Humira®) within 1 month prior to first study drug administration.
• Have any chronic disease, except asthma, atopic dermatitis or controlled seizure disorder.
• Have documented history of current active Hepatitis B or a history of Hepatitis C infection.
• Have a documented history of human immunodeficiency virus (HIV) infection.
• Have received a transplanted organ (with the exception of a corneal transplant performed \> 3 months prior to the first study drug administration).
• 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).
• Have a history of prior lymphoproliferative disease including lymphoma.
• Have multiple sclerosis or other central demyelinating disorder.
• Have received any previous treatment with infliximab or other monoclonal antibodies
• 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.
• Are participating in another investigative trial, involving investigational agents, during participation in this trial.

Sponsors & Collaborators

• University of California, San Diego: lead
• Nationwide Children's Hospital: collaborator

Study Sites (2)

University of California, San Diego

La Jolla, California, 92093, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, United States

Location

Related Publications (8)

• 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.

  PMID: 18672254 BACKGROUND

• 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.

  PMID: 18571548 BACKGROUND

• 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.

  PMID: 17301297 BACKGROUND

• 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.

  PMID: 15574639 BACKGROUND

• 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.

  PMID: 15870671 BACKGROUND

• 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.

  PMID: 24572997 DERIVED

• 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.

  PMID: 23901839 DERIVED

• 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.

  PMID: 23305955 DERIVED

MeSH Terms

Conditions

Mucocutaneous Lymph Node Syndrome

Interventions

Infliximab

Condition Hierarchy (Ancestors)

Vasculitis; Vascular Diseases; Cardiovascular Diseases; Lymphatic Diseases; Hemic and Lymphatic Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The major limitation of our study was the low rate of treatment-resistance in the placebo arm (11%, compared to historical IVIG resistance rates of 20%), which decreased our power to detect a difference in the primary outcome measure.

Results Point of Contact

• Title: Dr. Adriana H. Tremoulet
• Organization: University of California, San Diego

atremoulet@ucsd.edu

858-246-0012

Study Officials

• Jane C Burns, M.D.

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

• Adriana H. Tremoulet, M.D.

  University of California, San Diego

  STUDY DIRECTOR

• Octavio Ramilo, M.D.

  University of Texas

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 25, 2008
• First Posted: September 26, 2008
• Study Start: March 1, 2009
• Primary Completion: October 1, 2012
• Study Completion: October 1, 2012
• Last Updated: November 24, 2014
• Results First Posted: November 13, 2014

Record last verified: 2014-11

Locations

US (2)