A Randomized, Double Blind, Placebo Controlled Study of Etanercept in Children With Kawasaki Disease

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether Etanercept (Enbrel) when used in conjunction with IVIG and aspirin, improves treatment response to IVIG in patients with Kawasaki Disease. Funding Source- FDA/OOPD

Detailed Description
-----------------
Kawasaki Disease (KD) is a potentially life threatening acute vasculitis in children with a predilection for involvement of the coronary arteries. Aspirin and Intravenous gamma globulin (IVIG) are principally used for the treatment of the symptoms of Kawasaki Disease. Aspirin reduces inflammation and platelet formation, but has no effect in attenuating the development of coronary abnormalities. Although IVIG reduces inflammation and the prevalence of coronary artery abnormalities, it has a relatively high failure rate of 23-30%, warranting new treatment methods for Kawasaki Disease. We propose a placebo controlled double blinded randomized study to determine if etanercept 0.8 mg/kg subcutaneously (max 25 mg) given three times at weekly intervals starting at initial diagnosis is safe in this patient population and if it is a successful adjunct therapy with IVIG in reducing the incidence of persistent or recurrent fever.

Official Title
-----------------
A Randomized, Double Blind, Placebo Controlled Study of the Effects of Etanercept in Children Presenting With Kawasaki Disease

Conditions
-----------------
Mucocutaneous Lymph Node Syndrome, Kawasaki Disease

Intervention / Treatment
-----------------
* Drug: Etanercept
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male Age 2 months to 20 years of age Female Age 2 months to 11 years of age Provision of Parental Consent Kawasaki Disease Presentation Exclusion Criteria: Laboratory Criteria: Any laboratory toxicity, at the time of the screening visit or at any time during the study that in the opinion of the Investigator would preclude participation in the study or: Platelet count < 100,000/mm3 WBC count < 3,000 cells/mm3 Hemoglobin, hematocrit, or red blood cell count outside 30% of the upper or lower limits of normal for the Lab Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit. Female subjects diagnosed with KD 12 years of age and older. Subjects who have known hypersensitivity to Enbrel or any of its components or who is known to have antibodies to etanercept Prior or concurrent cyclophosphamide therapy Prior treatment with any TNF alpha antagonist or steroid within 48 hours prior to initiation of IVIG Concurrent sulfasalazine therapy Active severe infections within 4 weeks before screening visit, or between the screening and baseline visits. SLE, history of multiple sclerosis, transverse myelitis, optic neuritis, or chronic seizure disorder Known HIV-positive status or known history of any other immuno-suppressing disease. Any mycobacterial disease or high risk factors for tuberculosis, such as family member with TB or taking INH Untreated Lyme disease Severe comorbidities (diabetes mellitus requiring insulin, CHF of any severity, MI, CVA or TIA within 3 months of screening visit, unstable angina pectoris, uncontrolled hypertension (sitting systolic BP > 160 or diastolic BP > 100 mm Hg), oxygen-dependent severe pulmonary disease, history of cancer within 5 years [other than resected cutaneous basal or squamous cell carcinoma or in situ cervical cancer]) Exposure to hepatitis B or hepatitis C or high risk factors such as intravenous drug abuse in patient's mother, or history of jaundice (other than neonatal jaundice). SLE, history of multiple sclerosis, transverse myelitis, optic neuritis or chronic seizure disorder. Use of a live vaccine (Measles Mumps Rubella or Varicella) 30 days prior to or during this study. Any condition judged by the patient's physician to cause this clinical trial to be detrimental to the patient History of non-compliance with other therapies Must not have received immunosuppressive agents for at least three months prior to enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 2 Months
Maximum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Approximately 200 subjects will be randomized in a 1:1 ratio to receive Etanercept or Placebo. Subjects are randomized after hospital admission and diagnosis of Kawasaki Disease at eight participating sites. The primary analysis time-point is visit 5 (day 44). Sample size calculation is based on initial IVIG refractory rate at Seattle Children's. Assuming a 17.4% refractory rate in the control group and a 4.3% refractory rate in the Etanercept group, 200 subjects will provide 80% power at a 5% 2-sided type I error rate. Analyses will be based on a modified intention to treat population, including all subjects who were randomized and received at least 1 dose of study drug. Efficacy analyses will be based on randomization assignment, and safety analyses will be based on the treatment actually received. The statistical analysis plan will be finalized prior to database lock and study unblinding.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 -Etanercept<br>Drug - Treatment with Etanercept as adjunct to standard treatment with IVIG and aspirin | Drug: Etanercept<br>* etanercept 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis.<br>* Other names: Enbrel;|
| Placebo Comparator: 2<br>Placebo | Drug: Placebo<br>* Placebo 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IVIG Refractory | The primary outcome is the proportion of subjects who become refractory to IVIG. Subjects requiring 1 dose of IVIG are classified as responders and subjects requiring more than 1 dose are classified as IVIG refractory. | 42 days after initial dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine if Etanercept Treatment Alters the Rate of Coronary Artery Dilation and Disease (CAD) at 2 and 6 Weeks After Treatment in Patients With Dilated Coro | The primary echocardiographic outcome will be the proportion of subjects with improvement defined as (20% change in coronary artery) from the worst findings during the acute study period (scheduled visits from admission to visit 4, including any unscheduled visits) to the primary study outcome time-point at visit 5 (visit 5). This calculation will be based on changes in absolute values and not z-scores as initially planned. Groups will be compared using a logistic model including a binary term for age < versus > 1 year. Two aspects of the echo findings will be considered: Maximum aneurysm size and Maximum measurements for left main coronary artery (LMCA), left anterior descending artery (LAD) and right coronary artery (RCA). Change in diameter of each coronary artery will be determined at standard measurement location or aneurysm with the latter taking precedent. | 42 days after initial dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Etanercept