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

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

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

Study Overview

• Status: Completed
• Conditions: Kawasaki Disease; Mucocutaneous Lymph Node Syndrome
• Intervention / Treatment: Drug: Etanercept; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Sainte-Justine Hospital
• United States
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • New Hyde Park, New York, United States, 11040
      • Feinstein Institute for Medical Rsearch
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53201
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. Platelet count < 100,000/mm3
  2. WBC count < 3,000 cells/mm3
  3. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Coronary Artery Dimension by z Score Compared With General Estimating Equation	Overall change in coronary z score over time determined using General Estimating Equation in patients from baseline within patients. No change or improved defined by 20% change in z score. A Z score normalized for body surface area represents how much larger (or smaller) a measured coronary artery internal diameter by echocardiography is compared to the average coronary artery diameter for a child of the same size (body surface area includes both height and weight). There is no minimum or maximum value. Z score above 2.0 is at least 2 standard deviations above mean for population and is considered abnormal. A decrease in z score is favorable.	6 weeks
Overall Change in z Score Over Time in Patients With Dilated Coronary Artery at Baseline Within Patients.	Overall change in z score over time determined using General Estimating Equation in patients with dilated coronary artery at baseline within patients. Overall change in coronary z score over time determined using General Estimating Equation in patients from baseline within patients. A Z score normalized for body surface area represents how much larger (or smaller) a measured coronary artery internal diameter by echocardiography is compared to the average coronary artery diameter for a child of the same size (body surface area includes both height and weight). There is no minimum or maximum value. Z score above 2.0 is at least 2 standard deviations above mean for population and is considered abnormal. A decrease in z score is favorable.	6 weeks

Collaborators and Investigators

• Sponsor: Michael Portman
• Collaborators: Amgen

Publications and helpful links

General Publications

• Portman MA, Olson A, Soriano B, Dahdah N, Williams R, Kirkpatrick E. Etanercept as adjunctive treatment for acute Kawasaki disease: study design and rationale. Am Heart J. 2011 Mar;161(3):494-9. doi: 10.1016/j.ahj.2010.12.003.
• Portman MA, Dahdah NS, Slee A, Olson AK, Choueiter NF, Soriano BD, Buddhe S, Altman CA; EATAK Investigators. Etanercept With IVIg for Acute Kawasaki Disease: A Randomized Controlled Trial. Pediatrics. 2019 Jun;143(6):e20183675. doi: 10.1542/peds.2018-3675. Epub 2019 May 2.
• Sagiv E, Slee A, Buffone A, Choueiter NF, Dahdah NS, Portman MA. Etanercept with IVIg for acute Kawasaki disease: a long-term follow-up on the EATAK trial. Cardiol Young. 2022 May 12:1-6. doi: 10.1017/S1047951122001470. Online ahead of print.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): August 30, 2018

Study Registration Dates

• First Submitted: February 10, 2009
• First Submitted That Met QC Criteria: February 10, 2009
• First Posted (Estimate): February 11, 2009

Study Record Updates

• Last Update Posted (Estimate): May 5, 2023
• Last Update Submitted That Met QC Criteria: April 13, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Etanercept
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Lymphatic Diseases; Vasculitis; Skin Diseases, Vascular; Mucocutaneous Lymph Node Syndrome; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Etanercept
• Other Study ID Numbers: SEA-12652; FD003526 (Other Grant/Funding Number: FD)