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Etanercept in Kawasaki Disease

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Michael Portman, Seattle Children's Hospital
ClinicalTrials.gov Identifier:
NCT00841789
First received: February 10, 2009
Last updated: May 26, 2017
Last verified: May 2017
  Purpose
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

Condition Intervention Phase
Mucocutaneous Lymph Node Syndrome Kawasaki Disease Drug: Etanercept Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double Blind, Placebo Controlled Study of the Effects of Etanercept in Children Presenting With Kawasaki Disease

Resource links provided by NLM:


Further study details as provided by Michael Portman, Seattle Children's Hospital:

Primary Outcome Measures:
  • Determine if Etanercept at the dosing regimen of 0.8 mg/kg (50 mg max) SQ X3 doses given at weekly intervals, when used in conjunction with IVIG and aspirin will reduce the incidence of fever persistence or recrudescence. [ Time Frame: 42 days after initial dose ]
    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.


Secondary Outcome Measures:
  • Determine if the safety profile differs between the etanercept treated group and the placebo group. [ Time Frame: 42 days after initial dose ]
    The proportion of subjects with serious adverse events and hospital re-admissions prior to visit 5 will be compared using the chi-square test or Fisher's Exact test, as appropriate. The incidence of individual adverse events and serious adverse events will be tabulated using the Pediatric Heart Network Classification System.

  • Determine if Etanercept treatment alters the rate of coronary artery dilation and disease (CAD) defined by z-scores at 2 and 6 weeks after treatment. [ Time Frame: 42 days after initial dose ]

    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.

  • CRP Laboratory Measurements [ Time Frame: 42 days after initial dose ]

    Time to return to normal levels of C-Reactive protein (CRP) from admission to the visit 5 visit will be compared using Kaplan-Meier Curves. If the proportional hazards assumption is not violated, Cox Proportional Hazards Regression will be used to calculate hazard ratios.

    The proportion of subjects with normal CRP levels at the visit 5 visit will be tabulated and 95% confidence intervals will be produced.


  • Hemoglobin Laboratory Measurements [ Time Frame: 42 days after initial dose ]

    Continuous change in Hemoglobin will be compared longitudinally using mixed models for repeated measures.

    Maximum toxicity grade for anemia through visit 5 according to the common toxicity criteria for adverse events (Grade 1: See chart below * to < 10.0 g/dl, Grade 2: < 10.0 to 8.0 g/dl, Grade 3: < 8.0 g/dl) will be tabulated, and 95% confidence intervals will be produced for the proportions.



Estimated Enrollment: 196
Study Start Date: March 2009
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Enbrel
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.

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.
  Eligibility

Ages Eligible for Study:   2 Months to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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:

    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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00841789

Locations
United States, New York
Feinstein Institute for Medical Rsearch
New Hyde Park, New York, United States, 11040
Columbia University Medical Center
New York, New York, United States, 10032
Montefiore Medical Center
The Bronx, New York, United States, 10467
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Utah
Primary Children's Medical Center
Salt Lake City, Utah, United States, 84113
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
United States, Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53201
Canada, Quebec
Sainte-Justine Hospital
Montreal, Quebec, Canada, H3T 1C5
Sponsors and Collaborators
Michael Portman
Amgen
Investigators
Principal Investigator: Michael A Portman, MD Seattle Children's Hospital
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Michael Portman, Cardiologist, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT00841789     History of Changes
Other Study ID Numbers: SEA-12652
FD003526 ( Other Grant/Funding Number: FD )
Study First Received: February 10, 2009
Last Updated: May 26, 2017

Keywords provided by Michael Portman, Seattle Children's Hospital:
Etanercept

Additional relevant MeSH terms:
Mucocutaneous Lymph Node Syndrome
Vasculitis
Vascular Diseases
Cardiovascular Diseases
Lymphatic Diseases
Skin Diseases, Vascular
Skin Diseases
Etanercept
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gastrointestinal Agents
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on August 17, 2017