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Etanercept in Kawasaki Disease

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ClinicalTrials.gov Identifier: NCT00841789
Recruitment Status : Unknown
Verified April 2018 by Michael Portman, Seattle Children's Hospital.
Recruitment status was:  Active, not recruiting
First Posted : February 11, 2009
Last Update Posted : April 18, 2018
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Michael Portman, Seattle Children's Hospital

Tracking Information
First Submitted Date  ICMJE February 10, 2009
First Posted Date  ICMJE February 11, 2009
Last Update Posted Date April 18, 2018
Study Start Date  ICMJE March 2009
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 26, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 10, 2009)
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 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2017)
  • 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) 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 10, 2009)
  • Determine if the safety profile differs between the etanercept treated group and the placebo group. [ Time Frame: 42 days after initial dose ]
  • 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 ]
  • Determine the pharmacokinetics of Etanercept in KD patients. [ Time Frame: 42 days after initial dose ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Etanercept in Kawasaki Disease
Official Title  ICMJE A Randomized, Double Blind, Placebo Controlled Study of the Effects of Etanercept in Children Presenting With Kawasaki Disease
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE
  • Mucocutaneous Lymph Node Syndrome
  • Kawasaki Disease
Intervention  ICMJE
  • 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
  • Drug: Placebo
    Placebo 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis.
Study Arms  ICMJE
  • Experimental: Arm 1 -Etanercept
    Drug - Treatment with Etanercept as adjunct to standard treatment with IVIG and aspirin
    Intervention: Drug: Etanercept
  • Placebo Comparator: 2
    Placebo
    Intervention: Drug: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: November 11, 2013)
196
Original Estimated Enrollment  ICMJE
 (submitted: February 10, 2009)
220
Estimated Study Completion Date  ICMJE August 2018
Actual Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Months to 20 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00841789
Other Study ID Numbers  ICMJE SEA-12652
FD003526 ( Other Grant/Funding Number: FD )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Michael Portman, Seattle Children's Hospital
Study Sponsor  ICMJE Michael Portman
Collaborators  ICMJE Amgen
Investigators  ICMJE
Principal Investigator: Michael A Portman, MD Seattle Children's Hospital
PRS Account Seattle Children's Hospital
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP