Etanercept in Kawaski
      Disease
       Ada Kong
    IDS presentation
       May 2009
Etanercept in Kawasaki Disease

•   Overview of Kawasaki Disease
•   Current therapy of Kawasaki Disease
•   TNF in Kawasa...
Kawasaki Disease - Overview
• Acute, febrile, systemic,
  vasculitis syndrome of early
  childhood
• Etiology unknown –
  ...
Typical symptoms of KD



                                                               4.) Conjunctivitis
1.) Redness, s...
Current therapy for KD
• Standard of care = IVIG (2g/kg) plus ASA
  (80-100 mg/kg q6h until afebrile then
  3-5mg/kg/day)
...
Tumor necrosis factor-α in KD
• KD patients demonstrate marked elevation
  in serum soluble TNF-α despite IVIG
  therapy
•...
Open Label Etanercept Pilot Study
• Open label, nonrandomized pilot study in patients
  6 mos to 5 years
• To determine sa...
Etanercept in Kawasaki:
  Study Objectives and Endpoints
Primary Objective
• To determine effectiveness of etanercept
  vs...
Study Design and Methods
• Placebo-controlled, randomized, double-
  blinded, multi-center study
• Inclusion: age 2 months...
Study Design & Methods
• Dosing:
  Etanercept 0.8mg/kg (max 50mg) S.C.
  injection or placebo once a week for 3
  weeks (d...
Study Design & Methods

• Pharmacy is unblinded and will randomize
  subject to a treatment arm
• Subject will be inpatien...
Etanercept: Drug Info
• Drug stored in IDS refrigerator
• Requires reconstitution with 1mL of
  bacteriostatic water for i...
Patient #1
• AR: 11y.o. boy with 1 week history of sore throat,
  neck pain, intermittent fever, spreading
  erythematous ...
Patient #2
• JG: 6 y.o. boy admitted 5/19 with right neck
  pain/swelling x 2wks, fever~5d, bilateral
  conjunctivitis, cr...
REFERENCES
• Treatment of Refractory Kawasaki Disease.
  UpToDate Online 17.1. Accessed May 26, 2009
• Wallace et al. Init...
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Etanercept in Kawasaki Disease: Clinical Trial Overview

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Transcript of "Etanercept in Kawasaki Disease: Clinical Trial Overview"

  1. 1. Etanercept in Kawaski Disease Ada Kong IDS presentation May 2009
  2. 2. Etanercept in Kawasaki Disease • Overview of Kawasaki Disease • Current therapy of Kawasaki Disease • TNF in Kawasaki Disease • Study Design & Methods • Case studies
  3. 3. Kawasaki Disease - Overview • Acute, febrile, systemic, vasculitis syndrome of early childhood • Etiology unknown – immunologic, infectious, genetic Coronary aneurysm in KD • Major complications: Coronary artery aneurysm leading to MI, sudden death or ischemic heart disease
  4. 4. Typical symptoms of KD 4.) Conjunctivitis 1.) Redness, swelling, peeling in palms & soles 3.) Mucositis, “strawberry tongue” AHA/AAP Diagnostic criteria: FEVER at least 5 days with no known 2.) Swelling of cause plus at least 4 out 5.) Rash lymph nodes of 5 features
  5. 5. Current therapy for KD • Standard of care = IVIG (2g/kg) plus ASA (80-100 mg/kg q6h until afebrile then 3-5mg/kg/day) • ~10-15% patients are resistant/refractory to IVIG + ASA treatment • At Children’s, 23% require retreatment and 8% may develop coronary aneurysm Wallace et al. Pediatrics 2000;105(6) • Refractoriness/resistance increases risk of CA aneurysms, hospitalization & costs
  6. 6. Tumor necrosis factor-α in KD • KD patients demonstrate marked elevation in serum soluble TNF-α despite IVIG therapy • Animal models show TNF-α antagonism abolishes coronary artery inflammation • Etanercept: soluble human TNF receptor attached to Fc portion of human IgG1 • Etanercept inexpensive relative to cost of IVIG (e.g. 10kg patient: IVIG 2g/kg = $1200 vs. Enbrel 0.8mg/kg = $510) *calculations do not consider hospitalization, #doses, IV infusion etc…
  7. 7. Open Label Etanercept Pilot Study • Open label, nonrandomized pilot study in patients 6 mos to 5 years • To determine safety & pharmacokinetics • 12 patients enrolled. First 5 patients received 0.4mg/kg SC, 0.8mg/kg SC given to all others Results: • 1 serious AE occurred but unrelated to etanercept • Only 1 patient received 2nd dose IVIG • 10 patients showed CRP normalization by day 7 • No patients developed new coronary artery dilation or aneurysm after etanercept
  8. 8. Etanercept in Kawasaki: Study Objectives and Endpoints Primary Objective • To determine effectiveness of etanercept vs. placebo in reducing IVIG refractory rate and re-treatment rate Secondary Objective(s) • To determine safety profile of etanercept • To determine if etanercept alters rate of CAD at 2 & 6 weeks of treatment • To determine pharmacokinetics of etanercept in KD
  9. 9. Study Design and Methods • Placebo-controlled, randomized, double- blinded, multi-center study • Inclusion: age 2 months to 20 years with acute KD, begun IVIG infusion within 10 days of onset • Exclusion: any lab toxicities, females >12years, severe comorbidities, prior treatment with TNF-α antagonists/steroid, active severe infections, live vaccines, immunosuppressives in last 3 mos.
  10. 10. Study Design & Methods • Dosing: Etanercept 0.8mg/kg (max 50mg) S.C. injection or placebo once a week for 3 weeks (days 0, 7, 14) • First dose of study drug within 48 hours of initializing IVIG • Concomitant therapy with IVIG and ASA is permitted
  11. 11. Study Design & Methods • Pharmacy is unblinded and will randomize subject to a treatment arm • Subject will be inpatient for first dose • Investigator will enter orders in CIS • Serum blood draw, echo, EKG performed at first dose • Parents are to record daily temperature for 2 weeks after discharge
  12. 12. Etanercept: Drug Info • Drug stored in IDS refrigerator • Requires reconstitution with 1mL of bacteriostatic water for injection • Swirl gently to avoid foaming (may take 5-10 minutes to go into solution) • Draw up dose, attach safety needle (no larger than 27gauge) • Prepared doses should be refrigerated & used within 24 hours
  13. 13. Patient #1 • AR: 11y.o. boy with 1 week history of sore throat, neck pain, intermittent fever, spreading erythematous rash and bilateral nonexudative conjunctivitis. • 5/18: Presented at ED hypotensive, transferred to PICU with concern for sepsis. Dermatology, ID, Cardiology, Opthalmology consults followed. • 5/20: Echocardiogram performed. • 5/21: Initiated IVIG plus ASA. Patient consented to study. Withdrawn from study due to suspected viremia (HSV/adenovirus/EBV/CMV). No doses of study drug given. • 5/24: 2nd dose IVIG per Rheumatology, continued monitoring of CRP & magnesium Principle Diagnosis: Kawasaki disease
  14. 14. Patient #2 • JG: 6 y.o. boy admitted 5/19 with right neck pain/swelling x 2wks, fever~5d, bilateral conjunctivitis, cracked lips, fine rash on chest. • 5/20: Echocardiogram showed dilatation of right coronary artery • Cardiology & ID consults • 5/21: 1 dose of IVIG given, ASA initiated. Patient consented to study. • 5/22: Patient withdrawn from study due to unusual clinical presentation. No study drug given. • 5/23: Patient discharged afebrile x36h. Transitioned to PO ASA Principle Diagnosis: Kawasaki Disease
  15. 15. REFERENCES • Treatment of Refractory Kawasaki Disease. UpToDate Online 17.1. Accessed May 26, 2009 • Wallace et al. Initial Intravenous Gammaglobulin Treatment Failure in Kawasaki Disease. Pediatrics 2000;105(6):e78. • Freeman A, Stanford S. Kawasaki Disease: Summary of the American Heart Association Guidelines. Am Family Physician 2006;74:1141- 1148. • Etanercept in Kawasaki Disease. IDS Pharmacy Binder.

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