Clinical trial NCT00841789
Conditions: Mucocutaneous Lymph Node Syndrome Kawasaki Disease
Keywords: Etanercept
Sponsor: Michael Portman
Start date: 2009-03-01; Completion date: 2018-08-30
Enrollment: 205 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Drug - Treatment with Etanercept as adjunct to standard treatment with IVIG and aspirin arm 2: Placebo
Interventions: intervention 1: Etanercept intervention 2: Placebo
Intervention descriptions: intervention 1: etanercept 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis. intervention 2: Placebo 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis.

Protocol documents:
Prot_SAP_000.pdf: 
 
  Seattle Children’s Hospital 
 
 
 
 
 
 
  
 
ETANERCEPT IN KAWASAKI DISEASE 
IND 101,223 
 
A randomized, double blind, placebo controlled study of the effects of etanercept in subjects presenting 
with Kawasaki Disease 
 
Research Study Protocol 
 
Sponsor-Investigator: 
Michael A. Portman, MD 
Department of Pediatrics/ Cardiology 
1900 9th Avenue 
Seattle, WA 98101 
(206) 987-1014  
Funding Source: 
FDA 
5600 Fishers Lane 
Rockville, MD 20857-0001 
1-888-463-6332 
 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 
91320-1799 
(805) 447-1000 
Study Product: 
Etanercept (trade name: Enbrel) 
 
Date: 
28 JUL 2008 
Amendment: 
 
 
 
 
 
1    06 JAN 2009 
2    09 MAY 2009 
3    12 OCT 2009 
4    13 APR 2010 
5    22 NOV 2010 
6    05 MAY 2011 
7    04 APR 2013 
8    06 JUL 2015 
 


 
 
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CONFIDENTIAL 
This material is the property of the Seattle Children's Research Institute.  Do not disclose or use except as authorized in writing by the study 
sponsor-investigator. 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document is confidential and the property of the Children's Hospital and Regional 
Medical Center.  No part of it may be transmitted, reproduced, published, or used by other 
persons without prior written authorization from the study sponsor-investigator. 
 
 
 
 
 
 
 


 
 
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sponsor-investigator. 
Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................................. 7 
1.1 
BACKGROUND ............................................................................................................................................. 6 
1.2 
INVESTIGATIONAL AGENT ......................................................................................................................... 10 
1.3 
PRELIMINARY DATA .................................................................................................................................. 12 
1.4 
DOSE RATIONALE ...................................................................................................................................... 15 
2 
STUDY OBJECTIVES .................................................................................................................................... 16 
3 
RESEARCH DESIGN AND METHODS ...................................................................................................... 17 
3.1 
PRIMARY CLINICAL ENDPOINT .................................................................................................................. 17 
3.2 
SECONDARY CLINICAL ENDPOINTS ........................................................................................................... 18 
3.3 
DOSING ..................................................................................................................................................... 18 
4 
PATIENT POPULATION AND SAMPLE SIZE ......................................................................................... 19 
4.1 
INCLUSION CRITERIA ................................................................................................................................. 19 
4.2 
EXCLUSION CRITERIA ............................................................................................................................... 20 
4.3 
SAMPLE SIZE ............................................................................................................................................. 21 
4.4 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................. 22 
4.5 
EARLY WITHDRAWAL OF SUBJECTS .......................................................................................................... 22 
4.5.1 
When and How to Withdraw Subjects .................................................................................................. 22 
4.5.2 
Data Collection and Follow-up for Withdrawn Subjects ..................................................................... 22 
4.5.3 
Emergency Blind Breaking .................................................................................................................. 22 
 
5 
STUDY DRUG ................................................................................................................................................. 22 
5.1 
DESCRIPTION ............................................................................................................................................. 22 
5.2 
TREATMENT REGIMEN .............................................................................................................................. 23 
5.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................................................ 23 
5.4 
SUBJECT COMPLIANCE MONITORING ........................................................................................................ 23 
5.5 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 23 
5.6 
PACKAGING ............................................................................................................................................... 23 
5.7 
RECEIVING, STORAGE, DISPENSING AND RETURN ..................................................................................... 23 
5.7.1 
Receipt of Drug Supplies ..................................................................................................................... 23 
5.7.2 
Storage ................................................................................................................................................. 24 
5.7.3 
Dispensing of Study Drug .................................................................................................................... 24 
5.7.4 
Return or Destruction of Study Drug ................................................................................................... 24 
6 
STUDY PROCEDURES .................................................................................................................................. 24 
6.1 
VISIT 1 ...................................................................................................................................................... 25 
6.2 
VISIT 2 ...................................................................................................................................................... 27 
6.3 
VISIT 3 ...................................................................................................................................................... 28 
6.4 
VISIT 4 ...................................................................................................................................................... 27 
6.5 
VISIT 5 ...................................................................................................................................................... 27 
6.6 
ECHOCARDIOGRAPHY ................................................................................................................................ 27 
6.7 
PHARMACY PROCEDURES .......................................................................................................................... 27 
 
7 
STATISTICAL DESIGN AND ANALYSIS .................................................................................................. 27 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 28 
8.1 
DEFINITIONS .............................................................................................................................................. 28 
8.2 
RECORDING OF ADVERSE EVENTS............................................................................................................. 30 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................... 32 
8.3.1 
DMC Notification by Investigator ....................................................................................................... 32 


 
 
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sponsor-investigator. 
8.3.2 
IRB Notification by Investigator .......................................................................................................... 32 
8.4 
STOPPING RULES ....................................................................................................................................... 32 
8.5 
SAFETY MONITORING................................................................................................................................ 32 
8.5.1 
Indepedent Data Monitoring Committee ............................................................................................. 32 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 33 
9.1 
CONFIDENTIALITY ..................................................................................................................................... 33 
9.2 
SOURCE DOCUMENTS ................................................................................................................................ 34 
9.3 
CASE REPORT FORMS ................................................................................................................................ 34 
9.4 
RECORDS RETENTION ................................................................................................................................ 34 
10 
COMPLIANCE AND MONIOTRING .......................................................................................................... 34 
10.1 
DATA MANAGEMENT ................................................................................................................................ 35 
10.2 
CONFLICTS OF INETEREST.......................................................................................................................... 35 
10.3 
TIMING AND PURPOSE OF THE DMC MEETINGS ........................................................................................ 36 
10.4 
PROCEDURES TO ENSURE CONFIDENTIALITY AND PROPER COMMUNICATION ............................................ 36 
10.5 
DATA MONITORING GUIDELINES .............................................................................................................. 38 
10.6 
CONTENT OF THE DMC'S SESSION REPORTS .............................................................................................. 38 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 38 
12 
STUDY FINANCES ......................................................................................................................................... 39 
12.1 
FUNDING SOURCE ..................................................................................................................................... 39 
12.2 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................ 39 
13 
REFERENCES ................................................................................................................................................. 40 
14 
ATTACHMENTS ............................................................................................................................................ 43 
ATTACHMENT 1     CONSENT FORM .............................................................................................................................. 
ATTACHMENT 2     HIPAA AUTHORIZATION FORM ..................................................................................................... 
ATTACHMENT 3     CASE REPORT FORMS ..................................................................................................................... 
 
DISEASE HISTORY ......................................................................................................................................... 
 
IVIG TREATMENT DETAILS .......................................................................................................................... 
 
IVIG RETREATMENT DETAILS ...................................................................................................................... 
 
LAB TESTS .................................................................................................................................................... 
 
DEMOGRAPHIC DATA .................................................................................................................................... 
 
ECHOCARDIOGRAPHY DATA ......................................................................................................................... 
 
INTERNAL ADVERSE EVENTS FORM .............................................................................................................. 
 
INTERNAL SERIOUS ADVERSE EVENTS FORM ................................................................................................ 
 
TEMPERATURE LOG....................................................................................................................................... 
ATTACHMENT 4     ADVERSE EVENTS REPORTING FORM ............................................................................................. 
ATTACHMENT 5     DATA MONITORING COMMITTEE CHARTER ................................................................................... 
 
 
  


 
 
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sponsor-investigator. 
 
List of Abbreviations 
 
 
AE:  adverse event 
AHA:  American Heart Association 
AAP:  American Academy of Pediatrics 
AST:  aspartate aminotransferase  
ALT: alanine aminotransferase 
CBC:  complete blood count   
CHO:  Chinese hamster ovary  
CHRMC:  Children's Hospital and Regional Medical Center 
CRC:  Children’s Research Institute Clinical Research Center  
CRF:  case report form 
CRP:  C-reactive protein  
DMC: Data Monitoring Committee  
DNA:  deoxyribonucleic acid 
Echo:  echocardiogram  
EKG:  electrocardiogram 
ESR:  erythrocyte sedimentation rate  
FDA:  Federal Drug Administration 
HIPAA:  Health Insurance Portability and Accountability Act of 1996 
Ig:   immunoglobulin 
IV:  intravenous 
IVIG: intravenous immunoglobulin  
IRB:  Institutional Review Board 
KD:  Kawasaki Disease 
PCRC:  Pediatric Clinical Research Center 
PHI:  private health information 
PI:  Principal Investigator 
PK:  pharmacokinetics  
PPD:  purified protein derivative 
SAE: serious adverse event 
TNF:  tumor necrosis factor 
TNFR:  tumor necrosis factor receptor  
 
 


PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR         Portman, Michael A.  
CONFIDENTIAL 
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6
Study Summary 
 
 
Title 
Etanercept in Kawasaki Disease 
Study Phase 
Clinical phase II study 
Methodology 
Randomized double blind placebo controlled clinical study 
Study Duration 
4 years 
Study Centers 
Children's Hospital and Regional Medical Center, Primary Children’s 
Medical Center, Children’s Hospital of Wisconsin, Sainte-Justine 
Hospital, Steven & Alexandra Cohen Children's Medical Center of New 
York, Texas Children’s Hospital, Columbia University Medical Center, 
and Montefiore Medical Center. 
Objectives 
Determine if etanercept (0.8 mg/kg, maximum 50 mg) given 
subcutaneously reduces IVIG refractory rate and retreatment rate in the 
KD patient population. 
Number of Subjects 
196 
Diagnosis and Main 
Inclusion Criteria 
Patients aged 2 months to 20 years of age presenting with Kawasaki 
Disease as defined by the American Academy of Pediatrics and the 
American Heart Association. 
Study Product, Dose, 
Route, Regimen 
Etanercept (trade name: Enbrel) 
3 weekly subcutaneous injections at 0.8 mg/kg dosage 
Reference therapy 
Single infusion of IVIG (2 g/kg) with aspirin  


PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR         Portman, Michael A.  
CONFIDENTIAL 
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7
1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according to U.S. and 
international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures.  
1.1 Background 
We propose a clinical trial evaluating a novel therapy for Kawasaki Disease (Syndrome).  We intend to use the 
data obtained in this study to apply for an Orphan Product Designation for Etanercept (brand name Enbrel). 
Kawasaki is classified as an autoimmune disease and disseminated vasculitis.  It is characterized by fever, 
bilateral, nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, 
and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop and may lead to myocardial 
infarction (MI), sudden death, or ischemic heart disease. This disease is more prevalent in Japan and in children 
of Japanese ancestry with an annual incidence of 112 cases per 100 000 children < 5 years old.  The KD 
incidence in the United States has been estimated from hospital discharge data 1 at approximately 4000 cases 
per year.  Unfortunately, the data do not include many Western States such as Washington, which have large 
KD populations, and thus represent underestimates.  Nevertheless, Holman et al  estimated that 4248 
hospitalizations associated with Kawasaki disease occurred in the United States in 2000 with a median age of 2 
years.2    Accordingly, KD is becoming a major health problem in the United States, but qualifies for Orphan 
Disease status as less than 200,000 individuals are affected.   In the United States, the disease has surpassed 
Rheumatic Fever as the most frequent cause of acquired heart disease in children.  
A combination of aspirin and intravenous gamma globulin (IVIG) is the current standard regimen for 
treatment of acute KD3. Although aspirin has important anti-inflammatory activity at high doses and antiplatelet 
activity at low doses, it does not alter the risk for coronary artery disease.  Intravenous gamma globulin now 
represents the standard for treatment.  IVIG is not a specific therapy and the mechanism of action in KD still 
requires clarification.  Recent data support a hypothesis, that IVIG modulates immune response in KD through 
FcGamma receptors on inflammatory cells 4-7.  Some studies suggest that immune modulation by IVIG is 
impaired in patients with specific polymorphisms for FcGamma receptors.  This hypothesis is currently under 
investigation in our own laboratory using a large cohort of patient DNA collected in a multi-center consortium.  
Despite substantial research in the field including clinical trials, there has been no major shift in the 
treatment paradigm for acute Kawasaki Disease since the introduction and refinement of immune gamma 
globulin therapy in the 1980s 8; and 1990s9.  The vast majority of the research in this area focuses on 
epidemiology, identification of risk factors for coronary artery involvement, genetic susceptibility, refinement 
of current therapy such as the addition of corticosteroids, and the identification and treatment of long term 
sequela 10. Recent studies report the incidence of persistent coronary artery involvement in the 15-20% range 
despite treatment and as high as 30% in non-responders to IVIG. 11 This growing affected population will age, 
and the impact of coronary artery lesions attained in childhood may be immense.  Recent reports from Japan 
indicate that the mortality rate in males with coronary artery lesions is more than twice expected.10.   Therefore, 
the primary goals of therapy should be directed at reducing coronary artery dilation in addition to treating active 
inflammation.  
 
Efficacy of current treatment: The joint statement of the American Heart Association and the American 
Academy of Pediatrics states emphatically that “the efficacy of IVIG administered in the acute phase of 
Kawasaki disease in reducing the prevalence of coronary artery abnormalities is well established.” 3 The first 
major controlled randomized trials in KD patients in the United States (1986) showed superior prevention of 
coronary artery disease in children with acute KD by IVIG and ASA versus ASA alone8.  Subsequently, 
Newburger et al showed that a single high dose of IVIG (2g/kg) administered over 10 hours reduced the 


PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR         Portman, Michael A.  
CONFIDENTIAL 
This material is the property of the Seattle Children's Research Institute.  Do not disclose or use except as authorized in writing by the study sponsor-investigator. 
8
prevalence of coronary abnormalities compared to daily infusions of 400 mg per kilogram for four consecutive 
days.  Both groups also received ASA (100 mg per kilogram per day) for 14 days 12.  Accordingly, AHA/AAP 
guidelines recommend IVIG 2g/kg in a single dose with some modifications in ASA dosing.  In Japan, where 
prevalence of KD is substantially higher than in the U.S., IVIG is usually given two separate 1g/kg doses on 
consecutive days 13. 
Although the historical studies show that IVIG prevents coronary artery dilation 8, 12, the failure rate of 
this nonspecific treatment for KD remains high14. It is difficult to determine current IVIG efficacy, as criteria 
and technological advances have altered for reporting coronary artery disease (CAD), and we could not 
ethically perform a randomized placebo trial excluding affected patients from receiving IVIG.  Discrepancies 
exist between rates of IVIG failure reported from Japan and the United States 13, 14. These differences are 
partially due to methodology in defining coronary artery dilation.  The discrepancies create challenges in 
interpretation and performing comparisons of clinical trials, as well as evaluation of new adjunctive therapies. 
For instance, Inoue et al reported that only 3.4% of patients had CAD by 1 month after receiving the standard 
Japanese IVIG regiment13, while the most recent U.S. multicenter trial reported 18.9% CAD in all patients at 6 
weeks, and 9% for patients without CAD at baseline14.  
0
5
10
15
20
25
30
35
ASA-1986
IVIG+ASA-1986
IVIG+ASA-1991
IVIG+ASA- 2007
IVIG+ASA+IMP-2007
Baseline
2 Weeks
6 Weeks
 
Figure 1.  Percentage of patients with coronary artery disease extracted from several clinical studies 
performed in the U.S.   Data is reported chronologically along x-axis,  Newburger et al 19868,   groups 
receiving ASA or  IVIG + ASA;   Newburger et al 199112, group receiving single dose IVIG 2gm/kg with 
ASA;  Newburger et al, 200714, groups receiving IVIG 2gm/kg with ASA, or IVIG + ASA + pulse methyl-
prednisilone.   Note the discrepancy in CAD reporting between IVIG-ASA-1991 and IVIG-ASA-2007 (see 
text).   
 
 In figure 1, we show the incidence of coronary artery disease reported for three major multi-center 
clinical trials performed in the United States over a twenty year period.  This figure clearly shows an increase in 
the reported rate of CAD in KD patients undergoing these trials between 1986 and 2007.  The data suggest that 
changes in echocardiographic interpretation and reporting are largely responsible for the trend in the U.S. and 
differences with Japanese studies. The first paragraph of the 2004 AHA/AAP consensus statement, Newburger 
et al states: “coronary artery aneurysms or ectasia develop in ~15% to 25% of untreated children with the 
disease.” 3   However as noted, the Pediatric Heart Network (PHN) study in New England Journal 2007 reports 


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CONFIDENTIAL 
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9
18.9% of patients with CAD after standard IVIG treatment 14.  This rate for persistent CAD at 6 weeks falls 
within the range quoted in the 2004 consensus document for CAD in untreated patients.  The recent PHN data 
show that 30% of all KD patients have CAD involvement by 1 week, and 9% of patients without abnormalities 
at baseline still develop CAD despite treatment with IVIG.   Additionally, a recent retrospective review 
indicates that a high rate of persistent coronary artery dilation or aneurysms occurs in infants > 1 year of age 
despite treatment with IVIG 15. 
Disappearance of fever within 48 hours generally heralds a successful response to therapy.  However, 
Burns et al reported that 13% of 378 patients remained febrile after 48 hours 16.  From our institution Wallace et 
al reported 23% of patients either did not respond initially or had fever recurrence within 10 days 11.  New data 
from our institution suggest that the refractory rate may be somewhat higher (see section C). The published 
reports emphasize doubling in the relative risk of coronary artery disease in patients with initial IVIG treatment 
failure.  Recent studies by the Pediatric Heart Network support the tenet that we have been under diagnosing 
CAD in the KD population 17.   However, the published multi-center study did not directly evaluate rate of CAD 
in patients, refractory to initial IVIG.  Extrapolating from prior data relating two-fold increased risk in patients 
not receiving IVIG 8suggests that CAD may occur in up to 35% in these patients at 6 weeks after initial IVIG, 
and supports estimates of increased risk published by Burns et al18and Wallace et al11.  
Physicians treating KD have recognized the limited efficacy of IVIG, and have searched for adjunctive 
therapies, which would lessen CAD and reduce the IVIG refractory rate.  Corticosteroids are traditionally used 
in treatment of other types of vasculitis.  An early study by Kato suggested that steroids exert a detrimental 
effect when used as initial treatment for KD19.   Subsequent studies have established safety for corticosteroids 
during KD, but efficacy trials have shown mixed results with regard to reducing IVIG failure and CAD13, 14.  
Two recent prospective studies have been published examining these issues.   Inoue et al performed a 
prospective non-blinded randomized study using standard IVIG and ASA with or without daily doses of IV 
methylprednisilone until defervescence followed by daily oral predinisolone until normalization of CRP13.  In 
this multi-center Japanese study, the corticosteroid group showed a reduction in CAD early in the disease, 
which did not persist past 4 weeks.  Initial IVIG treatment failure was reduced in the corticosteroid group.  The 
primary end-point, CAD up to 1 month, was not determined in an unblinded fashion, and CAD was judged by 
Japanese Ministry of Health Criteria.  The rates of CAD at all time points were therefore far less than reported 
in most recent studies performed in the U.S, which employ coronary artery z-scores to grade CAD14.   This 
includes the recent study performed by Newburger and the Pediatric Heart Network Investigators14.  The PHN 
multi-center placebo controlled and double blinded study showed that a single pulse methyl-prednisilone dose 
in addition to IVIG did not reduce the rate of CAD at any time-point in the disease up to 5 weeks after 
treatment.  The rate of initial IVIG failure was also not reduced.  In summary, these latter randomized studies, 
whether performed in a blinded design or not did not show important clinical change in CAD or alteration in 
IVIG resistance.    
Data from Inoue et al suggest that more prolonged anti-inflammatory therapy in addition to IVIG and 
ASA may ameliorate early CAD in acute KD13.  It is not clear whether this amelioration is related to a reduction 
in the rate of IVIG refractoriness or to the prolonged nature of the treatment compared to the standard regimen.   
IVIG is a non-specific therapy, and its therapeutic mechanism in KD still requires clarification.  The 
infusions require hospitalization and adverse events are common.  Infusions are interrupted for fever spikes, 
which is obviously problematic in febrile illness such as KD.   
Replacement of IVIG will be difficult due to ethical issues caused by the putative therapeutic response.  
Despite development of new, specific, and more powerful anti-inflammatory agents, it is unlikely that a 
randomized trial between IVIG and a new therapy could be approved by an Institutional Review Board.  
Accordingly, the first step would be substantiation of a new therapy as an important adjunctive therapy.  
 
The overall data support the need for development or validation of adjunctive therapy for KD that should have 
the following attributes:  


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10
 
1) 
therapy is specific and directed at blocking an established inflammatory pathway, known to be 
activated in KD 
2) 
treatment is prolonged extending at least 2 weeks after initial IVIG treatment and through the 
entire phase of acute KD and into the convalescent phase 
3) 
therapy can be validated by maintenance of steady-state drug levels throughout the treatment 
period 
4) 
therapy has an excellent safety profile in children 
5) 
therapy is cost-effective and convenient  
 
Tumor necrosis factor-α (TNF-α) in KD 
Features of Kawasaki Disease including vascular inflammation, high fever and marked elevation of the acute 
phase protein, CRP, implicate cytokines as key role players in the pathogenesis. Several cytokines are elevated 
in the acute phase of KD including TNF-α, interleukin-1 and interleukin-620-24.   However, TNF-α has received 
particular attention for several reasons.  TNF-α activation of macrophages includes enhanced production and 
release of TNF-α receptor25.  Patients with KD demonstrate marked elevation in serum soluble TNF-α receptor 
with even higher levels in patients with coronary artery ectasia, despite IVIG treatment 26.   Immunochemistry 
studies show that CD14 peripheral blood monocytes/macrophages during acute KD strongly expressed TNF-α 
in their cytoplasm27. Expression of TNF-α weakens in the convalescent phase, suggesting that some of the 
intracytoplasmic granules in these monocytes/ macrophages are secretory granules, which secrete TNF-α27.  
TNF-α promotes migration of P-selectin and production of E-selectin promoting conformational changes in 
endothelium, which may promote vascular dilatation and coronary aneurysm noted in KD 28.    
 
The hypothesis that TNFα promotes coronary artery inflammation is supported by data obtained in a well 
established mouse model of KD, created through intraperitoneal injection of L. Casei wall extract.  These mice 
develop coronary artery inflammation, ectasia, and aneurysms, which histopathologically resemble coronary 
artery lesions seen in postmortem studies from children with KD.  Coronary artery inflammation and vessel 
wall damage are absent in wild-type mice treated with the TNF-α receptor blocker, Etanercept (8 mg/kg twice 
weekly times four weeks, intraperitoneal), and in TNFRI-deficient (TNFRI-/-) mice 20. Coronary artery 
inflammation and ectasia does occur in mice deficient for TNFRII, which does not bind TNF-α in mice. 
Therefore, TNF-α plays an important role in the pathogenesis of coronary artery inflammation in this model.   
In summary, KD patients show activation of TNF-α pathway, and animal models show that TNF-α antagonism 
abrogates coronary artery inflammation.     
 
Pentoxifylline is a methyl-xanthine compound and phosphodiesterase inhibitor that inhibits TNF-α messenger 
RNA transcription.  A single study showed a trend towards improved prevention of CAD when using 
pentoxifylline in addition to ASA and low dose IVIG, compared to ASA and low dose (IVIG 1 gm/kg total)29.  
The study had relatively few patients and was likely not empowered to detect significant differences between 
groups.  Furthermore, the subsequent development of more specific TNF antagonists relegates this strategy to 
obscurity.   The study does suggest that early and prolonged antagonism of the TNF-α pathway might prevent 
CAD in KD patients.  
 
The TNF antagonists fall into 2 classes: monoclonal antibodies and soluble receptors30. Etanercept (Enbrel®, 
Thousands Oaks, CA) is a soluble TNF receptor, while infliximab (Remicade®, Horsham, PA) and adalimumab 
(Humira®, Abbott Park, ILL) are monoclonal antibodies against TNF.  These agents are now widely used for 
the treatment of rheumatoid arthritis including juvenile onset and other inflammatory diseases. As of December 
2006, more than 400,000 patients worldwide had been treated with etanercept and more than 500,000 had been 


PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR         Portman, Michael A.  
CONFIDENTIAL 
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11
treated with infliximab 31. As of August 31, 2004, 10,050 patients with RA had enrolled in adalimumab 
clinical trials worldwide31.  Infliximab is used for inflammatory bowel disease in children, while Etanercept is 
FDA approved for use in JRA for children down to 2 years of age.  
1.2 Investigational Agent 
Etanercept, a dimeric fusion protein, consists of 2 molecules of the extracellular ligand-binding portion of 
human TNF receptor 2 attached to the Fc domain of human IgG131. Infliximab is a chimeric IgG1 monoclonal 
antibody composed of human constant and murine variable regions 32, whereas adalimumab is a recombinant 
human IgG1 monoclonal antibody33. Each infliximab or adalimumab molecule can bind up to 2 TNF molecules; 
a single TNF homotrimer can bind up to 3 molecules of infliximab or adalimumab 34. In contrast, etanercept 
binds to the interface of 2 TNF subunits in a 1:1 ratio 35.   These differences in binding avidity suggest that 
Etanercept may be easier to titrate according to treatment effect without inducing adverse effects or resistance.   
However, it is also possible that the monoclonal antibodies may be more potent and effective inhibitors of TNF.  
The pharmacokinetics of the drugs delivered by subcutaneous route, etanercept and adalimumab, show that 
blood concentration levels are subjected to less severe peaks and troughs than infliximab, delivered by 
intravenous infusion36, 37.  
 
In 2004, isolated case reports of infliximab use for refractory KD began to appear in the literature38.  Burns et al 
then retrospectively reviewed the experience of clinicians in the United States, who had used inflixmab for KD 
patients with either persistent vasculitis or persistent or recrudescent fever > 48 hours after treatment with IVIG 
39.   None of these publications discuss exactly why infliximab was chosen over other TNF inhibitors.  This is 
curious as pharmacokinetics and safety data in younger children, was and is available for Etanercept alone40, 41.  
The retrospective analysis performed by Burns et al showed that complete response, indicated by resolution of 
fever, was documented in 10/16 patients39.  Infliximab therapy was initiated late in the disease and the majority 
of these patients already had coronary vasculitis prior to administration of a TNF-α blocker.  One patient with 
severe coronary artery aneurysms preceding treatment died at home.  The data from this retrospective review 
served as background to initiate an ongoing clinical phase I trial of infliximab versus repeat IVIG infusion for 
refractory KS.  No information regarding the progress of this study has been published.  
 
Etanercept for the proposed study is available and will be provided free of charge by Amgen (see 
supporting letter).  
 
Etanercept is FDA-approved for use in the U.S. for reducing signs and symptoms of moderate to severe adult 
rheumatoid arthritis, moderate to severe juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, 
and chronic moderate to severe plaque psoriasis.  It has been approved for use in patients 2 years of age and 
older (ages < 17 yrs for juvenile rheumatoid arthritis patients only).  Since its market approval in November 
1998, over 400,000 patients have been estimated to have received etanercept therapy42.    
 
Etanercept lowers concentration of proinflammatory cytokines such as TNF-α, IL-3 and IL-6 in patients with 
several inflammatory diseases43, 44.   As noted above these cytokines, and in particular, TNF-α, are implicated 
as proinflammatory agents in KD.  Thus, Etanercept modulation of these cytokines may reduce inflammation in 
KD.  
 
Potential toxicity: Randomized, double-blind, placebo-controlled trials showed that etanercept treatment had 
significant clinical benefit with minimal toxicity in adults with active rheumatoid arthritis that did not respond 
to other disease modifying drugs45-47. In following, The Pediatric Rheumatology Collaborative Study Group 
evaluated safety and efficacy in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or 
had an inadequate response to methotrexate48. Patients 4 to 17 years old  received 0.4 mg of etanercept per 


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12
kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of 
a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly 
assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. At the 
end of the open-label study, 51 of the 69 patients (74 percent) had responses to etanercept treatment. In the 
double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, 
as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to 
disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). 
 
 In the open-label study, the most common adverse events were injection-site reactions (39 percent of patients), 
upper respiratory tract infections (35 percent), headache (20 percent), rhinitis (16 percent), abdominal pain (16 
percent), vomiting (14 percent), pharyngitis (14 percent), nausea (12 percent), gastrointestinal infection (12 
percent), and rash (10 percent).  In the double-blind study, there were no significant differences in the 
frequencies of adverse events between patients who received etanercept and those who received placebo. 
Injection-site reactions occurred in one patient in each of the treatment groups in the double-blind study. There 
were no laboratory abnormalities requiring urgent treatment in the etanercept group.    
 
In an open label extension study after 4 years of treatment 49, the rate of SAEs was 0.13 per patient-year, and the 
rate of serious infections was 0.04 per patient-year, in a total etanercept exposure of 225 patient-years.   Serious 
infections included postoperative chin implant infection (n=1), wound infection (n=1), severe gastroenteritis 
(n=1), herpes zoster (n =1), and appendicitis (n = 1).  The investigators concluded that Etanercept offered 
sustained benefit and an acceptable safety profile in children with JRA down to age 4 years.  
 
Heart Failure:   TNF-α antagonists have been linked to heart failure. This may be a concern as many patients 
with KD have myocarditis.   In fact, Etanercept (Enbrel) has not been implicated in worsening of heart failure. 
Two Enbrel studies for chronic heart failure were terminated due to lack of efficacy, not because of an increase 
in mortality or adverse events.   However, a study with infliximab was stopped early because of increased 
mortality in the treatment group. In this regard, Enbrel appears to have a superior safety profile compared to 
Infliximab.  In their review of TNFα antagonism and heart failure, Gullestad and Aukrust 50 highlight the 
differences between these two drugs.  The chimeric anti-TNF-α antibody (Infliximab), which is studied in 
patients with CHF, directly binds to the transmembrane form of TNF-α, resulting in damage of TNF-α–
expressing cells including cardiomyocytes by antibody-dependent cellular toxicity, by complement-dependent 
cytotoxic effector mechanisms, and by induction of apoptosis 51.  This is not an issue with Etanercept, which is 
a fusion protein containing two portions of the TNFα receptor.    Burns et al review of KD patients receiving 
Infliximab shows no cases of heart failure or complications in KD patients, except for one death 39. This patient 
died at home after diagnosis with very large coronary artery aneurysms, and had additional risk factors 
including multiple treatments with methyl-prednisolone and clopidogrel (no autopsy performed). Burns et al 
considered heart failure concerns in their review of these patients all of whom probably have subclinical 
myocarditis.  No adverse effect on myocardial contractility was noted.  Despite the study in adults with heart 
failure; showing increased mortality in infliximab patients, Dr. Jane Burns has a study registered on 
Clinicaltrials.gov entitled “Infliximab (Remicade) for Patients With Acute Kawasaki Disease”.   Subsequent to 
the report in the European Journal of Heart Failure regarding suspension of the Enbrel studies, the FDA and 
Duke Clinical Research Institute reviewed cases reported to Medwatch of heart failure after therapy with tumor 
necrosis factor antagonists52. The vast majority of these patients were elderly with risk factors for senescent 
cardiomyopathy or ischemic heart disease. Only 4 patients on Etanercept younger than 50 years of age reported 
new-onset heart failure with the youngest at 29 years and the shortest duration of drug treatment 5 months. It is 
unclear if the heart failure related to primary disease or drug. Safety data in the Pediatric population has been 
reported for Polyarticular JRA40, 48, 49.  No case of heart failure was reported in 69 patients receiving Etanercept 
in the open-label trial or in the 25 enrolled in the Etanercept trial. At present, there is absolutely no data 


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13
indicating increased risk of heart failure in young patients receiving Etanercept, and certainly no data 
substantiating increase risk after treatment with Etanercept for a very short term course, such as two  or three 
weeks.   
 
In summary: the data show that Etanercept is well-tolerated with few adverse effects in a Pediatric population, 
and no more SAEs occur in the treatment group than the placebo group when given for several months.    
 
Cost:   Etanercept (Enbrel at $170/25mg-vial) is inexpensive relative to cost of IVIG (pharmacy cost = $60/gm) 
for the majority of KD patients.   
 
 
TABLE 1.    Actual pharmacy cost for IVIG versus Etanercept per patient weight.  
 
Patient Weight 
(Kg) 
IVIG 2 gm/kg  
Enbrel – 3 
(0.8 mg/kg) 
doses 
10 
$  1200 
$510 
20 
$  2400 
$510 
30 
$  3600 
$510 
These calculations do not consider additional cost involved in readmission such as hospitalization days, IV 
infusion, etc.   
1.3 Preliminary Data 
 
Open Label Study.  The Principal Investigator proposed and initiated a pilot study.  The FDA waived IND for 
the pilot study.   After scientific review of Dr. Portman’s 
study, Amgen provided funding to support the research.  Dr. 
Portman serves as sponsor for the investigator initiated pilot 
study. We performed an open label nonrandomized study 
evaluating safety and pharmacokinetics of Etanercept in 
patients aged 6 months to 5 years.  The enrollment goal is 15 
patients. On January 30, 2008 we enrolled the 12th patient. 
The first 5 patients received 0.4mg/kg etanercept 
subcutaneously, and patients afterward received 0.8mg/kg.  
Doses were given within 12 hours of completing IVIG 
infusion, at 7 days and at 14 days (see study schema in Section 
D).  Demographics of patients are shown in Table 2.    
 
Safety:  No patient required readmission after initial 
discharge. Two patients had mild upper respiratory infections 
associated with similar symptoms in family members after 
discharge; one of these had a single fever spike 3 weeks after 
IVIG treatment, which resolved quickly without treatment 
other than acetaminophen. One additional patient had otitis 
media, which required antibiotics. One patient vomited several 
times after eating “Chinese Food”.   Only one serious adverse event occurred. One patient was treated with 
IViG and subsequently Etanercept.  Although, the patient had 4 criteria and persistent fever qualifying for the 
diagnosis of Kawasaki Disease as well as negative blood cultures, he developed hydrocephalus caused by 
TABLE 2.  DEMOGRAPHICS FOR 
ETANERCEPT SUBJECTS 
 
 
 
Subject 
Weight (kg) 
Age (months) 
 
 
 
1 
16.1 
46 
2 
13.1 
25 
3 
13.9 
27 
4 
6.9 
9 
5 
31.4 
67 
6 
9.9 
11 
7 
12.0 
35 
8 
23.5 
55 
9 
14.5 
41 
10 
7.7 
11 
11 
15.7 
57 
      12 
          12.2 
              27 
MEAN 
14.7 
34.25 
STDEV 
6.8 
19.3 


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14
meningococcal meningitis.  The patient was treated with antibiotics and recovered.  The DMC and IRB 
agreed that this SAE was unrelated to Etanercept, but emphasized the importance of eliminating other infectious 
diseases, when making the diagnosis of KD.  
 
Efficacy:   This was a single arm open label design and not an efficacy study.   However, we can make salient 
comments about these data.   Unfortunately, a protocol deviation resulted in one patient receiving a second dose 
of IVIG for a fever spike 12 hours after completing IVIG.  Clinical care guidelines recommend no second dose 
until 36 hours after completing IVIG, as many patients have a brief post-IVIG fever spike.  Otherwise, no other 
patient demonstrated IVIG refractoriness. According to our institutional data (Table 3), we expected at least two 
and possibly three patients with IVIG refractoriness in this group.  Among the 4 eligible patients refusing 
enrollment, one patient demonstrated recrudescent fever, was readmitted and treated with a second dose of 
IVIG. Ten study patients showed normalization of CRP by the 7 day visit indication suppression of acute phase 
proteins. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE 3.   CHRMC 
RACE DESCRIPTION 
TOTAL SINGLE DOSE 
MULTIPLE 
DOSE 
WHITE 
78 
48 
30 
ASIAN 
33 
26 
7 
DID NOT INDICATE 
16 
11 
5 
OTHER RACE 
13 
9 
4 
SPANISH/HISPANIC 
11 
8 
3 
BLACK 
10 
4 
6 
HAWAIIAN/PAC 
ISLANDER 
1 
1 
0 
MALE 
89 
60 
29 
FEMALE 
73 
47 
26 
MEAN AGE AT 
DIAGNOSIS 
3.3 
3.2 
3.6 
TOTAL 
162 
107 
55 
Table 3 shows 162 consecutive patients with KD treated with IVIG.  Ethnicity/race and demographics are 
reported.  The overall rate of retreatment with a second dose of IVIG is 34%.   Review of patient records shows 
that approximately 6-9 % of patients received IVIG before 36 hours after completing IVIG dose.   Refractory rate 
according to AHA guidelines is then between 25 – 30%, as we can’t be sure how many of these last patients 
would have had persistent fever > 36 hours after IVIG.  


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15
Coronary artery z-scores are shown for each patient in Table 4. No patient showed new coronary artery 
dilation or aneurysm after etanercept.  Three patients showed coronary aneurysm or dilation prior to etanercept.  
One of these was an 11 month old infant with two large right coronary artery aneurysms at presentation, which 
persisted throughout the study.  However, the other two patients showed resolution of CAD.  This results in a 
10% rate of CAD.  Remember that the PHN study reported 18.9% at 5 weeks.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary: As noted, the study design precludes any statistical analyses for efficacy.  However, as a pilot study 
these results are promising.  We demonstrate safety, pharmacokinetics consistent with previous studies 
performed in adults and children, and suggestion of therapeutic responses superior to standard therapy alone.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAXIMAL CORONARY ARTERY Z-SCORES
Baseline
2- week
6-week
1
2.6
2.5
2.7
2
1.7
1.2
1.2
3
0.5
-0.12
-0.12
            4*
7.1
7.4
7.4
5
1
0.91
1.08
6
0.5
0.5
0.5
7
2
1.6
1.3
8
0.6
0.6
0.6
9
0.5
-0.15
-0.5
10
2.8
0.9 NA
11
0.7
0.7 NA
Mean
1.49
1.1
STDV
1.864381244
2.011634
P(T<=t) two-tail
0.046
Table 4 shows maximal z-score from each 
patient.  Subject # 4 showed aneurysm of right 
proximal coronary artery.  NA- patients have not 
yet completed protocol.  Results of paired T-test  
two-tailed, comparing baseline z-score with 2 
week z-score are shown at bottom. NA , not 
available as these patients have not completed 
protocol. Pt 12 recruited data not available. 


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1.4 Dose Rationale 
 Etanercept is slowly absorbed after subcutaneous (SC) injection, and the absolute bioavailability is 
approximately 58% in adults37. Etanercept has a relatively small volume of distribution of 12 ±6 and is slowly 
absorbed to reach its peak serum concentration about 50 hours after injection and cleared from the body with a 
reported median half-life of 115 hours37. The recommended dosing regimen for JRA patients (4-17 years) at the 
time of its initial approval was 0.4 mg/kg (up to 25 mg) twice weekly by SC injection40. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 However, based on its slow absorption and elimination and pharmacokinetic (PK) profile, a doubled dose with 
a half-frequency regimen (ie, 0.8 mg/kg [up to 50mg]) of a once-weekly SC injection was sought and FDA 
approved for patient convenience.  PK simulation studies using data from juvenile rheumatoid arthritis (JRA) 
patients receiving 0.4 mg/kg SC twice weekly show similar steady-state levels at 1 and 8 weeks for children 
receiving 0.8 mg/kg41.  After repeated subcutaneous treatment mean serum etanercept concentration was 2100 
ng/ml (range 700 to 4300 ng/ml).  Although eighteen JRA patients were between age 4 and 8 years, relatively 
few patients were under age 5 years.  The data in Figures 2 A and 3A  illustrate drug concentrations from the 
JRA population and are extracted from Yim et al 41.    These can be compared to the PK profiles for the two 
different drug doses used in the pilot study (data shown in Figs 2B and 3B).  The pharmacokinetic profiles for 5 
pilot study patients, receiving 0.4mg/kg weekly (Figure 2.B), show lower than therapeutic levels, defined by 5th 
to 95th %tile range in shown in 2A for JRA patients receiving twice weekly doses. Steady state concentrations 
after 0.8 mg/kg after 1 week (Figure 3 B) are within the simulated and therapeutic range calculated for the JRA 
group (3A).    
Etanercept 0.4 mg/kg
0
1000
2000
3000
4000
5000
6000
0
120
240
360
480
elapsed time (hr)
concentration (ng/mL)
patient 001
patient 002
patient 003
patient 004
patient 005
Figure 2 A.  Data below is extracted from Yim et al, and 
shows overlay of observed and simulated data for children 
in JRA group receiving 0.4 mg/kg twice weekly.   
Figure 2B.  Data from 5 patients in pilot study receiving 0.4 
mg/kg etanercept starting immediately after IVIG infusion and 
then weekly x 2.  1000 ng/ml = 1 mg/L 


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These data suggest that 0.8 mg/kg weekly is adequate to maintain levels within the therapeutic range defined by 
the earlier JRA trials.   The younger age of the KD patients does not substantially affect absorption and 
metabolism of etanercept.  Three enrolled patients less than 2 years of age showed similar pharmacokinetic 
profile to all other patients and JRA patients.  These patients also showed no adverse events from Etanercept.  
 
2 Study Objectives 
 
Kawasaki Disease (KD) or Syndrome is the leading cause of acquired heart disease in children the United 
States.  The Center for Disease Control estimates that over 4000 U.S. children per year are diagnosed with KD.    
Although, KD qualifies for Orphan Disease status by NIH and FDA standards, it is a growing and important 
health problem for children in the U.S. and worldwide.  KD is an autoimmune disease and vasculitis with a 
specific predilection for coronary arteries, causing aneurysm and/or ectasia.  Although, the majority of patients 
do well, many experience long term coronary artery abnormalities.   Studies in Japan where KD demonstrates 
exceptionally high prevalence indicate that the mortality rate in males with coronary artery lesions is more than 
twice expected.  Treatment with intravenous immunoglobulin and aspirin currently represent the standard of 
care for acute Kawasaki Disease.  New and emerging data show that this treatment is only partially effective for 
reducing the risk of coronary artery disease.  Additionally, KD in many patients demonstrates resistance or 
refractoriness to IVIG, and requires retreatment.   This refractoriness represents a primary risk factor for 
development of coronary artery dilation. Attempts at developing effective adjunctive therapy for IVIG and 
aspirin have failed.   Over the past 15 -20 years, multiple investigators have provided strong evidence 
implicating tumor necrosis-α (TNF-α) as a primary agent for inflammation in acute KD.  TNF-α antagonism 
with etanercept abrogates coronary artery disease in a validated mouse model of KD.  Etanercept, a dimeric 
fusion protein, consists of 2 molecules of the extracellular ligand-binding portion of human TNF receptor 2 
attached to the Fc domain of human IgG.  Etanercept is FDA approved for multiple indications in adults and in 
children down to four years of age for juvenile rheumatoid arthritis (JRA).   We performed a pilot study in acute 
Etanercept 0.8 mg/kg
0
1000
2000
3000
4000
5000
6000
0
120
240
360
480
elapsed time (hr)
concentration (ng/mL)
patient 006
patient 007
patient 008
patient 009
patient 010
Figure 3A.   The data extracted from Yim et al represents 
simulation for 0.8 mg/kg (once weekly) and 0.4 mg/kg 
(twice weekly).  These simulations consider drug levels 
after 8 weeks of therapy,  
A 
Figure 3B shows our patient data obtained in first two weeks 
of etanercept treatment.  We were able to maintain levels in 
the therapeutic range even at trough within this time period.  


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KD patients (age 6 months to 5 years). In this population, we demonstrated that etancercept (0.8 mg/kg) 
given subcutaneously at weekly intervals in 3 doses provides concentrations within the therapeutic range 
defined for JRA patients.  The results of the pilot study support the safety of etanercept in children and show 
promise for efficacy in reducing IVIG resistance.   
 
We will test the hypothesis that TNF-α antagonism with etanercept improves the clinical response to standard 
of care treatment with IVIG and aspirin therapy in KD patients between 2 months and 20 years of age.  To test 
this hypothesis we will perform a double-blinded placebo controlled trial in 196 children with KD and obtain 
data in order to achieve an orphan designation for etanercept.  
 
Primary Aim 
1. Determine if etanercept (0.8 mg/kg, maximum 50 mg) given subcutaneously reduces IVIG refractory rate and 
retreatment rate in the KD patient population.  Our goal is to randomize and complete the trial in 110 patients in 
the etanercept treatment group and 110 patients in the placebo group.  
 
Secondary Aims  
1. Determine if the safety profile differs between the etanercept treated group and the placebo group.  
2. 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.  
3. Determine the pharmacokinetics of etanercept in KD patients 
 
3 Research Design and Methods 
 
 
We propose a placebo-controlled randomized double blind multi-center study in patients, age 2 months to 20 
years, with acute Kawasaki disease. All study investigators will be blinded except for pharmacists.  
 
3.1 Primary clinical endpoint 
The primary aim of  this study is to determine if Etanercept (Enbrel) 0.8 mg/kg given subcutaneously to patients 
with acute Kawasaki Disease will reduce the incidence of IVIG refractoriness as defined in the joint American 
Heart Association and American Academy of Pediatrics Endorsed Clinical Report:  “Refractory Kawasaki 
Disease will be defined as the persistence or recrudescence of fever (≥38.0°C or 100.4°F) at least 36 hours after 
the end of the IVIG infusion”3.   
 
Rationale for primary endpoint:  Refractory KD is an objective clinically important and easily measured 
parameter.  Orphan product indications by the FDA are likely to be influenced by clinical parameters as 
opposed to sonographic measures. Refractoriness increases risk of coronary artery disease, number of 
hospitalization days and cost of treatment11.  Several studies have unsuccessfully used coronary artery dilation 
(CAD) as a primary endpoint to evaluate adjunctive therapy 13, 14.Risks in using CAD are:  intra-observer and 
inter-observer variability.  Although, we will have a central echocardiographic reader, subjectivity is introduced 
by the sonographer actually performing the study.  Coronary artery dimensions can be skewed by angle, 
machine settings and other parameters beyond the control of the reader.  Therefore, coronary artery dilation 
parameters will be relegated to secondary endpoints.  
 
 


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3.2   Secondary Clinical Endpoints 
 
Determine if the safety profile differs between the etanercept treated group and the placebo group. 
 
Secondary safety endpoints will be number of adverse events, serious or otherwise within 30 days of treatment, 
with specific focus on serious infections, defined as “those requiring hospital admission” for treatment. The 
latter have been noted in patients receiving much longer courses of etanercept than proposed for this protocol, 
and for different diseases.    
 
Our study will be the first to evaluate efficacy of Etanercept in reducing inflammation in an acute inflammatory 
disease in children, as opposed to chronic inflammatory diseases.  The acute phase reactant, C-reactive protein, 
will be followed throughout the study as a laboratory measure of inflammation.   We will also determine if 
etanercept modifies serum concentrations of cytokines, interleukin-3, interleukin-6, and TNF-α.  
 
We propose the largest cohort for study of Etanercept in children performed to date.   
 
Secondary clinical endpoints will be directed to determine if etanercept treatment alters the rate of coronary 
artery disease defined by z-scores at 2 and 6 weeks after treatment.  
 
We will also determine if  etanercept treatment  1) alters development of coronary artery dilation or disease in 
patients with normal coronaries on initial echocardiogram, 2) promotes healing of coronary artery disease, when 
apparent on initial echocardiogram, 3) alters treatment course by reducing total number of hospitalization days, 
and 4) incidence of CRP normalization by 7 days.   
 
3.3 Dosing 
 
Etanercept or placebo will be administered in three separate doses (0.8 mg/kg subcutaneously, maximum 50 
mg) at 1 week intervals with the first dose concurrent with IVIG or within 48 hours of initiating IVIG.    
 
Rationale for extended therapy: Current KD treatment with IVIG and ASA in the United States is based on 
efficacy comparison with ASA alone8.  Subsequently, studies showed no difference in efficacy between IVIG 
(400 mg/kg) given in 4 separate doses on consecutive days versus a single infusion IVIG (2 gm/kg) over 10 
hours12.   Nevertheless, data across more than 2 decades show that coronary artery involvement increases during 
the 2 week period following treatment.  Furthermore, refractoriness to IVIG can manifest up to 2 weeks after 
completion of IVIG.   Inoue13 et al showed some increased benefit of continuing oral steroids until 
inflammatory parameters such as CRP normalized. In that study, laboratory studies were performed at least 
twice weekly.  Normalization of CRP level in the placebo group (receiving IVIG and ASA, no corticosteroid) 
occurred in 9.0 days (median) range 4 to 42 and mean 11.2 ± 6.2 days.   These data,  along with the their results 
showing some mild efficacy by more prolonged corticosteroid therapy, strongly support the contention that anti-
inflammatory therapy for KD should be extended to near 3 weeks, provided therapy is convenient and low-risk.   
Accordingly, we will maintain treatment for 3 weeks to cover all patients within this vulnerable period.  As our 
pilot data suggest that Etanercept levels are maintained at a near steady-state by week 2, we will give the final 
dose at 14 days ± 2 in order to maintain levels at least 3 weeks.  
 
 
 


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4 
 Patient Population and Sample Size 
 
196 study participants will be recruited from the four participating medical center admissions for suspected 
Kawasaki Disease with IVIG administration. Seattle Children’s Hospital is the coordinating site for the study. 
Most patients will be on the Cardiology or General Medicine Service.   
 
4.1 Inclusion criteria:  
  
Identification of patients with KD: 
The American Academy of Pediatrics and the American Heart Association have published guidelines for 
epidemiological case definition.   KD treatment, including IVIG and aspirin, is recommended for patients fitting 
these criteria.  Generally, supportive laboratory data also exist including elevation of erythrocyte sedimentation 
rate and C reactive protein (CRP > 3.0, although usually much higher). Thrombocytosis (platelet count > 
500,000) usually occurs in the second week.     
 
- 
Patients in this study (age 2 months to 20 years) will fit the standard epidemiological definition of acute 
KD as recommended by the joint AHA/AAP guidelines or fit criteria for diagnosis of incomplete KD as 
described below.  Patients will be enrolled only after a clinical decision to treat with IVIG has been 
made by the treating physician.  
- 
Patients may be enrolled if they begin IVIG infusion within 10-13 days of onset of illness with day 1 
defined as the first day of fever. A patient may be enrolled with greater than 10 days of fever upon 
written approval or email confirmation from the study Principal Investigator (Dr. Portman) on a case by 
case basis. 
- 
Parents of subject or non-minor subject must be able and willing to give written informed consent and 
comply with the requirements of the study protocol and must authorize release and use of protected 
health information. 
 
Patients will fit American Heart Association, American Academy of Pediatric guidelines for diagnosis of 
Kawasaki Disease 
Fever persisting at least 5 days† 
Presence of at least 4 principal features: 
1) Changes in extremities 
Acute: Erythema of palms, soles; edema of hands, feet 
Subacute: Periungual peeling of fingers 
2) Polymorphous exanthem 
3) Bilateral bulbar conjunctival injection without exudate 
4) Changes in lips and oral cavity: Erythema, lips cracking, 
strawberry tongue, diffuse injection of oral and 
pharyngeal mucosae 
5) Cervical lymphadenopathy (1.5-cm diameter), usually 
unilateral 
 
Patients with fever at least 5 days and 3 principal criteria can be diagnosed with Kawasaki disease when 
coronary artery abnormalities are detected by 2 dimensional echocardiography (see section on 
Echocardiography). A qualifying echocardiogram is defined as coronary artery z score >2.5 in the proximal 
coronary artery or left anterior descending, or aneurysm by Japanese Ministry of Health criteria.   
 


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Patients with fever at least 5 days and 2-3 principal criteria without coronary artery abnormalities can be 
diagnosed with Kawasaki Disease when the patient has a CRP of 3.0 mg or greater and 3 or more of the 
supplementary lab criteria listed below: 
 
albumin   <3.0 g/dL  
anemia for age 
elevation of alanine aminotransferase 
platelets after 7 days >450 000/mm3 
white blood cell count >15 000/mm3   
urine >10 white blood cells/high-power  field 
 
 
† In the presence of all 5 principal criteria, Kawasaki disease diagnosis can be made on day 4 of illness.   
 
 
4.2   
Exclusion Criteria 
 
1. 
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:  
a. Platelet count < 100,000/mm3 
b. WBC count < 3,000 cells/mm3 
c. Hemoglobin, hematocrit, or red blood cell count outside 30% of the upper or lower limits of 
normal for the Lab 
 
2. 
General Exclusion Criteria 
a. 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. 
b. Female subjects diagnosed with KD 12 years of age and older. 
c. Subjects who have known hypersensitivity to Enbrel or any of its components or who is known 
to have antibodies to etanercept 
d. Prior or concurrent cyclophosphamide therapy 
e. Treatment with any TNFα antagonist or steroid within 48 hours prior to initiation of IVIG 
f. Concurrent sulfasalazine therapy 
g. Active severe infections within 4 weeks before screening visit, or between the screening and 
baseline visits. 
h. SLE, history of multiple sclerosis, transverse myelitis, optic neuritis, or chronic seizure disorder 
i. Known HIV-positive status or known history of any other immuno-suppressing disease. 
j. Any mycobacterial disease or high risk factors for tuberculosis, such as family member with TB 
or taking INH. * (see below) 
k. Untreated Lyme disease. 
l. 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]) 
m. 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.  


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22
n. Use of a live vaccine (Measles Mumps Rubella or Varicella) 30 days prior to or during this 
study with the exception that a patient who has received Influenza mist vaccine may be enrolled 
after 14d from administration of the vaccine. 
o. Any condition judged by the investigator to cause this clinical trial to be detrimental to the 
patient  
p. History of non-compliance with other therapies 
q. Must not have received immunosuppressive agents for at least three months prior to enrollment. 
*Note, liver enzymes, AST or ALT are frequently elevated in KD, and will not be used as an exclusion.  
 * PPD testing will not be performed in these patients.  Reactivation of chronic granulomatous disease 
including tuberculosis from chronic treatment with TNFα antagonists is a valid safety concern.31   The 
risk of TB reactivation for patients on etanercept therapy still requires clarification.  A recent review at 
Cook County and Rush Hospital in Chicago showed that none of the 48 patients with positive PPDs who 
were treated with etanercept for average of 17 months developed active TB 53.  Additionally, Mohan et 
al reported the earliest reactivation occurred after 1 month of initiating etanercept with a mean of 11.5 
months 54.  Use of additional immunosuppressive agents other than etanercept was a risk factor.   Our 
cohort will receive a very short course (~ 2 weeks) of etanercept and will not receive other 
immunosuppressive drugs, thereby markedly reducing the already very low risk of TB in this 
population.  For instance, the incidence of TB in King County, WA in children is 1 -2.5/100,000 or 8-12 
per year.  To be effective in acute Kawasaki Disease, etanercept must be given at the same time or 
immediately after IVIG treatment.   We cannot delay while awaiting mandatory 48-72 hours for results 
of skin testing.  The new Quantiferon gold test for TB is not yet widely available (and not in Seattle) and 
would still require at least 24 hours.  We have considered placing TB skin testing after initial dose and 
discontinuing if positive.   However, it is likely that TNF-α antagonism could affect the test and provide 
a false negative.  Therefore patient exclusion will be performed based on high risk history, such as 
immediate family or household member with positive PPD.   
 
4.3 
  SAMPLE SIZE 
 
Calculation of sample size is based on initial IVIG refractory rate at Children’s Hospital and Regional Medical 
Center.  The last 200 patients over 4 years admitted to CHRMC 52 patients (26%) required two or more doses 
of IVIG.  Power analyses reveal the following:   
Proportion failing in 
the control group 
Proportion failing in the 
experimental group 
given Etanercept 
N per group needed to achieve 80% power 
NOTE:  TOTAL enrollment =2 x N 
0.25 
0.15 
270 
0.25 
0.10 
110 
0.25 
0.05 
59 
0.25 
0.02 
42 
 
Sample size 110 is reasonable, considering the potential population and budget.  The table below that shows 
power for a range of effect sizes, holding the N at 110.  
 
The table below provides the relationship between effect size and study power.  
Proportion failing in 
the control group 
Proportion failing in the 
experimental group 
given Etanercept 
 
N per group 
 
Statistical Power  
0.25 
0.08 
97 
80% 


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0.25 
0.05 
97 
90% 
 
The table below provides anticipated numbers of patients eligible from four U.S. and one Canadian Center, and 
anticipated numbers of recruited patients based on recruitment rates from prior studies.   From CHMRC, 
estimates are based on KD patients per year and our recruitment rate in the pilot study, which enrolled patient in 
the narrow age range 6 months to 5 years. From Primary Children’s in Utah, estimates are based on their 
recruitment rate and participation in the Pediatric Heart Network “Randomized trial of pulsed corticosteroid 
therapy for primary treatment of Kawasaki disease”.  From Milwaukee Children’s and Cohen Children’s 
Medical Center, estimates are based on KD admission rate and recruitment rate as adjunctive center for PHN 
protocols. Sainte-Justine Hospital estimates are based on high enrollment for Bristol-Myers-Squibb sponsored 
studies evaluating Cardiolite in Kawasaki Patients (Study # 301 (see description under Key Personnel and Sites 
of Investigation).   Each center has clinical research structure and team permanently in place and structured.   
 
 
4.4 
Subject Recruitment and Screening 
 
Patients will be recruited from admissions at participating centers for suspected KD with IVIG administration.  
Families of Kawasaki Disease patients will be referred to the research team by physicians involved in patients 
care.   In general, the Cardiology service is involved with KD patient’s evaluation and care immediately after 
admission. Standard clinical care usually includes a screening or baseline echocardiogram. Patients will be 
screened for study suitability by the research staff.  If the family shows interest in the study, they will undergo 
consent procedures, which will be conducted by the research team.  The study will be described verbally to the 
patient and family. After the introduction and description of the study, the family will be given adequate time to 
read and review the written consent/ assent forms. Time will be allotted for questions and additional discussion 
if necessary. Family friends, relatives or additional support persons (at the request of the parent/guardian) may 
also be present to hear and read what is being asked of the patient/family. 
 
Patients will be enrolled only after the necessary criteria for KD diagnosis has been documented in the medical 
record and serious infection as the source of fever has been reasonably eliminated. Patients will be screened 
prior to IVIG, but will not be enrolled until IVIG orders are written. 
 
 
4.5 Early Withdrawal of Subjects 
4.5.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study prior to the expected completion of that subject for health, 
logistical, or personal reasons (i.e. serious adverse events, failure of subject to adhere to protocol 
requirements, subject consent withdrawal, disease progression, etc).  No safety consequences are anticipated 
with early withdrawal from the study since etanercept is adjunctive therapy.   
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
Follow-up calls will be made to the patient’s family upon early withdrawal from the study.  
4.5.3 Emergency Blind Breaking 
At the beginning of the study each site will be instructed on the method for emergency blind-breaking. 
Blinding codes should be broken in emergency situations only if this is required for proper treatment. The 


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24
primary investigator at the site will contact Dr. Portman to assess the necessity for un-blinding. In the 
unlikely event that Dr. Portman is unreachable; the primary investigator will be responsible for making the 
decision to un-blind the patient.  
The study investigator will instruct the participating site pharmacy to break the blind to the treating 
physician only. The study investigators at the site as well as Dr. Portman are to remain blinded to protect the 
integrity of the data. 
5 Study Drug  
5.1 Description 
Etanercept is a recombinant TNF receptor Fc Fusion protein.  It is pharmacologically classified as a TNF 
antagonist, with the sole active ingredient being etanercept.   
 
Etanercept powder is to be reconstituted with sterile diluent supplied by Amgen, Inc. prior to its subcutaneous 
injection such that the final dosage achieved is 0.8 mg/kg.  Each vial of powdered etanercept contains 25 mg 
etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine.  
5.2 Treatment Regimen 
Subjects will be given subcutaneous injections of 0.8 mg/kg etanercept 3 times at weekly intervals, starting at 
initial diagnosis.   
5.3 Preparation and Administration of Study Drug 
Participating Hospital’s Investigational Pharmacy will prepare the study drug according to the manufacturer and 
research protocol’s directions. Amgen will provide study drug and placebo to each site’s pharmacy.  Etanercept 
will be reconstituted aseptically with the Amgen-supplied Sterile Bacteriostatic water for Injection, USP (0.9% 
benzyl alcohol) so that the desired study dosage is met. Following drug preparation, the Investigational 
Pharmacy will dispense the study drug to the study investigators so that it may be administered to the patient. 
5.4 Subject Compliance Monitoring 
The study coordinator will track subject compliance with the study treatment regimen.   Subjects non-compliant 
with the study treatment regimen will be contacted to so that conflicts which may be hindering their compliance 
may be resolved. 
5.5 Prior and Concomitant Therapy 
The following medical therapies are not permitted for study participation: 
- 
Treatment with any TNFα antagonist or steroid within 48 hours prior to initiation of IVIG  
- 
Current use of an investigational device or drug trial(s), or receipt of other investigational agent(s) 
within 28 days of baseline visit 
- 
Prior or concurrent cyclophosphamide therapy 
- 
Concurrent sulfasalazine therapy 
- 
Concurrent isonicotinic acid hydrazide therapy 
- 
Any live vaccine 30 days prior to, or during the study.  Patient may be enrolled in the study 14 days after 
administration of Influenza mist vaccine. 
- 
Prior (within 3 months preceding enrollment) or concurrent use of immunosuppressive agents  
 
In addition, any medical therapies that may cause harm to the patient, as judged by the patient’s physician on a 
case-by-case basis, will not be permitted.   


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25
 
IVIG (2 g/kg) and aspirin (80-100mg/kg Q6 hr until afebrile then 3-5 mg/kg/day) are standard treatment 
regiments for acute Kawasaki Disease, their concomitant therapy is to be expected and permitted.  
5.6 Packaging 
• Etanercept will be shipped by Amgen, Inc in bulk.  
• Each package of etanercept will be supplied with its diluent, Sterile Bacteriostatic Water for Injection, 
USP (0.9% benzyl alcohol).    
5.7 Receiving, Storage, Dispensing and Return 
 
5.7.1 Receipt of Drug Supplies 
Amgen, Inc will ship the study drug to the participating Hospital’s Investigational Pharmacy.  Upon receipt of 
the of the study treatment supplies, an inventory must be performed and a drug receipt log filled out and signed 
by the person accepting the shipment.  It is important that the designated study staff counts and verifies that the 
shipment contains all the items noted in the shipment inventory.  Any damaged or unusable study drug in a 
given shipment (active drug or comparator) will be documented in the study files.  The investigator must notify 
Amgen, Inc of any damaged or unusable study treatments that were supplied to the investigator’s site. 
5.7.2 Storage 
Etanercept is not to be used beyond the expiration date stamped on the carton, dose tray label, or diluent syringe 
label.  The dose tray containing etanercept in powder form must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF), 
and NOT FROZEN. 
Solutions of etanercept  reconstituted with Amgen-supplied Bacteriostatic Water for Injection, USP (0.9% 
benzyl alcohol) may be stored for up to 14 days if refrigerated at  2ºC to 8ºC (36ºF to 46ºF).  Reconstituted 
product should be discarded after 14 days as stability and sterility cannot be assured after 14 days. 
5.7.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, and signed and dated by the 
study team. 
5.7.4 Return or Destruction of Study Drug 
Study drug that remains at the end of the study will be shipped back to Amgen, Inc or destroyed on site.  
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files. 
 
6 Study Procedures   
 
Etanercept 0.8mg/kg (maximum 50 mg) or placebo will be given within 48 hours of initiating IVIG infusion.  
Randomization will be performed by internal Pharmacy, unblinded (see Pharmacy procedures).  Placebo format 


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26
will be: Etanercept placebo (Amgen), TMS Lyo, B20 UnLBL 2mL vial Pink Cap. Study schema and 
procedures are outlined below.  
 
TIME 
0* 
12-84  
hours  # 
7 ± 3  
days 
14 ± 3 
days 
44 ± 4 days 
Physical Exam 
x 
 
x 
x 
X 
Etanercept/Placebo 
x 
 
x 
x 
 
PK  
x 
x 
x 
X  
 
Cytokines 
x 
x 
x 
 
 
CBC^ 
x 
 
x 
x 
X 
CRP 
x 
 
x 
x 
X 
ESR 
x 
 
 
 
 
Echo 
x 
 
 
x 
X 
EKG 
x 
 
 
x 
X 
AST, ALT 
x 
 
x 
x 
 
Albumin 
x 
 
x 
x 
X 
 
 
* Time 0 or baseline is defined as time first dose of study drug is given. Time 0 or baseline labs are almost 
always done before the patient has consented to the study.  These labs are optional unless the patient is 
qualifying into the study through supplementary lab data. In general, admission laboratory values used to 
confirm diagnosis of KD can be used for the study, provided that they were within 24 hours prior to initiating 
IVIG. If a time zero lab value is not drawn as part of the clinical course prior to the patient enrolling in the 
study, it will not be collected and will be recorded as missing data  After enrollment, coordinators should try to 
retrieve extra serum obtained along with admission laboratory studies. This serum can be used for baseline 
pharmacokinetic assay, PK.    
 
An EKG is normally done at time zero as part of clinical care. This EKG is optional, if an EKG is not 
performed at baseline it will not be recorded as a protocol deviation.  
 
Parents are to record temperature after discharge daily between 4PM and 6PM for two weeks, as well as if and 
when they believe child has fever, and notify study coordinator if > 38.0 ° C.    If patient temperature > 38° C 
and the investigator or treating cardiologist feels the patient needs to be readmitted, an extra study visit will 
occur within 12-24 hours of re-admission with PE, CBC, CRP, ESR, Echo, and ECG.  This extra visit concurs 
with clinical guidelines for standard of care.   ^CBC includes WBC with differential and platelet count.  Parents 
are also to notify coordinator if any sign of infection. # PK, for this time point will be 48 hours (window 12 – 48 
hours) after Etanercept.  
 
We will define failure to respond to IVIG using the AHA guidelines: as persistent fever > 38.0°  C extending 
beyond 36 hours after completion of IVIG infusion or recurrent fever > 38.0° C after 36 hours of completion of 
the initial IVIG infusion. 
 
All patients with disease-related complications will receive standard care by their primary Pediatric Cardiologist 
and other treating physicians.  This will include anticoagulation therapy when the primary Cardiologist feels it 
is necessary.  AHA/AAP guidelines recognize the use of various types of anti-coagulation.  Low dose ASA as 
described above represents the primary antiplatelet therapy.  “Clopidogrel in combination with aspirin has been 
shown to be more effective than either agent alone in preventing vascular events in both coronary and cerebral 
territories in adults (theClopidogrel in Unstable Angina to Prevent Recurrent Events study).”  However, there is 
no evidence in children that this is effective therapy.  Many Pediatric Cardiologists use heparin infusion often 


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27
followed by Warfarin for rapidly expanding or giant coronary artery aneurysms.   The current protocol does 
not preclude their use.  We have proposed an adjunctive therapy for KD.  Accordingly, we are not interfering 
with standard of care, and do not specify concomitant medications.  All medications prescribed by primary care 
providers are permitted. Additionally, no live vaccine may be given for at least 11 months after receiving IVIG 
as recommended by the American Academy of Pediatrics. 
 
Treatment with high dose steroids and/or infliximab during the course of the study is permitted if recommended 
by Rheumatology for the treatment of recurrent Kawasaki Disease.  
 
6.1 Visit 1 -  Hospital 
 The patient is admitted into the hospital. Patient family is referred to the research staff for study discussion and 
consent.  The patient is screened for eligibility, study discussion is conducted, and consent is obtained.  Assent 
will also be obtained if deemed required by IRB.   (see section entitled “Protection of Human Subjects”).   
 
All patients will receive standard treatment for KD as stated in the AHA-AAP guidelines.  This includes IVIG 2 
gm/kg over 10 hours or longer if interruptions occur in the infusion and high dose ASA, administered at 80 to 
100 mg/kg per day in 4 doses until patients have been afebrile for 48 hours.  Subsequently, patients will 
continue low dose ASA 3-5 mg/kg per day until 6 weeks or longer at the discretion of the treating Pediatric 
Cardiologist. 
  
The blood for the baseline measurements can be drawn with the IV start or from the IV line. Labs obtained 
upon hospital admission will be used for baseline data. The PK blood sample will be processed and stored for 
later shipping by the lab or study personnel, while the other blood samples shown in study schema are sent to 
the central hospital laboratory for processing and results. An Echo and EKG are performed.    A nurse 
administers a subcutaneous injection of study drug or equivalent volume of placebo at the appropriate dosage 
0.8 mg/kg (maximum 50 mg).  Etanercept must be administered within 48 hours after initiating IVIG therapy, 
and as early as possible.  Etanercept should not be given prior to starting IVIG infusion.   After discharge, the 
parents of the patient are to record daily temperatures between 4PM and 6PM for the next two weeks in a log 
provided by the nurse coordinator.  Thermometer will be given to family if not already available or provided by 
hospital and coordinator will instruct patients regarding the proper procedure for taking and recording 
temperature.  If the parents believe that their child has a fever, they are to record the child’s temperature 
regardless of the time of day and notify the study coordinator if temperature is > 38.0ºC. If the study 
coordinator is unavailable the family should call the on-call cardiologist. If the child is readmitted, an extra 
study visit will occur within 12-24 hours of the patient being readmitted, and a physical exam, CBC, CRP, ESR, 
ECG, and Echo will be completed.  Parents are to notify the study coordinator if they find any signs of infection 
in the patient.  
6.2 Visit 2 (12-84 hours) - Hospital 
This visit is optional, and would be timed within 12-84 hours of etanercept administration. If the intravenous 
line is still in place, or a blood draw is clinically indicated within this window, approximately 4 cc of blood is 
drawn for the PK test. A numbing agent may be used to decrease the discomfort associated with phlebotomy. 
The blood is sent to the laboratory for the necessary blood work.  Patients are generally observed for 24 to 48 
hours after completion of IVIG dose prior to discharge.    Study investigators will observe patients through that 
period in the hospital.  Observation will continue if patient hospitalization extends beyond that period for 
complications of disease or therapy until the patient is discharged. 


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6.3 Visit 3 (Day 7 ± 72 hours)- Clinic 
A physical assessment and a blood draw (approximately 7 cc) are required. A nurse may perform an abbreviated 
physical exam as part of the nursing assessment, since a physician investigator is not required to be present at 
this visit. A numbing agent may be used to decrease the discomfort associated with phlebotomy and/or study 
drug administration. The blood sample is sent to the laboratory for the tests listed in the study schema, while 
study personnel will process the PK sample and store for later shipping. A nurse administers a subcutaneous 
injection of study medication at the appropriate dosage. 
 
6.4 Visit 4 (Day 14 ± 72 hours)- Clinic 
A physical exam and a blood draw (approximately 7 cc) are required. A numbing agent may be used to decrease 
the discomfort associated with phlebotomy or study drug administration.  The blood sample is sent to the 
laboratory for the tests listed in the schema while study personnel will process the PK sample and store for later 
shipping. An Echo and EKG are performed.  A nurse administers a subcutaneous injection of study drug at the 
appropriate dosage. 
 
6.5 Visit 5 (Day 44 ± 4 days)- Clinic 
A physical exam and a blood draw (approximately 7 cc) are required.  . The blood sample is sent to the 
laboratory for the tests listed in schema.  An Echo/ EKG is performed. No study drug is administered. 
6.6   Treatment for refractoriness to IVIG.   
All patients who fit the requirements for refractoriness to IVIG (see section 3.1) will receive standard clinical 
treatment as determined by the attending physician.  Standard treatment is usually a second dose of IVIG, and is 
defined in the American Heart Association guidelines.  Retreatment with IVIG will not interrupt the study and 
study medication should still be administered.   
 
6.6 Follow-up Echocardiogram Surveillance 
Follow up data will be collected for patients who had a positive echo (z score ≥ 2.5 or aneurysm) at visit 5 for 
14 months following their diagnosis or until their echo normalizes. De-identified visit notes and 
echocardiogram and angiogram reports that fall within this window should be sent to the study sponsor.  
 
 
6.7  Echocardiography 
In order to maintain consistency with other U.S clinical trials in KD17, coronary artery dimensions will be 
normalized for body surface area as z scores (SDs from a predicted normal mean).  Coronary artery Z-scores are 
based on nonlinear regression equations derived from a normal nonfebrile population,  comprised of 221 
healthy children aged 0 to 18 years seen in the noninvasive laboratory at Boston Children’s Hospital for 
echocardiographic evaluation during the years 1987 to 2000 55.  These patients had no evidence of structural or 
functional heart disease.  Z-scores algorithms are available and will be determined for the left main coronary 
artery, proximal left anterior descending, and proximal right coronary artery 
LMCA=0.31747 · (BSA0.36008)–0.02887, SD=0.03040+(0.01514 · BSA)  
pLAD=0.26108 · (BSA0.37893)–0.02852, SD=0.01465+(0.01996 · BSA)  
pRCA=0.26117 · (BSA0.39992)–0.02756, SD=0.02407+(0.01597 · BSA)  


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where LMCA indicates left main coronary artery, in centimeters; pLAD, proximal anterior descending 
coronary artery, in centimeters; pRCA, proximal right coronary artery, in centimeters; and BSA, body surface 
area, in meters squared calculated by the Haycock method 55. 
 In order to limit interobserver variability, a central Echocardiography reader will adjudicate these 
interpretations.  Presence of coronary artery aneurysms will be determined using Japanese Ministry of Health 
Criteria:  aneurysm diameter ≥ 1.5 times the diameter of the vessel immediately proximal.  All centers will 
forward digital echocardiograms to the Seattle Center for central reading by a single observer.   Dr. Brian 
Soriano is a Boston trained Pediatric Cardiologist and spent an extra year in an imaging fellowship, prior to 
taking a faculty position at CHRMC-UW.   He is intimately familiar with procedures used to develop z-scores 
from the cohort of patients at Boston Children’s and will provide consistency for the echo determinations.        
 
6.8   Pharmacy Procedures    
The pharmacist and pharmacy technical staff will be not be blinded.  The study statistician will provide each 
site pharmacy with randomization table.   Pharmacists will supply each patient with drug or placebo, both 
provided by Amgen in separate labeled vials.   Pharmacists will draw dose in syringes and dispense to nursing 
for administration.    Drug accountability will be monitored by the CRO as described below.  Study 
randomization codes and links to patients will be kept in secure records in pharmacy. All other study personnel 
involved in administration of drug will be blinded.  
 
6.9 IVIG Retreatment 
As noted in section 3.1: The primary aim of  this study is to determine if Etanercept (Enbrel) 0.8 mg/kg given 
subcutaneously to patients with acute Kawasaki Disease will reduce the incidence of IVIG refractoriness as 
defined in the joint American Heart Association and American Academy of Pediatrics Endorsed Clinical 
Report:  “Refractory Kawasaki Disease will be defined as the persistence or recrudescence of fever (≥38.0°C or 
100.4°F) at least 36 hours after the end of the IVIG infusion”3.    Persistent or recrudescent fever is the sole 
criteria for determining the need for retreatment.  The clinical decision can be supported by persistent symptoms 
and persistent elevation or rebound of inflammatory parameters such as CRP. The protocol requires waiting at 
least 36 hours after completing the first IVIG dose before initiating the second dose.   
 
 
7 Statistical Design and Analysis 
 
The primary outcome variable is the Y/N determination of whether the subject is refractory to IVIG 
treatment, defined as persistence of fever >38° C beyond 36 hours from completion of IVIG treatment, or 
recurrence of fever within 10 days, and clinical decision to retreat with IVIG.  Chi-square testing will be used to 
compare the proportions of subjects classified as refractory to IVIG treatment between the group randomized to 
receive Etanercept as an adjunctive therapy and the group randomized to receive placebo.  If necessary (due to 
low cell counts), a Fisher’s Exact test can be substituted.  Stratified versions of the chi-square and Fisher’s tests 
are available in StatXact (Cytel Incorporated) to allow stratification by center.   
Secondary outcome variables that are measured on a continuous scale include the coronary artery 
diameters obtained on the LMCA, pLAD and pRCA and the corresponding Z-scores (normalized for the 
patient’s BSA) at each of those locations.  Z-scores will be summarized at each time point by treatment group 
and the within-subject changes in Z-score relative to baseline will be summarized for the post-treatment time 
points (week 1 and week 5) as well.  The within-subject changes in actual artery diameter will also be 
summarized at week 1 and week 5.  Summary statistics will include the mean, SD and selected percentiles.  


PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR         Portman, Michael A.  
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30
Change values will be summarized both overall for the treatment group as a whole and then stratified by 
whether or not the subject has evidence of dilation at baseline (Z-score ≥2.5).  A Generalized Estimating 
Equation (GEE) model will be used to compare change values between the Etanercept and placebo groups.  The 
GEE model is needed to accommodate adjustment for the correlation between observations obtained on the 
same individual at 1 and 5 weeks.  Since the addition of Etanercept may have a differing magnitude of impact 
on change in artery diameter depending on whether the artery was dilated at baseline, terms for dilation status at 
baseline and the interaction between dilation and treatment group will be included in the model.   
Another secondary outcome is the presence of aneurysm as defined by the Japanese Health Ministry 
criteria (see Echo criteria above).  The pre- and post-treatment proportions of subjects in each group having an 
aneurysm detected will be calculated along with the exact binomial 95% confidence interval.  Comparison of 
post-treatment aneurysm proportions will be done via a stratified Chi-square test, with strata for 
presence/absence of aneurysm at baseline.    
Adverse events will be tabulated for each treatment group by severity, relationship to study drug and 
body system affected (according to the NCI CTC grading and MEDDRA classification system). The outcome of 
any SAE episodes that occur will be summarized. Adverse event rates will be compared between treatment 
groups using Poisson or negative binomial regression modeling.  The proportions of subjects experiencing an 
adverse event of any type and the proportions experiencing an SAE will be compared using chi-square or 
Fisher’s Exact testing.  
 
Pharmacokinetic analyses:     PK analyses will be performed after completion of the study and unblinding, so 
as not to unblind study investigators. Samples from patients receiving etanercept will be forwarded to the 
Seattle site for storage and then later submitted to Amgen for determination of serum drug concentrations.  Peak 
and trough analyses will be performed.   Drug clearance, volume of distribution and ½ life will be determined 
using etanercept modeling and algorithms 41 and  loaded on SAAM2 software available at the University of 
Washington.  
 
CRP and other standard laboratory studies will be performed in the clinical laboratory of each participating 
hospital.  Serum cytokines, IL-3, IL-6, and TNFα will be performed in Center of Developmental Therapeutics 
at Children’s Hospital Research Institute in Seattle.  Assay will be performed on Luminex-200 multiplex 
system, which resides in center.  
 
8 Safety and Adverse Events 
8. 1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during 
the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal 
results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 


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• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the other 
serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization or intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse 
events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.   
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end of 
the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event must 
also be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject is 
lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the investigator 
should instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.   
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation of 
the drug, more frequent follow-up assessments, further diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for and 
adverse event.  
 


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Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event 
in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting 
condition.  Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as judged by the clinical investigator.  (Note:  
This study population includes a notable proportion of patients requiring hospital readmissions due to 
refractory IVIG therapy. A clear definition of a serious adverse event relating to readmissions will be 
determined at the Organizational Meeting with the Data Monitoring Committee.) 
Expected Adverse Events 
The following AEs are expected with Kawasaki Disease and IVIG: 
Fever, chills, sore throat, chest tightness, rash, redness of the eyes, vomiting, diarrhea, headache, nausea, 
irritability, meningismus, anaphylaxis or hypersensitivity, hypotension, rash, skin peeling or desquamation, 
extremity swelling, coronary arteritis, coronary aneurysms, myocardial infarction, myocarditis, mitral 
regurgitation, pericarditis, hydropic gall bladder, joint swelling or pain, lymphadenopathy, arrhythmias, blood 
clots. 
Lab abnormalities; elevated CRP and ESR; thrombocytosis, hypoalbunemia, anemia, pyuria, elevation of liver 
transaminases.   
Additionally, localized redness and swelling at injection site are expected AEs for etanercept.   A full list of 
AEs is included in the Etanercept package insert. 
Serious Adverse Events expected are readmission due to recurrent or persistent fever.  
8.2 Recording of Adverse Events 
 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report form 
(CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded in the 
source document, though should be grouped under one diagnosis. 
 
 
 
 
Table  3 Adverse Event (Experience) Reporting Summary 
 
DMC/DSMB 
IRB* 
FDA  
Investigator(s)/Sponsor 
I.  RELATED, 
UNEXPECTED  
 
Requirements may 
vary according to 
institution 
 
 


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All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period must 
be followed up to determine the final outcome.  Any serious adverse event that occurs after the study period and 
 
Fatal or  
Life-Threatening 
Telephone/email 
within 24 hours 
Written notification 
within 3 working 
days of telephone 
report 
Written notification 
within 3 calendar 
days 
Follow up reports as 
soon as information 
becomes available 
Telephone or fax 
within 7 calendar 
days 
Written notification 
within 15 calendar 
days using FDA 
form 3500A per 
21CFR312.32 
Telephone/email within 24 
hours 
Written notification within 3 
working days of telephone 
report 
Serious/severe 
(including 
disability) 
Written notification 
within 7 calendar 
days 
Written notification 
within 15 calendar 
days. 
Written notification 
within 15 calendar 
days using FDA 
form 3500A per 
21CFR312.32 
Telephone/email within 24 
hours 
Written notification within 3 
working days of telephone 
report 
Mild/moderate 
As per protocol 
Quarterly 
Annual report per 
21CFR312.33 
As per protocol 
II.  
RELATED, 
EXPECTED 
 
 
 
 
Fatal, Life-
Threatening 
Telephone/email 
within 24 hours 
Written notification 
within 3 working 
days of telephone 
report 
Written notification 
within 3 calendar 
days 
Follow up reports as 
soon as information 
becomes available 
Telephone or fax 
within 7 calendar 
days 
Written notification 
within 15 calendar 
days using FDA 
form 3500A per 
21CFR312.32 
Written notification within 7 
days 
Serious/severe 
(including 
disability) 
Written notification 
within 7 calendar 
days 
IRB status report 
(annual) 
Written notification 
within 15 calendar 
days using FDA 
form 3500A per 
21CFR312.32 
Written notification within 7 
calendar days 
Mild/moderate 
As per protocol  
IRB status report 
(annual) 
Annual Report per 
21CFR312.33 
As per protocol 
II.   NOT-    
RELATED 
 
 
 
 
 
 
Fatal, Life-
Threatening 
Written notification 
within 10 days 
IRB status report 
(annual) 
Annual Report per 
21CFR312.33 
Written notification within 10 
days 


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34
is considered to be possibly related to the study treatment or study participation should be recorded and 
reported immediately. 
 
Table 3 summarizes regulatory guidelines for reporting adverse events. 
 
8.3 Reporting of Serious Adverse Events 
8.3.1 DMC Notification by Investigator 
Serious adverse events will be reported to Dr. Portman within 24 hours of when investigators are first aware of 
SAE by telephone and/or fax.  Dr. Portman will forward SAE data to the Data Monitoring Committee within 24 
hours. Dr. Portman will oversee that the data and safety letter are sent to the appropriate entities within an 
appropriate time frame. 
8.3.2 IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to the Institutional 
Review Board (IRB).  The timeline of reporting procedures varies by the anticipation level and the severity of 
the adverse event [see Table].  Copies of each report and documentation of IRB notification and receipt will be 
kept in the Investigator’s binder.   
 
8.4 Stopping Rules  
The DMC shall review clinical and laboratory data provided by the Principal Investigator to guide their 
recommendations regarding termination or continuation of the trial.  If the evidence indicates the experimental 
intervention has an unfavorable benefit-to-risk-profile, the DMC shall recommend termination of the trial.   
 
8.5 Safety Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as well 
as the construction and implementation of a site data and safety-monitoring plan (see section 10 Auditing, 
Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the number and type of 
serious adverse events. 
8.5.1 Independent Data Monitoring Committee 
The Data Monitoring Committee (DMC) will be composed of a pediatric rheumatologist, and a pediatric 
cardiologist to oversee the study.  Safety data of the 196 patients with regards to adverse events, specifically 
focusing on infections, will be closely monitored in these patients 
• The DMC will meet at least once every 6 months via telephone conference. 
• The safety data will be supplied to the DMC by the principal investigators team. . 
• The DMC will prepare minutes to record the summary of its various meetings. 
• The DMC will appropriately report its findings and/or recommendations to the PI and regulatory 
bodies.   
 
 
The Data Safety Plan and Data Monitoring Committee (DMC) 
The data safety plan for this study is also included in detail in the Human Subject section. The DMC was 
established and chartered in order to monitor the progress of the pilot study.  The DMC will continue this 


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35
function with amendments and additional support personnel for the larger controlled study proposed in this 
application.  
 
PRIMARY RESPONSIBILITIES OF THE DMC 
The DMC will be responsible for safeguarding the interests of trial participants, assessing the safety of the 
interventions during the trial, and for monitoring the overall conduct of the clinical trial.  The DMC will provide 
recommendations about stopping or continuing the trial.  To contribute to enhancing the integrity of the trial, 
the DMC may also formulate recommendations relating to the selection/recruitment/retention of participants, 
their management, improving adherence to protocol-specified regimens and retention of participants, and the 
procedures for data management and quality control. 
 
The DMC will be advisory to the Principal Investigator.  The Principal Investigator will be responsible for 
promptly reviewing the DMC recommendations, to decide whether to continue or terminate the trial, and to 
determine whether amendments to the protocol or changes in study conduct are required. The Principal 
Investigator will be required to forward all DMC recommendations to the IRB.  
 
Members 
The DMC will be an independent multidisciplinary group consisting of clinicians, whom collectively have 
experience in the management of patients with Kawasaki Disease and in the conduct and monitoring of clinical 
trials.  Generally, three pediatric subspecialties deal with KD.  These are cardiology, rheumatology, and 
infectious disease.  Each of these subspecialties will be represented on the DMC.   
 
DMC Chair: Mark Lewin, MD, Dr. Lewin is a senior pediatric cardiologist at CHRMC, division chief, and 
Associate Professor of Pediatrics.  He has experience in serving on DMC and as a clinical investigator in 
pediatric cardiology.   Dr. Lewin is currently DMC chair for the pilot trial, which is near completion.  To lend 
continuity to the DMC he will continue as DMC chair for the proposed controlled randomized trial.  Unlike, the 
pilot trial the proposed protocol will be multi-center.  Therefore, we are engaging consultants outside of the 
Seattle Center.  Dr. Carlos Rose, Nemours- Division of Pediatric Rheumatology, duPont Children's Hospital, 
Wilmington, DE has agreed to serve as consultant.  We will identify an infectious disease expert as well.   
 
Do Petersen will serve as bio-statistical consultant to the DMC.  He will perform interim statistical analyses and 
present the results to the DMC.  
 
9 Data Handling and Record Keeping 
 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  


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36
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
The Permission to Use, Create and Share Health Information for Research (aka HIPAA Authorization) 
furnished by the parents of the study participants is valid until January 31, 2017 [Attachment 2].   
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source documents   
Examples of these original documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested on 
the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank because the 
procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable to the 
individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry and enter the correct data 
above it.  All such changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and date it. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated marketing 
applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  These documents should be retained for a longer period if required.  
In such an instance, it is the responsibility of the Principal Investigator to determine when these documents no 
longer need to be retained, abiding by regulatory guidelines that pertain to protected health information. Study 
data will be retained for a minimum of 5 years. 
10 Compliance and Monitoring 
 
IND # 101,223 has been assigned by the FDA.  Additionally, we currently are submitting a Clinical Trial 
Application to Health Canada for our Canadian site.  We will subcontract with an independent clinical research 
organization (CRO) to perform monitoring for our study.   The CRO, DP Clinical, has considerable experience 
in monitoring the conduct of clinical trials in children.  They have worked in collaboration with Dr. Portman 
and monitored the Triostat in Children during Cardiopulmonary Bypass Trial, funded by the OPD program, and 
now completed with recruitment and within the data analysis stage. The study will be performed under the 
Guidelines of Good Clinical Practices as outlined in FDA document “Guidance for Industry E6 Good Clinical 
Practice: Consolidated Guidance”. 


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Dr. Portman as PI and holder of the IND will serve as sponsor.  Division of responsibilities between the PI 
and the CRO are included in the table below.  X = responsible; NR –not responsible, SIV – site initiation visit, 
IMV, interim monitoring visit, COV- close out visit.  
 
PI
CRO
X
NR
NR
X
NR
X
NR
X
NR
X
NR
X
NR
X
NR
X
NR
X
X
NR
NR
X
NR
X
X
NR
X
NR
x
NR
3.  Provide essential regulatory documents (e.g. CV of PI, FDA1572 Form, IRB 
approval) to Dr. Portman for submission to regulatory agency (FDA)
Regulatory
2.  Review and approve essential documents
9.  Track IND safety reports
5.  Conduct drug accountability at site during IMVs  (see below)
6.  Review SAEs during IMVs
5.  Track regulatory documents for all sites
6.  Assist sites with regulatory submission to IRBs
7.  Submit SAEs to regulatory agency
8.  Prepare IND safety reports for submission to sites, DMC, and regulatory agency
4.  Submit essential documents to regulatory agency
Monitoring
1.  Collect required essential documents including CRFs from each site
2.  Provide Monitoring services (SIV, IMV, COV) at  US and Canadian sites; 220 
patients; First IMV after enrollment of 2 patients; subsequent visits after enrollment of 5 
patients at each site.
1.  Qualify sites
3.  Provide monitoring reports and follow up letters to sites after each visit
4.  Final review and approval of monitoring reports
 
 
Monitors will be blinded.  Therefore, they cannot perform on-site drug accountability monitoring.  At IMVs 
they will collect drug accountability records in sealed envelopes and forward them to un-blinded monitor in 
same CRO for review.  
 
 10.1   Data Management  
Children’s Hospital and Regional Medical Center will serve as the central site and data repository.  The CRO 
will oversee completion of clinical research forms (CRFs) and transfer original CRFs to CHRMC for input into 
the central data base.  Dr. Portman’s staff will generate final queries to each site.   Additionally, CHRMC will 
serve as the central site for echocardiographic reading and interpretation (see Echocardiography).  Dr. Portman 
has previously developed an Access data-base during the currently funded FDA OPD program “Triostat in 
Children During Cardiopulmonary Bypass”.  This data-base will be amended to accept input for Kawasaki 
Disease Data.   The Access data-base requires double entry to avoid input errors.   Data will be stripped of 
identifiers (according to HIPAA) prior to transfer. Each patient will be assigned a study number with code to 
identifiers kept securely at each individual site.    
 
The database will undergo intermittent internal audit to ascertain that CRF data are correctly inputted.  The 
auditor, not yet assigned, will be a different individual than Data-base manager.  
 
10.2  Conflicts of Interest 
The DMC membership has been restricted to individuals free of apparent significant conflicts of interest.  The 
source of these conflicts may be financial, scientific or regulatory in nature.  Thus, neither study investigators 
nor individuals employed by the sponsor, nor individuals who might have regulatory responsibilities for the trial 
products, are members of the DMC. 
 


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The DMC members should not own stock in the companies having products being evaluated by the clinical 
trial.  The DMC members will disclose to fellow members any consulting agreements or financial interests they 
have with the sponsor of the trial or with other sponsors having products that are being evaluated or having 
products that are competitive with those being evaluated in the trial.  The DMC will be responsible for deciding 
whether these consulting agreements or financial interests materially impact their objectivity. 
 
The DMC members will be responsible for advising fellow members of any changes in these consulting 
agreements and financial interests that occur during the course of the trial.  Any DMC members who develop 
significant conflicts of interest during the course of the trial should resign from the DMC. 
 
DMC membership is to be for the duration of the clinical trial.  If any members leave the DMC during the 
course of the trial, the Principal Investigator will promptly appoint their replacements. 
 
10.3  Timing And Purpose Of The DMC Meetings 
 
Organizational Meeting 
The initial meeting of the DMC will be an Organizational Meeting.  It will be held during the final stages of 
protocol development, to provide advisory review of scientific and ethical issues relating to study design and 
conduct, to discuss the standard operating procedures for the role and functioning of the DMC, and to discuss 
the format and content of the Session Reports that will be used to present trial results at future DMC meetings. 
The Organizational Meetings will be attended by the DMC and the lead trial investigators.  The DMC will be 
provided the drafts of the clinical trial protocol, the DMC Charter, and the current version of the case report 
forms.  The DMC will also receive the initial draft of the Session Reports. 
 
 Interim Safety/Trial Integrity Reviews 
One or more ‘Safety/Trial Integrity Reviews’ will be held during the progress of the study to review safety 
information and to review factors relating to quality of trial conduct.  Unless circumstances necessitate 
otherwise, these meetings will be held by phone and be attended by all members of the DMC.   The DMC will 
meet at least every 6 months.  
 
10.4   Procedures To Ensure Confidentiality & Proper Communication 
To enhance the integrity and credibility of the trial, procedures will be implemented to ensure the DMC has 
access to evolving information from the clinical trial regarding results of safety data.  The study’s Principal 
Investigator will be provided immediate access on an ongoing basis to patient-specific information on serious 
adverse events (AEs) to satisfy the standard requirement for prompt reporting to the regulatory authorities. 
 
At the same time, procedures will be implemented to ensure proper communication is achieved between the 
DMC and the trial investigators.  To provide a form for exchange of information among various parties who 
share responsibility for the successful conduct of the trial, a format for Open Sessions and Closed Sessions will 
be implemented.  The intent of the format is to enable the DMC to provide opportunities for interaction between 
the DMC and others who have valuable insights into trial-related issues. 
 
 
Closed Sessions 
 
Sessions involving only DMC membership (called Closed Sessions) will be held to allow discussion of 
confidential data from the clinical trial.  The DMC will have full disclosure of the study’s safety data to achieve 
its mission of safeguarding the interest of participating patients. 


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At a final Closed Session, the DMC will develop a consensus on its list of recommendations. 
 
Open Sessions 
In order to allow the DMC to have adequate access to information provided by the study investigators, or by 
members of the regulatory authorities, a joint session between these individuals and DMC members (called an 
Open Session) will be held between the Closed Sessions.  This session gives the DMC an opportunity to query 
these individuals about issues that have arisen during their review in the initial Closed Session.  With this 
format, important interactions are facilitated through which problems affecting trial integrity can be identified 
and resolved.  These individuals will either be present at the DMC meeting or be provided a telephone link. 
 
Session Reports 
For each DMC meeting, Session Reports will be provided (see Section 7 for outlines of the content of these 
reports).  Session Reports, available to all who attend the DMC meeting, will include data on recruitment and 
baseline characteristics, study endpoints, eligibility violations, completeness of follow-up, and compliance.  The 
study coordinator will prepare these Session Reports. 
The Session Reports should provide information that is accurate, with follow-up that is complete to within two 
months of the date of the DMC meetings.  The Reports should be provided to DMC members approximately 
three days prior to the date of the meeting. 
   
Minutes of the DMC Meeting 
The DMC will prepare minutes of their meetings.  Two sets will be prepared: the Open Minutes and the Closed 
Minutes. 
 
The Open Minutes will describe the proceedings in the Open Session of the DMC meeting, and will summarize 
all recommendations by the DMC.  These minutes will be circulated immediately to the Principal Investigator. 
 
The Closed Minutes will describe the proceedings from all sessions of the DMC meeting, including the listing 
of recommendations by the Committee.  Copies of the Closed Minutes will be archived by the DMC chair for 
distribution to the Principal Investigator and regulatory authorities at the time of study closure. 
 
The sponsors will provide a complete collection of Open and Closed Minutes to regulatory authorities at the 
time of new drug application and biologic licensing application. 
 
Recommendations to the Principal Investigator 
At each meeting of the DMC during the conduct of the trial, the DMC will make a recommendation to the 
Principal Investigator to continue or to terminate the trial.  This recommendation will be based primarily on 
safety considerations. 
 
The Principal Investigator is jointly responsible with the DMC for safeguarding the interests of participating 
patients and for the conduct of the trial.  Recommendations to amend the protocol or conduct of the study made 
by the DMC will be considered and accepted or rejected by the Principal Investigator.  The Principal 
Investigator will be responsible for deciding whether to continue or to stop the trial based on the DMC 
recommendations. 
 
The DMC will be notified of all changes to the protocol or to study conduct.  The DMC concurrence will be 
sought on all substantive recommendations or changes to the protocol or study conduct prior to their 
implementation. 
 


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10.5   Data Monitoring Guidelines 
The DMC shall review clinical and laboratory data provided by the Principal Investigator to guide their 
recommendations regarding termination or continuation of the trial.  If the evidence indicates the experimental 
intervention has an unfavorable benefit-to-risk-profile, the DMC shall recommend termination of the trial.  The 
Principal Investigator will promptly report all unanticipated adverse events to the DMC for their review. The 
DMC will evaluate data separately for patients under 2 years of age to ensure the safety of etanercept in 
children in this age group.  
 
10.6   Content Of The DMC’s Session Reports 
An Outline of Session Reports: 
• 
One-page outline of the study design, possibly with a schema 
• 
Summary of Session Report data presented at prior DMC meetings 
• 
Major protocol changes 
• 
Information on patient screening 
• 
Study accrual by month  
• 
Eligibility violations 
• 
Baseline characteristics  
 
Demographics 
 
Laboratory values and other measurements 
 
Previous treatment usage and other similar information 
• 
Analyses of primary and secondary endpoints 
• 
Analyses of adverse events and overall safety data 
• 
Adherence to medication schedule  
• 
Discontinuation of medications 
• 
Attendance at scheduled visits  
• 
Reporting delays for key events 
• 
Length of follow-up data available 
• 
Participant treatment and study status  
 
11 Ethical Considerations 
 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 
21 part 312 and International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to the Children's Research Institute’s IRB, in agreement 
with local legal prescriptions, for formal approval of the study conduct.  The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator and a copy of this decision will be provided to 
the sponsor before commencement of this study.  The investigator should provide a list of IRB members and 
their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  See Attachment 1 
for a copy of the Informed Consent Form.  This consent form will be submitted with the protocol for review and 
approval by the IRB for the study.  The formal consent of a subject, using the IRB-approved consent form, must 
be obtained before that subject is submitted to any study procedure.  This consent form must be signed by the 


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41
subject or legally acceptable surrogate, and the investigator-designated research professional obtaining the 
consent.  
 
12 Study Finances 
12.1 Funding Source 
This study is financed through a FDA grant and support from Amgen 
Relationship with Amgen:   As noted previously Dr. Portman initially approached Amgen to support the pilot 
trial.  Dr. Portman remains the Principal Investigator and sponsor of the pilot study and will serve as sponsor for 
the proposed trial.   Amgen will supply drug, support for performance of pharmacokinetic analyses, and 
ancillary funds as described in the budget justification.  There are no reporting requirements to Amgen.   
However as the manufacturer is an important component of safety monitoring, Dr. Portman will send Amgen 
copies of any safety data sent to the FDA.  All data will be de-identified.   
 
12.2 Subject Stipends or Payments 
Study subjects will not receive payments for study participation. Travel costs will be reimbursed for visit 3 (7 
day visit) if participant would otherwise not be able to travel to Hospital.  


PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR         Portman, Michael A.  
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13 References 
 
 
1. 
Belay ED, Holman RC, Clarke MJ, et al. The incidence of Kawasaki syndrome in West Coast health 
maintenance organizations. Pediatr Infect Dis J. Sep 2000;19(9):828-832. 
2. 
Holman RC, Shahriari A, Effler PV, et al. Kawasaki syndrome hospitalizations among children in 
Hawaii and Connecticut. Arch Pediatr Adolesc Med. Aug 2000;154(8):804-808. 
3. 
Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of 
Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, 
Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart 
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