Pilot Study of Atorvastatin and Anakinra in Children With Coronary Artery Abnormalities Secondary to Kawasaki Disease
Phase: EARLY_PHASE1
Conditions: Kawasaki Disease
Sponsor: University of California, San Diego

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Study Protocol 
 
 
 
 
Anakinra (Kineret®) and Atorvastatin (Lipitor®) in Infants and Children  
with Coronary Artery Abnormalities in Acute Kawasaki Disease  
 
 
July 25, 2022 
 
 
Adriana H. Tremoulet, MD, MAS (PI) 
Jane C. Burns (Co-investigator) 
Sonia Jain, PhD (Biostatistician) 
 
 
 

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Table of Contents 
1. 
Introduction…… .............................................................................................................................. 4 
2. 
Product name .................................................................................................................................... 4 
2A. Product names for Combination therapy pilot study .................................................................. 4 
3. 
Chemical name ................................................................................................................................. 5 
3A. Chemical name for Combination therapy pilot study ................................................................. 5 
4. 
Proposed indication .......................................................................................................................... 5 
4A. Proposed indication for Combination therapy pilot study ........................................................... 5 
5. 
Dosage form, route, and dosing regime ............................................................................................ 5 
5A. Dosage form, route, and dosing regimen for Combination therapy pilot study........................... 5 
6. 
List of investigators at UC San Diego .............................................................................................. 5 
7. 
Study Overview ................................................................................................................................ 6 
7A. Overall objective ....................................................................................................................... 6 
7B. Hypothesis ................................................................................................................................ 6 
7C. Study Type ............................................................................................................................... 6 
7D. Study Population ...................................................................................................................... 6 
7E. Study Duration .......................................................................................................................... 6 
7F. Primary Outcome ...................................................................................................................... 6 
7G. Secondary Outcomes ................................................................ Error! Bookmark not defined. 
8. 
Background & Significance.............................................................................................................. 7 
8A. Significance .............................................................................................................................. 7 
8B. Use and safety of anakinra in infants and children .................................................................... 8 
8C. Safety of atorvastatin in children ............................................................................................. 10 
8D. Importance of the problem ...................................................................................................... 10 
8E. KD European clinical trial of anakinra ..................................................................................... 10 
8F. Potential to effect change in clinical practice ........................................................................... 10 
8G. Paradigm shift if Specific Aims are achieved .......................................................................... 11 
9. Hypotheses and Specific Aims .......................................................................................................... 11 
9A. Specific Aims of Combination therapy pilot study .................................................................... 11 
10. Study design ..................................................................................................................................... 11 
10B. Inclusion ............................................................................................................................... 11 
10C. Exclusion .............................................................................................................................. 11 
10D. Data Collection ..................................................................................................................... 12 
10E. Laboratory Samples .............................................................................................................. 12 
10F. Echocardiography Core Lab ................................................................................................. 12 
10G. Data Management ................................................................................................................ 13 
10H. Patient adherence: ............................................................................................................... 13 
11. Dosing Protocol ............................................................................................................................... 13 
11A. Drug Dosing .......................................................................................................................... 13 
11B. Duration of Study Drug ......................................................................................................... 13 
11C. Dose Limiting Toxicity/Adverse Drug Toxicity ....................................................................... 14 
12D. Stopping Rules ..................................................................................................................... 14 
12. Monitoring Side Effects ................................................................................................................... 14 
13. Additional Therapy .......................................................................................................................... 16 
13a. Management of Treatment-resistant Subjects ....................................................................... 16 
13b. Additional Therapy for Coronary Artery Abnormalities ........................................................... 16 
14. Sample Size ...................................................................................................................................... 16 
15. Statistical Analyses .......................................................................................................................... 16 
15A. Statistical analysis of safety .................................................................................................. 16 

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16. Data and Safety Monitoring Plan ..................................................................................................... 16 
Appendix A: Preparation of Anakinra (Kineret®) in the Hospital for Doses < 20 mg ......................... 17 
References: ............................................................................................................................................. 18 
 

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1. Introduction 
 
Our recent work has demonstrated that the inflammasome-dependent interleukin (IL)-1 pathway is 
upregulated with increased transcript abundance and levels of proteins including IL-1β and IL-1 
receptor type 1 (IL-1R1) in infants and children with acute Kawasaki disease (KD).(Hoang 2014) In 
addition, our preliminary studies indicate that KD sera induce expression of TIFA (TNF-receptor-
associated factor [TRAF]-interacting protein with a forkhead-associated [FHA] domain) in endothelial 
cells (ECs) (Figure 1). Notably, TIFA, an upstream activator of NF-κB through IL-1R signaling, has 
emerged as a key mediator in innate immunity and a likely participant in the activation of the NLRP3 
(nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3) 
inflammasome leading to IL-1β production.(Ea 2004, Huang 2012, Lin 2016). Our recent publication of 
a Phase I/IIa study of anakinra in KD patients with coronary artery abnormalities (CAA) demonstrated 
that up to 6 weeks of anakinra (up to 11 mg/kg/day) is safe and well tolerated by infants and children 
with acute KD. (Yang 2021) Anakinra clearance increased with illness day at diagnosis. Simulations 
demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations 
without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. Thus, 
both IV and SC anakinra are safe in infants and children with acute KDD  and CAA.  
 
Additional recent work by our group has 
demonstrated that it is not only the blocking of 
the IL-1 pathway that is important to prevent 
CAA in KD. The transformation of endothelial 
cells to a myofibroblast phenotype through 
endothelial-mesenchymal transition (EndoMT) in 
the coronary artery wall also contributes to 
aneurysm formation. (Shimizu 2013) Statins, 
commonly prescribed as cholesterol-lowering 
agents, have pleotropic effects on vascular ECs 
that include improving EC function, decreasing oxidative stress, and modulating innate and acquired 
immune responses. (Liao 2005, Oesterle 2017) Using an in vitro model with human ECs, we 
demonstrated that the krüppel-like factor 4 (KLF4)-microRNA-483 (miR-483) axis is suppressed and 
markers of EndoMT, including connective tissue growth factor (CTGF), are induced following incubation 
with sera from acute KD patients (Figure 1). This effect is reversed when ECs are cultured with sera 
from atorvastatin-treated KD patients.(He 2017) Given the pleotropic effects of statins, we conducted a 
Phase I/IIa, dose-escalation trial of atorvastatin for acute KD patients with early CAA (IND # 113304 
held by Dr. Jane C. Burns (co-I of this proposal); NCT01431105). (Tremoulet 2015) In this study, a 6-
week course of up to 0.75 mg/kg/day (max 80 mg/day) of atorvastatin was well tolerated with no 
serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its 
metabolite were larger in the study subjects compared with those reported in adults, suggesting a 
slower rate of metabolism in children.  
 
These in vitro data, in combination with the safety of anakinra and atorvastatin in Phase I/IIa, dose-
escalation studies, serve as the motivation to propose a pilot study combining anakinra at 8 mg/kg/day 
and atorvastatin at 0.75 mg/kg/day in children with acute KD at least 1 year old who are suffering from 
CAA. Throughout this protocol, this study is referred to as the “Combination therapy pilot study”.  
2. Product name  
2A. Product names for Combination therapy pilot study 
Anakinra (Kineret) 
Fig 1. Molecular rationale for anakinra/atorvastatin 
combination therapy 
 
Upregulated during KD (red); downregulated during 
KD (blue) 

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Atorvastatin (Lipitor) 
3. Chemical name  
3A. Chemical name for Combination therapy pilot study 
Recombinant-Methionyl Human Interleukin-1 Receptor Antagonist (r-metHuIL-1ra) 
Atorvastatin 
4. Proposed indication 
4A. Proposed indication for Combination therapy pilot study 
 Treatment of children with coronary artery abnormalities from acute KD. 
 
5. Dosage form, route, and dosing regime 
5A. Dosage form, route, and dosing regimen for Combination therapy pilot study 
Anakinra at 8 mg/kg/day up to a maximum of 200 mg and atorvastatin at 0.75 mg/kg/day up to a 
maximum of 80 mg will be administered as part of a pilot study.  
6. List of investigators at UC San Diego 
 
Adriana H. Tremoulet, MD, MAS (PI) 
Professor 
Associate Director, Kawasaki Disease Research Center 
Division of Host Microbe & System Therapeutics 
Department of Pediatrics 
University of California, San Diego 
Rady Children’s Hospital San Diego 
 
Jane C. Burns, MD 
Professor 
Director, Kawasaki Disease Research Center 
Division of Allergy, Immunology and Rheumatology 
Department of Pediatrics 
University of California, San Diego 
Rady Children’s Hospital San Diego 
 
Sonia Jain, PhD 
Professor 
Co-Director, Biostatistics Research Center 
Division of Biostatistics and Bioinformatics 
Department of Family and Preventive Medicine 
University of California, San Diego 
 

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7. Study Overview 
7A. Overall objective  
The goal of this study is to determine the safety and activity of anakinra and atorvastatin in combination 
in acute KD patients with coronary artery Z score ≥ 2.5. The goal will be to find a treatment regimen that 
could prevent or attenuate coronary artery damage in acute KD.  
7B. Hypothesis  
We postulate that anakinra and atorvastatin in combination will be safe in children with acute KD. We 
also postulate that this combination therapy will reduce inflammation in children with acute KD more 
than using anakinra or atorvastatin alone.    
7C. Study Type 
This is a pilot study. 
7D. Study Population  
Children with acute KD who have a Z-score ≥ 2.5 of the LAD or RCA will be eligible for this study. 
7E. Study Duration 
The entire study will last 5 years. Each subject will be in the study for up to 6 weeks.  
7F. Primary Outcome  
Safety of anakinra and atorvastatin in combination will be the primary outcome.  

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8. Background & Significance 
8A. Significance 
KD, the most common cause 
of acquired heart disease in 
children in Western developed 
countries and Asia, is a 
systemic vasculitis of unknown 
etiology. In the United States, 
there are at least 5-6,000 new 
cases each year (Kaneko 
2011). However, without a 
specific diagnostic test, the 
true burden of disease is 
unknown. At Rady Children’s 
Hospital San Diego, we care 
for over 100 new KD patients 
annually and follow over 1,200 
families in our outpatient KD 
Clinic (350 outpatient 
visits/year), of whom 9% 
developed aneurysms and 
25% developed dilated 
coronary arteries. In Japan, the 
country of highest incidence 
(>215/100,000 children < 5 
yrs.), there are more than 
12,000 new cases each year 
and rates continue to rise 
(Nakamura 2010). KD causes 
both a myocarditis and a 
vasculitis that damages the 
coronary arteries and other 
medium-sized muscular 
arteries (Yutani 1980, 
Yonesaka 1989). The major 
sequelae of aneurysms include 
thrombosis, late coronary 
artery stenosis, myocardial 
ischemia, myocardial 
infarction, and death (Kato 
1996, Gordon 2009). Clearly, 
aneurysm prevention is a 
primary goal of treatment 
during the acute phase of 
the disease, which leads us to focus on treatment of patients with early signs of coronary artery 
abnormalities (CAAs) in this pilot study. 
 
Intravenous immunoglobulin (IVIG) in combination with aspirin is the only approved therapy for KD. The 
major acute risk of aneurysm formation is thrombosis, which can be prevented with systemic anti-
coagulation with warfarin or enoxaparin in addition to antiplatelet therapy with aspirin or clopidogrel in 
patients with large aneurysms (>6 mm). However, there is no recommended therapy to halt the 
Figure 2. IL1signaling pathway was the key upregulated pathway in 
acute KD 
 
A) Transcripts involved in IL1 signaling pathways were more 
abundant in acute KD; differentially abundant transcripts between 
acute and convalescent KD samples are highlighted in red. B) and 
C) IL1R1 and IL1receptor associated protein (RAP) were 
differentially expressed only in acute vs. convalescent KD but not in 
other diseases. ** P value < 0.01 

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progression of arterial wall destruction and prevent aneurysm formation beyond the initial dose 
of IVIG.  
 
8A1. Role of IL-1 pathway in KD and blockade by anakinra  
In KD, the IL-1 pathway is upregulated, as demonstrated by increased transcript abundance by 
microarray and by increased levels of pathway proteins in the plasma (Maury 1988, Leung 1989, 
Popper 2007, Hoang 2014). (Figure 2 and Table 1) 
 
Table 1. Comparison of the gene pathway analysis of up-regulated pathways in each group of patients 
Most abundant transcripts for the top upregulated pathways (KD acute vs. conv., other groups vs. healthy 
controls) and shared among KD, viral and bacterial infection groups. Pathways are ordered by descending 
log (p-value). Individual probe P values are uncorrected. Yellow highlighting identifies transcripts that were 
significant in more than one pathway. Red box identifies transcripts in the IL-1 pathway.  
 
Furthermore, in the Lactobacillus casei cell wall extract mouse model that develops a KD-like coronary 
arteritis, the IL-1 receptor antagonist, anakinra, prevented the development of coronary lesions, as did 
knocking out the IL-1 receptor (Lee 2012). Anakinra has been used to treat a severe KD patient who 
was non-responsive to IVIG treatment (Cohen 2012).Treatment with anakinra was safe and coincided 
with a decrease in systemic and coronary artery inflammation. The proposed study will determine if 
anakinra in combination with atorvastatin is safe to use in young children with KD and has 
demonstrable anti-inflammatory activity at a well-tolerated dose.  
8B. Use and safety of anakinra in infants and children 
Anakinra is currently used in several inflammatory diseases in infants and children, including systemic 
juvenile idiopathic arthritis and the autoinflammatory syndromes known as cryopyrin-associated 
periodic syndromes (CAPS)(Hoffman 2009, Ringold 2013). In a study of 26 patients with the 
autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID), treatment with 
anakinra for 36 months had a low adverse event rate, with upper respiratory infection as the most 
commonly reported complication (Sibley 2012). A similar study using anakinra in another CAPS, 
Muckle Wells syndrome, did not demonstrate any SAEs in the 12 patients treated with anakinra, of 
whom 5 were children (Kuemmerle-Deschner 2011). Two case reports have been published reporting 
the use of anakinra in children with refractory, acute KD. A 2 year old with giant aneurysms who failed 
therapy with IVIG and steroids and developed giant aneurysms was treated with a 6 week course of 
anakinra at 1 mg/kg (Cohen 2012). He suffered no adverse effects and at 6 months coronary 

9 
 
angiography demonstrated resolution of the aneurysms, which was unexpected in such a severe case 
of KD. An 11 week old with KD and giant aneurysms was refractory to three doses of IVIG, steroids and 
a dose of infliximab (Shafferman 2014). She was treated with anakinra initially at 6 mg/kg/day and then 
increased to 9 mg/kg/day. She too did not suffer any adverse effects and at an 8 month follow up visit 
her coronary artery status had also significantly improved.   
 
Given that this medication is administered once daily as a subcutaneous injection, the most common 
adverse reaction is irritation at the injection site. Table 2 is a summary of published and unpublished 
data on the use of anakinra in children <2 years old: 
 
Table 2. Use of anakinra in children < 2 years old 
Ages Treated  
(in months) 
Max Dose 
(mg/kg) 
Diagnosis 
Reference 
17 
1.6 
CINCA 
(Matsubara 2006) 
3 and 4 
6 & 10 
NOMID 
(Neven 2010) 
2,4,13 and 22 
1-4 
DIRA 
(Aksentijevich 2009) 
1 
1 
DIRA 
(Stenerson 2011) 
8 
11 
sJIA 
(Record 2011) 
10 and 18 
2-4 
sJIA 
(Nigrovic 2011) 
5 
3 
DIRA 
(Minkis 2012) 
10, 13, 16, 20 
2-4 
NOMID 
(Sibley 2012) 
18 
8 
MVK 
(Ruiz Gomez 2012) 
24 
9 
KD 
(Cohen 2012) 
6 
2-4 
Def IL-36Ra 
(Rossi-Semerano 2013) 
8 
2-10 
sJIA  
(Urien 2013) 
3 and 14 
2-3 
MVK 
(Levy 2013) 
6 
2 
NOMID 
(Montealegre 2014) 
2 
9 
KD & MAS 
(Shafferman 2014) 
12 and 15 
6 & 8 
CAPS 
(Hoffman 2014) 
18 
15 
sJIA & MAS 
(Cartwright 2014) 
11 
8 
CAPS 
(Jerath 2014) 
13** 
4 
sJIA 
(Momborquette 2014) 
15 and 18 
3.5 & 4 
CINCA & sJIA 
(Guedes 2014) 
8, 10, 15, 17, and 22  
1 to 9  
sJIA 
(Punaro 2014) 
6, 9 and 15 
1-3 
CAPS 
(Ombrello 2014) 
20 
5 
Hyper IgD Syndrome 
(Ombrello 2014) 
CINCA = chronic infantile, neurological, cutaneous and arthritis; NOMID = neonatal onset multi-system 
inflammatory syndrome (CINCA and NOMID are the same syndrome); DIRA = deficiency of the IL-1 
receptor antagonist; sJIA = systemic juvenile idiopathic arthritis; MVK = mevalonate kinase deficiency; 
KD = Kawasaki disease; MAS = macrophage activation syndrome; CAPS = cryopyrin associated 
periodic syndrome 
 
No adverse effects noted besides mild local reaction unless otherwise noted; **coxsackie virus while 
also on methotrexate and steroids;  
 
Thus, at least 39 children < 2 years of age, and as young as 2 months of age, have been treated with 
anakinra with doses ranging from 1 to 15 mg/kg.  
 

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Our recent publication of a Phase I/IIa study of anakinra in KD patients with coronary artery 
abnormalities (CAA) demonstrated that up to 6 weeks of anakinra (up to 11 mg/kg/day) is safe and well 
tolerated by infants and children with acute KD. (Yang 2021) Anakinra clearance increased with illness 
day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in 
more sustained concentrations without significantly increasing the peak concentration compared with 
subcutaneous (SC) dosing. Thus, both IV and SC anakinra are safe in infants and children with acute 
KDD  and CAA.  
8C. Safety of atorvastatin in children 
The safety of atorvastatin in children as young as 2 years of age with acute KD was assessed in a 
Phase I/IIa dose escalation study (IND 113304 issued to Dr. Jane C. Burns, co-investigator of this 
study). On May 19, 2016, the DSMB for this Phase I/IIa study evaluated the data from the Phase I 
dose-escalation study of atorvastatin for 6 weeks in children at least 2 years with acute KD and 
coronary artery damage. The DSMB determined that a 6 week course of atorvastatin was safe and 
well-tolerated in children ≥ 2 years with acute KD. In addition, based on the review of the safety of the 
Phase I study, the DSMB determined 0.75 mg/kg/day of atorvastatin to be the maximum tolerated dose. 
An additional 10 subjects were enrolled at 0.75 mg/kg/day as part of the dose expansion cohort study 
and further demonstrated the safety and tolerability of this dose in acute KD.  The level of the 
cholesterol brain metabolite, 24-OH cholesterol, was measured in both statin-treated KD patients and in 
those treated with standard therapy for KD. No significant difference was found between the groups in 
the levels of 24-OH cholesterol, further demonstrating the safety of atorvastatin in acute KD as it does 
not reduce the levels of 24-OH cholesterol, which are important for normal brain development. In this 
study, a 6-week course of up to 0.75 mg/kg/day (max 80 mg/day) of atorvastatin was well tolerated with 
no serious adverse events attributable to the study drug (Tremoulet et al 2019). The areas under the 
curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported 
in adults, suggesting a slower rate of metabolism in children.  
8D. Importance of the problem 
Once aneurysms have formed, there is no way to turn back the biologic clock and undo them. The 
transmural inflammation destroys the normal architecture and even in children who remodel the 
aneurysm to form a more normal lumen, the vessel is never functionally normal again. The remodeled 
segment cannot dilate normally during increased myocardial oxygen demand and thus serves as a 
functional stenosis. It has been estimated that there are currently over 24,000 young adults in the 
United States with a history of KD, including over 8,000 with a history of coronary artery abnormalities. 
Without a new therapeutic approach this number is expected to grow by 1,400 individuals each year 
(Gordon 2009). An important study found that over 5% of all young adults (<40 years) evaluated by 
cardiac catheterization for suspected myocardial ischemia have aneurysms compatible with antecedent 
KD (Daniels 2012). 
8E. KD European clinical trial of anakinra 
A clinical trial in Europe, treating IVIG-resistant KD patients (≥ 8 months of age) with a 14-day course of 
anakinra, demonstrated that anakinra was well tolerated in the study patients and may have some 
efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in 
individuals with IVIG-refractory KD. (Kone-Paut et al. 2021)  
8F. Potential to effect change in clinical practice 
 
Our goal is to translate our findings on the role of the IL-1 pathway and EndoMT in acute KD and 
“repurpose” anakinra and atorvastatin in combination to test the hypothesis that the anti-inflammatory 
properties of these drugs in combination will prevent or attenuate coronary artery aneurysms in children 
with KD.  

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8G. Paradigm shift if Specific Aims are achieved 
By performing this study, we will bring to the forefront the need for new therapies for the subset of KD 
patients who are genetically predisposed to develop coronary artery damage. The paradigm shift will be 
to intensify initial therapy for KD patients, thus acknowledging the urgency of early intervention to 
prevent the permanent disability associated with aneurysm formation. Furthermore, given the unique 
immunological expertise within our group, demonstration of the immunomodulatory effects in a 
cardiovascular disease could pose a novel treatment for other cardiovascular diseases. 
9. Hypotheses and Specific Aims 
9A. Specific Aims of Combination therapy pilot study 
 
Specific Aim 1 will test the hypothesis that a 2 to 6 week course of anakinra and atorvastatin in 
combination will be safe and well-tolerated in children with acute KD who have a Z-score of ≥2.5 
of LAD or RCA.  
 
While the safety of anakinra will be assessed by monitoring for leukopenia, infection and injection site 
reactions, the safety of atorvastatin will be assessed by monitoring for liver and muscle toxicity. 
 
 
10. Study design  
 
 
10A. Accrual and study duration for Combination therapy pilot study 
We estimate enrolling 0-2 patients every 6 months with a target enrollment of 10 patients over a 5-year 
period. All subjects enrolled will be in the study for 6 weeks during which time they will receive once or 
twice daily subcutaneous injections of anakinra and once daily oral administration of atorvastatin 
administered by the parents at home.  
10B. Inclusion 
1. Meets clinical criteria for KD according to American Heart Association guidelines (Table 4): 
Fever (T≥38oC or 100.4oC)  ≥ 3 days and ≥ 2 clinical criteria with LAD or RCA z-score ≥ 2.5  
2. Patient at least 1yo  
3. Patient presents within the first 20 days after fever onset  
4. Parent or legal guardian able and willing to provide informed consent  
 
Table 4. Diagnostic criteria for KD with CAA (Adapted from American Heart Association 
(Newburger 2004)):  
KD standard clinical criteria : 
• 
Bilateral conjunctival injection 
• 
Changes of the mucous membranes of the upper respiratory tract: injected pharynx, 
injected, fissured lips, strawberry tongue 
• 
Changes of the peripheral extremities: peripheral edema, peripheral erythema, 
periungual desquamation 
• 
Polymorphous rash 
• 
Cervical adenopathy >1.5 cm 
10C. Exclusion 
 
1. Use of an IL-1beta antagonist within the 3 months prior to enrollment 

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2. Have any chronic disease, except asthma, atopic dermatitis, autism or controlled seizure 
disorder  
3. History of hypersensitivity to anakinra  
4. Personal or immediate family history of tuberculosis (TB) or TB exposure 
5. Active, culture-positive bacterial infection 
6. Baseline eGFR lower than 45 mL/min/1.73m2 (as subjects ≥ 1 year old) 
7. Use of a statin, fibrate, or niacin within the 3 months prior to enrollment 
8. Screening creatine phosphokinase (CK) ≥ 3x upper limit of normal for age 
9. Taking a CYP3A4 inhibitor (i.e. cyclosporine, clarithromycin or doxycycline) in the last 7 days 
10. History of allergy to atorvastatin or its derivatives 
10D. Data Collection 
 
1. Demographic data:  
a. Patient's age at KD onset, sex, self-reported ethnicity of each biologic parent  
2. Clinical data:  
a. Physical findings confirming the KD case definition (Newburger 2004) 
b. Illness day at study entry 
c. Response to IVIG (IVIG-resistance will be defined as persistent or recrudescent fever 
(T≥38.0˚C rectally) ≥36 h and < 7d following the end of the IVIG infusion (2g/kg) (Tremoulet 
2008). 
d. Name, dose and indication of concomitant medications taken while on study 
e. Serum creatinine at baseline prior to receiving study drug 
f. Severity and duration of infections (with any associated cultures or diagnostic testing) during 
study 
g. Complete blood count, CRP, hsCRP, ESR, aspartate aminotransferase (AST), and ALT at 
baseline, 48 hours (not ESR as IVIG recently administered), and 2 and 6 weeks  
h. CK and fasting lipid panel at baseline (after enrollment), 48 hours, and 2 and 6 weeks (if still 
on study drug) 
i. 
Echocardiographic data at baseline, 48 hours, and 2 and 6 weeks (standard of care for 
patients with CAA) 
10E. Laboratory Samples 
 
Subjects will have the following samples collected at baseline (pre- anakinra and -atorvastatin), 48 
hours and 2 and up to 6 weeks (if still on study drug) (+/- 7 days) from enrollment: 
1. RNA collection: Whole blood RNA will be collected using PAX gene tubes. RNA will be isolated 
according to the manufacturer’s instructions and aliquoted and stored at -80°C.  
2. Plasma and serum: EDTA plasma and serum will be collected for measures of inflammation.  
10F. Echocardiography Core Lab  
An echocardiogram will be performed at the following time points:  
• 
During initial hospitalization (as soon after admission as possible) 
• 
48 hours after enrollment in this study 
• 
Study week 2 (Study day 14 ± 7 days)  
• 
Study week 6 (Study day 42 ± 7 days) 
 
2-D transthoracic echocardiograms (2-D Echo) will be performed on all KD subjects according to a strict 
pre-determined protocol at standard of care time points. All echocardiographic images will be analyzed 
by Dr. Beth Printz, Director of Non-Invasive Cardiovascular Imaging at Rady Children’s Hospital San 
Diego. She will be blinded to patient data and clinical status. Dr. Printz will also assure adherence to 
the echo protocols across all echocardiogram technicians. 2-D Echo will be performed at KD diagnosis 
(within 24h of IVIG infusion) and again at two and six weeks following enrollment with sedation when 

13 
 
clinically indicated. The internal lumen diameters of the left main (LMCA), proximal and distal LAD, 
circumflex, posterior descending, and proximal and distal RCA will each be measured.  Dimensions of 
the LMCA, proximal LAD, and proximal RCA will be adjusted for body surface area and expressed in 
standard deviation units (Z-scores) (Manlhiot 2009). A variable “Z worst any vessel” will be created to 
capture the maximal Z score of the RCA or LAD at any time point, as well as the Z-score of the LMCA if 
an aneurysm is present there with a Z-score larger than that of the RCA or LAD. Coronary artery 
aneurysm will be defined as a Z-score of 2.5 or larger of the RCA or LAD(Nishiike 2006).  
 
Additional echocardiographic data will be collected to assess aortic root dimensions and left ventricular 
dimensions and function, including indices of diastolic ventricular function (mitral inflow Doppler and 
tissue Doppler imaging), as recent reports have demonstrated abnormalities in each of these 
parameters following acute KD (Kato , Printz) Aortic root and ventricular dimensions and function will be 
expressed as body surface area (BSA)- or age-adjusted Z scores. A dilated aortic sinus diameter will 
be defined as a BSA-adjusted Z score ≥ 2.0 (Ravekes 2001). LV systolic dysfunction will be defined as 
an age-adjusted LV fractional shortening Z score < -2; LV diastolic dysfunction will be defined as an 
abnormal age-adjusted mitral inflow Doppler E’-wave, E’/A’ ratio, or mitral deceleration time according 
to published normative data (Chaudhuri).  
10G. Data Management  
Subjects will be assigned a unique study number. Demographic and clinical information including all 
numerical echo data parameters will be entered into an established, password-protected, database in 
use by our research group since 2001 (http://www-pediatrics.ucsd.edu/kawasaki) that currently contains 
data on over 1,200 KD subjects. The web portal uses the secure web application Research Electronic 
Data Capture (REDCap) (Harris 2009). 
10H. Patient adherence:  
Remaining syringes of anakinra and tablets of atorvastatin will be counted at the 2 and 6 week visits to 
assess patient adherence. 
11. Dosing Protocol 
11A. Drug Dosing  
All subjects will be treated with IVIG (2g/kg) and aspirin (30-50 mg/kg/day divided every 6 hours; 
lowered to 3-5 mg/kg/day once sent home), which is the standard of care. All subject will also receive 
10 mg/kg of infliximab for CAA, which is standard of care at Rady Children’s Hospital San Diego. 
Anakinra will be administered once or twice daily subcutaneously up to 8 mg/kg/day with a maximum 
dose of 200 mg/day. If the daily dose of anakinra for a subject is ≤ 100mg, then the subject will receive 
a subcutaneous injection of anakinra once daily. If the daily dose of anakinra is greater than 100 mg 
(with a max dose of 200 mg daily), then the dose will be split in half with administration subcutaneously 
every 12 hours (i.e. a total daily dose of 150 mg will be administered as 75 mg subcutaneously every 
12 hours).  
 
Atorvastatin will be administered orally once daily at 0.75 mg/kg/day with a maximum dose of 80 
mg/day.  
11B. Duration of Study Drug 
All subjects will receive 2 weeks of combination therapy. Subjects with an echo at 2 weeks that shows 
either a LAD or RCA z-score ≥ 2.0 will receive an additional 4 weeks of combination therapy to 
complete a total course of 6 weeks. All subjects will remain on study for the full 6 weeks whether or not 
they are receiving anakinra and atorvastatin. 

14 
 
11C. Dose Limiting Toxicity/Adverse Drug Toxicity 
 
An adverse drug toxicity will be defined as any of the following at the 2 or 6 week time point: 
• 
Serious infection qualifying as an SAE (see Section 13) and requiring intervention  
• 
A decrease in the white blood cell count (WBC) to <1500/mm3 (Grade 3 severity by NIH/NIAID) 
(NIH 2009) 
• 
An anaphylactoid reaction to an injection of anakinra 
• 
ALT or AST more than 3x the upper limit of age and sex-adjusted normal AND >50% increase 
over baseline (pre-IVIG) 
• 
CK elevation > 10 times the upper limit of normal or symptoms of muscle pain due to myositis  
• 
A decrease in total cholesterol (TC) level that is at least 10% lower than entry level AND below 
100 mg/dl (~2.5th percentile for children age 2 yrs.) 
 
A low absolute neutrophil count (ANC) is considered part of the natural course of KD and usually 
occurs 2 weeks after the initial illness (Tremoulet 2011). Given this, a low ANC will not be considered 
an adverse drug toxicity or an adverse event in this study. 
12D. Stopping Rules 
 
Individual stopping rules:  
A subject who experiences any of the following adverse drug toxicities will discontinue anakinra 
immediately: 
• 
Serious infection qualifying as an SAE (see Section 12) and requiring intervention  
• 
A decrease in the white blood cell count (WBC) to <1500/mm3 (Grade 3 severity by NIH/NIAID) 
(NIH 2009) 
• 
An anaphylactoid reaction to an injection of anakinra  
A subject who experiences any of the following adverse drug toxicities will discontinue atorvastatin 
immediately: 
• 
ALT or AST more than 3x the upper limit of age and sex-adjusted normal AND >50% increase 
over baseline (pre-IVIG) 
• 
CK elevation > 10 times the upper limit of normal or symptoms of muscle pain due to myositis  
• 
A decrease in total cholesterol (TC) level that is at least 10% lower than entry level AND below 
100 mg/dl (~2.5th percentile for children age 2 yrs.) 
 
Any subject who experiences an adverse drug toxicity that warrants discontinuation of a study drug will 
be monitored for resolution of the toxicity as medically appropriate. All subjects will be monitored for 6 
weeks from the time of enrollment or until resolution of the adverse drug toxicity, whichever is later.  
 
Study stopping rule:  The study will be discontinued if three subjects experience adverse drug 
toxicities.   
12. Monitoring Side Effects 
Subjects will be monitored for 6 weeks to evaluate for AEs. The main side effect of anakinra is an 
infusion site reaction. The most serious adverse event would be an infection or hypersensitivity 
reaction. See Table 8 for definition of AEs associated with anakinra and Table 9 for grading severity of 
a decrease in WBC. Subjects will also be monitored for AEs associated with atorvastatin (Table 10).  
 
All subjects will be monitored for both AEs and SAEs. An adverse event is any unfavorable or 
unintended change in a sign (i.e. abnormal laboratory), symptom or disease temporally associated with 
the study treatment, whether or not it is considered to be related to the study product.   
 
 

15 
 
Table 8: Definition of Adverse Events Associated with Anakinra 
Adverse Event 
NOT an Adverse Event (Expected with KD) 
Infusion site reaction 
Atopic dermatitis or psoriasis  
Decrease in WBC as per Table 9 
Eosinophilia (<35%) or ANC (>500) 
Any infection 
Worsening coronary artery dilatation or aneurysm 
compared to baseline 
 
Laboratory values compared to baseline: 
• 
Worsening anemia 
• 
Increasing platelet and lymphocyte counts 
• 
Increasing ESR 
 
 
 
Table 9: Grading Severity of Decrease in WBC Adverse Event (NIH 2009) 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Potentially Life 
Threatening 
2,000 – 2,500/mm3 
 
1,500 – 1,999/mm3 
 
1,000 – 1,499/ mm3 
 
< 1,000/mm3 
 
 
Table 10: Definition of Adverse Events Associated with Atorvastatin 
ALT or AST more than 3x the upper limit of age and sex-adjusted normal AND >50% increase over 
baseline (pre-IVIG) 
 
CK elevation > 10 times the upper limit of normal or symptoms of muscle pain due to myositis  
 
A decrease in total cholesterol (TC) level that is at least 10% lower than entry level AND below 100 
mg/dl (~2.5th percentile for children age 2 yrs.) 
 
A SAE is defined as any event which:  
1. Is fatal; or  
2. Is life-threatening (the patient was, in the view of the Principal Investigator, in immediate danger of 
death from the event as it occurred); or  
3. Requires hospital admission or prolongs hospitalization; or  
4. Is persistent or causing significant disability; or  
5. Required medical intervention, such as major surgery, to prevent a serious outcome; or  
6. The Clinical Site Principal Investigator considers it to be a serious adverse event.  
 
SAEs for this trial include, but are not limited to, anaphylaxis, arrhythmia, cardiac arrest, cardiogenic 
shock, death, hearing loss, hepatitis, hypertension, hypotension, myocardial infarction, renal failure, 
seizures, sepsis (confirmed), or shock.  
 
Any SAE, independent of causality, which occur in a subject in the Trial, assigned to receive Product 
will be reported to Sobi. Reports shall be sent to the Sobi Drug Safety Department by email 
(drugsafety@sobi.com), or by fax (+46 8 697 32 30), within 24 hours of first awareness. Similar 
reporting will occur with the FDA and IRBs as stipulated by their reporting rules.  

16 
 
13. Additional Therapy  
13a. Management of Treatment-resistant Subjects 
Treatment-resistance will be defined as persistent or recrudescent fever (T≥38.0˚C rectally) ≥36 hours 
and <7 days following end of IVIG infusion. Subjects who meet criteria for treatment-resistance will be 
treated at the Center PI’s discretion.  
13b. Additional Therapy for Coronary Artery Abnormalities  
Additional therapy for coronary artery abnormalities will be at the Center PI’s discretion. A Phase III, 
double-blind, randomized controlled trial of the addition of infliximab to primary treatment with IVIG 
demonstrated that early treatment of infants and children with acute KD with infliximab plus IVIG had a 
more rapid decrease in inflammation, fewer days of fever, and a more rapid decrease in the internal 
diameter of a dilated coronary artery compared to IVIG therapy alone (Tremoulet 2014). Thus, subjects 
in this study will be eligible to receive infliximab at the discretion of the Center PI.  
14. Sample Size  
 
This study is not powered to show a difference in echocardiographic measurements or treatment 
response compared to controls.  
15. Statistical Analyses 
15A. Statistical analysis of safety  
Descriptive statistics will be calculated for demographic and baseline characteristics, variables related 
to biologic activity, immunologic variables, PK variables, and safety data. The study population will be 
described using summary descriptive statistics such as mean, median, standard deviation, and range 
for continuous variables and frequencies for categorical variables. All events (AEs, SAEs, and UPRs) 
will be recorded, documenting the course, outcome, severity, and relationship to the study treatment. 
Incidence rates of events and the proportion of subjects prematurely withdrawn from the study due to 
events will be compiled. Analyses will be performed for all patients who have received at least one dose 
of study treatment. Deviation from the treatment plan will be recorded in the case report forms. The 
percentage of subjects failing to complete the study or discontinuing prematurely (as well as the times 
and reasons for discontinuation) will be reported.   
 
16. Data and Safety Monitoring Plan 
 
As this is a study that involves children and the investigators must protect this vulnerable population, a 
DSMP has been established. To assure the safety of subjects participating in this trial, Drs. Burns and 
Tremoulet will meet after enrollment of every two subjects to discuss progress of the trial and possible 
safety issues. Safety and clinical data will be tabulated and presented by the biostatistician to the 
investigators after all subjects have been enrolled. An earlier meeting can be convened by Dr. 
Tremoulet, Dr. Burns or Dr. Jain if safety questions or other unanticipated problems arise.  
 
The UCSD IRB, FDA, Pfizer and Sobi Pharmaceuticals will be immediately notified (within 48h) of any 
UPRs. For anticipated SAEs and AEs, the UCSD IRB will receive a report as per their reporting 
guidelines. 
  

17 
 
Appendix A: Preparation of Anakinra (Kineret®) in the Hospital for 
Doses < 20 mg 
 
 
The following protocol is completed using a single dose, pre-filled syringe of 
commercially available Kineret® (100 mg/0.67ml syringe) by a pharmacist or pharmacy 
technician who is gowned and gloved, and is wearing a cap, face mask, and shoe 
covers. 
 
1. Aseptically transfer the anakinra directly into a sterile one ml syringe in an ISO Class 5 IV hood 
located in the hospital inpatient pharmacy IV Class 10,000 clean room.  
 
2. The prepared dose syringe is then capped and labeled and given a 4-hour expiration under 2-
8C refrigerated.  
 

18 
 
 
 
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