Study Protocol for the RAISE Study- Randomized controlled trial to Assess Immunoglobulin plus
Steroid Efficacy for Kawasaki disease This study is supported by the Ministry of Health, Labour and Welfare (MHLW),
Health and Labour Sciences Research Grants for the Comprehensive Research
on Practical Application of Medical Technology:
Research Organization: RAISE Study Group
RAISE Study Principal Investigator: Tsutomu Saji
Toho University Omori Medical Center, the First Department of Pediatrics
6-11-1 Omori-nishi, Ota-ku, Tokyo, Japan 143-8541
TEL:（+81）（0）- 3-3762-4151 FAX:（+81）（0）- 3-3298-8217 e-mail: saji34ben@med.toho-u.ac.jp

RAISE Study Office: Tohru Kobayashi
Gunma University Graduate School of Medicine, Department of Pediatrics
3-39-22 Showa-machi, Maebashi, Gunma, Japan 371-8511
TEL:（+81）（0）- 27-220-8205 FAX:（+81）（0）- 27-220-8215 e-mail: raise-discussion@umin.ac.jp

Corresponding to Tohru Kobayashi
Gunma University Graduate School of Medicine, Department of Pediatrics
3-39-22 Showa-machi, Maebashi, Gunma, Japan 371-8511
TEL:（+81）（0）- 27-220-8205 FAX:（+81）（0）- 27-220-8215 e-mail: raise-discussion@umin.ac.jp

January 12, 2007
February 23, 2007
July 29, 2007
December 8, 2007
March 24, 2008
July 10, 2009
July 25, 2011

First draft of Protocol completed
Second draft of Protocol completed
Study protocol was fixed (Ver. 3.0)
Registered at UMIN-CTR (No. UMIN000000940)
Approved by Institutional Review Board of Toho University
Study protocol revised (Ver. 3.1)
English version completed (Ver. 3.1.E)1. RESEARCH GOALS… ……………………………………………………………………

4

2. BACKGROUND AND RATIONALE FOR THE STUDY… ……………………………………

4

2.1. Subjects… …………………………………………………………………………

4

2.2. Rationale for establishing treatment regimen………………………………………

5

2.3. Study Design… ……………………………………………………………………

6

3. DEFINITIONS USED IN THE STUDY………………………………………………………

7

3.1. Diagnosis of KD… …………………………………………………………………

7

3.2. Using risk score to identify severe KD patients… …………………………………

7

3.3. Definition of fever……………………………………………………………………

8

3.4. Definition of treatment nonresponse… ……………………………………………

9

3.5. Definition of coronary artery abnormalities………………………………………… 10
4. PATIENT SELECTION CRITERIA AND TREATMENT ASSIGNMENT… …………………… 10
4.1. Inclusion criteria… ………………………………………………………………… 10
4.2. Exclusion criteria…………………………………………………………………… 10
5. TREATMENT PLAN… …………………………………………………………………… 11
5.1. Treatment protocol… ……………………………………………………………… 11
5.2. Concomitant therapy… …………………………………………………………… 12
5.3. Withdrawal criteria… ……………………………………………………………… 13
6. RANDOMIZATION AND ASSIGNMENT ADJUSTMENT… ………………………………… 14
6.1. Case registration…………………………………………………………………… 14
6.2. Random assignment and assignment adjustment factors………………………… 14
7. POSSIBLE ADVERSE EFFECTS AND CLASSIFICATION OF SEVERITY… ………………… 15
8. CATEGORIES EVALUATED AND THE SCHEDULE FOR CLINICAL TESTING AND EVALUATION… … 18
8.1. Categories evaluated before patient registration… ……………………………… 18
8.2. Testing and evaluation during study period………………………………………… 18
9. ETHICAL CONSIDERATIONS……………………………………………………………… 19
9.1. Patient protection…………………………………………………………………… 19
9.2. Informed consent…………………………………………………………………… 19
9.3. Approval from the facility’s ethics review committee (institutional review board) ……… 19
10. DATA COLLECTION… ………………………………………………………………… 19
10.1. Documents for patient registration, etc.… ……………………………………… 20
10.2. Data Cleaning…………………………………………………………………… 20
11. REPORTING ADVERSE EVENTS………………………………………………………… 20
11.1. Adverse events that must be reported…………………………………………… 20
11.2.The duties and procedures of reporting to facility chief investigators
participating in this study… ……………………………………………………… 21
11.3 Responsibilities of the RAISE Study Principal Investigator and RAISE Study Office… … 2200

12. STATISTICS… ………………………………………………………………………… 23
12.1. Principal analyses and criterion… ……………………………………………… 23
12.2.Target number of subjects/ registration period/ follow-up periods… …………… 23
12.3. Interim analysis and early termination of study … ………………………………… 24
12.4. Analysis of secondary endpoints …………………………………………………… 25
12.5. Termination of the study if the incidence of giant coronary aneurisms in the trial
treatment group is high … ………………………………………………………… 26
12.6. Final Decision ……………………………………………………………………… 26
13. ETHICAL CONSIDERATIONS… ………………………………………………………… 27
13.1. Patient protection… ……………………………………………………………… 27
13.2. Informed consent… ……………………………………………………………… 27
13.3. Protection of privacy and patient identification…………………………………… 28
13.4. Treatment in strict accordance with the study protocol… ……………………… 29
13.5. Approval by the Ethics Committee (Institutional Review Board) of eachparticipating facility… …………………………………………………………… 29
14. MONITORING AND AUDITING…………………………………………………………… 29
14.1. Regular monitoring… …………………………………………………………… 29
14.2. Onsite inspection of facilities……………………………………………………… 31
15. REPORTING THE STUDY RESULTS……………………………………………………… 31
16. RAISE Study Group… ………………………………………………………………… 32
16.1. Principal Investigator……………………………………………………………… 32
16.2. RAISE Study Office………………………………………………………………… 32
16.3. Data Coordination Center… ……………………………………………………… 33
16.4. Data and Safety Monitoring Board… …………………………………………… 33
16.5. Steering Committee of RAISE Study……………………………………………… 33
17. REFERENCES…………………………………………………………………………… 3400

1. RESEARCH GOALSThis study will investigate whether initial treatment with high-dose intravenous immunoglobulin
plus prednisolone (PSL) yields better results than standard treatment (high-dose intravenous
immunoglobulin) in patients with Kawasaki disease (KD). The primary endpoint of this study
is incidence of coronary artery abnormalities (CAA) during the study period. The secondary
endpoints include incidence of CAA at 4 weeks after enrollment, Z scores for the rightcoronary artery and left main coronary trunk and anterior descending artery, days of feverafter enrollment, incidence of need for additional rescue therapy, serum levels of C-reactive
protein (CRP) at Weeks 1 and 2 after enrollment, and incidence of severe adverse events.

2. BACKGROUND AND RATIONALE FOR THE STUDY
2.1. Subjects
2.1.1. Disease studied and current standard treatment
KD is a vasculitis syndrome of unknown cause, first reported by Tomisaku Kawasaki in 1967.1)
It is the leading cause of acquired heart disease in developed countries.2) Because the causesof KD have not been identified, there are no specific therapies for KD patients. Furusho
et al3) in 1984 and Newburger et al4) in 1986 reported that treatment with intravenous
immunoglobulin (400 mg/kg×4 or 5 days) plus aspirin reduced the incidence of CAA as
compared with aspirin alone (Furusho: 19/45 [42%] vs. 6/40 [15%]; Newburger: 14/79 [18%]vs. 3/79 [4%]).
In 1991, Newburger et al5) reported the efficacy of high-dose intravenous immunoglobulin(2 g/kg×single day) plus aspirin therapy: the relative risk of CAA formation was 1.94
(95%CI 1.01-3.71) at Week 2 and 1.84 (95%CI 0.89-3.82) at Week 7. Since then, highdose intravenous immunoglobulin plus aspirin therapy (IVIG) has become the standard
therapy for acute KD. 6) IVIG is clearly effective and has adequate safety. However,approximately 20% of KD patients did not become afebrile despite IVIG administration7)-9);those IVIG nonresponders are considered to be at high risk for CAA. These facts suggest
the importance of establishing a new therapeutic strategy for severe KD patients, particularly
IVIG nonresponders.

2.1.2. Reasons for selection of subject groups
IVIG is an excellent therapy in resolving inflammation from KD and reducing the occurrenceof CAA. However, approximately 20% of KD patients have persistent or recurrent fever after
IVIG; further, many studies have shown that these patients are at increased risk of developing
CAA. Early identification of likely IVIG nonresponders who will require additional therapy

4might reduce the risk of coronary artery injury. For this purpose, Kobayashi et al10) developed
a risk score to predict IVIG nonresponse among KD patients before the initiation of IVIG.
Characteristic
Threshold value≤133 mmol/L
Sodium≥100 IU/L
AST
4 illness days
Days of illness at diagnosis≥80%% neutrophils≥10 mg/dL
CRP≤12 months
Age in months≤300,000/mm3
Platelet count

Points

2
2
2
2
1
1
1

%
100

Incidence of IVIG nonresponse%
50

Incidence of CAA
44

80

40

60

30

40

20

20

10

38

37
32

12

0

0 1 2 3 4 5 6 7 8 9 10

score

0

7

6
1

0

1

3

0 1 2 3 4 5 6 7 8 9 10

score

Using this risk score, KD patients can be stratified as being at high (5 points or more) or
low risk (4 points or less) for IVIG nonresponse; IVIG nonresponders were identified with asensitivity of 74% and a specificity of 80%, and CAA was identified with a sensitivity of 77%
and a specificity of 71%. The risk score thus might enable us to identify KD patients who
require more intensive initial therapy. High-risk patients can then be started on more intensive
initial treatments. Moreover, identification of patients for whom standard IVIG will likely sufficeallows such patients to be spared unnecessary treatment.

2.2. Rationale for establishing treatment regimen
Corticosteroids are administrated for various forms of vasculitis because of their strong
anti-inflammatory effects. However, many physicians have hesitated to use corticosteroids
in KD because an early report11) showed a high incidence of CAA in a group that received aprolonged course of oral PSL alone. However, subsequent retrospective studies12)-16) of theeffects of corticosteroids in KD have shown either no adverse effects or possible benefits.
Wooditch and Aronoff17) concluded in a meta-analysis that inclusion of corticosteroids inaspirin-containing regimens for initial therapy of KD reduced the incidence of CAA.
In 2006, Inoue et al18) reported in a randomized, open-label, unblinded trial that IVIG plus
PSL therapy decreased the incidence of CAA and treatment nonresponse, although potential
methodological flaws were noted in the study.19) In 2007, Newburger et al20) conducted arandomized, double-blinded, placebo-controlled trial of the efficacy of adding a single doseof pulsed intravenous methylprednisolone to conventional IVIG therapy. Although pulsed
corticosteroid therapy with IVIG did not improve coronary artery outcomes, post-hoc
subgroup analysis suggested that initial therapy with intravenous methylprednisolone plus
IVIG might provide a benefit for children at highest risk for resistance to initial IVIG.
The principal difference between the 2 studies was the duration of corticosteroid administration.

5

Although the total dose of corticosteroids was similar, the median duration of PSL administration
was 21 days in the earlier study, as compared with 1 course of 30 mg/kg methylprednisolone
in the US study. The serum half-life of a pulsed dose of methylprednisolone is approximately
3 hours21), and PSL was administered for 3 weeks in the Japanese study. Although KD is selflimiting, fever persists approximately 2-3 weeks if untreated.1) Duration of corticosteroid
administration might be more important than maximum concentration of corticosteroid
in suppressing inflammation and vasculitis in KD. Thus, the RAISE Study group selected
conventional PSL therapy combined with IVIG plus aspirin, as reported by Inoue et al.

2.3. Study Design
2.3.1. Planned Phase III study design
Interventional, Prospective, Randomized, Open-label, Blinded-Endpoint (PROBE) study

2.3.2. Endpoints
Primary     • Incidence of CAA during the study period
Secondary     • Incidence of CAA at Week 4 after enrollment     • Z scores22) for right coronary artery and left main coronary trunk and anterior        descending artery     • Incidence of need for additional rescue therapy     • Days of fever after enrollment     • Serum levels of CRP at Weeks 1 and 2 after enrollment     • Incidence of severe adverse events

2.3.3. Clinical hypotheses and reason for number of registrants
The principal hypothesis of the present study is that patients with severe KD who receive thestudy treatment (IVIG with PSL) will have a significantly lower incidence of CAA during the study
period as compared with the group receiving standard treatment (IVIG). If this does indeed prove
to be true, then initial treatment with IVIG plus PSL will be judged to be more effective.
The target enrollment was set using data obtained from 1123 consecutive KD patients from
August 2000 to August 2007 at 13 hospitals in Gunma and Saitama prefectures, Japan.23)
Eight KD patients who presented with CAA at admission and 109 KD patients with missing
values were excluded from this study. Thus, data from 1006 KD patients (IVIG group n=896,
IVIG+PSL group n=110) were analyzed. Of the 110 patients in the IVIG+PSL group, 90
were participants of a previously reported randomized trial.18) The other 20 patients were
given IVIG+PSL according to the attending doctor’s recommendations, except for 1 patient6whose parents desired treatment with IVIG+PSL. The table below shows clinical and coronary
outcomes in the high-risk group.
IVIG (n=298)
51.7
18.1
8.4

Nonresponse to treatment
Incidence of coronary artery abnormality during 1 month
Incidence of coronary artery abnormality at 1 month

IVIG+PSL (n=48)
20.8
6.3
4.2

The primary endpoint of the RAISE Study is to assess whether the incidence of CAA in the study
treatment is significantly lower than that of the standard treatment during the study period.
Based on the above data, the required sample size was calculated with the assumption that IVIG
plus PSL would reduce the fraction of patients with CAA during the study period from 18% to
8%. With a 2-sided test, an α level of 0.05, and a power of 80% and assuming that 10% of
the patients would not complete the study, a total sample of 392 patients would be required.
Analyses were intent-to-treat. Fisher’s exact test was used to test the null hypothesis, i.e. thatthe incidence of CAA would be equal between the 2 treatment groups during the study period.

3. DEFINITIONS USED IN THE STUDY
3.1. Diagnosis of KD
A diagnosis of KD is based on the presence of fever accompanied by at least 4 of the following
symptoms: bilateral conjunctival injection, changes in the lips and oral cavity, nonpurulent
cervical lymphadenopathy, polymorphous exanthema, and changes in the extremities. Patientswith incomplete KD (fever with 3 or fewer of the above symptoms) at diagnosis will be enrolled
if they receive a diagnosis of KD from the attending physician. These diagnostic criteria
comply with the Diagnostic Guidelines for Kawasaki Disease (Fifth Revised Edition).24)

3.2. Using risk score to identify severe KD patients
Disease severity will be assessed using the risk score developed by Kobayashi et al.10) Thisrisk scoring system was based on a multiple logistic regression analysis of 750 consecutive
KD patients given IVIG. Seven variables were included in the risk score. Points are assigned
using the threshold values shown below (higher scores indicate greater disease severity).

Variable
SodiumAST
Illness days at diagnosis%neutrophils
CRP
Age in months
Platelet countThreshold value

Points≤133 mmol/L≥100 IU/L≤ 4 illness days
≥80%
≥10 mg/dL≤12 months≤300,000/mm3

2
2
2
2
1
1
1

7

The total number of points assigned to a patient is that patient’s risk score. If a laboratory test
was performed twice or more before initial therapy, the highest value was chosen for AST, %neutrophils, and CRP, while the lowest value was chosen for sodium and platelet count. In thepresent study, patients will be defined as high risk if they have a total score of 5 points or higher,
and only these high-risk patients will be randomly assigned to the 2 treatment groups.

3.3. Definition of fever
Febrile: ≥37.5°
C
Afebrile: <37.5°
C for ≥24 hours.
Absence of fever is defined as a body temperature lower than 37.5°
C for at least 24 hours, using
an electronic thermometer in the axilla. In calculating time to resolution of fever, start of treatment
is defined as Hour 0. Fever resolution within 24 hours is defined as“on the first day,”within 48
hours as“on the second day,”etc., with subsequent 24-hour periods each counted as a“day.”Start of treatment
40℃
39℃
Fever resolution (because fever resolved in less than 24 hours, it is counted as “1 day”)

38℃
37℃
36℃
35℃

24hr

48hr

72hr

96hr

120hr

Start of treatment
40℃
39℃

The patient’s fever resolves between 48 and 72 hours after thestart of treatment, so it is classified as having resolved on Day 3

38℃
37℃
36℃
35℃

8

The patient’s temperature decreases to below 37.5°C, but because it did not remain
continuously below 37.5°C for 24 hours, it is not classified as having resolved on Day 1
24hr

48hr

72hr

96hr

120hr

3.4. Definition of treatment nonresponse
Treatment nonresponse is defined as no response to initial treatment, or a relapse.
1. Nonresponse to initial treatment: fever does not resolve within 24 hours after completionof initial IVIG administration.

At 24 hours after final IVIG administration,
fever has not resolved: defined as“nonresponse to initial treatment”
Additional treatment

Start of treatment
40℃
39℃
38℃
37℃
36℃
35℃

24hr

48hr

72hr

96hr

120hr

Fever resolved at this point (96-120 hours after end of initial
treatment: classified as 5 days until resolution of fever)
2. Relapse: fever initially resolves, but then returns, and is accompanied by other symptomsof KD, in the absence of other causes of fever (eg, bacterial or viral infections)

Additional treatment

Start of treatment
40℃
39℃

Fever resolves(1 day after end of initial treatment)

38℃
37℃
36℃
35℃

Fever recurs on Day 3: defined as “Relapse,”
not as “nonresponse to initial treatment”
24hr

48hr

72hr

96hr

120hr

9

3.5. Definition of coronary artery abnormalities
The coronary artery will be assessed using 2-dimensional echocardiography obtained atbaseline, week 1 (6-8 days after enrollment), week 2 (12-16 days after enrollment), and week
4 (24-32 days after enrollment). The coronary artery must be measured at segments 1, 5,
and 6. Segments 2, 3, 7, and 11 will also be measured, if possible. Cardiac function andpresence of cardiac effusion (more than 1 mm: posterior wall of left ventricle during systole)
should also be assessed. All echocardiographic examinations will be recorded from start tofinish using a digital video recorder provided by the RAISE Study Office. All examinations will
be recorded on DVD and sent to the RAISE Study Data Coordination Center. Using video ofdigitally recorded 2-dimensional echocardiograms at facilities, all echocardiograms will beinterpreted at a core laboratory by 2 pediatric cardiologists blinded to patient identity andillness day. If these cardiologists disagree, a third pediatric cardiologist will make the final
decision regarding the presence of abnormalities.
A coronary artery will be defined as abnormal when the luminal diameter is ≥3.0 or ≥4.0 mm
in a child aged <5 or ≥5 years, respectively, when the internal diameter of a segment is ≥1.5
times that of an adjacent segment, or when the luminal contour is clearly irregular.25)

4. PATIENT SELECTION CRITERIA AND TREATMENT ASSIGNMENT
Eligible patients must fulfill the following inclusion criteria.

4.1. Inclusion criteria
1. Severe KD with a risk score of 5 points or higher
2. Receipt of written informed consent from parents or legal guardians, as per the guidelinesof the local institutional review boards that approved the study protocol.
3. Exclusion of other conditions that mimic KD, eg, scarlet fever, Epstein-Barr infection,adenovirus infection, Yersinia infection, measles, and Stevens-Johnson syndrome.

4.2. Exclusion criteria
The following patients will be excluded.
1. Patients who do not provide informed consent for study enrollment
2. Patients with a previous history of KD
3. Patients who present 9 days or later after disease onset (onset defined as first day of fever)
4. Patients with CAA before study enrollment
5. Patients with fever resolution before study enrollment
6. Patients who received corticosteroid in the previous 28 days, either orally, intravenously,10

or by intramuscular or subcutaneous injection
7. Patients who received IVIG in the previous 180 days
8. Patients with any of the following severe diseases: immunodeficiency, chromosomal
anomalies, congenital heart diseases, metabolic diseases, nephritis, collagen diseases.
9. Patients with suspected infectious disease, including sepsis, septic meningitis, peritonitis,
bacterial pneumonia, varicella, influenza, and others.

5. TREATMENT PLAN
5.1. Treatment protocol
5.1.1. Initial treatment(IVIG Group: treated with IVIG)
Patients will be treated with intravenous immunoglobulin 2 g/kg given over 24 hours. Aspirin
will also be given at a dose of 30 mg/kg/day until the patient is afebrile, followed by aspirin
3–5 mg/kg/day until 28 days after enrollment. Aspirin should be continued until 2 months
after enrollment

IV immunoglobulin (2 g/kg over a period of 24 hours)
Aspirin 30 mg/kg/day (after fever resolves, 5 mg/kg/day)(IVIG+PSL Group: treated with IVIG plus PSL)
Patients in the IVIG+PSL group will also receive the same IVIG with aspirin regimen plus
prednisolone sodium succinate (2 mg/kg/day, in 3 divided doses) given by intravenous
injection for 5 days. After fever resolves, PSL will be given orally. When CRP level normalizes(≤0.5 mg/dL), the PSL dose will be tapered over 15 days in 5-day steps from 2 to 1 to 0.5
mg/kg/day. Famotidine will be administered with PSL. The maximum dose of PSL is 60 mg/day;
thus, patients weighing more than 30 kg will be tapered from PSL 60 to 30 to 15 mg/day.

Immunoglobulin

CRP ≤0.5 mg/dl
5 daysPSL(intravenously)≥5 days
2mg/kg/day

oral PSL

5 days
1mg/kg/day

5 days0.5mg/kg/day

Aspirin 30 mg/kg/day (5 mg/kg/day after fever resolves) + famotidine (during PSL administration)

11

5.1.2. Prohibited medications
Use of nonsteroidal anti-inflammatory drugs (NSAIDs; e.g. acetaminophen, mefenamic acid)except aspirin and flurbiprofen is not allowed, because a secondary endpoint of the study isdays of fever after enrollment, and the use of NSAIDs could influence the results.

5.2. Concomitant therapy
Attending doctors should provide additional rescue therapy for nonresponders, using therecommendations of the“ Guidelines for Acute Phase Therapy for Kawasaki Disease ”, promulgated by
the Japanese Society of Pediatric Cardiology and Cardiac Surgery in 2003.26) The following isa general outline of these supplementary treatment modalities.

5.2.1. Treatment options for treatment nonresponse
Although additional rescue therapy for IVIG nonresponders has been examined, the evidence
is insufficient due to the lack of a controlled study. In Japan, retreatment with IVIG is the mostcommon rescue therapy. The RAISE Study group allows additional rescue therapy and leaves
the choice of such therapy to the attending doctor.
(1)Retreatment with IVIG 2 g/kg or 1 g/kg.
At present, the most common treatment option for nonresponders is retreatment with IVIG.
Clinical experience suggests that this is the safest supplementary treatment. The American
Heart Association Guidelines recommend a single dose of 2 g/kg IVIG, but no controlled
trials have confirmed the efficacy of retreatment with IVIG (Evidence level C).6)(2)Corticosteroid (pulsed methylprednisolone and/or PSL)
Corticosteroids are widely used for various forms of vasculitis. However, the use ofcorticosteroids for KD patients has been limited because of an early report showing ahigh incidence of CAA in a group that received a prolonged course of oral PSL alone.11)
However, recent reports indicate that treatment with oral or intravenous PSL, or pulsed
methylprednisolone, might indeed be effective ether as an initial treatment for all patients or inpatients who fail to respond to initial IVIG.12),13) Some studies have reported that corticosteroid
treatment might lead to quicker suppression of serum inflammatory cytokines.27),28)(3)Ulinastatin
In Japan, several centers have reported the efficacy of ulinastatin. However, this is an offlabel use for the drug, and optimal doses and administration durations are not established.
In addition, adverse effects such as rashes and neutropenia have been reported.
Ulinastatin should not be simultaneously administered with IVIG via the same route.
(4)Increased dose of aspirin(5)Nonsteroidal immunosuppressants (eg, cyclosporin A, methotrexate)
Patients unresponsive to IVIG and standard supplementary therapies have been treated12with a variety of immunosuppressants, and occasional case reports have reported
successful outcomes.29),30)(6)Anti-TNFα antibodies (e.g. infliximab)
Anti-TNF-α antibodies suppress production of various inflammatory cytokines by specifically
blocking TNFα activity. Recently, this treatment was reported to be effective for severe
KD patients.31)-33) Studies have investigated the use of anti-TNFα antibodies in adults
with worsening infectious diseases, such as progressive cardiac insufficiency or recurrent
tuberculosis, as well as in infusion events and for treatment of malignant tumors.34)(7)Plasma exchange
Successful use of plasma exchange has been reported in severe KD patients who do notrespond to other treatments.35)

Drug name

Schedule

Adverse effects andother considerations

Prednisolone

Start at 2 mg/kg/day, then tapered(as in present study)

Methylprednisolone

10-30 mg/kg/day in 1-3 doses, IV

Fever might return whendosage is reduced, infection,
hypertension, thrombosis,
electrolyte imbalance

Ulinastatin

5000 units /kg; 3-6 times/day,several days IV

Leukopenia, rash

Nonsteroidal
immunosuppressants

Cyclosporin A

1-4 mg/kg/day in 2-3 divided doses

Methotrexate

10 mg/body surface area

Anti-TNFα antibodies

Infliximab

5 mg/kg/day x 1 day,2-hour IV drip

Shock, worsened cardiac
insufficiency, tuberculosis

Amount equivalent to circulating
blood volume, 1-3 days

Shock, vascular injury

Treatment

Corticosteroids

Neutrophil elastase
inhibitors

Plasma exchange(5% albumin solution)

Infection, cyclosporin
encephalopathy, abnormalliver function, mucous
membrane disorders

5.3. Withdrawal criteria
1. If a patient is identified as ineligible after enrollment, due to misdiagnosis, misclassificationof severity, etc.
2. If the RAISE study office determines that the patient should be excluded due to an
unacceptable violation.
3. If the patient or their guarantor requests termination of the protocol treatment.
4. If the patient’s attending physician determines that treatment should be terminated.
5. If a patient dies during the protocol treatment.
6. If the Data and Safety Monitoring Board decides to be terminate the study because ofadverse events.
7. If patient information is no longer obtainable due to the patient having changed hospitals, etc.

13

6. RANDOMIZATION AND ASSIGNMENT ADJUSTMENT
6.1. Case registration
Randomization and allocation of participants is performed via a web-based central allocation
system at the University hospital Medical Information Network (UMIN). Among patients that
fulfill the inclusion criteria, the attending doctor will explain the study plan to the patients
and/or their parents. If informed consent is obtained, the attending physician will enroll thepatient after entering the required items (initials of participant, sex, age in months, days ofillness at diagnosis, % neutrophils, platelet count, AST, sodium, CRP, and inclusion andexclusion criteria)  via the web-based allocation system on the homepage of the RAISE Study.
All case registration and group assignment will be done by accessing the Internet home pagefor RAISE Study researchers: registration and group assignment will not be done by phoneor email, except in emergencies. Patient registration and group assignment will be kept on
file on the Internet Medical Research Data Coordinating Center (INDICE) server, and online
access to this information is possible only through the RAISE Study researcher home page(for security reasons). To access the RAISE Study researchers’site, a UMIN ID and generalpassword are required. To proceed further, to the patient registration page, a UMIN ID and
UMIN INDICE password are required.

6.2. Random assignment and assignment adjustment factors
Dynamic random assignment of patients to their respective groups will be done using theminimization method at a 1:1 ratio. The adjustment factors include sex, age, and institution,
classified by method of additional rescue therapy (Group A; IVIG retreatment only, Group B;
IVIG retreatment and/or conventional dose of PSL, Group C; IVIG retreatment and/or pulsed
dose methylprednisolone with or without subsequent PSL, Group D; IVIG retreatment and/or
conventional dose of PSL and/or pulsed dose methylprednisolone with or without subsequent
PSL and/or infliximab).

14

7. POSSIBLE ADVERSE EFFECTS AND CLASSIFICATION OF SEVERITY① Infection
Minor Adverse Effects

Infection

Severe Adverse Effects
Viral infections without severe symptoms
Viral infections with severe symptoms
Bacterial infections treatable with oral antibiotics Bacterial infections curable with intravenous
antibacterial administrations② Allergy / immunity (allergic effects / hypersensitivity)
Skin symptoms

Systemic symptoms

Minor Adverse Effects
Localized urticaria
Pruritus

Severe Adverse Effects
Widespread rash
Oculomucocutaneous syndrome
Toxic epidermal necrosis
Stevens-Johnson syndrome

Angioedema(except pharyngeal edema)

Hypersensitivity syndrome
Anaphylaxis
Pharyngeal edema③ Cardiovascular system
Hypotension
Hypertension
Arrhythmia

Impairment ofcardiac function
Thromboembolism

Minor Adverse Effects
Asymptomatic hypotension
Asymptomatic hypertension
Supraventricular extrasystole
Ventricular extrasystole (single)
First-degree atrioventricular block

Severe Adverse Effects
Symptomatic hypotension
Symptomatic hypertension
Supraventricular tachycardia
Ventricular extrasystole (couplet or more)
Ventricular tachycardia
Second- or third-degree atrioventricular block
Ventricular fibrillation
Torsades de pointes, Cardiac arrest

Ejection fraction of left ventricle(on echocardiogram) ≤60%

Ejection fraction of left ventricle(on echocardiogram) ≤40%
Deep vein thrombosis, Arterial thrombosis

AnemiaWhite blood cell count
Neutrophil countMinor Adverse Effects
20-25% hematocrit
3000-4000/mm3
1000-2000/mm3

Severe Adverse Effects<20% hematocrit<3000/mm3<1000/mm3

Platelet countBleeding

50,000-100,000/mm3
Subcutaneous hemorrhage<50,000/mm3
Mucosal hemorrhage,Intraorgan hemorrhage④ Blood⑤ SkinMinor Adverse Effects
Ecchymosis
Rash

Localized
Limited erythema or papules with norelated symptoms

Severe Adverse Effects
Generalized
Generalized erythroderma
Erythema or papules with itching or othersymptoms

15

⑥ Digestive organs
Minor Adverse Effects

Severe Adverse Effects
Gastric ulcer
Duodenal ulcer
Hemorrhagic ulcer
Perforation of digestive tract

Ulceration

ErosionPancreatitis

Asymptomatic increase in pancreatic
enzyme levels

Increase in pancreatic enzyme levels withrelated symptoms
Pancreatic necrosis
Hemorrhagic pancreatitis

Enteritis

Frequent bowel movements, Sometimes
bloodstained with occasional rectal discomfort

Diarrhea requiring major transfusions
Hemorrhagic enteritis

MelenaPositive fecal occult blood testing

Melena accompanied by shock or drop in
hemoglobin requiring blood transfusions

Hematemesis

Transfusion not required

Transfusion required

Vomiting

Additional 2 to 5 times as compared withpretreatment average (per 24 hours)

Additional 6 or more times as compared withpretreatment average (per 24 hours)⑦ Liver
Total bilirubin
AST, ALT (because these values rise in
response to Kawasaki vasculitis, patientsshould be carefully monitored for increases)

Minor Adverse Effects
3.0-9.9 mg/dl
100-499 IU/l

Clinical symptoms, etc.

Severe Adverse Effects≥10.0 mg/dl≥500 IU/l

Jaundice
Hepatomegaly
Hepatic failure accompanied by bleeding
tendency or mental confusion⑧ Endocrine system/metabolism
Hyperglycemia

Minor Adverse Effects
Asymptomatic hyperglycemia

Severe Adverse Effects
Symptomatic hyperglycemia

Hypoglycemia
Hypercholesteremia

Asymptomatic hypoglycemia
Total cholesterol 220- 399 mg/dl

Symptomatic hypoglycemia
Total cholesterol ≥400mg/dl

Minor Adverse Effects
Blood transfusion not required
Scattered petechiae

Severe Adverse Effects
Blood transfusion required
Petechiae all over body

⑨ Bleeding
Nasal hemorrhage
Subcutaneous hemorrhage
Intracranial hemorrhage

Hemorrhage visible on CT or MRI.
Intracranial hemorrhage with symptoms⑩ Musculoskeletal system
Minor Adverse Effects
Mild discomfort accompanying joint
Inflammation or swelling with no impairment
in normal functioning

Severe Adverse Effects
Pain (moderate to severe) accompanying joint
Inflammation or swelling with normal
functioning impaired

Muscular weakness

Asymptomatic
Discovered only by medical examination

Related symptoms impair normal functioning

Osteonecrosis

Asymptomatic
Visible only on imaging

Related symptoms impair normal functioning

Arthritis16

⑪ Neurological disorders
Minor Adverse Effects
Accompanied only by mild headache
and/or vomiting

Severe Adverse Effects
Cerebrospinal fluid testing reveals increased
cerebrospinal fluid cell count,
Accompanied by severe clinical symptoms

Glaucoma

Minor Adverse Effects
Increased ocular pressure without visual
impairment

Severe Adverse Effects
Increased ocular pressure accompanied byretinal changes
Vision impaired

Cataracts
Visual disorders

No clinical symptoms
Minor, with no functional impairment

Clinical symptoms such as visual impairment
Impairs normal functioning

Minor Adverse Effects
Mild discomfort with no functional impairment

Severe Adverse Effects
Analgesics required
Normal functioning impaired

Aseptic meningitis⑫ Eyes and vision⑬ PainAbdominal or joint pain,
head or muscle aches⑭ Respiratory disorders
Cough

Minor Adverse Effects
General (non-narcotic) antitussive
relieves coughSevere Adverse Effects
Narcotic antitussive required torelieve coughApnea
Dyspnea, Hypoxemia

Oxygenation required
Oxygenation required

Mechanical ventilation required
Dyspnea on exertion and at rest
Mechanical ventilation required

Pneumonia

Resolves with standard treatment

Mechanical ventilation required⑮ Renal and urinary disorders
Hematuria

Minor Adverse Effects
Microscopic hematuria only

Severe Adverse Effects
Gross hematuria
Blood transfusion required

Albuminuria
Micturition pain
Renal failure

2+ or lower (qualitative analysis)
Mild symptoms, no intervention required−

3+ or higher (qualitative analysis)
Prominent symptoms requiring treatment
Dialysis required

Minor Adverse Effects
34.0-35.0°C (axillar)

Severe Adverse Effects<34.0°C (axillar)⑯ Others
Low body temperature

178. CATEGORIES EVALUATED AND THE SCHEDULE FOR CLINICAL TESTING
AND EVALUATION
8.1. Categories evaluated before patient registration
1)Patient backgroundAge in months, sex, height, weight, date at enrollment, past history of KD
2)Blood testing
Blood count: white blood cell count, % neutrophils, hematocrit, platelet count
Biochemical tests: total bilirubin, AST, ALT, LDH, sodium, potassium chloride, BUN, Cr,
total protein, albumin, blood glucose, total cholesterol, HDL cholesterol
Immune serum: CRP, IgG, BNP
3)Urine testing (may be ignored if not collected)
Urine characteristics (sugar, albumin, occult blood), urine sediment4)Echocardiography
Diameter of coronary artery, left ventricular ejection fraction, presence or absence ofvalvular disease, presence or absence of pericardial effusion

8.2. Testing and evaluation during study period1）Laboratory testing: the recommended schedule for laboratory testing is as follows.
•	 2 days after enrollment (1 to 3 days after enrollment is allowed)•	 1 week after enrollment (6 to 9 days after enrollment is allowed)• 	2 weeks after enrolment (12 to 16 days after enrollment is allowed)•	 4 weeks after enrollment (24 to 32 days after enrollment is allowed)
Laboratory testing should be performed 2 to 3 times per week until serum CRP level
decreases to ≦0.5 mg/dl.
2）Urine testing: as decided by attending physician
3）Echocardiography: the recommended schedule for echocardiography (all echocardiography
exams must be digitally recorded)•	 1 week after enrollment (6 to 9 days after enrollment is allowed)•	 2 weeks after enrolment (12 to 16 days after enrollment is allowed)• 	4 weeks after enrollment (24 to 32 days after enrollment is allowed)4）Adverse events: Daily during the study period.

18

9. ETHICAL CONSIDERATIONS
9.1. Patient protection
All researchers involved in the present study shall carefully abide by the Helsinki Declaration
while conducting this research.

9.2. Informed consent
9.2.1. Explanation given to patients and their families
Before patients are registered, the attending physician will give a copy of an explanatory
document (approved by the facility’s IRB) to the patient and/or their family member(s) andverbally explain the details of the procedures to them.

9.2.2. Consent
After the above explanation is given and the patient and/or their family member(s) confirm
that they clearly understand the procedures involved, they will be asked if they wish toparticipate in the study. If the patient or their family member(s) consent to participate in
the study, the physician who explained the procedures, together with the patient and/or
their family member(s) who consented to participate in the study, will write their names, thepatient’s name, and the date consent is given on the attached consent form (or other official
consent form approved by the facility). Then, both the physician and patient and/or theirfamily member(s) will sign the form.

9.3. Approval from the facility’s ethics review committee (institutional review board)
For participation in the study to be confirmed, the document describing the study procedures,
as well as the explanation given to the patient and/or their family member(s), must both beconfirmed by the facility’s ethics review committee or IRB

10. DATA COLLECTION
The following documents are to be submitted by fax to the Data Coordinating Center (+8127-220-8741). They may also be sent by post, in which case the facilities are to retain
the original documents and send copies to the Data Coordinating Center. When submitting
documents, all names that might permit identification of the patient concerned should
be changed to initials. The registration number should be clearly indicated on the form.
DVDs or videotapes containing the echocardiographic data should be sent by post to the
Data Coordinating Center. If the echocardiographic data contain information permitting
identification of the patient (patient name or ID), this information will be masked by the Data

19

Coordinating Center and rerecorded so as not to permit patient identification, after which theoriginal data will be destroyed.
RAISE Study Data Coordinating Center
Department of Clinical Investigation and Research Unit, Gunma University Hospital
3-39-15 Showa-machi, Maebashi, Gunma, Japan  371-8511
Tel: (+81)-(0)27-220-8740  Fax: (+81)-(0)27-220-8741

10.1. Documents for patient registration, etc.
1) Form for facilities to request permission to participate in the study2) Form to request patient assignment by fax (if online assignment is impossible)
3) Data sheet4) Express form for preliminary reports of adverse events
5) Form for full report of adverse events
6) DVD or videotape for recording and submitting patient echocardiogram findings

10.2. Data Cleaning
The Data Coordinating Center will check the registration information and submitted
documents. If there are any questions regarding this information, the Data Coordinating
Center staff will contact the attending physician by email, fax, or telephone to request
necessary clarifications. As for the treatment protocol, any cases in which the treatment
or laboratory or echocardiographic examinations may have diverged from the pre-planned
acceptable ranges will be reported to the RAISE Study Office for evaluation and judgment.
Obvious violations from the protocol will immediately be reported to the RAISE Study Group
Principal Investigator (Tsutomu Saji), who will quickly deal with such cases.

11. REPORTING ADVERSE EVENTSAdverse events should be reported by fax to the Data Coordinating Center.

11.1. Adverse events that must be reported
11.1.1. Adverse events that must be reported immediately
All patient deaths that occur during the protocol treatment or during the 30-day period
immediately after the last day of treatment (regardless of whether this was a result of adheringto the treatment protocol)

2011.1.2. Adverse events that must be reported at earliest convenience
1) Cases of shock that appear to be related to the administration of the study medication
2) Cases in which the patient contracted a severe infectious disease3) Hyperglycemia or hypertension accompanied by clear symptoms
4) A body temperature <35.0°
C5) The appearance of eye disorders such as cataracts or glaucoma
6) Thromboembolism
7) Severe hemorrhage8) Other important clinical phenomena not in the above list but judged to be potentially
important should be shared with the RAISE Study Group Principal Investigator, the RAISE
Study Office, and other participating facilities

11.2. The duties and procedures of reporting to facility chief investigators participating in this study
There are 2 methods of reporting adverse events: express and standard reporting, which are
explained below.

11.2.1. Express report
When an adverse event occurs that requires express reporting, the attending physician shouldreport it to the facility chief investigator as quickly as possible. If it is not possible to contact
the chief investigator, the attending physician must report the adverse event. The adverse
event shall be reported to the RAISE Study Group Principal Investigator in the following
manner.

Initial report :Within 72 hours of the occurrence of an adverse event, the facility chief investigator will fillin the necessary information in the Adverse Event Preliminary Express-Report Form. Aftercontacting the RAISE Study Office, the facility chief investigator will fax this form directly to
the Data Coordinating Center. Because this report should be submitted as quickly as possible,
any information requested on the form that is not available at the time it is completed shouldbe left blank. After receiving this preliminary report from the facility, the Data Coordinating
Center will then inform both the RAISE Study Office and the RAISE Study Principal
Investigator of the details they have received concerning the adverse event.

Secondary report :The facility chief investigator will then complete the Adverse Event Report Form (Second
Express Report), with the more detailed information requested on the form, and fax it to the
Data Coordinating Center within 15 days after the appearance of the event. After receiving it,
the Data Coordinating Center will then inform the RAISE Study Office and the RAISE Study
Principal Investigator of this additional information as quickly as possible. The RAISE Study

21

Principal Investigator will then quickly inform the Efficacy and Safety Review Board of theevent. They will discuss its significance with regard to the progress of the research and futureof the RAISE study.

11.2.2. Standard report
Within 15 days of the appearance of the adverse event, the facility chief investigator willcomplete the Adverse Event Report Form (Final Report) with the required information and
fax it to the Data Coordinating Center. After receiving it, the Data Coordinating Center willthen inform the RAISE Study Office and the RAISE Study Principal Investigator of any further
relevant information as quickly as possible.

11.3. Responsibilities of the RAISE Study Principal Investigator and RAISE Study Office
11.3.1. Judgment of suspension and emergency information to the facilities
When the RAISE Study Principal Investigator receives information from an express report
regarding adverse events from facility chief investigators, he will determine the urgency andimportance of this information, evaluate its effect on the future of the study, and consider
approaches and remedies for it. If immediate action is required, he may contact the Data
Coordinating Center and/or facility concerned by telephone; however, this will be followed, as
quickly as possible, with a written communication (fax, mail, or e-mail)11.3.2. Reporting to the Efficacy and Safety Review Board
Once the RAISE Study Principal Investigator has received either the express or final reportfrom a facility about an adverse event, he will determine, based on the list in section 11.1.
above “( Adverse events that must be reported”), whether the reported adverse event is
indeed one that requires reporting. If it is, after consulting with the RAISE Study Office, hewill prepare a written report for the Efficacy and Safety Review Board regarding the event,within 15 days of having been informed of it, inform them of his opinions with regard to theevent, and ask the Board to decide whether the clinical response to the event was suitable.
This should include the results of his analysis of the adverse event report received from the
medical facility, together with how he plans to deal with this information (including whether
the study should be continued or terminated).

11.3.3. Analysis of adverse events based on regular monitoring
When regular monitoring is carried out, the RAISE Study Principal Investigator and RAISE
Study Office will carefully review reports produced by the Data Coordinating Center regarding
adverse events that have been reported, to ensure that no important information has been
omitted and is thus still required from the medical facility concerned.

2211.3.4. Analysis of the Efficacy and Safety Review Board
The Efficacy and Safety Review Board will inspect and analyze the content of all reports andstate in writing its decisions on responses to adverse event to the RAISE Study Principal
Investigator, including whether the patient(s) concerned should be removed from the study
and whether the treatment protocol should be modified or not.

12. STATISTICS
12.1. Principal analyses and criterion
The main goal of the present study is to determine whether, as compared with standard
IVIG treatment, treatment with IVIG plus PSL results in a significant reduction in the primary
endpoint, i.e. the incidence of CAA during the study period. To test the null hypothesis (namely,that the incidence of such complications will be the same in both groups), Fisher’s exact
test will be used to compare all applicable cases in the 2 groups. Because it is possible thatthe trial treatment could result in worse outcomes than standard treatment, all testing will be
2-sided. The significance level for all tests will be 5% (2-sided).
If statistical analysis reveals that the incidence of CAA during the study period is significantly
lower in the trial treatment group than in the standard treatment group, the conclusion willbe that the trial treatment with IVIG plus PSL is the more effective treatment. If no suchsignificant decrease is found, the conclusion will be that treatment with IVIG remains thestandard treatment for KD.

12.2. Target number of subjects/ registration period/ follow-up periods
As mentioned in the background of the study (section 2.3.3.,“Clinical hypotheses and reason
for number of registrants”), the rate of CAA in the IVIG group is expected to be the sameas in previous studies of this treatment, ie, approximately 18%. The study design has been
established to determine whether the trial treatment (IVIG plus PSL) can achieve at leastan additional 10% absolute reduction in the incidence of CAA during the study period, i.e.
reduce the incidence rate to 8% or less. If the study requires a 3-year registration period anda 1-month follow-up period, and α is equal to 5% (2-sided) with a statistical power of 80%,the number of cases required for each group will be 176, for a total of 352 in the 2 groups. If
a 10% drop-out rate is assumed, the final enrollment numbers are as follows.
    Target number of subjects: 196 per group, for a total of 392 patients.
    Registration period: 3 years. Follow-up period: 1 month after enrollment.

23

12.3. Interim analysis and early termination of study
12.3.1. Purpose and timing of the interim analysis
One interim analysis is planned to evaluate whether the study is achieving its principal
objectives. The purpose of this interim analysis will be to decide on the suitability ofcontinuing to enroll patients in the study. If it is determined that the principal objectives ofthe study have been achieved, then the study will be terminated and its results reported atconferences and published in relevant journals as quickly as possible.
The interim analysis will be started after the first year of the study has been completed, using
the initial monitoring data accumulated since the start of the study. In the event that 200
patients have not yet been enrolled in the study at 1 year after initiation of the study, theinterim analysis will be done when data for 200 patients become available. Finally, as a rule,patient enrollment will continue while the interim analysis is being conducted.

12.3.2. Method of interim analysis
The interim analysis will be carried out by the staff of the RAISE Study Statistical Center. To
keep overall α error of the RAISE study below 5%, the Lan-DeMets α-spending function36)
with the O’Brien-Fleming monitoring boundaries was used to adjust for multiple comparisons.
Differences in values between the 2 study groups will be analyzed to determine if they arestatistically significant or not. If the interim analysis reveals a lower rate of CAA during study
period in the group receiving IVIG plus PSL as compared with the group receiving standard
IVIG and Fisher’s exact test yields a p value <0.0034, this will be considered sufficient
statistical evidence to accept the study’s main hypothesis and, barring other importantconsiderations, the study will, in principle, be terminated.

12.3.3. Reporting and evaluating the interim analysis results
The report of the interim analysis will be submitted to the Efficacy and Safety Review Board,which will decide whether the study should be terminated or not. Based on the results of
the interim analysis, the Efficacy and Safety Review Board will discuss the continuation of
the study at the Steering Committee and inform the RAISE Study Principal Investigator ofthe decisions they have reached with respect to continuation of the study and publication of
its results. If, based on careful review of the interim-analysis report, the Efficacy and Safety
Review Board decides that all or part of the study should be terminated or its protocol
changed, the RAISE Study Principal Investigator will carefully consider this recommendationand issue a final decision as to whether to terminate the study or change part of its protocol.
If the study is to be terminated or continued with an amended protocol, the RAISE Study
Principal Investigator will submit the corresponding documents to the Efficacy and Safety
Review Board: either the Request for Permission to Terminate the Study or Request for24

Protocol Amendment, respectively. Once permission is granted by the Efficacy and Safety
Review Board, the study may be terminated or its protocol amended.

12.4. Analysis of secondary endpoints
Analysis of the secondary endpoints will also be carried out to provide additional datafor consideration of the results of the principal analysis of the study. Correction forthe multiplicity of tests will not be performed because of the exploratory nature of thesecondary endpoints. Comparisons between groups will be performed as necessary, but it isimportant to note that, although no statistically significant differences can be reported, thisshould not be interpreted to mean that there are no real differences between the treatmentgroups.

12.4.1. Analysis of the secondary endpoint related to safety
Of the several secondary endpoints studied, the endpoint related to safety is based on theincidence of adverse events, and this endpoint will therefore require regular monitoring.

12.4.2. Analysis of secondary endpoints related to efficacy
The secondary endpoints related to treatment efficacy include incidence of CAA at week 4
after enrollment, Z scores for the right coronary artery and left main coronary trunk andanterior descending artery, days of fever after enrollment, incidence of need for additional
rescue therapy, and serum levels of CRP at Weeks 1 and 2 after enrollment. These secondary
endpoints will only be analyzed during the interim analysis and at the end of the study, andonly as secondary endpoints; there will be no correction for the multiplicity of tests whenthese endpoints are analyzed.
It is expected that the incidence of CAA at week 4 after enrollment will be lower in the IVIG
plus PSL group than in the IVIG group, as this result is expected to be correlated withthe largest diameter attained during the enlargement of the coronary artery, while thesetreatments are being administered.
As for incidence of need for additional rescue therapy, this can be considered to reflect theeffectiveness of the treatments. It is therefore expected that this incidence will be lower in the
IVIG plus PSL group than in the IVIG group.
As for days of fever after enrollment and serum levels of CRP at Weeks 1 and 2 after
enrollment, these can be considered endpoints that depend on the suppression of KD
vasculitis achieved by the treatments. It is therefore expected that, as compared with standard
IVIG treatment, the period required for days of fever after enrollment will be shorter, and that
serum levels of CRP at Weeks 1 and 2 after enrollment will be lower, in the IVIG plus PSL
group.  
Fisher’s exact test will be used to evaluate the incidence of CAA at Week 4 after enrollment

25

and the incidence of need for additional rescue therapy; the interval estimation will be donewith exact confidence intervals based on the binomial distribution.
Z scores for the right coronary artery and left main coronary trunk and anterior descending
artery, days of fever after enrollment, and serum levels of CRP at Weeks 1 and 2 after
enrollment will first be tested for normality with the Kolmogorov-Smirnov test. Variables thatare found to have a normal distribution will be compared using the unpaired t-test; those witha non-normal distribution will be compared using the Mann-Whitney U-test.

12.5. Termination of the study if the incidence of giant coronary aneurisms in the trial treatmentgroup is highIn general, the most important goal in treating KD patients is to prevent giant coronary
aneurysms, which require lasting medical treatment. Thus, if the incidence of giant coronary
aneurysms is higher for patients receiving the trial treatment than for those receiving thestandard treatment, the trial treatment will be considered ineffective in reducing the incidenceof such aneurysms and the study will be promptly terminated.
In the most recent national survey in Japan, the incidence of giant coronary aneurysms
was 0.35%.7) If we assume that these patients would be stratified as high-risk patients, theincidence of giant coronary aneurysm among patients in this study could ultimately be as
high as 1.1%. Therefore, if 4 patients in the trial treatment group develop giant coronary
aneurysms, the Data Coordinating Center will immediately report this fact to both the RAISE
Study Principal Investigator and the Efficacy and Safety Review Board, and the Board willthen carefully review the cases and decide whether the study should be terminated.

12.6. Final Decision
When the follow-up period is completed and all the results of the final investigations have been
determined, an analysis of all the study endpoints will be conducted. Until then, there will be
no comparisons between groups with respect to either the primary endpoint or the secondary
endpoints concerned with treatment effectiveness, unless such comparisons are added to thestudy protocol or special permission is received from the Efficacy and Safety Review Board.
The final results of all analyses will be assembled by the Data Coordinating Center into a
Final Analysis Report, which will be submitted to the RAISE Study Office and the RAISE Study
Principal Investigator. The RAISE Study Principal Investigator and the RAISE Study Office willthen write a Summary Report for the use of clinical practitioners, based on the summarized
contents of this Final Analysis Report, after careful consideration of the general conclusionsof the study and an analysis and discussion of its problems and results, as well as suggestions
for further research in this area. The study will then be considered finished.

26

13. ETHICAL CONSIDERATIONS
13.1. Patient protection
All researchers involved in the present study will strictly abide by the Helsinki Declaration incarrying out all the procedures of this study.

13.2. Informed consent
13.2.1. Explanation given to patients and their families
Before the patient is enrolled in the study, their attending physician will give the patient
and/or the patient’s family an explanatory document that has been approved by the IRB ofthat facility. If the patient is younger than 16 years, this document is to be handed to theirguardian, and the following details are to be verbally explained:
1. The diagnosis of KD, its severity, and an explanation regarding its prognosis
2. The fact that they have the option of being enrolled in a clinical trial, with a detailed
explanation of the difference between the meanings of“clinical trial”and“clinicalpractice”
3. The study design and its rationale (including its importance, the number of patients tobe enrolled, its necessity, and its goals)
4. The content of the treatment protocol (the names and doses of the drugs to beadministered, methods of administration, total duration of treatment and follow-up, andother important details, as requested)
5. The expected effect of the protocol treatment
6. Possible adverse events, complications, and sequelae, and clinical responses to these(known severity and incidence rates of various adverse events, as well as the clinicalresponses that will be undertaken in the event of their occurrence)
7. Responsibility for treatment costs and compensation (the physician will explain thatthe costs of the treatment will be covered by insurance, and that if permanent healthproblems arise from participating in the study, that compensation will be paid, theamount of which shall be equivalent to the compensation given for such events if they
had arisen as a result of general medical practice)
8. The expected advantages and possible disadvantages to the patient arising fromparticipation in the study
9. Access to patient medical history (an explanation of the external inspection of patientdata, eg,“To ensure quality control, medical personnel from other facilities may receive
permission from our hospital president to have direct visual access to patient medical
records.”)27

10. Non-consent and withdrawal of consent (the fact that they are free to decline toparticipate in the study before the patient is enrolled and that, even after enrollment,
they remain free at any time to withdraw from the study, and that such withdrawal will
not in any way lessen the quality of care the patient receives)
11.Protection of human rights (the fact that all involved in the study will do their utmost to
guarantee the confidentiality of the patient’s identity and personal information)
12. The reuse of patient information (the possibility that the patient’s data may be reusedfor scientific research, such as in meta-analyses, etc.), while maintaining patientanonymity
13. The right to ask questions (the patient and/or guardian(s) will be provided with a written
document containing contact information for the attending physician, the facility chief
investigator, and the RAISE Study Principal Investigator [and/or the RAISE Study
Office]. The patient and/or guarantor(s) shall be informed that they are free to contact
them and ask them any questions they might have, whether about the study or thetreatment protocol).

13.2.2. Consent
After the patient and/or guarantor(s) have received the above explanations and have had achance to confirm that they have indeed understood the contents of the study, they will be
asked to participate in the study. If they consent to do so, the names of the physician who
explained the above information and the patient and guarantor who consent to participate
in the study will be written on the consent form appended to this protocol (or other suitableconsent form as determined by the physician’s institution), after which the physician andpatient or guarantor will sign the document and add the date consent was given. Two copies
will be made of this consent form, with one being given to the patient and/or guarantor(s),and one being retained by the facility coordinator. The original document will be kept in thefile with the patient’s medical records.

13.3. Protection of privacy and patient identification
The patient’s full name will never be communicated to the Data Coordinating Center by theparticipating facility where s/he is receiving treatment. All references to patient identity will
use the case number received at the time of patient registration and the patient’s initials. The
medical staff at the facility where the patient is being treated will know the patient’s name,but there will be no record in the database at the Data Coordinating Center of personal
information that could potentially be used by a third party to directly identify the patient.

28

13.4. Treatment in strict accordance with the study protocol
All investigators participating in the present study will strictly abide by all the rules detailed in thisstudy protocol, except in cases where respecting these rules would require the investigators toendanger the patient or infringe upon the patient’s human rights.

13.5. Approval by the Ethics Committee (Institutional Review Board) of each participating facility
13.5.1 Approval must be received before the facility can participate in the study
In order for a facility to participate in the study, this study protocol, together with the
document that explains the treatment procedure to the patient and their family members, must
be approved by that facility’s Ethics Committee or Institutional Review Board (IRB). Onceapproval has been given by the facility’s IRB, the facility coordinator shall fax a copy of the
document showing their IRB approval to the Data Coordinating Center and keep the original
document on file at their own facility.

14. MONITORING AND AUDITING
14.1. Regular monitoring
Regular monitoring will be carried out twice a year to guarantee the safety of the study
subjects by ensuring study protocol adherence with regard to patient treatment and to
confirm that all data are being correctly collected.
Central monitoring will be done with the aid of the information entered on the data sheets
and collected at the Data Coordinating Center. If the Data Coordinating Center deems it
necessary, onsite monitoring may also be done—by visiting respective facilities and comparing
the original documents retained at these facilities with information stored in the Data
Coordinating Center—together with other monitoring activities as required.
The Data Coordinating Center will produce regular Monitoring Reports and submit thesereports to the RAISE Study Office, the RAISE Study Principal Investigator, and the Efficacy
and Safety Review Board.

14.1.1. Monitoring items
The following items will be monitored:
1) Whether planned enrollment numbers are being reached: the number of patientsenrolling during any given period and the cumulative number of patients enrolled at any
given point, for all facilities and at each individual facility2) Eligibility: the ineligibility and possible ineligibility of certain patients, per group and per
facility293) Differences during and after receiving the protocol treatment, per group and per facility4) Background factors before enrollment, per group5) Severe and minor adverse events, per group and per facility6) Protocol violations, per group and per facility7) Other points as required, including the general progress of the study and safetyconcerns

14.1.2. Protocol deviations and violations
If the administration of medication, conduct of clinical tests, evaluation of the toxicity or
efficacy of therapy, or the conduct of any other clinical procedure or medical treatment is notfaithfully carried out according to the protocol detailed in this document, it shall be deemed a
deviation of protocol.
On monitoring, any deviations from the study protocol that exceed what the Data Coordinating
Center, together with the RAISE Study Principal Investigator and RAISE Study Office, deem
acceptable, on a case-by-case basis, will be included in a list of Cases of Possible Protocol
Deviations to be included in the monitoring report. The RAISE Study Office and RAISE Study
Group will then carefully analyze these deviations and classify them according to the followingclassification scheme:
Violations
As a rule, any deviation that satisfies 2 or more of the following conditions will be considereda violation of the study protocol:
1) A deviation that makes evaluation of an endpoint problematic or impossible
2) A deviation caused by the attending physician or the facility concerned3) A deviation that was intentional or systematic4) A deviation that was dangerous or differed greatly from the study protocol5) A deviation that was clinically inappropriate
In general, the specific content of each of these violations will be described in detail inpublished papers describing the study.
Acceptable deviations
Acceptable deviations are those deviations that remain within the limits of what had been
agreed to, on a case-by-case basis, by the Data Coordinating Center in consultation with
the RAISE Study Principal Investigator and RAISE Study Office, and shall be regarded
as permissible deviations from the standard protocol (either before or after the deviation
occurred). Deviations that remain within acceptable limits, agreed to before the deviation
occurred, will not be noted in the monitoring report.
Deviations
Deviations will be defined as anomalies when they are not classified as either of the above 230

categories, ie, violations or acceptable deviations. If a particular anomaly occurs often during
the study, it will be noted in future articles reporting the findings of the study.

14.2. Onsite inspection of facilities
Facilities participating in the study will be visited and inspected to maintain and improve
the study’s scientific and ethical conduct. The inspector will visit participating facilities as
required, examine that facility’s original IRB document approving its participation in the
study and the original consent forms signed by the patients, compare the information on eachpatient’s data sheet with their actual medical records kept at the facility, and effect otherinspections as deemed necessary. The results of these facility inspections will be reported to
the research coordinator of the given facility, and to the Data Coordinating Center, RAISE
Study Office, and RAISE Study Principal Investigator. If the details of such inspections are
ever made public, the name of the facility in question will not be revealed.

15. REPORTING THE STUDY RESULTS
When reporting the results from the study at conferences and in written publications,
all existing policies established by the steering committee relating to such reporting will
be respected and adhered to. If no clear policies have been decided upon at the time ofreporting, it shall be done in accordance with the following conditions:
All principal reports describing the study will be written only after the final analysis has been
done and will be submitted to English-language journals for publication.
Except in the case of written permission given by the Efficacy and Safety Review Board,
no findings of this study will be made public until either the final analysis described in the
protocol has been completed or an interim analysis has been carried out for the express
purpose of reporting its findings, as described in the study protocol. However, the RAISE
Study Principal Investigator, or the RAISE Study Office with the permission of the RAISE
Study Principal Investigator, may present relevant findings at academic conferences or publish
articles for the purpose of introducing the study to a wider audience, without including theactual results of an analysis of the endpoints of the study.
In principle, the main reports describing the results of the study will list the RAISE Study
Office as the first author. After that, in order, will be listed the RAISE Study Principal
Investigator and the person in charge of the statistical analysis required to report the results.
After that, in accordance with the limits placed on the number of authors of written reports,
coauthors will include members of the steering committee and the facility chief investigator (orfacility coordinators) of the facilities that had the most patients enrolled in the study, listed in31descending order of enrollment.
All coauthors will have an opportunity to review the content of the finished report before itis submitted for publication and only those who agree with it will be listed as coauthors on
the final manuscript. If a researcher who was involved in the study disagrees with part of themanuscript, even after discussing their opinion with other authors, the RAISE Study Principal
Investigator reserves the right to exclude this researcher as a coauthor in the final version of
the manuscript.
Because the study contents might be presented several times at various conferences, the
RAISE Study Office, RAISE Study Principal Investigator, and the facility chief Investigator/
facility coordinator at the facilities that had the most patients involved in the study will share
the responsibility of making such presentations, and the RAISE Study Principal Investigator
will decide who will have the right to publically present the study findings. However, when
the study results are presented at academic conferences, the RAISE Study Office will be
responsible for preparing the presentation and determining its content and will assemble thisinformation with the assistance of the Data Coordinating Center. Presenters other than thosein the RAISE Study Office will not have direct access to the data and analysis results on fileat the Data Coordinating Center, except with the written permission of both the RAISE Study
Office and the Head of the Data Coordinating Center.

16. RAISE Study Group
16.1. Principal Investigator
Tsutomu Saji
Toho University Omori Medical Center, The First Department of Pediatrics
6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan
TEL：+81-3-3762-4151
FAX：+81-3-3298-8217
E-mail：saji34ben@med.toho-u.ac.jp

16.2. RAISE Study OfficeGunma University Graduate School of Medicine, Department of Pediatrics
Chief: Tohru Kobayashi
3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
TEL：+81-27-220-8205 Mobile：090-9101-1996
FAX：+81-27-220-8215
E-mail：raise-discussion@umin.ac.jp

32

16.3. Data Coordination Center
Gunma University Hospital, Department of Clinical Investigation and Research Unit
3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan
TEL：+81-27-220-8740
FAX：+81-27-220-8741
Chief：Tetsuya Nakamura
Data Managers：Mami Okada, Sayuri Fukushima, Atsushi Matsumoto, Etsuko Saito, Fumie Tokuda

16.4. Data and Safety Monitoring Board
Chief: Takeshi Tomomasa
PAL Children’s Clinic
3303-2, Tsunatori-machi, Isesaki, Gunma, 372-0812, Japan
E-mail：tomomasa@gunma-u.ac.jp

16.5. Steering Committee of RAISE Study   Tsutomu Saji

Toho University Omori Medical Center   Tomoyoshi Sonobe

Japan Red Cross Medical Center   Akihiro Morikawa

Gunma University Graduate School of Medicine

   Kenji Hamaoka

Kyoto Prefectural University of Medical Graduate Schoolof Medhical Science   Toshiro Hara

Kyusyu University Graduate School of Medical Sciences

   Shunichi Ogawa

Nippon Medical School

   Hirokazu Arakawa

Gunma University Graduate School of Medicine

   Kazuo Takeuchi

Saitama University

   Fukiko IchidaToyama University   Jun Abe

Center for Child Health and Development

   Tetsuya Nakamura

Gunma University Hospital   Yuichi Nomura

Kagoshima University Graduate School of Medical
and Dental Science

   Masaru Miura

Tokyo Metropolitan Children's Medical Center

   Mamoru Ayusawa

Nihon University

   Yoshihiro Onouchi

RIKEN

   Yoshinari Inoue

Inoue Children’s Clinic

   Taichi Kato

Nagoya University Graduate School of Medicine

   Tohru Kobayashi

Gunma University Graduate School of Medicine

   Tetsuya Otani

Center for Child Health and Development

33

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