Infliximab for intensification of primary
therapy for
Kawasaki disease: a phase 3
randomised, double-blind,
placebo-controlled trial
Journal Club
General Medicine C- 4/3/14
Background- Mx of KD
Treatment resistance
•Fever persists or returns in 10 -20 % of patients
with KD who are initially treated with IVIG and
aspirin
•Subset of IVIG resistant patients is at highest risk
of coronary artery aneurysms
Proposed Mx of treatment resistant KD
•Corticosteroids
•TNFα inhibitors e.g. infliximab
Clinical Question
P- Population
• children aged 4 weeks–17 years who had a fever
(3-10 days) and met (modified) American Heart
Association criteria for Kawasaki disease
I- Intervention
• addition of infliximab to standard therapy (IVIG and
aspirin)
C- Comparison
• Placebo
O- Outcome
• Reduction in the rate of treatment resistance
Participants
• Key Selection Criteria
• Children aged 4 weeks – 17 years
• Fever (temp > 38) for 3-10 days
• Adapted American Heart Association Criteria
for Kawasaki disease
• Presenting to two tertiary paediatric hospitals
in USA
Inclusions / exclusions appropriate for study
question?
Interventions and Comparison
• Assignment to intervention and
comparison groups
• Permuted block design (block size 2 and 4)
stratified by age, sex, centre
• Allocation- 1:1
• Randomly allocated to 2 treatment groups
 infliximab 5mg/kg at 1 ml IV over 2 hrs
 placebo: normal saline
 Randomised
 Randomisation concealed
• Baseline
characteristics
were similar
between 2 study
groups
Randomisation
successful
Interventions and Comparison
• Modified intention to treat
(analysed 97/98 who received placebo)
X Participants analysed in groups to
which randomised
• Patients, treating physicians and staff,
study team members, and
echocardiographers were all masked to
treatment assignment
 Randomisation blind
Interventions and Comparison
• Apart from study interventions, were
groups treated equally?
Antihistamine
Paracetamol
Study drug
IVIg
Aspirin
Outcomes
• Primary outcome measures
• Difference in treatment resistance defined by:
 temperature of >38 between 36 hrs – 7 days
post completion of infusion of IVIg without another
likely source
 Well defined:
• however no indication of what investigations would
be done to rule out another source of fever
• article defined treatment resistance as fever 36h –
7 days post IVIg however guardian measured temp
for 3 days post discharge
Outcomes
• Secondary outcomes
•
•
•
•
•
•
•
Coronary artery Z score (pRCA and LAD)
Change in coronary artery Z score from baseline to weeks 2 and 5
Change in concentrations of age-adjusted Hb, CRP, ALT, albumin, GGT,
ESR, platelet count, WCC, absolute cell counts
No days with fever > 38C from enrolment
Duration of hospital stay
IVIg reactions
Infliximab reactions
? Well defined
- Z scores well defined, same echo cardiographer
- IVIG reaction?
? Replicable
? secondary outcomes clinically relevant
Outcomes
• Follow Up Primary Outcomes
• Family were contacted by study coordinator 3 days and
10 weeks after discharge to monitor child’s progress
• All 196 were successfully contacted at 3 days
• 94/98 who received treatment completed 10 wk f/u
• 93/97 who received placebo completed 10 wk f/u
 Completion: sufficient
 Blind outcome assessment
? Adequate time-course
Outcomes
• Follow Up Primary Outcomes
• Family were contacted by study coordinator 3 days and
10 weeks after discharge to monitor child’s progress
• All 196 were successfully contacted at 3 days
• 94/98 who received treatment completed 10 wk f/u
• 93/97 who received placebo completed 10 wk f/u
 Completion: sufficient
 Blind outcome assessment
? Adequate time-course
Outcomes
• Follow up of Secondary Outcomes
• Lab data: at baseline, 24hr after completion
IVIg, week 2, week 5
• Echo: initial hospitalisation, week 2, week 5
 Completion: sufficient
 Blind outcome assessment
? Adequate time-course
Primary Outcome
• Modified ITT
• Logistic regression model
• No difference in outcome
• p = 0.81
Illness days
ALT, GGT
Age-adjusted Hb
bands
• ? Insufficient power – based on
reduction from 20%-5% but treatment
resistance only 11% in this study
Secondary Outcomes
• Days of fever
•
•
•
•
ITT
Wilcoxon rank sum test
Median
p = <0.0001
• Days of hospital
• ITT
• Wilcoxon rank sum test
• Not significant
Secondary outcomes - IVIG
• IVIG reaction = “fever with chills or
hypotension for age that warranted
interruption of IVIG”
• Modified ITT
• Fishers exact test
• None in infliximab, N = 13 (13.4%)
control
• p = <0.0001
Secondary Outcomes - Coronary
• Zmax
•
•
•
•
Linear regression model
Only included if well seen
No significant difference
Mean Z 1.8 (p = 0.87)
Secondary Outcomes - Coronary
• Change in Z scores from baseline
• Mixed model reported measures
• Unstructured variance/covariance error matrix
• 2-fold greater decrease in mean Z score of
proximal LAD @ 2/52
• p = 0.045 (nb. CI crosses 0)
• No change in L MCA
or proximal RCA
Secondary Outcomes - Lab
• Mixed model / ANCOVA analysis
• Few reached
statistical significance
• Absolute neutrophil
• CRP @ 24 hours
• ESR @ 2/52
Safety
• Data and safety
monitoring board r/v
• Fishers exact test
• P values not reported
• No of pts with 1 or more
adverse events p=0.18
• “No serious adverse event
related to study drug”
Applicability
• Source population not specifically
described but presumably similar
• Inpatient setting in 2 paediatric referral
centres in San Diego and Columbus
• Different criteria for Dx
• Adapted from AHA guidelines
• Complete KD fever >/= 5/7 – in this study
>/= 3/7
Applicability
• Important outcomes considered?
• Cost?
• Some benefit in reducing IVIG reactions,
but implication in clinical practice?