1. Journal Club General Medicine C- 4/3/14
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

2. Background- Mx of KD Treatment resistance
Fever persists or returns in % 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

3. 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

4. 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?

5. 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

6. Baseline characteristics were similar between 2 study groups
Randomisation successful

7. 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

8. Interventions and Comparison
Apart from study interventions, were groups treated equally?
Antihistamine
Paracetamol Study drug
IVIg Aspirin

9. Outcomes Primary outcome measures Well defined:
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

10. 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

11. Outcomes Follow Up Primary Outcomes Completion: sufficient
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

12. Outcomes Follow Up Primary Outcomes Completion: sufficient
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

13. Outcomes Follow up of Secondary Outcomes Completion: sufficient
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

14. Primary Outcome Modified ITT Logistic regression model
No difference in outcome
p = 0.81
? Insufficient power – based on reduction from 20%-5% but treatment resistance only 11% in this study
Illness days
ALT, GGT
Age-adjusted Hb
bands

15. Secondary Outcomes Days of fever Days of hospital ITT
Wilcoxon rank sum test
Median
p = <0.0001
Days of hospital
Not significant

16. 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

17. Secondary Outcomes - Coronary
Zmax
Linear regression model
Only included if well seen
No significant difference
Mean Z 1.8 (p = 0.87)

18. 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 2/52
p = (nb. CI crosses 0)
No change in L MCA or proximal RCA

19. Secondary Outcomes - Lab
Mixed model / ANCOVA analysis
Few reached statistical significance
Absolute neutrophil
24 hours
2/52

20. 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”

21. 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

22. Applicability Important outcomes considered? Cost?
Some benefit in reducing IVIG reactions, but implication in clinical practice?