Post on 13-Feb-2017
Infliximab for intensification of primary therapy forKawasaki disease: a phase 3 randomised, double-blind,placebo-controlled trialJournal 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 aneurysmsProposed 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 diseaseI- 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?AntihistamineParacetamolStudy 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
• ? Insufficient power – based on reduction from 20%-5% but treatment resistance only 11% in this study
Illness daysALT, GGTAge-adjusted Hbbands
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 MCAor 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?