Infliximab for intensification of primary therapy forKawasaki 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 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 eventrelated 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?