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

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 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

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 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

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

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

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

Secondary Outcomes Days of fever Days of hospital ITT Wilcoxon rank sum test Median p = <0.0001 Days of hospital 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?