Maarten Cozijnsen

62 top-down therapy may be further reduced compared to step-up by its hypothesized higher efficacy, which may reduce medication use, hospitalization and surgery.(6) We therefore hypothesize that after 5 years of follow-up healthcare related costs of top-down therapy will be comparable to those of step-up therapy. We will also look for biologic markers that may predict treatment response. Additional biopsies and blood samples are collected from patients to measure RNA and protein expression, both before the start of treatment and during follow-up (additional biopsies are taken in pairs from affected and unaffected mucosal tissue in the ileum and colon with a maximum of 8 biopsies). This may help unravel the underlying mechanisms of treatment response of both strategies and preferentially lead to markers predictive of treatment response. The ability to predict treatment response prior to its initiation would allow for tailored treatment, aimed at maximal effect and safety hereby decreasing health-care cost. Lastly, the pharmacokinetic and pharmacodynamic properties of IFX in children will be assessed during follow-up. Currently, only few controlled trials assessed these properties of IFX in children and by gathering more, high-quality data, we expect to further optimize IFX dosing in children. Based on clinical experience, we hypothesize that younger patients will obtain lower trough levels and lower drug efficacy with fixed IFX dosing of 5 mg/kg. Sample size calculation Our sample size calculation was based on week 52 remission ratios in three studies; two retrospective trials in pediatric CD patients and one prospective RCT among adult CD patients. The first retrospective trial compared top-down infliximab use with conventional step-up in pediatric CD and found a remission difference at week 52 of 38% (15/18 [83%] vs 5/11 [45%]).(23) The second trial compared early IFX use versus early immunomodulator use and found a remission difference of 24% (58/68 [85%] vs 152/248 [61%]).(24) The only prospective RCT, comparing top-down versus step-up in adult CD patients, reported a remission difference of 19% at week 52 (40/65 [61.5%] vs 27/64 [42.2%]).(19) Based on this data, we calculated to need 100 inclusions (50 patients in each arm, considering a drop-out rate of 2%) to find a 25% difference in clinical remission at week 52 with a power of 80% (2-sided α 0.05). A low drop-out rate was considered appropriate, because there are only few reasons for drop-out: only if the patient wishes to, or if after randomization the assigned treatment is not started.