Maarten Cozijnsen

60 time of induction treatment cessation. In both groups, methotrexate may be given instead of AZA for instance in patients with low or absent TPMT activity. Screening for serum positivity to varicella zoster virus – as well as Epstein Barr virus and hepatitis B – is part of routine clinical care, and if vaccination is required and if time allows, treatment initiation will be postponed. The top-down and step-up groups differ in the type of induction treatment that is started after diagnosis, but may switch to similar treatments during follow-up. Treating physicians are allowed to change treatment or increase dosing during follow-up when clinically indicated, for instance in case of drug inefficacy (non-response or loss of response) or intolerance. IFX may thus also be given to a step-up patient, but only as second-line treatment. Note that the step-up group may thus include patients stepping-up to IFX early after diagnosis, which, as explained in the introduction, was associated with better efficacy in retrospective trials than starting IFX late. Overall, this study thus compares two treatment strategies and not two different drugs, like in regular drug-trials. Study endpoints Comparative efficacy and safety In total, patients will be followed for 5 years from randomization (Figure 1). The primary endpoint is clinical remission at week 52 (defined as a wPCDAI score<12.5) without need for additional CD-related therapy or surgery, i.e. additional to the treatment scheme described in the previous section.(Table 1) Secondary endpoints include assessment off endoscopic disease activity, growth, quality of life and medication use. Endoscopic disease activity is an important outcome in this trial due to the expected difference between the two treatment strategies. To assess endoscopic disease activity, an endoscopic examination is scheduled at week 10, and another offered at week 52. The week 52 endoscopy is performed on a voluntary basis, as most patients may not benefit from this assessment while it does pose risk and discomfort. Endoscopic disease activity is also indirectly assessed via measuring the fecal marker calprotectin. To address longitudinal growth during follow-up, height and BMI Z-scores will be calculated at baseline and during follow-up for all patients with use of age and gender specific anthropometric reference values (preferably country specific, otherwise global reference values). Additionally, bone age will be measured with hand X-ray, and pubertal development will be assessed. Safety endpoints include the rate of adverse events and complications during follow-up. Besides comparing top-down with step-up, we planned two sub-analyses. Firstly, we aim to compare both the efficacy and safety of the two step-up treatment options, and secondly, to assess the correlation between clinical and endoscopic disease activity measures.