Maarten Cozijnsen

59 Chapter 3 TISKids: an international multicenter RCT Eligibility criteria and recruitment Newly diagnosed CD patients, according to revised Porto criteria (1), are eligible if untreated, aged 3 up to and including 17 years, with bodyweight above 10 kg, presenting with moderate- to-severe disease activity (weighted Pediatric Crohn’s Disease activity Index [wPCDAI] above 40).(25) Patients are excluded in case of a need for primary surgery, such as symptomatic bowel stenosis or stricture, active perianal fistulas, or if they have serious co-morbidity, such as a severe infection, sepsis, opportunistic infection, positive stool culture ( Salmonella enterica/Shigella species /Yersinia enterocolitica/Campylobacter species), positive Clostridium difficile toxin assay, positive tuberculosis screening, or if they present with a suspected or definite pregnancy. Patients suspected of CD and undergoing routine diagnostic work-up are potential candidates and screened for this trial when presenting to one of the participating sites. After a CD diagnosis is established and eligibility criteria are met, patients and/or parents/guardians are informed about the trial and asked to consider participation. After a waiting period of a minimum of 2 days, written consent is asked by the treating physician or researcher. Note that before the initial, diagnostic endoscopy and study consent, preliminary consent is sought for the collection of additional biopsies, which will be used for search for biomarkers predictive for treatment response – one of the additional study objectives. Randomization, blinding and treatment allocation Eligible patients are equally (1:1 ratio) randomized by a computer-generated list into two treatment groups, stratified by center. Randomization is incorporated in the web-based Case Record Form database used for this trial (Castor EDC).(26) Collaborators at each site have access to this database and can register and randomize their patients. Treatment groups Participants are randomized into two groups, either the experimental ‘ top-down ’ group or the control group named ‘ step-up ’, which is the current standard treatment strategy (5). The top-down group will receive five IFX infusions (Inflectra ® , IFX induction at week 0, 2 and 6, followed by 2 maintenance infusions every 8 weeks, dosed at 5 mg/kg) combined with oral AZA as maintenance treatment (once daily, dosed 2-3 mg/kg). Step-up treatment consists of standard induction treatment with either oral prednisolone (1 mg/kg daily with a maximum of 40 mg for 4 weeks, followed by tapering down 5 mg per week until stop) or EEN (polymeric feeding for 6-8 weeks after which normal diet is gradually reintroduced within 2 to 3 weeks). (2) Similar to the top-down group, both prednisolone and EEN will be combined with oral AZA as maintenance treatment (2-3 mg/kg, once daily). AZA dosing may be altered based on TPMT genotype, but TPMT testing is not obligatory. Following its initiation, routine complete blood count are performed as part of routine clinical care (weekly in 1 st month, monthly in 2 nd and 3 rd month, and thereafter once every three months) and AZA metabolites are measured about the