de-escalation of anti-tnf therapy in inflammatory bowel disease

Conditions: Inflammatory Bowel Diseases; Crohn Disease; Colitis, Ulcerative

Summary: background/rationale: treatment outcomes of patients with inflammatory bowel disease (ibd) have improved enormously during the past decade due to the use of anti-tumour necrosis factor (anti-tnf) therapy. as a result, 67 to 91% of paediatric patients and 66% of adult patients is still in sustained remission two years after the initiation of anti-tnf therapy. prolonged use of anti-tnfs comes with disadvantages such as dose dependent susceptibility to infections and dermatological adverse effects. preliminary, mostly uncontrolled studies suggest that dose reduction by dosing interval lengthening is a realistic option in a relevant proportion of patients with ibd, provided that intensive follow-up is applied. objective: to evaluate whether a faecal calprotectin (fc) guided strategy of anti-tnf dosing interval lengthening is non-inferior in maintaining remission in patients with ibd, compared with an unchanged dosing interval.

study design: international, multi-centre, prospective, partially randomised patient-preference trial. study population: study population: eligible patients are aged 12-25 years with luminal crohn's disease (cd) or ulcerative colitis (uc), who have three consecutive faecal calprotectin (fc) results in the target range (i.e. \<250 µg/g for cd patients; \<150 µg/g for uc patients) over a period of 6 months at study entry or recently confirmed endoscopic remission. de-escalation strategy: in patients treated with adalimumab, the dosing interval will be lengthened from 2 to 3 weeks. in patients treated with infliximab, the dosing interval will be lengthened from 8 to 12 weeks. fc rapid tests will be performed every 4 weeks and rapid tests for anti-tnf trough levels will be performed every 12 weeks. main study endpoints: the primary outcome is the cumulative incidence of out-of-range fc results at 48 weeks follow-up. secondary endpoints include time to get out-of-range fc results, cumulative incidence of anti-tnf associated adverse effects, proportion of patients progressing from out-of-range fc to loss-of-response and identification of predictors of successful de-escalation. ethical considerations: patients with reduced anti-tnf exposure may have a higher risk of out-of-range fc results and, on the other hand, may benefit from fewer hospital visits or injections and possibly a decrease in adverse effects of anti-tnf therapy. tight monitoring of fc levels (i.e. 4-weekly) will allow institution of re-escalation before the patient manifests clinical signs of relapse. this study cannot be conducted without the participation of minors and young adults, who typically have a short disease duration. early treatment with anti-tnf agents possibly modifies the course of their disease, which makes provision for safe deescalation.

Eligibility criteria:
inclusion criteria: * aged 12-25 years * diagnosed with luminal crohn's disease or ulcerative colitis * treated with either 8-weekly infliximab or 2-weekly adalimumab * current anti-tnf agent as first ever anti-tnf agent or prior anti-tnf agent discontinued for reason other than primary non-response or secondary loss-of-response * no previous attempts to lengthen the dosing interval * three consecutive faecal calprotectin (fc) results in the target range (i.e. \<250 μg/g for cd patients; \<150 μg/g for uc patients) in the previous 6 months or confirmed endoscopic remission within 2 months before study entry (i.e. simple endoscopic score for crohn's disease (ses-cd) \<3 points for cd patients; ulcerative colitis endoscopic index of severity (uceis) ≤1 point for uc patients) * absence of symptoms associated with active ibd (judged by the local ibd-team) * written informed consent granted exclusion criteria: * perianal fistula * presence of ileostomy or ileoanal pouch (as fc cut-off is not validated for small bowel faeces) * any inflammatory comorbidity, such as rheumatoid arthritis * current treatment with corticosteroids (prednisone or budesonide) * current pregnancy

Keywords: infliximab adalimumab tumor necrosis factor-alpha inflammatory bowel diseases crohn disease colitis, ulcerative