Title
De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
De-escalation of Anti-TNF Therapy in Adolescents and Young Adults With IBD With Tight Faecal Calprotectin and Trough Level Monitoring
Phase
Phase 4Lead Sponsor
University of GroningenStudy Type
InterventionalStatus
Enrolling by invitationIndication/Condition
Inflammatory Bowel Diseases Crohn Disease Colitis, UlcerativeIntervention/Treatment
Infliximab AdalimumabStudy Participants
148BACKGROUND/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.
Dosing interval lengthening from 8 to 12 weeks
Dosing interval lengthening from 2 to 3 weeks
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. Consists of two groups: Patients randomised to the intervention group and patients allocated to the intervention group based on preference.
Unchanged dosing interval. Consists of two groups: Patients randomised to the control group and patients allocated to the control group based on preference.
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
