De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease

Study Overview
=================
Brief 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.

Detailed Description
-----------------
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.

Official Title
-----------------
De-escalation of Anti-TNF Therapy in Adolescents and Young Adults With IBD With Tight Faecal Calprotectin and Trough Level Monitoring

Conditions
-----------------
Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative

Intervention / Treatment
-----------------
* Biological: Infliximab
* Biological: Adalimumab


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 25 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>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. | Biological: Infliximab<br>* Dosing interval lengthening from 8 to 12 weeks<br>* Other names: Zessly;Biological: Adalimumab<br>* Dosing interval lengthening from 2 to 3 weeks<br>* Other names: Imraldi;|
| No Intervention: Control group<br>Unchanged dosing interval. Consists of two groups: Patients randomised to the control group and patients allocated to the control group based on preference. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative incidence of out-of-range fecal calprotectin results at 48 weeks follow-up | Out-of-range FC results are defined as fecal calprotectin above the target range (i.e. >250 μg/g for CD patients; >150 μg/g for UC patients) and at least 100 μg/g increase compared with the previous result, unless the previous result was already above the target range. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to get out-of-range fecal calprotectin results | The time from study baseline until the first out-of-range fecal calprotectin result | up to 48 weeks | 
| Cumulative incidence of anti-TNF-associated respiratory infections and dermatological adverse effects at 48 weeks follow-up | Dermatological adverse effect include skin infections, new-onset or worsening of psoriasis, psoriasiform lesions, eczema, acne and alopecia | 48 weeks | 
| Evolution of FC and anti-TNF trough levels in the first 16 weeks after reverting to previous dosing interval | Proportion of patients with return of FC levels to target range without switch to out-of-class biological | Up to 48+16 weeks | 
| Proportion of patients developing loss-of-response in the first 16 weeks after reverting to the previous dosing interval | Loss-of-response is defined as the appearance of symptoms of active IBD in combination with persistent out-of-range fecal calprotectin results | Up to 48+16 weeks | 
| Identification of predictors of successful de-escalation. | Predictors of successful de-escalation will be assessed by calculating odds ratios with the use of univariate logistic regression analysis. Candidate predictors with p<0.10 in univariate analysis will be selected for use in the multivariate analysis. | 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Adalimumab, Infliximab, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative