Clinical trial NCT04646187: De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
Official title: De-escalation of Anti-TNF Therapy in Adolescents and Young Adults With IBD With Tight Faecal Calprotectin and Trough Level Monitoring
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Inflammatory Bowel Diseases
Crohn Disease
Colitis, Ulcerative
Keywords: Infliximab
Adalimumab
Tumor Necrosis Factor-alpha
Inflammatory Bowel Diseases
Crohn Disease
Colitis, Ulcerative
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: European Crohn´s and Colitis Organisation
name: Bühlmann Laboratories AG
First posted: 2020-11-27
Enrollment: 148
Sex: ALL
Minimum age (years): 12
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: cumulative incidence of out-of-range fecal calprotectin results at 48 weeks follow-up
timeFrame: 48 weeks
Secondary outcomes:
measure: Time to get out-of-range fecal calprotectin results
timeFrame: up to 48 weeks
measure: Cumulative incidence of anti-TNF-associated respiratory infections and dermatological adverse effects at 48 weeks follow-up
timeFrame: 48 weeks
measure: Evolution of FC and anti-TNF trough levels in the first 16 weeks after reverting to previous dosing interval
timeFrame: Up to 48+16 weeks
measure: Proportion of patients developing loss-of-response in the first 16 weeks after reverting to the previous dosing interval
timeFrame: Up to 48+16 weeks
measure: Identification of predictors of successful de-escalation.
timeFrame: 48 weeks
Other outcomes:
measure: Patients' attitudes towards deprescribing anti-TNF agents
timeFrame: 48 weeks
Locations:
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Liège
country: Belgium
facility: Centre hospitalier universitaire de Liège
city: Liège
country: Belgium
facility: Centre hospitalier régional de la Citadelle
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital
city: Eindhoven
country: Netherlands
facility: Catharina Hospital Eindhoven
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
Study officials:
affiliation: University Medical Center Groningen
name: Patrick F van Rheenen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bouhuys M, Lexmond WS, Dijkstra G, Lobaton T, Louis E, van Biervliet S, Groen H, Guardiola J, Rheenen PV. Efficacy of anti-TNF dosing interval lengthening in adolescents and young adults with inflammatory bowel disease in sustained remission (FREE-study): protocol for a partially randomised patient preference trial. BMJ Open. 2021 Nov 3;11(11):e054154. doi: 10.1136/bmjopen-2021-054154.