De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease (FREE)

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

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 Overview

• Status: Enrolling by invitation
• Conditions: Inflammatory Bowel Diseases; Crohn Disease; Colitis, Ulcerative
• Intervention / Treatment: Biological: Infliximab; Biological: Adalimumab

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.

• Study Type: Interventional
• Enrollment (Estimated): 148
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Liège, Belgium, B-4000
    • Centre Hospitalier Universitaire de Liege
  • Liège, Belgium
    • Centre Hospitalier Regional de la Citadelle
• Netherlands
  • Arnhem, Netherlands, 6816 AD
    • Rijnstate Hospital
  • Eindhoven, Netherlands, 5623 EJ
    • Catharina Hospital Eindhoven
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen
  • Heerlen, Netherlands, 6419 PC
    • Zuyderland Medical Center
• Spain
  • L'Hospitalet De Llobregat, Spain, 08907
    • Hospital Universitari de Bellvitge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; 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; Dosing interval lengthening from 8 to 12 weeks; Other Names: Remicade; Remsima; Inflectra; Flixabi; Zessly; Biological: Adalimumab; Dosing interval lengthening from 2 to 3 weeks; Other Names: Humira; Imraldi; AMGEVITA; Hyrimoz; Idacio; Hulio
No Intervention: Control group; 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients' attitudes towards deprescribing anti-TNF agents	We will use the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire	48 weeks

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Bühlmann Laboratories AG; European Crohn´s and Colitis Organisation
• Investigators: Principal Investigator: Patrick F van Rheenen, MD PhD, University Medical Center Groningen

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2021
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: November 20, 2020
• First Submitted That Met QC Criteria: November 20, 2020
• First Posted (Actual): November 27, 2020

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Tumor Necrosis Factor-alpha; Crohn Disease; Inflammatory Bowel Diseases; Infliximab; Adalimumab; Colitis, Ulcerative
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Inflammatory Bowel Diseases; Crohn Disease; Intestinal Diseases; Colitis; Colitis, Ulcerative; Anti-Inflammatory Agents; Antirheumatic Agents; Gastrointestinal Agents; Dermatologic Agents; Tumor Necrosis Factor Inhibitors; Adalimumab; Infliximab
• Other Study ID Numbers: 202000261; 2020-001811-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No