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

University Medical Center Groningen (UMCG)

Status and phase: Invitation-only; Phase 4

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

Treatments: Biological: Infliximab; Biological: Adalimumab

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT04646187

202000261

2020-001811-26 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 148 estimated patients

Sex: All

Ages: 12 to 25 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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148 participants in 2 patient groups

Intervention group

Experimental group

Description:

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.

Treatment:

Biological: Adalimumab

Biological: Infliximab

Control group

No Intervention group

Description:

Unchanged dosing interval. Consists of two groups: Patients randomised to the control group and patients allocated to the control group based on preference.