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

Crohn Disease Clinical Trial

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Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04646187
• Other study ID #: 202000261
• Secondary ID: 2020-001811-26
• Status: Enrolling by invitation
• Phase: Phase 4
• Start date: March 11, 2021
• Est. completion date: March 2025

Study information

• Verified date: November 2023
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 148
• Est. completion date: March 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 25 Years

Eligibility

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

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Crohn Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases

Intervention

Biological:
• Infliximab
Dosing interval lengthening from 8 to 12 weeks
• Adalimumab
Dosing interval lengthening from 2 to 3 weeks

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Centre hospitalier régional de la Citadelle	Liège
Belgium	Centre hospitalier universitaire de Liège	Liège
Netherlands	Rijnstate Hospital	Arnhem
Netherlands	Catharina Hospital Eindhoven	Eindhoven
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Zuyderland Medical Center	Heerlen
Spain	Hospital Universitari de Bellvitge	L'Hospitalet De Llobregat

Sponsors (3)

Lead Sponsor	Collaborator
University Medical Center Groningen	Bühlmann Laboratories AG, European Crohn´s and Colitis Organisation

Countries where clinical trial is conducted

Belgium,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patients' attitudes towards deprescribing anti-TNF agents	We will use the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire	48 weeks
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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