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

Primary Purpose

Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative

Status
Recruiting
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Infliximab
Adalimumab
Sponsored by
University Medical Center Groningen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Inflammatory Bowel Diseases focused on measuring Infliximab, Adalimumab, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative

Eligibility Criteria

12 Years - 25 Years (Child, Adult)All SexesDoes not accept 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

Sites / Locations

  • Universitair Ziekenhuis Gent
  • Centre hospitalier universitaire de Liège
  • Rijnstate Hospital
  • Catharina Hospital Eindhoven
  • University Medical Center GroningenRecruiting
  • Zuyderland Medical Center
  • Hospital Universitari de Bellvitge

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Intervention group

Control group

Arm 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.

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Time to get out-of-range fecal calprotectin results
The time from study baseline until the first out-of-range fecal calprotectin result
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
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
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
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.

Full Information

First Posted
November 20, 2020
Last Updated
May 17, 2022
Sponsor
University Medical Center Groningen
Collaborators
European Crohn´s and Colitis Organisation, Bühlmann Laboratories AG
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1. Study Identification

Unique Protocol Identification Number
NCT04646187
Brief Title
De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
Acronym
FREE
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

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 11, 2021 (Actual)
Primary Completion Date
June 2023 (Anticipated)
Study Completion Date
June 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Medical Center Groningen
Collaborators
European Crohn´s and Colitis Organisation, Bühlmann Laboratories AG

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative
Keywords
Infliximab, Adalimumab, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
148 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Intervention group
Arm Type
Experimental
Arm 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.
Arm Title
Control group
Arm Type
No Intervention
Arm Description
Unchanged dosing interval. Consists of two groups: Patients randomised to the control group and patients allocated to the control group based on preference.
Intervention Type
Biological
Intervention Name(s)
Infliximab
Other Intervention Name(s)
Remicade, Flixabi, Inflectra, Remsima, Zessly
Intervention Description
Dosing interval lengthening from 8 to 12 weeks
Intervention Type
Biological
Intervention Name(s)
Adalimumab
Other Intervention Name(s)
Humira, AMGEVITA, Hulio, Hyrimoz, Idacio, Imraldi
Intervention Description
Dosing interval lengthening from 2 to 3 weeks
Primary Outcome Measure Information:
Title
cumulative incidence of out-of-range fecal calprotectin results at 48 weeks follow-up
Description
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.
Time Frame
48 weeks
Secondary Outcome Measure Information:
Title
Time to get out-of-range fecal calprotectin results
Description
The time from study baseline until the first out-of-range fecal calprotectin result
Time Frame
up to 48 weeks
Title
Cumulative incidence of anti-TNF-associated respiratory infections and dermatological adverse effects at 48 weeks follow-up
Description
Dermatological adverse effect include skin infections, new-onset or worsening of psoriasis, psoriasiform lesions, eczema, acne and alopecia
Time Frame
48 weeks
Title
Evolution of FC and anti-TNF trough levels in the first 16 weeks after reverting to previous dosing interval
Description
Proportion of patients with return of FC levels to target range without switch to out-of-class biological
Time Frame
Up to 48+16 weeks
Title
Proportion of patients developing loss-of-response in the first 16 weeks after reverting to the previous dosing interval
Description
Loss-of-response is defined as the appearance of symptoms of active IBD in combination with persistent out-of-range fecal calprotectin results
Time Frame
Up to 48+16 weeks
Title
Identification of predictors of successful de-escalation.
Description
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.
Time Frame
48 weeks
Other Pre-specified Outcome Measures:
Title
Patients' attitudes towards deprescribing anti-TNF agents
Description
We will use the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire
Time Frame
48 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Patrick F van Rheenen, MD PhD
Phone
050 3614151
Ext
+31
Email
p.f.van.rheenen@umcg.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Marleen Bouhuys, MD MsC
Email
m.bouhuys@umcg.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick F van Rheenen, MD PhD
Organizational Affiliation
University Medical Center Groningen
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitair Ziekenhuis Gent
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Triana Lobatón Ortega, Prof MD PhD
First Name & Middle Initial & Last Name & Degree
Triana Lobatón Ortega, Prof MD PhD
First Name & Middle Initial & Last Name & Degree
Stephanie van Biervliet, Prof MD PhD
Facility Name
Centre hospitalier universitaire de Liège
City
Liège
ZIP/Postal Code
B-4000
Country
Belgium
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edouard Louis, Prof MD PhD
Facility Name
Rijnstate Hospital
City
Arnhem
ZIP/Postal Code
6816 AD
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Margreet Wessels, MD PhD
First Name & Middle Initial & Last Name & Degree
Margreet Wessels, Md PhD
Facility Name
Catharina Hospital Eindhoven
City
Eindhoven
ZIP/Postal Code
5623 EJ
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Janneke Stapelbroek, MD PhD
First Name & Middle Initial & Last Name & Degree
Janneke Stapelbroek, MD PhD
First Name & Middle Initial & Last Name & Degree
Lennard Gilissen, MD PhD
Facility Name
University Medical Center Groningen
City
Groningen
ZIP/Postal Code
9700 RB
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Patrick F van Rheenen, MD PhD
Phone
050 3614151
Ext
+31
Email
p.f.van.rheenen@umcg.nl
First Name & Middle Initial & Last Name & Degree
Marleen Bouhuys, MD MsC
Email
m.bouhuys@umcg.nl
First Name & Middle Initial & Last Name & Degree
Patrick F van Rheenen, Md PhD
First Name & Middle Initial & Last Name & Degree
Gerard Dijkstra, Prof MD PhD
Facility Name
Zuyderland Medical Center
City
Heerlen
ZIP/Postal Code
6419 PC
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
P Rosias, MD PhD
First Name & Middle Initial & Last Name & Degree
P Rosisas, MD PhD
Facility Name
Hospital Universitari de Bellvitge
City
L'Hospitalet De Llobregat
ZIP/Postal Code
08907
Country
Spain
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jordi Guardiola, MD PhD
First Name & Middle Initial & Last Name & Degree
Jordi Guardiola, MD PhD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34732500
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.
Results Reference
derived

Learn more about this trial

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

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