Inflammatory Bowel DiseasesPhase 4FREENCT04646187
De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
A Phase 4 study testing Infliximab and Adalimumab in people with Inflammatory Bowel Diseases and Crohn Disease, run by University Medical Center Groningen at 7 sites in 3 countries.
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. Read more about this study
- Who is it for?
- Ages 12 to 25 years
- Conditions the study is for
- Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative
- What is being tested?
- Infliximab and Adalimumab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 148 participants
- Where
- 7 sitesin 3 countries
- Study dates
- 11 Mar 2021to Mar 2026
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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 locations and contacts
7 sites in 3 countries. Contact the study team or a site near you to ask about taking part.
7 sites in 3 countries
Belgium3 sites
Universitair Ziekenhuis Gent
Ghent, 9000
Centre hospitalier universitaire de Liège
Liège, B-4000
Centre hospitalier régional de la Citadelle
Liège
Netherlands3 sites
Rijnstate Hospital
Arnhem, 6816 AD
Catharina Hospital Eindhoven
Eindhoven, 5623 EJ
University Medical Center Groningen
Groningen, 9700 RB
About this study
Official title: 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.
Read more
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.
Read the 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.
- Being tested
- Infliximab, Adalimumab
- Keywords
- Infliximab, Adalimumab, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative
- Medical subject headings
- Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InfliximabBiological
Also called Remicade, Flixabi, Inflectra, Remsima
Dosing interval lengthening from 8 to 12 weeks
AdalimumabBiological
Also called Humira, AMGEVITA, Hulio, Hyrimoz
Dosing interval lengthening from 2 to 3 weeks
| Study group | Role | What they receive |
|---|---|---|
| Intervention group | Experimental | 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. Receives: Biological: Infliximab; Biological: Adalimumab |
| Control group | No intervention | 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 being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 48 weeks
Secondary outcomes (5)
Time to get out-of-range fecal calprotectin results
The time from study baseline until the first out-of-range fecal calprotectin result
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Nov 2020
- Study start11 Mar 2021
- Primary completionMar 2026 (estimated)
- Study completionMar 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Inflammatory Bowel DiseasesStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 148 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- European Crohn´s and Colitis Organisation, Bühlmann Laboratories AG
- Responsible party
- Principal investigator, P.F. van Rheenen, University Medical Center Groningen
- Investigators
- Patrick F van Rheenen, MD PhD, Principal investigator, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04646187
- Sponsor's protocol ID
- 202000261
- Other IDs
- 2020-001811-26
- Acronym
- FREE
- Status last verified
- Jan 2025
- First submitted
- 20 Nov 2020
- Last updated
- 6 Jan 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Bouhuys M, Wessels MMS, de Vries W, Lambeck AJA, Touw DJ, van Rheenen PF. Lateral flow test versus enzyme-linked immunosorbent assay to measure infliximab trough concentrations: A head-to-head comparison. J Pediatr Gastroenterol Nutr. 2024 Dec;79(6):1134-1141. doi: 10.1002/jpn3.12372. Epub 2024 Oct 10.
PubMed 39390697Bouhuys 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.
PubMed 34732500
Study at a glance
From the registry record, last updated by the sponsor on 6 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- De-escalation of Anti-TNF Therapy in Adolescents and Young Adults With IBD With Tight Faecal Calprotectin and Trough Level Monitoring
- ClinicalTrials.gov ID
- NCT04646187
- Acronym / sponsor ID
- FREE / 202000261
- Keywords
- Infliximab, Adalimumab, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Crohn Disease, Colitis, Ulcerative
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Enrolling by invitation
- Enrolment
- 148 participants (estimated)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- European Crohn´s and Colitis Organisation, Bühlmann Laboratories AG
- Study start
- 11 Mar 2021 (actual)
- Primary completion
- Mar 2026 (estimated)
- Study completion
- Mar 2026 (estimated)
- First posted
- 27 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Intervention group | Experimental | Biological: Infliximab, Biological: AdalimumabIn 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. |
| Control group | No intervention | –Unchanged dosing interval. Consists of two groups: Patients randomised to the control group and patients allocated to the control group based on preference. |
Who may qualify
- Ages
- 12 to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| InfliximabAlso: Remicade, Flixabi, Inflectra, RemsimaDosing interval lengthening from 8 to 12 weeks | Biological | Intervention group |
| AdalimumabAlso: Humira, AMGEVITA, Hulio, HyrimozDosing interval lengthening from 2 to 3 weeks | Biological | Intervention group |
Primary outcome
cumulative incidence of out-of-range fecal calprotectin results at 48 weeks follow-up
Time frame: 48 weeks
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.
5 secondary outcomes
Time to get out-of-range fecal calprotectin results
Time frame: up to 48 weeks
Cumulative incidence of anti-TNF-associated respiratory infections and dermatological adverse effects at 48 weeks follow-up
Time frame: 48 weeks
Evolution of FC and anti-TNF trough levels in the first 16 weeks after reverting to previous dosing interval
Time frame: Up to 48+16 weeks
Proportion of patients developing loss-of-response in the first 16 weeks after reverting to the previous dosing interval
Time frame: Up to 48+16 weeks
Identification of predictors of successful de-escalation.
Time frame: 48 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jan 2025.
- Derived from this study: PubMed 39390697Bouhuys M, Wessels MMS, de Vries W, Lambeck AJA, Touw DJ, van Rheenen PF. Lateral flow test versus enzyme-linked immunosorbent assay to measure infliximab trough concentrations: A head-to-head comparison. J Pediatr Gastroenterol Nutr. 2024 Dec;79(6):1134-1141. doi: 10.1002/jpn3.12372. Epub 2024 Oct 10.
- Derived from this study: PubMed 34732500Bouhuys 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Patrick F van Rheenen, MD PhD principal investigator
University Medical Center Groningen
7 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Infliximab and Adalimumab in people with Inflammatory Bowel Diseases and Crohn Disease, run by University Medical Center Groningen at 7 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: enrolling by invitation, as of the sponsor's last update on 6 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Belgium, Netherlands, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
cumulative incidence of out-of-range fecal calprotectin results at 48 weeks follow-up (time frame: 48 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04646187, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jan 2025.