Inflammatory Bowel DiseasesNCT01971970
Biomarkers of Anti-TNF Treatment in Inflammatory Bowel Disease (IBD)
An observational study of Inflammatory Bowel Diseases, run by Erasmus Medical Center at 1 site in Netherlands.
Trial summary
Anti-TNF treatment (infliximab (IFX), adalimumab (ADA)) has become standard therapy for refractory pediatric and adult Crohn's disease (CD) patients, and is used for the induction (primary response) and maintenance of remission. When effective, clinical and endoscopic remission is reached within weeks. Read more about this study
- Who is it for?
- Ages 6 years and older
- Conditions the study is for
- Inflammatory Bowel Diseases
- What is being tested?
- Infliximab and Adalimumab
- Type of treatment
- Injection or infusion
- How many people
- 45 participants
- Where
- 1 siteNetherlands
- Study dates
- Oct 2013to 30 Jan 2017
- Phase
- Observational
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 6 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Pediatric and adult IBD patients from the Department of Pediatric Gastroenterology of Erasmus MC-Sophia Children's Hospital and from the Department of Gastroenterology of Erasmus MC respectively.
Who may be able to join
- Anti-TNF naïve CD patients (≥ 6 years) who initiate anti-TNF treatment (IFX or ADA) because of active luminal disease, failing treatment with immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) and corticosteroids.
- Anti-TNF naïve UC patients (≥ 6 years) who initiate anti-TNF treatment (IFX or ADA) because of active disease despite corticosteroid treatment or because of failing of immunomodulator treatment.
- Anti-TNF naïve CD or UC patients (≥ 6 years) who initiate anti-TNF treatment (IFX or ADA) because of intolerance to treatment with immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) or corticosteroids.
- Informed consent by patients and parents (when required).
Who cannot join
- IBD patients who initiate IFX or ADA immediately after diagnosis.
- Presence of severe perianal disease as primary indication to start anti-TNF treatment.
- Age < 6 years when anti-TNF maintenance treatment is initiated.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Biomarkers Predicting the Effect of Anti-TNF Treatment in Pediatric and Adult Inflammatory Bowel Disease
Anti-TNF treatment (infliximab (IFX), adalimumab (ADA)) has become standard therapy for refractory pediatric and adult Crohn's disease (CD) patients, and is used for the induction (primary response) and maintenance of remission. When effective, clinical and endoscopic remission is reached within weeks. However, primary non-response is observed in 20% of pediatric patients, and in 40% of adult CD patients, suggesting a more robust acute response to anti-TNF therapy in children as compared to adults.During maintenance treatment, 60 - 80% of patients have secondary loss of response, necessitating dose adjustments to maintain clinical response. Anti-TNF treatment is also increasingly used in ulcerative colitis (UC), and has been shown to induce remission in active disease. For UC, the comparison between the efficacy in children versus adults is more difficult to report as studies in children are scarce. Anti-TNF treatment is associated with rare but potentially fatal side effects, infusion reactions, and is an expensive treatment. To avoid overtreatment it is necessary to early identify non-responders to treatment, and therefore it is important to develop predictive biomarkers of treatment response.
Read the detailed description
Crohn's disease (CD) is a lifelong disease that may present during childhood in 20 - 25% of patients. There seems to be a worldwide trend towards increasing incidence rates of CD, especially in children. Patients with CD suffer from diarrhea, abdominal pain, nausea, malaise, and chronic malnutrition, in children often accompanied by growth failure and pubertal delay. CD is characterized by a transmural, granulomatous inflammation, involving any part of the gastrointestinal tract in a discontinuous manner.
Increased concentrations of tumor necrosis factor-α (TNFα) are found in the mucosa of CD patients , suggesting that TNF-α plays a pivotal role in the cytokine cascade of the inflammatory process. This key role of TNF-α has led to the development of biologic therapy based on the administration of monoclonal antibodies which bind and inactivate TNF-α. Infliximab (IFX, Remicade®) is a chimeric monoclonal antibody (75% human, 25% murine), while adalimumab (ADA, Humira®) is a fully human monoclonal antibody. Both antibodies bind with high affinity and specificity to soluble and membrane-bound TNF-α.
Anti-TNF drugs have become an important treatment strategy for CD patients who do not respond to or are intolerant of treatment with immunosuppressants (azathioprine, methotrexate) and corticosteroids. Anti-TNF induction therapy can induce complete clinical remission within weeks, often accompanied by mucosal healing. Interestingly, response to initial anti-TNF treatment is higher in pediatric CD patients (about 80%) than in adult CD patients (about 60%). Anti-TNF drugs do not cure CD: after their impressive initial effects, repeated infusions every 8 weeks or repeated subcutaneous injections every 2 weeks are necessary, while there is great concern about the long-term risks (infections, auto-immune disease, malignancy). Anti-TNF treatment is also increasingly used in ulcerative colitis, and has been shown to induce remission in active disease. For UC, the comparison between the efficacy in children versus adults is more difficult to report as studies in children are scarce. There are likely multiple host factors that influence the inter-individual variation in initial treatment response, such as disease phenotype, immune phenotype, and genetic background.
- Conditions
- Inflammatory Bowel Diseases
- Being tested
- Infliximab, Adalimumab
- Keywords
- Inflammatory bowel disease, Pediatric, Adult, Biomarker, Anti-TNF response, Infliximab, Adalimumab
- Medical subject headings
- Inflammatory Bowel Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InfliximabBiological
Also called Remicade
Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6.
AdalimumabBiological
Also called Humira
ADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2
| Study group | Role | What they receive |
|---|---|---|
| Pediatric IBD patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Receives: Biological: Infliximab; Biological: Adalimumab | |
| Adult IBD patients | Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab Receives: Biological: Infliximab; Biological: Adalimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pre-treatment Serum Level of Endogenous Anti-TNF in Relation to Primary Clinical Response or Non-response
Pre-treatment serum level of endogenous anti-TNF are measured and analyzed in relation to primary clinical response or non-response
Measured: 8 weeks
RNA Expression Profiles in Relation to Clinical Endpoints
Changes in week 0 and week 8 RNA expression profiles were evaluated in relation to the overall population and by study arm, i.e. either pediatric IBD or adult IBD.
Measured: 8 weeks
Secondary outcomes (3)
Number of Participants With Clinical Endpoints of Interest.
Clinical endpoints of Interest were the following:
- Primary non-response was defined as no effect of anti-TNF after induction.
- Remission and response were assessed at week 8 based on the appropriate disease activity scores for either children with Crohn's disease or ulcerative colitis (PCDAI and PUCAI respectively), or adults with Crohn's disease or ulcerative colitis (CDAI or Mayo score, respectively).
- Continued use of anti-TNF was assessed 12 months and 18 months after start of anti-TNF.
Measured: Duration of study (start anti-TNF until 1 year after start of anti-TNF)
Anti-TNF Treatment Specific Outcomes
Anti-TNF treatment specific outcomes that were considered were:
- Dose intensification; increase in dose of anti-TNF compared to standard therapy
- Interval shortening; shortening of the interval of anti-TNFadministration compared to standard therapy.
- Overall treatment intensification, the number of participants who underwent either dose intensification, interval shortening or both.
- Development of Antibodies to infliximab during the course of follow-up
- An infliximab serum trough level ≤ 3 mg/ml threshold (standard accepted therapeutic lower threshold) at week 14
Measured: Duration of study (start anti-TNF until 1 year after start of anti-TNF)
Number of Participants With Concommitant Treatment
Number of participants with concommitant treatment during the study was assessed. Concomitant treatment was defined as:
- Additional use of immunomodulators such as methotrexate or azathioprine were registered.
- Need for systemic prednisone, for instance in the case of an exacerbation, was assessed.
Measured: Duration of study (start anti-TNF until 1 year after start of anti-TNF)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2013 (estimated)
- Study startOct 2013
- Primary completion30 Oct 2016
- Study completion30 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)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 Erasmus Medical CenterThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Erasmus Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Principal investigator, J.C. Escher, M.D., Ph.D, Erasmus Medical Center
- Investigators
- J C Escher, MD, PhD, Principal investigator, Erasmus Medical Center - Sophia Children's HospitalC J van der Woude, MD, PhD, Principal investigator, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01971970
- Sponsor's protocol ID
- NL-42736.078.13
- Status last verified
- Nov 2021
- First submitted
- 24 Oct 2013
- Last updated
- 27 Jan 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Winter DA, de Bruyne P, van der Woude J, Rizopoulos D, de Ridder L, Samsom J, Escher JC. Biomarkers predicting the effect of anti-TNF treatment in paediatric and adult inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2024 Jul;79(1):62-75. doi: 10.1002/jpn3.12221. Epub 2024 May 2.
PubMed 38698646
Study at a glance
From the registry record, last updated by the sponsor on 27 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Biomarkers Predicting the Effect of Anti-TNF Treatment in Pediatric and Adult Inflammatory Bowel Disease
- ClinicalTrials.gov ID
- NCT01971970
- Acronym / sponsor ID
- NL-42736.078.13
- Conditions
- Inflammatory Bowel Diseases
- Keywords
- Inflammatory bowel disease, Pediatric, Adult, Biomarker, Anti-TNF response, Infliximab, Adalimumab
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Erasmus Medical CenterUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- Oct 2013
- Primary completion
- 30 Oct 2016 (actual)
- Study completion
- 30 Jan 2017 (actual)
- First posted
- 30 Oct 2013 (estimated)
- Results
- Posted 27 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Anti-TNF treatment (infliximab (IFX), adalimumab (ADA)) has become standard therapy for refractory pediatric and adult Crohn's disease (CD) patients, and is used for the induction (primary response) and maintenance of remission. When effective, clinical and endoscopic remission is reached within weeks. However, primary non-response is observed in 20% of pediatric patients, and in 40% of adult CD patients, suggesting a more robust acute response to anti-TNF therapy in children as compared to adults.During maintenance treatment, 60 - 80% of patients have secondary loss of response, necessitating dose adjustments to maintain clinical response. Anti-TNF treatment is also increasingly used in ulcerative colitis (UC), and has been shown to induce remission in active disease. For UC, the comparison between the efficacy in children versus adults is more difficult to report as studies in children are scarce. Anti-TNF treatment is associated with rare but potentially fatal side effects, infusion reactions, and is an expensive treatment. To avoid overtreatment it is necessary to early identify non-responders to treatment, and therefore it is important to develop predictive biomarkers of treatment response.
Detailed description
Crohn's disease (CD) is a lifelong disease that may present during childhood in 20 - 25% of patients. There seems to be a worldwide trend towards increasing incidence rates of CD, especially in children. Patients with CD suffer from diarrhea, abdominal pain, nausea, malaise, and chronic malnutrition, in children often accompanied by growth failure and pubertal delay. CD is characterized by a transmural, granulomatous inflammation, involving any part of the gastrointestinal tract in a discontinuous manner.
Increased concentrations of tumor necrosis factor-α (TNFα) are found in the mucosa of CD patients , suggesting that TNF-α plays a pivotal role in the cytokine cascade of the inflammatory process. This key role of TNF-α has led to the development of biologic therapy based on the administration of monoclonal antibodies which bind and inactivate TNF-α. Infliximab (IFX, Remicade®) is a chimeric monoclonal antibody (75% human, 25% murine), while adalimumab (ADA, Humira®) is a fully human monoclonal antibody. Both antibodies bind with high affinity and specificity to soluble and membrane-bound TNF-α.
Anti-TNF drugs have become an important treatment strategy for CD patients who do not respond to or are intolerant of treatment with immunosuppressants (azathioprine, methotrexate) and corticosteroids. Anti-TNF induction therapy can induce complete clinical remission within weeks, often accompanied by mucosal healing. Interestingly, response to initial anti-TNF treatment is higher in pediatric CD patients (about 80%) than in adult CD patients (about 60%). Anti-TNF drugs do not cure CD: after their impressive initial effects, repeated infusions every 8 weeks or repeated subcutaneous injections every 2 weeks are necessary, while there is great concern about the long-term risks (infections, auto-immune disease, malignancy). Anti-TNF treatment is also increasingly used in ulcerative colitis, and has been shown to induce remission in active disease. For UC, the comparison between the efficacy in children versus adults is more difficult to report as studies in children are scarce. There are likely multiple host factors that influence the inter-individual variation in initial treatment response, such as disease phenotype, immune phenotype, and genetic background.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Pediatric IBD patients | – | Biological: Infliximab, Biological: AdalimumabAnti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab |
| Adult IBD patients | – | Biological: Infliximab, Biological: AdalimumabAnti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab |
Who may qualify
- Ages
- 6 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Pediatric and adult IBD patients from the Department of Pediatric Gastroenterology of Erasmus MC-Sophia Children's Hospital and from the Department of Gastroenterology of Erasmus MC respectively.
Key inclusion criteria (4 listed)
- Anti-TNF naïve CD patients (≥ 6 years) who initiate anti-TNF treatment (IFX or ADA) because of active luminal disease, failing treatment with immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) and corticosteroids.
- Anti-TNF naïve UC patients (≥ 6 years) who initiate anti-TNF treatment (IFX or ADA) because of active disease despite corticosteroid treatment or because of failing of immunomodulator treatment.
- Anti-TNF naïve CD or UC patients (≥ 6 years) who initiate anti-TNF treatment (IFX or ADA) because of intolerance to treatment with immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) or corticosteroids.
- Informed consent by patients and parents (when required).
Key exclusion criteria (3 listed)
- IBD patients who initiate IFX or ADA immediately after diagnosis.
- Presence of severe perianal disease as primary indication to start anti-TNF treatment.
- Age < 6 years when anti-TNF maintenance treatment is initiated.
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: RemicadeRemission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6. | Biological | Adult IBD patients, Pediatric IBD patients |
| AdalimumabAlso: HumiraADA is administered as subcutaneous injections every other week.In children (age below 18 years), remission induction in anti-TNF naïve patients will be achieved by an initial loading dose of 80 mg, followed by 40 mg 2 weeks later. In adults, remission is induced by 160 mg at week 0, followed by 80 mg at week 2 | Biological | Adult IBD patients, Pediatric IBD patients |
Primary outcome
Pre-treatment Serum Level of Endogenous Anti-TNF in Relation to Primary Clinical Response or Non-response
Time frame: 8 weeks
Pre-treatment serum level of endogenous anti-TNF are measured and analyzed in relation to primary clinical response or non-response
RNA Expression Profiles in Relation to Clinical Endpoints
Time frame: 8 weeks
Changes in week 0 and week 8 RNA expression profiles were evaluated in relation to the overall population and by study arm, i.e. either pediatric IBD or adult IBD.
3 secondary outcomes
Number of Participants With Clinical Endpoints of Interest.
Time frame: Duration of study (start anti-TNF until 1 year after start of anti-TNF)
Anti-TNF Treatment Specific Outcomes
Time frame: Duration of study (start anti-TNF until 1 year after start of anti-TNF)
Number of Participants With Concommitant Treatment
Time frame: Duration of study (start anti-TNF until 1 year after start of anti-TNF)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38698646Winter DA, de Bruyne P, van der Woude J, Rizopoulos D, de Ridder L, Samsom J, Escher JC. Biomarkers predicting the effect of anti-TNF treatment in paediatric and adult inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2024 Jul;79(1):62-75. doi: 10.1002/jpn3.12221. Epub 2024 May 2.
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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. This study is not recruiting at the moment.
J C Escher, MD, PhD principal investigator
Erasmus Medical Center - Sophia Children's Hospital
C J van der Woude, MD, PhD principal investigator
Erasmus Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Inflammatory Bowel Diseases, run by Erasmus Medical Center at 1 site in Netherlands.
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 4 inclusion and 3 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: finished, as of the sponsor's last update on 27 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. 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.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Pre-treatment Serum Level of Endogenous Anti-TNF in Relation to Primary Clinical Response or Non-response (time frame: 8 weeks). The study lists 2 primary outcomes in all. 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 NCT01971970, which also lists 1 linked publication.
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 27 Jan 2022.