Biomarkers of Anti-TNF Treatment in Inflammatory Bowel Disease (IBD)

Study Overview
=================
Brief 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. 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.

Official Title
-----------------
Biomarkers Predicting the Effect of Anti-TNF Treatment in Pediatric and Adult Inflammatory Bowel Disease

Conditions
-----------------
Inflammatory Bowel Diseases

Intervention / Treatment
-----------------
* Biological: Infliximab
* Biological: Adalimumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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). Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pediatric IBD patients<br>Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab | Biological: Infliximab<br>* Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6.<br>* Other names: Remicade;Biological: Adalimumab<br>* 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<br>* Other names: Humira;|
| Adult IBD patients<br>Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab | Biological: Infliximab<br>* Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6.<br>* Other names: Remicade;Biological: Adalimumab<br>* 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<br>* Other names: Humira;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 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. | Duration of study (start anti-TNF until 1 year after start of anti-TNF) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Inflammatory bowel disease, Pediatric, Adult, Biomarker, Anti-TNF response, Infliximab, Adalimumab