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Biomarkers of Anti-TNF Treatment in IBD

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ClinicalTrials.gov Identifier: NCT01971970
Recruitment Status : Completed
First Posted : October 30, 2013
Last Update Posted : February 5, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
J.C. Escher, M.D., Ph.D, Erasmus Medical Center

October 24, 2013
October 30, 2013
February 5, 2018
October 2013
October 30, 2016   (Final data collection date for primary outcome measure)
  • 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
  • Pre-treatment RNA expression profiles in relation to primary clinical response or non-response [ Time Frame: 8 weeks ]
    Pre-treatment RNA expression profiles will be evaluated in relation to primary clinical response or non-response
  • Pre-treatment serum level of endogenous anti-TNF in relation to primary clinical response or non-response [ Time Frame: 8 weeks ]
  • Pre-treatment RNA expression profiles in relation to primary clinical response or non-response [ Time Frame: 8 weeks ]
Complete list of historical versions of study NCT01971970 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
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Biomarkers of Anti-TNF Treatment in IBD
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.

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.

Observational
Observational Model: Cohort
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:
whole blood, gastrointestinal tract biopsies,buccal epithelium
Probability Sample
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.
Inflammatory Bowel Diseases
  • Biological: Infliximab
    Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6.
    Other Name: Remicade
  • Biological: Adalimumab
    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
    Other Name: Humira
  • Pediatric IBD patients
    Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab
    Interventions:
    • 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
    Interventions:
    • Biological: Infliximab
    • Biological: Adalimumab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
45
60
January 30, 2017
October 30, 2016   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
6 Years and older   (Child, Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Netherlands
 
 
NCT01971970
NL-42736.078.13
No
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Not Provided
J.C. Escher, M.D., Ph.D, Erasmus Medical Center
Erasmus Medical Center
Merck Sharp & Dohme Corp.
Principal Investigator: J C Escher, MD, PhD Erasmus Medical Center - Sophia Children's Hospital
Principal Investigator: C J van der Woude, MD, PhD Erasmus Medical Center
Erasmus Medical Center
February 2018