ClinicalTrials.gov
ClinicalTrials.gov Menu

Biomarkers of Anti-TNF Treatment in IBD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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

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.

Condition or disease Intervention/treatment
Inflammatory Bowel Diseases Biological: Infliximab Biological: Adalimumab

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 Type : Observational
Actual Enrollment : 45 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Biomarkers Predicting the Effect of Anti-TNF Treatment in Pediatric and Adult Inflammatory Bowel Disease
Study Start Date : October 2013
Actual Primary Completion Date : October 30, 2016
Actual Study Completion Date : January 30, 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Group/Cohort Intervention/treatment
Pediatric IBD patients
Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab
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
Adult IBD patients
Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab
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



Primary Outcome Measures :
  1. 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

  2. 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


Biospecimen Retention:   Samples With DNA
whole blood, gastrointestinal tract biopsies,buccal epithelium


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   6 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
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.
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01971970


Locations
Netherlands
Erasmus Medical Center
Rotterdam, Netherlands, 3015 GJ
Sponsors and Collaborators
Erasmus Medical Center
Merck Sharp & Dohme Corp.
Investigators
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

Responsible Party: J.C. Escher, M.D., Ph.D, Associate Professor, Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT01971970     History of Changes
Other Study ID Numbers: NL-42736.078.13
First Posted: October 30, 2013    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by J.C. Escher, M.D., Ph.D, Erasmus Medical Center:
Inflammatory bowel disease
Pediatric
Adult
Biomarker
Anti-TNF response
Infliximab
Adalimumab

Additional relevant MeSH terms:
Intestinal Diseases
Inflammatory Bowel Diseases
Gastrointestinal Diseases
Digestive System Diseases
Gastroenteritis
Adalimumab
Infliximab
Anti-Inflammatory Agents
Antirheumatic Agents
Dermatologic Agents
Gastrointestinal Agents