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

NCT ID: NCT01971970

Last Updated: 2022-01-27

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 45 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2017-01-30

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.

Conditions

Inflammatory Bowel Diseases

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Pediatric IBD patients

Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab

Infliximab

Intervention Type: BIOLOGICAL

Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6.

Adalimumab

Intervention Type: BIOLOGICAL

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

Adult IBD patients

Anti-TNF naive patients with either Crohn's disease or ulcerative colitis will be treated with either Infliximab or Adalimumab

Infliximab

Intervention Type: BIOLOGICAL

Remission induction in anti-TNF naïve patients will be achieved by administration of 5 mg/kg IFX infusions at week 0, 2 and 6.

Adalimumab

Intervention Type: BIOLOGICAL

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

Interventions

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.

Intervention Type: 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

Intervention Type: BIOLOGICAL

Other Intervention Names

Remicade; Humira

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.

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Erasmus Medical Center

OTHER

Sponsor Role: lead

Responsible Party

J.C. Escher, M.D., Ph.D

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

J C Escher, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center - Sophia Children's Hospital

C J van der Woude, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Locations

Erasmus Medical Center

Rotterdam, , Netherlands

Countries

Netherlands

Other Identifiers

NL-42736.078.13

Identifier Type: -

Identifier Source: org_study_id