The Impact of 6MP Metabolite Levels on Infliximab Pharmacokinetics and Anti-infliximab Antibodies in Crohn's Disease

NCT ID: NCT02453607

Last Updated: 2017-02-16

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 225 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2014-11-17
• Study Completion Date: 2020-06-30

Brief Summary

In this research proposal, the investigators will focus on methods to optimize the therapeutic response to anti-TNF antibodies, by determining a correlation of 6-mp metabolite levels with IFX trough levels, anti-IFX antibody levels and clinical response. The study will also evaluate (in vitro) the possible impact of vitamin D on the interaction of IFX with dendritic cells in both healthy subjects and patients with Crohn's disease (proliferation, maturation, cytokine profile, apoptosis, gene expression).

Detailed Description

Despite the evidence for the beneficial effects of thiopurine/IFX combined therapy on both the prevention of the development of anti-IFX antibodies (ATI) and improved clinical outcomes, no study has employed the proven clinical usefulness of measuring 6- MP metabolite levels. We hypothesize that targeting the established threshold of 6-TGN levels (between 235-400), shown to result in superior clinical efficacy, would reduce the development of ATI and enhance trough IFX levels. It is also conceivable that excessive6TGN levels may increase the risk of adverse events such as infections and neoplasms such as lymphomas, the major drawbacks to combination therapy. If a significant correlation between 6-TGN levels and diminished risk of ATI development or higher trough serum IFX levels can be demonstrated, it will allow for an improved approach towards pharmacological monitoring of these patients with optimization of the long term response of CD patients on anti-TNF therapy.

Vitamin D possesses profound immunomodulatory effects, mediated primarily through the innate immune system. Low serum levels of vitamin D are associated with worse outcomes in CD. IFX was reported to have a significant impact on maturation and phenotype of dendritic cells (DC). Previous work from our laboratory demonstrated a significant effect of vitamin D on expression of NOD2 along with a profound effect onthe cytokine profile of DC exposed to PRR stimulation85. We hypothesize that vitamin Ddeficiency may be associated with a lower clinical response to anti-TNF therapy. IFX and vitamin D may have a synergistic effect in modulating the immune system in IBD via interactions through innate or adaptive mechanisms. We expect that vitamin D may enhance IFX-induced shift in the maturation pathway and cytokine profile of DC exposed to intestinal microbes through pattern recognition receptors (PRR). Demonstration of a synergistic effect of vitamin D with anti-TNF antibodies may have important clinical implications for the care of IBD patients, particularly in Canada where the prevalence of vitamin D deficiency is very high. Such an effect was demonstrated for lymphocytes but was never examined for the innate immune system, considered to have a profound role in the pathogenesis of CD. The data from this study may provide further justification for the need of monitoring vitamin D status in CD patients, and its supplementation as an additional therapeutic tool for optimizing response to anti-TNF in CD.

This is a prospective cross-sectional and longitudinal multicentre non-interventional study. The patients will be recruited at the following centers: McGill University Health Center, Mount Sinai Medical Centre, Toronto, Canada; University of Calgary, U Alberta, Edmonton. This study will recruit patients (18-70 yrs) with Crohn's disease who are starting treatment with infliximab or combo therapy of infliximab and azathiopurine. This study will look at therapeutic monitoring end points to evaluate the impact of drug level and antibodies on the clinical effectiveness of treatment (mono or combo therapy). .

Conditions

Inflammatory Bowel Disease; Crohn's Disease

Study Design

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

Study Groups

CD Monotherapy

Crohn's disease treated with infliximab (monotherapy)

Infliximab

Intervention Type: DRUG

Drug is prescribed by treating physician and is not a part of the study. This study is non-interventional. Patients, to be elgibile, are being prescribed either monotherapy inlfiximab or combo therapy infliximab with azathiopurine.

CD Combo therapy

Crohn's disease treated with infliximab in combination with thiopurine (a 6MP metabolite) (combo therapy)

Infliximab

Intervention Type: DRUG

Drug is prescribed by treating physician and is not a part of the study. This study is non-interventional. Patients, to be elgibile, are being prescribed either monotherapy inlfiximab or combo therapy infliximab with azathiopurine.

thiopurine

Intervention Type: DRUG

Drug is prescribed by treating physician and is not a part of the study. This study is non-interventional. Patients, to be elgibile, are being prescribed either monotherapy inlfiximab or combo therapy infliximab with azathiopurine.

Interventions

Infliximab

Drug is prescribed by treating physician and is not a part of the study. This study is non-interventional. Patients, to be elgibile, are being prescribed either monotherapy inlfiximab or combo therapy infliximab with azathiopurine.

Intervention Type: DRUG

thiopurine

Drug is prescribed by treating physician and is not a part of the study. This study is non-interventional. Patients, to be elgibile, are being prescribed either monotherapy inlfiximab or combo therapy infliximab with azathiopurine.

Intervention Type: DRUG

Other Intervention Names

Remicade; Imuran

Eligibility Criteria

Inclusion Criteria

• Patients with a diagnosis of CD ,
• age 18-70 years,
• who are treated with IFX (standard 5 mg/kg/q8 weeks maintenance dose) or IFX (standard maintenance dose)/thiopurine (stable dose for at least 3 months) combination for <12 months.-

Exclusion Criteria

• Age< 18 years;
• Patients treated with IFX at non-standard doses;
• diagnosis of ulcerative colitis, pouchitis, indeterminate colitis or Crohn's disease involving the upper GI tract or perianal disease without involvement of small bowel or colon;
• concomitant therapy with cyclosporine, methotrexate or other immunosuppressant other than thiopurine and IFX, treatment with IFX or IFX/thiopurine combination for > 12 months;
• pregnancy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Toronto

OTHER

Sponsor Role: collaborator

University of Calgary

OTHER

Sponsor Role: collaborator

University of Alberta

OTHER

Sponsor Role: collaborator

Ernest Seidman

OTHER

Sponsor Role: lead

Responsible Party

Ernest Seidman

Professor of Medicine & Pediatrics

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Ernest Seidman, MDCM

Role: PRINCIPAL_INVESTIGATOR

McGill University Health Centre/Research Institute of the McGill University Health Centre

Locations

Montreal General Hospital

Montreal, Quebec, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Melissa Diamond, BSc.,JD/MSEL

Role: CONTACT

melissa.diamond@mail.mcgill.ca

5149341934 ext. 44385

Facility Contacts

Melissa Diamond, BSc. JD/MSEL

Role: primary

melissa.diamond@mail.mcgill.ca

5149341934 ext. 44385

Other Identifiers

14-158-GEN

Identifier Type: -

Identifier Source: org_study_id