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

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).

Study Overview

• Status: Unknown
• Conditions: Crohn's Disease; Inflammatory Bowel Disease
• Intervention / Treatment: Drug: Infliximab; Drug: thiopurine

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). .

• Study Type: Observational
• Enrollment (Anticipated): 225

Contacts and Locations

• Study Contact: Name: Melissa Diamond, BSc.,JD/MSEL; Phone Number: 44385 5149341934; Email: melissa.diamond@mail.mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • Recruiting
      • Montreal General Hospital
      • Contact: Melissa Diamond, BSc. JD/MSEL; Phone Number: 44385 5149341934; Email: melissa.diamond@mail.mcgill.ca
      • Principal Investigator: Ernest Seidman, MDCM

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

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.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CD Monotherapy; Crohn's disease treated with infliximab (monotherapy)	Drug: 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.; Other Names: Remicade
CD Combo therapy; Crohn's disease treated with infliximab in combination with thiopurine (a 6MP metabolite) (combo therapy)	Drug: 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.; Other Names: Remicade; 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.; Other Names: Imuran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of 6-TGN serum levels with IFX serum trough levels	Evaluate the correlation of 6-TGN serum levels with IFX serum trough levels , prevalence of ATI and clinical response treatment in CD patients treated with a combination of IFX and a thiopurine.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of 6-TGN serum levels and IFX trough levels	Evaluate the correlation of 6-TGN serum levels at the initial visit (week 14 or visit 1) with IFX serum trough levels, prevalence of ATI and clinical response at week 52.	52 weeks
6 TGN levels and dose escalation or disconinuation of IFX	Determine the correlation of 6-TGN levels with need for dose escalation and discontinuation of IFX for the duration of the study.	52 plus 6 months for data calculation
Vitamin D levels and efficacy of anti-TNF therapy	Evaluate the correlation of vitamin D levels (sufficient, insufficient, deficient) on the efficacy of anti-TNF therapy in patients with Crohn's disease.	duration of study and 1 additional year for data analysis
Vitamin D status and effect on ATI levels	Determine the correlation between vitamin D status with trough IFX levels and the prevalence of ATI.	duration of study and 1 additional year for data analysis

Collaborators and Investigators

• Sponsor: Ernest Seidman
• Collaborators: University of Alberta; University of Toronto; University of Calgary
• Investigators: Principal Investigator: Ernest Seidman, MDCM, McGill University Health Centre/Research Institute of the McGill University Health Centre

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 17, 2014
• Primary Completion (ANTICIPATED): June 30, 2019
• Study Completion (ANTICIPATED): June 30, 2020

Study Registration Dates

• First Submitted: May 21, 2015
• First Submitted That Met QC Criteria: May 22, 2015
• First Posted (ESTIMATE): May 25, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 16, 2017
• Last Update Submitted That Met QC Criteria: February 14, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Antirheumatic Agents; Gastrointestinal Agents; Dermatologic Agents; Infliximab
• Other Study ID Numbers: 14-158-GEN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO