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

Crohn's Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02453607
• Other study ID #: 14-158-GEN
• Status: Recruiting
• Phase: N/A
• First received: May 21, 2015
• Last updated: February 14, 2017
• Start date: November 17, 2014
• Est. completion date: June 30, 2020

Study information

• Verified date: February 2017
• Source: McGill University Health Center
• Contact: Melissa Diamond, BSc.,JD/MSEL
• Phone: 5149341934
• Email: melissa.diamond[@]mail.mcgill.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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).

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). .

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 225
• Est. completion date: June 30, 2020
• Est. primary completion date: June 30, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Crohn Disease
• Crohn's Disease
• Inflammatory Bowel Disease
• Inflammatory Bowel Diseases

Intervention

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.
• 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.

Locations

Country	Name	City	State
Canada	Montreal General Hospital	Montreal	Quebec

Sponsors (4)

Lead Sponsor	Collaborator
Ernest Seidman	University of Alberta, University of Calgary, University of Toronto

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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