Preemptive HLA Genotyping for the Safe Use of Infliximab-combination Therapy in Inflammatory Bowel Disease

Summary

Inflammatory bowel disease (IBD) is a common disease in Canada, leading to significant morbidity as a result of remitting and relapsing intestinal inflammation. Currently, tumor necrosis factor (TNF) antagonists such as infliximab, make up 30% of the biologic agents available to individuals with IBD. There is a high risk of losing response or having a hypersensitivity reaction to infliximab, necessitating treatment discontinuation. This is due, in part, to the formation of anti-drug antibodies (ADAs). ADA formation can result in loss of response to therapy which may eliminate an intestine-saving therapy and increases their risk of progressing to surgical resection. There are few tools clinicians can implement to minimize the risk of ADA formation. The current approach is to add a second drug (known as combination therapy), specifically an immunomodulator (methotrexate or azathioprine), exposing the patient to additional medication-related risks, intensive monitoring with bi-weekly blood work and potential side effects including infection and malignancy.

Preliminary data from our group as well as others suggests that individuals who carry a variant in the class 2 human leukocyte antigen (HLA) gene (HLADQA1\*05A\>G, rs2097432) are more likely to form ADAs to infliximab. Pre-emptive screening for this variant may allow clinicians to more selectively use combination therapy, recommending it only in IBD patients at high risk of developing ADAs to infliximab. Additionally, this may result in fewer drug-associated adverse events.

With this project, we aim to explore the value of prospective HLADQA1\*05 screening (pharmacogenomic screening) in IBD patients being considered for treatment with infliximab and using the result to guide the application of combination therapy compared to IBD patients treated with infliximab (with or without a second agent) as per current practice. We will assess the incidence of infliximab ADA formation, as well as the incidence of infliximab loss of response, treatment discontinuation, and adverse drug events. Additionally, we will assess the time to each of these events.

Conditions

• Inflammatory Bowel Diseases
• Ulcerative Colitis
• Crohn Disease

Interventions

GENETIC

HLADQA1*05A>G screening

DNA will be extracted from whole blood collected from subjects in both arms using the MagNA Pure Compact instrument (Roche, Laval, Quebec, Canada). A custom TaqMan allelic discrimination assay (Applied Biosystems, Carlsbad, CA) will be used to determine the presence of wild-type and/or variant alleles in the class II HLA gene region at rs2097432 mapped to the HLA-DQA1\*05 region in infliximab-exposed IBD subjects. Genetic data will be used to determine whether or not one of methotrexate or azathioprine should be applied to the patient in the experimental arm.

OTHER

Standard of Care

The treating physician will use clinical judgement to determine need for the addition of one of methotrexate or azathioprine to infliximab therapy.

Sponsors & Collaborators

• Western University, Canada

  lead OTHER

Principal Investigators

• Aze A Wilson, MD, PhD · Western University

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

85 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-09-01

Primary Completion

2023-09-01

Completion

2023-09-01

Countries

• Canada

Study Locations