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Clinical Trials

1 Pharmacogenomic Strategies in Inflammatory Bowel Disease: Evaluating the Role of Pre-emptive HLADQA1 Genotyping for the Application of Targeted Infliximab-based Combination Therapy (INHERIT)

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.

NCT04109300 Inflammatory Bowel Diseases Ulcerative Colitis Crohn Disease Genetic: HLADQA1*05A>G screening Other: Standard of Care

MeSH:Crohn Disease Colitis, Ulcerative Intestinal Diseases Inflammatory Bowel Diseases

HPO:Abnormal intestine morphology Crohn's disease Inflammation of the large intestine Ulcerative colitis

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.

Recently, in an peer-reviewed dataset, a group demonstrated that variation in the class 2 human leukocyte antigen (HLA) gene region (HLADQA1*05A>G, rs2097432) is linked to an increased risk of ADA formation against infliximab and to a lesser extent, its sister TNF-antagonist, adalimumab18.

In a separate, retrospective study, we have confirmed that variation in HLADQA1*05A>G (rs2097432) is independently-associated with a significantly higher incidence of and faster progression to infliximab ADA formation.

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