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

NCT04109300 | Unknown

• 1 other identifier: HLAADA1
• Study Type: interventional
• Target: 162
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

Pharmacogenomics; Combination therapy; Infliximab

Outcome Measures

Primary Outcomes (1)

• incidence of infliximab anti-drug antibodies

  Evaluate the impact of pharmacogenomic screening and the administration of targeted-combination infliximab therapy to high risk (variant-carrying) individuals compared to an unscreened IBD population receiving standard of care (where combination therapy is administered at the discretion of the physician) on the incidence of infliximab ADA formation. Infliximab ADA formation is defined as any detectable amount of ADA in the absence of detectable serum infliximab (measured by enzyme-linked immunosorbent assay, ELISA).

  1 year

Secondary Outcomes (8)

• incidence of infliximab loss of response

  1 year

• incidence of infliximab discontinuation

  1 year

• incidence of infliximab-related adverse drug events

  1 year

• incidence of immunomodulator-related adverse drug events

  1 year

• incidence of combination therapy (infliximab and one of methotrexate or azathioprine) -related adverse drug events

  1 year

Study Arms (2)

preemptive screening

EXPERIMENTAL

prospective HLADQA1\*05A\>G screening and targeted administration of combination therapy of infliximab with one of either methotrexate or azathioprine.

Genetic: HLADQA1*05A>G screening

standard of care

ACTIVE COMPARATOR

administration of combination therapy with infliximab and one of methotrexate or azathioprine is at the discretion of the treating physician. HLADQA1\*05A\>G genotyping will be performed retrospectively.

Other: Standard of Care

Interventions

HLADQA1*05A>G screening GENETIC

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.

preemptive screening

Standard of Care OTHER

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

standard of care

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults (\>17 years of age) with a histopathologic diagnosis of CD or UC being initiated on therapy with infliximab by their treating gastroenterologist
• Individuals with prior biologic exposure to a non-TNF-based therapy are eligible
• Individuals on prednisone are eligible

You may not qualify if:

• Absence of histopathologic diagnosis of CD or UC
• Prior exposure to a TNF-based therapy (infliximab, golimumab, adalimumab)
• Pregnancy
• Known contraindication to both azathioprine and methotrexate
• Non-english speaking
• Being ineligible for infliximab based on insurance plan

Sponsors & Collaborators

• Western University, Canada: lead

Study Sites (1)

Western University

London, Ontario, N6A 3K7, Canada

Location

MeSH Terms

Conditions

Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Colitis; Colonic Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Aze A Wilson, MD, PhD

  Western University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Aze A Wilson, MD, PhD

CONTACT

15196633832; azesuzanne.wilson@lhsc.on.ca

Reena Khanna, MD

CONTACT

519-685-8500; reena.khanna@lhsc.on.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: This will be a single-blinded study. The treating gastroenterologist will be unblinded to the participant's allocation, while the assessor seeing the patient at the initial visit (PM Clinic) and at the subsequent follow up visits (week 14, week 26, week 52) will be blinded to the intervention (preemptive screening versus standard do care).
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomized 1:1 to prospective HLADQA1\*05A\>G screening and targeted administration of combination therapy or standard of care (administration of combination therapy is at the discretion of the treating physician) and followed up to one year or until infliximab discontinuation. HLADQA1\*05A\>G genotyping will be performed in the standard of care group; however, investigators will remain blinded to this outcome until study completion.

Study Record Dates

• First Submitted: September 27, 2019
• First Posted: September 30, 2019
• Study Start: September 1, 2020
• Primary Completion: September 1, 2023
• Study Completion: September 1, 2023
• Last Updated: September 30, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)