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

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ClinicalTrials.gov Identifier: NCT04109300
Recruitment Status : Not yet recruiting
First Posted : September 30, 2019
Last Update Posted : September 30, 2019
Sponsor:
Information provided by (Responsible Party):
Western University, Canada

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.


Condition or disease Intervention/treatment Phase
Inflammatory Bowel Diseases Ulcerative Colitis Crohn Disease Genetic: HLADQA1*05A>G screening Other: Standard of Care Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 162 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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.
Masking: Double (Participant, Outcomes Assessor)
Masking Description: 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).
Primary Purpose: Other
Official Title: Pharmacogenomic Strategies in Inflammatory Bowel Disease: Evaluating the Role of Pre-emptive HLADQA1 Genotyping for the Application of Targeted Infliximab-based Combination Therapy (INHERIT)
Estimated Study Start Date : September 1, 2020
Estimated Primary Completion Date : September 1, 2023
Estimated Study Completion Date : September 1, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Infliximab

Arm Intervention/treatment
Experimental: preemptive screening
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
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.

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




Primary Outcome Measures :
  1. incidence of infliximab anti-drug antibodies [ Time Frame: 1 year ]
    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).


Secondary Outcome Measures :
  1. incidence of infliximab loss of response [ Time Frame: 1 year ]
    defined as a relapse in clinical symptoms after week 14 of infliximab dosing, with an increase in the Harvey Bradshaw index (HBI) ≥ 3 points or the partial Mayo score ≥ 3 points, following a response to infliximab induction therapy where a 3-point reduction was seen in the HBI or partial Mayo score

  2. incidence of infliximab discontinuation [ Time Frame: 1 year ]
    when stopped by treating physician

  3. incidence of infliximab-related adverse drug events [ Time Frame: 1 year ]
    defined as any injury presumed secondary to infliximab exposure as deemed by the treating gastroenterologist. This is including but not limited to: infection, immediate infusion reaction, delayed infusion reaction, psoriaform rash

  4. incidence of immunomodulator-related adverse drug events [ Time Frame: 1 year ]
    defined as any injury presumed secondary to azathioprine or methotrexate exposure as decided by the treating gastroenterologist. This is including, but not limited to: infection, nausea and dyspepsia, myelotoxicity, hepatoxicity, pancreatitis

  5. incidence of combination therapy (infliximab and one of methotrexate or azathioprine) -related adverse drug events [ Time Frame: 1 year ]
    defined in outcome 4 and 5

  6. time to infliximab anti-drug antibody formation [ Time Frame: 1 year ]
    measured from the time of treatment initiation to the time of antibody formation

  7. time to infliximab loss of response [ Time Frame: 1 year ]
    measured from the time of treatment initiation to the time of infliximab loss of response defined as a relapse in clinical symptoms after week 14 of infliximab dosing, with an increase in the Harvey Bradshaw index (HBI) ≥ 3 points or the partial Mayo score ≥ 3 points, following a response to infliximab induction therapy where a 3-point reduction was seen in the HBI or partial Mayo score.

  8. time to infliximab discontinuation [ Time Frame: 1 year ]
    measured from the time of treatment initiation to the time of cessation as decided by the treating physician.



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04109300


Contacts
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Contact: Aze A Wilson, MD, PhD 15196633832 azesuzanne.wilson@lhsc.on.ca
Contact: Reena Khanna, MD 519-685-8500 ext 34945 reena.khanna@lhsc.on.ca

Locations
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Canada, Ontario
Western University
London, Ontario, Canada, N6A 3K7
Contact: Aze A Wilson    5196633832    azesuzanne.wilson@lhsc.on.ca   
Principal Investigator: Aze A Wilson, MD, PhD         
Sub-Investigator: Reena Khanna, MD         
Sub-Investigator: Melanie D Wilson, MD         
Sub-Investigator: Vipul Jairath, MD, PhD         
Sub-Investigator: Richard B Kim, MD         
Sponsors and Collaborators
Western University, Canada
Investigators
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Principal Investigator: Aze A Wilson, MD, PhD Western University

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Responsible Party: Western University, Canada
ClinicalTrials.gov Identifier: NCT04109300    
Other Study ID Numbers: HLAADA1
First Posted: September 30, 2019    Key Record Dates
Last Update Posted: September 30, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Western University, Canada:
Pharmacogenomics
Combination therapy
Infliximab
Additional relevant MeSH terms:
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Crohn Disease
Colitis, Ulcerative
Intestinal Diseases
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colitis
Colonic Diseases
Methotrexate
Azathioprine
Infliximab
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Gastrointestinal Agents