Ignite Creation Date:
2024-05-06 @ 1:43 PM
Last Modification Date:
2024-10-26 @ 1:19 PM
Study NCT ID:
NCT04109300
Status:
UNKNOWN
Last Update Posted:
2019-09-30
First Post:
2019-09-27
Brief Title:
Preemptive HLA Genotyping for the Safe Use of Infliximab-combination Therapy in Inflammatory Bowel Disease
Sponsor:
Western University Canada
Organization:
Western University Canada
Study Overview
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
Status:
UNKNOWN
Status Verified Date:
2019-09
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
INHERIT
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 HLADQA105AG 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 HLADQA105 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
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 HLADQA105AG 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 HLADQA105 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
Detailed Description:
Inflammatory bowel disease IBD affects over 250000 individuals in Canada It is comprised of ulcerative colitis UC and Crohns disease CD The dysregulated inflammatory response targeting the gastrointestinal GI tract is the hallmark of IBD and can lead to significant physical and psychological morbidity amongst affected individuals Hallmarks of the disease include hematochezia diarrhea and abdominal pain Individuals with IBD are committed to long-term immunosuppressive therapy to drive disease into remission however such treatments are associated with significant cost as well as a risk for significant drug-related toxicities Individuals who are resistant or lose response to traditional therapies may require hospitalization and intestinal resection or colectomy This is also associated with significant costs to the health care system and to patients
The last decade has seen an expansion in the number of therapies specifically monoclonal antibodies biologics available for the treatment of IBD targeting and inhibiting different proteins involved in perpetuating the inappropriate inflammatory response There is growing evidence to support the use of biologics early in the disease course bypassing other less effective and older treatments In Canada there are currently five biologic agents approved for the management of IBD infliximab adalimumab golimumab vedolizumab and ustekinumab Infliximab the first biologic approved for the management of IBD in Canada and the most widely used is a chimeric human-murine monoclonal antibody directed against the pro-inflammatory cytokine tumour necrosis factor-α TNF The efficacy of infliximab in CD and UC has been demonstrated in landmark trials ACCENT and ACT respectively It is considered a standard of care for moderate to severe IBD in treatment algorithms
Unfortunately up to 40 of patients who initially respond to a TNF antagonist such as infliximab will lose response by the one-year mark Additionally up to 23 of individuals with IBD exposed to infliximab will have an immediate infusion reaction with flushing urticaria presyncope and dyspnea necessitating treatment cessation A leading contributor to both loss of response and infusion reactions is the development of anti-drug antibodies ADAs
ADAs are a consequence of the immunogenicity of TNF antagonists Immunogenicity refers to the immune response of the exposed individual against large molecule therapeutic proteins such as infliximab The underlying mechanisms of immunogenicity in TNF antagonist-exposed IBD patients are poorly defined Clinically ADAs are very relevant to IBD treatment as some ADAs can inhibit drug function or induce hypersensitivity in exposed patients Studies have shown that the presence of ADAs correlates with a loss of response to infliximab as well as with a high risk of infusion reaction
Therapeutic drug monitoring the ability to measure ADAs in addition to serum drug concentrations has revolutionized IBD treatment algorithms by providing objective evidence to inform clinical decision-making Unfortunately the current tools are only able to identify ADAs once they have developed and thus treatment adjustments are reactive as opposed to preemptive Patients are often only screened for ADAs once loss of response or a hypersensitivity reaction have occured One way clinicians attempt to reduce the risk of ADA formation is to empirically combine a second immune-suppressing agent such as methotrexate or azathioprine immunomodulators with infliximab The addition of an immunomodulator to infliximab-based therapy combination therapy is associated with reduced ADA formation The downside is that combination therapy may be associated with an increased risk of infection malignancy and other side effects related to the immunomodulator pancreatitis myelotoxicity hepatotoxicity There is also concern over the use of dual immunosuppression in certain patient populations including frail elderly or patients at high risk of infection or malignancy
Currently there are no clinical tools that predict who will develop ADAs lose response to or have a hypersensitivity reaction to infliximab Additionally there are few ways to predict the risk of adverse events in IBD patients treated with combination therapy Recently in an peer-reviewed dataset a group demonstrated that variation in the class 2 human leukocyte antigen HLA gene region HLADQA105AG 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 HLADQA105AG rs2097432 is independently-associated with a significantly higher incidence of and faster progression to infliximab ADA formation Moreover we demonstrated that variant carriers had a higher risk of infliximab loss of response treatment discontinuation as well as a faster progression to these outcomes Wilson etal 2019 unpublishedGastro submitted Interestingly the addition of co-immunosuppression methotrexate or azathioprine to infliximab therapy reduced the risk of antibody formation in variant carriers compared to that of an individual with a wild type genotype
Having the capacity to identify individuals at high risk of ADA formation and apply targeted combination therapy to those individuals and avoid combination therapy in others would be exceedingly valuable in clinical practice Thus we propose to assess the utility of preemptively screening patients with IBD who are being considered for infliximab therapy for HLADQA105AG and applying co-immunosuppression with an immunomodulator methotrexate or azathioprine to the variant carriers AG or GG compared to those received the current standard of care We will assess the resultant impact on infliximab ADA formation in addition to highly relevant clinical outcomes such as infliximab loss of response treatment discontinuation and adverse drug events
The last decade has seen an expansion in the number of therapies specifically monoclonal antibodies biologics available for the treatment of IBD targeting and inhibiting different proteins involved in perpetuating the inappropriate inflammatory response There is growing evidence to support the use of biologics early in the disease course bypassing other less effective and older treatments In Canada there are currently five biologic agents approved for the management of IBD infliximab adalimumab golimumab vedolizumab and ustekinumab Infliximab the first biologic approved for the management of IBD in Canada and the most widely used is a chimeric human-murine monoclonal antibody directed against the pro-inflammatory cytokine tumour necrosis factor-α TNF The efficacy of infliximab in CD and UC has been demonstrated in landmark trials ACCENT and ACT respectively It is considered a standard of care for moderate to severe IBD in treatment algorithms
Unfortunately up to 40 of patients who initially respond to a TNF antagonist such as infliximab will lose response by the one-year mark Additionally up to 23 of individuals with IBD exposed to infliximab will have an immediate infusion reaction with flushing urticaria presyncope and dyspnea necessitating treatment cessation A leading contributor to both loss of response and infusion reactions is the development of anti-drug antibodies ADAs
ADAs are a consequence of the immunogenicity of TNF antagonists Immunogenicity refers to the immune response of the exposed individual against large molecule therapeutic proteins such as infliximab The underlying mechanisms of immunogenicity in TNF antagonist-exposed IBD patients are poorly defined Clinically ADAs are very relevant to IBD treatment as some ADAs can inhibit drug function or induce hypersensitivity in exposed patients Studies have shown that the presence of ADAs correlates with a loss of response to infliximab as well as with a high risk of infusion reaction
Therapeutic drug monitoring the ability to measure ADAs in addition to serum drug concentrations has revolutionized IBD treatment algorithms by providing objective evidence to inform clinical decision-making Unfortunately the current tools are only able to identify ADAs once they have developed and thus treatment adjustments are reactive as opposed to preemptive Patients are often only screened for ADAs once loss of response or a hypersensitivity reaction have occured One way clinicians attempt to reduce the risk of ADA formation is to empirically combine a second immune-suppressing agent such as methotrexate or azathioprine immunomodulators with infliximab The addition of an immunomodulator to infliximab-based therapy combination therapy is associated with reduced ADA formation The downside is that combination therapy may be associated with an increased risk of infection malignancy and other side effects related to the immunomodulator pancreatitis myelotoxicity hepatotoxicity There is also concern over the use of dual immunosuppression in certain patient populations including frail elderly or patients at high risk of infection or malignancy
Currently there are no clinical tools that predict who will develop ADAs lose response to or have a hypersensitivity reaction to infliximab Additionally there are few ways to predict the risk of adverse events in IBD patients treated with combination therapy Recently in an peer-reviewed dataset a group demonstrated that variation in the class 2 human leukocyte antigen HLA gene region HLADQA105AG 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 HLADQA105AG rs2097432 is independently-associated with a significantly higher incidence of and faster progression to infliximab ADA formation Moreover we demonstrated that variant carriers had a higher risk of infliximab loss of response treatment discontinuation as well as a faster progression to these outcomes Wilson etal 2019 unpublishedGastro submitted Interestingly the addition of co-immunosuppression methotrexate or azathioprine to infliximab therapy reduced the risk of antibody formation in variant carriers compared to that of an individual with a wild type genotype
Having the capacity to identify individuals at high risk of ADA formation and apply targeted combination therapy to those individuals and avoid combination therapy in others would be exceedingly valuable in clinical practice Thus we propose to assess the utility of preemptively screening patients with IBD who are being considered for infliximab therapy for HLADQA105AG and applying co-immunosuppression with an immunomodulator methotrexate or azathioprine to the variant carriers AG or GG compared to those received the current standard of care We will assess the resultant impact on infliximab ADA formation in addition to highly relevant clinical outcomes such as infliximab loss of response treatment discontinuation and adverse drug events
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None