Impact of concomitant baseline medication, advanced age and racial differences on efficacy of biologics and small molecules for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a condition that causes chronic inflammation to the gastrointestinal (GI) tract. The two types of IBD include ulcerative colitis (UC) and Crohn’s Disease (CD). In UC, inflammation occurs in the colon and rectum, mainly affecting the inner lining of the colon. For CD, inflammation occurs in any part of the GI tract from mouth to anus, affecting multiple layers of the small intestinal and colon. IBD is a common disease, with 6.8 million people around the world who suffer from it (Global Burden of Disease Inflammatory Bowel Disease Collaborators, 2020). There is currently no cure for IBD, however there are several types of medications that can be used to treat the disease including aminosalicylates, corticosteroids, immunomodulators, antibiotics, biologic therapies and small molecule drugs.

Given that patients with IBD may be on a variety of different medications to help manage their condition, it is important to understand whether the medications a patient is currently taking at the start of a trial modifies the efficacy of the new drug being studied (Feuerstein et al., 2020; Bressler et al., 2015). For example, we would be interested in whether the new drug is more or less effective for patients on steroids at the start of a study, compared to patients not on steroids. This is important to establish as the results could influence how we interpret the results of clinical trials and how clinicians use treatments in routine practice, such as prescribing the drug to most effective groups of patients. The results will also guide the design of future clinical trials. Published clinical trials usually do not present effect modification of new drug by baseline medications. Such results can only be obtained through access to patient level data from clinical trials.

In this study, we want to specifically look at whether the use of concomitant steroids, aminosalicylates (5ASA), immunosuppressants (azathioprine, methotrexate), protein pump inhibitors (PPI), histamine receptor agonists (H2RA), antibiotics, cholesterol lowering drugs, anti-hypertensive agents, drugs for management of diabetes, antidepressants, or opioid use at baseline in patients with IBD, impacts the efficacy of the investigational drug (Lu et al., 2021; Macer et al., 2017; Niccum et al., 2021).

In addition to baseline medications, we plan to assess impact of racial differences in the efficacy of drugs. Historically, IBD has been predominantly studied in White population than patients from other racial backgrounds. There is limited evidence on the impact of race/ethnicity on differences in clinical response, especially amongst Asians and Hispanics, which are reflecting an increase in disease incidence. The treatment response and utilization of advanced biological agents vary amongst different racio-ethnic backgrounds. This difference has been implicated to arise from socioeconomic factors and access to specialist gastroenterologists. While non-modifiable factors like genetic and demographic variables cannot be changed, the effect of modifiable factors such as healthcare access and environmental factors can be abridged. Previous studies have shown response rates by Infliximab, a biological agent, differ between black and white patients despite adjusting for income, demographic and disease characteristics. This suggests that factors other than socioeconomic differences also impact treatment results across different races/ethnicities. It is crucial to investigate other factors influencing this disparity in treatment response and hospitalization rate after balancing the access to specialist healthcare resources, socioeconomic and financial factors through clinical trials. The different advanced biological agents have distinct mechanism of action than the previously cited biologic agent, Infliximab, which may also influence difference in treatment response. The proposed study will assess the impact of racial-ethnic differences on treatment efficacy and safety in IBD across diverse medication options. This will provide an opportunity to better understand the differential outcomes across races and select appropriate treatment tailored to the individual.

By identifying the impact of racio-ethnic differences and the medications used at baseline, it may help improve the design of future studies as well as help guide treatment decisions for patients with IBD.

We will further assess the analysis in age groups (< 60 years and ≥ 60 years age) to study the impact of advanced age. The highly efficacious agents also pose a risk of serious adverse events which can have poorer outcomes in elderly because of multiple co-morbidities and a weakened immune system. The data for less than 60 years age is often limited in a single trial and combination of multiple trials will facilitate enough sample size for this population in a trial setting.