Impact of Baseline Fecal Calprotectin and Histologic Activity Thresholds on Clinical and Endoscopic Outcomes in Ulcerative Colitis Trials: A Post-Hoc Analysis

Ulcerative colitis (UC) is a long-term disease that causes swelling and sores in the large intestine, leading to symptoms like stomach pain, diarrhea, and bleeding. It affects over 900,000 people in the United States and millions more worldwide. Although many new treatments are being developed, it can be difficult to tell how well they work in clinical trials. This is partly because some patients improve even when they receive a placebo (a treatment with no active medicine), which can make it hard to see the real benefit of the new drug.

One idea to improve trial results is to include only patients who have high levels of gut inflammation at the beginning of the study. Inflammation can be measured through a stool test called fecal calprotectin (FC) or by looking at tissue samples under a microscope. In clinical trials, these tissue samples are scored using a scoring system called the Geboes histologic score, although this may not be readily available. FC measures proteins that indicate inflammation in stool, while the Geboes score shows how much inflammation is present in tissue from the gut.

In this project, we will study data from five large, previously completed clinical trials for moderate-to-severe UC. These trials—called GEMINI 1, LUCENT-1/2, PURSUIT, U-ACCOMPLISH, and UNIFI—included patients who were randomly assigned to receive either a new medicine or a placebo. We will focus on the “induction phase,” which is the early part of treatment when the initial effects of the therapy are measured.

Our goal is to find out if setting a minimum level of FC or Geboes score at the start of a trial would reduce placebo responses and make it easier to detect whether the treatment works. We will compare how patients with different levels of inflammation responded to treatment and placebo, both overall and within subgroups. These subgroups include people who have never used biologic medications (treatments made from living organisms or cells that target the immune system to reduce inflammation) and those who are taking corticosteroids (medications that quickly reduce swelling and immune activity).

This research is important because it could help improve the way future clinical trials are designed. If using inflammation thresholds does not make trial results more accurate, researchers may need to consider other strategies. Our findings will help ensure that new treatments for UC are tested more effectively, which can ultimately benefit patients by speeding up access to better therapies. Specifically, if future trial eligibility criteria is restricted to patients with high level of gut inflammation at the beginning of the study, then this work may indicate greater robustness to a placebo effect. However, this may reduce the generalisability outside of the trial to patients with UC that have lower levels of gut inflammation.