Just as new therapeutics have been developed throughout the past 2 decades for treatment of inflammatory bowel disease (IBD), new endpoints for clinical trials and goals for IBD management have evolved as well, said Séverine Vermeire, MD, PhD, at Crohn’s & Colitis Congress 2022.

“We’ve seen quite an impressive progression of drugs and of clinical trial endpoints, from clinical response to sustained steroid-free remission, and from endoscopic improvement to histo-endoscopic healing,” she stated. “Now on the horizon are disease clearance and molecular healing as potential endpoints for clinical trials.”

Dr Vermeire is a professor of medicine and head of the Department of Chronic Diseases & Metabolism (CHROMETA) at the Katholieke Universiteit Leuven in Leuven, Belgium.

Looking back at 2000-2001, Dr Vermeire noted that gastroenterologists studying Crohn disease were just beginning to use anti-tumor necrosis factor (TNF) inhibitors and typically evaluating patients at week 4, using the Crohn Disease Activity Index (CDAI).

“We very soon confronted the limitations of disease activity scores such as CDAI and the Mayo score,” she noted. “Some of the measures used were highly subjective.” For example, Dr Vermeire explained, the Mayo score used to include a “physician’s global assessment.”

But as new therapeutics began clinical trials, the endpoints had to change to enable more precise and less subjective measures of response and remission.

The physician’s assessment of the Mayo score was dropped, she said, and patients began to be assessed at week 8 to week 12 for clinical response and/or remission. “We started to include patient-reported outcomes and health-related quality of life measures, which reflected real-world impacts of therapies—a very good evolution.”

Gastroenterologists also began to focus not just on remission, but on corticosteroid-free remission, as well, Dr Vermeire noted, especially in ulcerative colitis. “It used to be if a patient at week 52 was in remission and not using steroids, that was considered steroid-free remission. However, if the patient had to use steroids several times over the year, is that truly a steroid-free mission? Now we look at sustained steroid-free remission, measured at 6 months or more.”

She added, “We’re all more or less harmonized now on this issue. We want to see sustained remission without corticosteroids and quality of life improvements.”

Dr Vermeire further explained, “We knew pretty early that infliximab and other anti-TNFs were capable of generating more than clinical response.” This led to the increasing use of endoscopy to provide an objective assessment of disease and in turn drove the evolution of endoscopic improvement as a clinical endpoint. “Endoscopic endpoints are now mandatory,” she said. “This is a very important evolution.

Baseline endoscopy is also mandatory today, Dr Vermeire noted. “In the SONIC trial, some patients included had no lesions at all, and that resulted in the endpoints being flat. That would be impossible today. Now we must scope and look for lesions and inflammation before determining if a patient is eligible for a trial.” She also cautioned that “you should have someone looking over your shoulder” to ensure that patient selection for a trial is based on objective criteria and not influenced by the provider’s desire to help the patient get into a trial.

Criteria for scores have become more stringent. “We now want a Mayo score of 0, because we know that 30% of patients can still have some inflammation at 0, and at a Mayo 1, up to 40% may have active disease.”

Endpoints have now evolved to include not only endoscopic healing but also histologic healing as a secondary endpoint, she continued. However, Dr Vermeire said, there remain some open questions, including whether histologic healing is truly superior to endoscopic remission, how to define endoscopic and histologic healing precisely in both Crohn disease and ulcerative colitis, and whether such a level of healing is equally important for both induction and maintenance.

“How deep goes deep remission go?” she asked. “Is it true that the deeper you go the better the outcomes?” That remains an unknown. However, Dr Vermeire concluded, “Biomarker-enriched patient enrollment and central endoscopic reading are critical for successful trial conduct and outcome assessment.”

—Rebecca Mashaw

Reference:
Vermeire, S. The evolution of clinical trial endpoints in IBD. Presented at: Crohn’s & Colitis Congress 2022. January 21, 2022. Virtual.