Addition of baseline histology and fecal calprotectin does not reduce placebo rates in ulcerative colitis clinical trials: post-hoc analysis of patient-level data.

BACKGROUND

Placebo response rates in ulcerative colitis (UC) trials are highly variable. It is uncertain whether adding objective measures of inflammation, such as fecal calprotectin (FC) or histologic activity, to conventional eligibility criteria could reduce placebo response and strengthen treatment effect estimates. This study evaluated whether applying baseline FC or histology thresholds would alter outcomes in UC clinical trials.

METHODS

We conducted a post-hoc pooled analysis of individual patient-level data from five phase 3, randomized, placebo-controlled trials including 1918 patients on active therapy and 1149 on placebo. Baseline FC thresholds (>150, >200, >250, >500 µg/g) and Geboes histological thresholds (≥3.1, ≥3.2) were applied as hypothetical inclusion criteria. Outcomes assessed were post-induction clinical remission (CR: modified Mayo score with stool frequency ≤1 and ≥1-point decrease, rectal bleeding = 0, and endoscopic subscore ≤1) and endoscopic improvement (EI: endoscopic subscore ≤1).

RESULTS

Applying FC or Geboes thresholds did not meaningfully reduce placebo response rates or increase treatment-placebo differences for CR or EI. For example, for vedolizumab, the CR difference vs placebo was 11% (95% CI: 3.5-18.5) in the unrestricted population and 10.4%-13% with thresholds applied, with up to 91 (33.6%) of participants excluded. For upadacitinib, EI differences were 36.2% (95% CI: 28.5-43.8) unrestricted and 35.9%-37.3% with restrictions, with up to 248 (38.7%) of participants excluded. Results were consistent across therapies and in subgroup analyses.

CONCLUSION

Restricting trial enrollment based on elevated FC or histological activity did not meaningfully lower placebo response rates in phase 3 UC trials.