S1329 Effects of Mirikizumab versus Placebo on Histologic Inflammation Evaluated by Comprehensive Assessment in 5 Intestinal Segments in a Randomized, Controlled Phase 3 Trial of Participants With Crohn’s Disease
Bibliographic record
Abstract
Introduction: Histologic inflammation persists in up to 1 quarter of patients with Crohn’s Disease (CD) despite endoscopic mucosal healing. Responsiveness of histologic inflammation to treatment is an evolving outcome measure in CD. Mirikizumab (MIRI) increased histologic response (H-Res) and remission (H-Rem) relative to placebo (PBO) in the Phase 2 SERENITY trial. Methods: We compared the effect of MIRI on H-Res and H-Rem at week (W)12 and W52 to PBO by composite endpoints of response (clinical response by Patient-Reported Outcome [PRO] at W12 and W52 H-Res) and of remission (clinical response by PRO at W12 and W52 H-Rem) at W52. The overall population of patients with moderate-to-severe active CD, patients without prior biologic failure (non-BF), and patients with prior BF were assessed, using data from the Phase 3 VIVID-1 trial. Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized patients at screening, W12, and W52. Criteria for H-Res: absence of epithelial neutrophils and epithelial damage, erosions, and ulceration or ≥50% decrease in either the sum of the 5 segments of Robarts Histopathology Index or the Global Histologic Disease Activity Score. H-Rem: complete absence of mucosal neutrophils (in epithelium and lamina propria), and no epithelial damage, erosions, and ulcers; these criteria had to be met in all biopsy specimens. Clinical response by PRO: ≥30% decrease in stool frequency and/or abdominal pain with neither score worse than baseline. H-Res, H-Rem, composite H-Res, and composite H-Rem in all patients were prespecified, non-multiplicity-controlled endpoints. Analyses in non-BF and BF patients were post hoc. Results: At W12: treatment with MIRI resulted in nominally statistically significantly higher rates of H-Res in all 3 patient groups, differences between MIRI vs PBO were nominally significant in achieving H-Rem in all patients and in non-BF and BF patients. For W52: composite H-Res differences between MIRI vs PBO were nominally statistically significant in all patient groups, composite H-Rem differences were nominally statistically significant between MIRI vs PBO in all patients, in non-BF patients, and in BF patients (Table 1). Conclusion: MIRI achieved nominally significantly higher rates of H-Res and H-Rem compared to PBO in all patients at W12 and W52. The statistical difference was more pronounced in the BF population after 1 year of treatment. Table 1. - Effect of Mirikizumab on Histologic-Response and Histologic-Remission at W12 and W52 to Placebo by Composite Endpoints of Response and of Remission at W52 All patients Without Prior Biologic failure With Prior Biologic Failure PBO (N=199) MIRI (N=579) Difference (95% CI) PBO (N=91) MIRI (N=273) Difference (95% CI) PBO (N=88) MIRI (N=255) Difference (95% CI) W12 H-Res 30.7 52.7 22.2 (14.6-29.7)*** 37.4 58.6 21.2 (9.7-32.8)*** 22.7 47.8 25.1 (14.4-35.8)*** W12 H-Rem 12.1 22.1 10.2 (4.7-15.7)** 14.3 27.5 13.2 (4.3-22.1)* 4.5 12.2 7.6 (1.7-13.5)* W52 Composite H-Res 16.1 44.4 28.2 (21.6-34.7)*** 26.4 46.5 20.1 (9.3-31.0)*** 6.8 45.9 39.1 (31.0-47.1)*** W52 Composite H-Rem 8.5 23.3 14.7 (9.5-19.9)*** 14.3 24.9 10.6 (1.8-19.5)* 2.3 21.6 19.3 (13.4-25.2)*** Data are %; *P < .05; **P < .01; ***P < .001 vs PBO“Without prior biologic failure“ and “With prior biologic failure“ were subgroups of all patients with active histologic disease at baseline. P-values for “All patients” were from the Cochran–Mantel–Haenszel test adjusting for baseline covariates. P-values for the “Without prior biologic failure“ and “With prior biologic failure“ subgroups were from the Fisher's exact test.CI=confidence interval; H=histologic; MIRI=mirikizumab; PBO=placebo; Rem=remission; Res=response; W=week.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".