S1330 Effects of Mirikizumab and Ustekinumab 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: Responsiveness of histologic inflammation and of combined endoscopic-histologic endpoints to treatment are evolving measures of disease activity in Crohn’s Disease (CD). Mirikizumab (MIRI) increased histologic response (H-Res) and remission (H-Rem) relative to placebo in the Phase 2 SERENITY trial. Methods: This study evaluated the impact of MIRI and ustekinumab (USTE) on H-Res and H-Rem and combined endoscopic-histologic response (EH-Res) and remission (EH-Rem) in all patients (pts), pts with prior biologic failure (BF), pts without prior BF in moderately to severely active CD, in the randomized, double-blind, double-dummy, treat-through 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 pts at screening, and weeks (W)12, and 52. Criteria for H-Res: absence of epithelial neutrophils and epithelial damage, erosions and ulceration or ≥50% decrease in either the active Robarts Histopathology Index or the active 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. Endoscopic response: ≥50% improvement from baseline in Simple Endoscopic Score for CD (SES-CD). Endoscopic remission: SES-CD total score ≤4 and ≥2-point reduction from baseline and no subscore >1 in any individual variable. Results: At W52, nominally significant differences between MIRI and USTE were observed in achieving H-Res in all pts (P =.007) and in BF pts (P =.006). For EH-Res, differences of MIRI vs USTE were numerically greater but not statistically significant in all pts (P =.063) but were nominally significant among BF pts (P =.023). While numerical differences between MIRI and USTE were observed in H-Rem and EH-Rem in all pts (H-Rem: P =.685; EH-Rem: P =.363) and in BF pts (H-Rem: P =.365; EH-Rem: P =.237), no significant differences were observed in these endpoints (Table 1). Conclusion: Using strict definitions, all histology-based endpoints were achieved by MIRI vs PBO. For comparison vs USTE, MIRI also showed nominal statistical difference for H-Res, which was prespecified and is considered the most sensitive to change, particularly driven by BF pts. The implication of these results on clinical endpoints and long-term outcomes, including hospitalization rates and surgeries, requires further evaluation. Table 1. - Impact of Mirikizumab and Ustekinumab on Histologic Response, Histologic Remission and Combined Endoscopic-Histologic Response and Remission MIRI USTE P Difference (95%CI) Histologic Response (%) All patients 58.2 48.8 0.007 9.6 (2.6, 16.6) Without prior biologic failure 61.9 56.9 0.383 5.0 (-5.3, 15.3) With prior biologic failure 56.5 41.3 0.006 15.2 (4.7, 25.7) Endoscopic-Histologic Response (%) All active patients 41.1 34.4 0.063 6.8 (-0.3, 14.0) Without prior biologic failure 42.5 40.8 0.829 1.7 (-8.6, 12.0) With prior biologic failure 39.6 27.8 0.023 11.8 (2.0, 21.7) Histologic Remission (%) All active patients 30.2 28.9 0.685 1.3 (-5.0, 7.7) Without prior biologic failure 33.3 34.6 0.822 -1.3 (-11.2, 8.6) With prior biologic failure 24.3 19.8 0.365 4.5 (-4.3, 13.2) Endoscopic-Histologic Remission (%, 95% CI) All active patients 17.2 14.8 0.363 2.6 (-2.8, 7.9) Without prior biologic failure 20.9 20.8 >0.999 0.1 (-8.4, 8.6) With prior biologic failure 13.3 8.7 0.237 4.6 (-1.9, 11.1) All active patients are patients with active histologic disease at baseline. Histologic response and histologic remission in all patients were prespecified, non-multiplicity-controlled endpoints. All analyses in patients without prior biologic failure, patients with biologic failure and combined endoscopic-histologic response and remission were analyzed post hoc. For achieving histologic response, the sum of 5 segments active RHI or active GHAS needed to be reduced by ≥50% from baseline.CI=confidence interval; GHAS=Global Histologic Disease Activity Score; MIRI=mirikizumab; RHI=Robarts Histopathology Index; USTE=ustekinumab.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".