S845 Risankizumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Efficacy and Safety in the Randomized Phase 3 INSPIRE Study
Bibliographic record
Abstract
Introduction: Risankizumab (RZB), a monoclonal antibody neutralizing interleukin (IL)-23p19, was evaluated for efficacy and safety of induction therapy in patients with moderately to severely active ulcerative colitis (UC) in a large phase 3 trial, INSPIRE (NCT03398148). Methods: Eligible patients (18-80 years) with moderately to severely active UC (Adapted Mayo score of 5–9 points) and an endoscopic subscore of 2-3 (per central review) were enrolled. Patients were required to have a diagnosis of UC for at least 3 months prior to baseline, and demonstrated intolerance or inadequate response to conventional and/or advanced therapies (biologics, JAK inhibitors, and S1P receptor modulators). Patients (N=975) were randomized 2:1 to receive either RZB 1200 mg intravenously (IV) or placebo (PBO) at Weeks (Wks) 0, 4, and 8. The primary endpoint was clinical remission (per Adapted Mayo score) at Wk 12 (see Figure 1 legend for definitions). Key, ranked secondary endpoints included clinical response, endoscopic improvement, endoscopic remission, histologic-endoscopic mucosal improvement (HEMI), and histologic-endoscopic mucosal remission (HEMR), which were measured at Wk 12, unless otherwise noted. Results: Baseline characteristics were similar between treatment groups. Significantly more patients receiving RZB achieved clinical remission vs PBO (20.3% vs 6.2%, adjusted treatment difference 14.0% [95% CI, 10.0%-18.0%], P< .00001, Figure 1A). All ranked secondary endpoints were met. RZB attained higher rates of clinical response (per Adapted Mayo score at Wk 12 and per Partial Adapted Mayo score at Wk 4), endoscopic improvement, endoscopic remission, HEMI, and HEMR, compared to PBO (P< .00001 for all endpoints, Figure 1B). Adverse event (AE) rates were 42.1% in RZB vs 49.7% PBO, serious AEs (2.3% vs 10.2%), severe AEs (2.5% vs 10.2%), AEs leading to discontinuation of study drug (0.6% vs 3.7%), and serious infections (0.6% vs 1.2%) were numerically lower in the RZB arm. No adjudicated major adverse cardiovascular events, adjudicated anaphylaxis, or serious hepatic events were reported. One death occurred in the RZB group due to COVID-19 pneumonia. Conclusion: In patients with moderately to severely active UC, RZB was superior to PBO as an induction therapy for clinical remission and all secondary clinical, endoscopic, and endoscopic-histologic endpoints. RZB was well-tolerated, and no new safety risks were observed.Figure 1.: Primary and Key Secondary Endpoints All patients in this dataset were included here within the ITT population. Endpoints were assessed at Week 12 unless otherwise noted. Clinical Remission per Adapted Mayo score: Stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 without friability Clinical Response per Adapted Mayo: Decrease from baseline ≥ 2 points and ≥ 30%, in addition to a decrease in RBS ≥ 1 or an absolute rectal bleeding score (RBS) ≤ 1 Clinical Response per Partial Adapted Mayo: Decrease from baseline ≥ 1 point and ≥ 30% a decrease in RBS ≥ 1 or an absolute RBS ≤ 1 Endoscopic Improvement: Endoscopic subscore of 0 or 1 without friability Endoscopic Remission: Endoscopic subscore = 0 Histologic-Endoscopic Mucosal Improvement (HEMI): Endoscopic subscore of 0 or 1 without friability and Geboes score ≤ 3.1 Histologic-Endoscopic Mucosal Remission (HEMR): Endoscopic subscore of 0 and Geboes score < 2.0 Results were stratified by baseline corticosteroid use (yes vs no), baseline Adapted Mayo score (≤ 7 vs > 7), and the number of advanced therapy failures (0, 1, >1). Results are based on non-responder imputation incorporating multiple imputation (NRI-MI) to handle missing data due to COVID-19 or due to geopolitical conflict in Ukraine or surrounding areas. ***P-value <.00001 vs PBO. P-value for treatment difference between RZB 1200 mg IV and PBO, using Cochran-MantelHaenszel (CMH) test for categorical endpoints, controlling for stratification factors. IR, inadequate response.
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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 | 0.004 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| 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) | 0.004 | 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".