Introduction

Extended mesenteric resection has recently been proposed to improve clinical outcomes after an ileocolic resection (ICR) for Crohn’s disease (CD).

Aims & Methods

The aim of this study was to analyse the clinical relevance of an extended mesenteric resection, up to the level of the ileocolic trunk (intervention group), when compared to conventional mesenteric sparing resection (control group) with respect to postoperative outcomes in patients undergoing primary ICR for CD. In a multicentre international RCT, patients ≥16 years, undergoing elective surgery, were assigned 1:1 to either the intervention- or the control-group. The anastomotic technique was standardised (side-to-side stapled). To demonstrate a relevant decrease of 25% in postoperative endoscopic recurrence ((ER), according to local scoring; modified Rutgeerts score ≥i2b) at 6 months, a minimum of 62 evaluable patients per arm were required. Secondary outcome parameters were postoperative morbidity and the need to (re-)start medication within 6 months following surgery. The last patient (n=139) was included in April 2023 and the final analyses will be available from October 2023.

Results

Currently, the primary endpoint is available in 90/139 included patients: 47 in the intervention group, and 43 in the control group. Overall, there were 41 (46%) men with a median age of 39 (IQR 25 – 55). There were no statistically significant differences in baseline characteristics between the two groups, although numerically more patients received postoperative medical prophylaxis in the intervention group (30% vs 16%, Table 1: baseline characteristics). ER was observed in 19/47 (40%) of patients in the intervention group and in 22/43 (51%) in the control group (p=0.3). In the control group, more patients (re-)started medication after endoscopy (intervention group 23% vs control group 35%). This resulted in an overall comparable number of patients in both groups being on Crohn’s medication after six months. There was no significant difference in length of resection-specimens between groups (median length coecum/colon 7 cm; ileum 24.5 cm). A trend was seen towards more active inflammation in the distal resection margin in the control group when compared to the intervention group (23% vs 7%). Overall, a postoperative complication was reported in 28 patients (31%), with 4 suffering from an anastomotic leak. There were no significant differences between the groups.

Conclusion

This is the first RCT presenting data on the effect of an extended mesenteric resection during ICR for CD. Preliminary results on the first 90 out of 139 included patients do not demonstrate the hypothesized reduction in endoscopic recurrence, which suggests that final analysis of the primary outcome in October 2023 will not be able to demonstrate superiority of this surgical technique.

Disclosure

none to declare

Introduction

Many ulcerative colitis (UC) patients (pts) are suboptimally controlled on conventional therapies but are hesitant to move to biologics, indicating an unmet need for oral advanced therapies early in the treatment paradigm. Ozanimod (OZA), an oral, selective sphingosine 1-phosphate receptor modulator, is approved for the treatment of moderately to severely active UC in adults.

Aims & Methods

This post hoc analysis of the phase 3 True North clinical trial explored the efficacy of OZA in advanced therapy–naive UC pts who had active, symptomatic disease while on conventional therapies. OZA efficacy was assessed at Week (W) 10 in pts who had either moderate (Mayo endoscopy subscore [MES]=2) or severe (MES=3) endoscopic disease activity at baseline. Pts in Cohort 1 (C1) were randomized to OZA 0.92 mg or placebo (PBO) or received open-label OZA in Cohort 2 (C2) through W10. Pts were required to be on oral 5-aminosalicylate and/or corticosteroid for ≥2 wk before screening and continue through induction. Clinical endpoints (clinical remission, clinical response, endoscopic improvement, and mucosal healing) were assessed at W10. Treatment differences for OZA (C1) vs PBO were based on the Cochran-Mantel-Haenszel test, stratified by corticosteroid use at screening. Symptomatic clinical response and symptomatic clinical remission were assessed from W2 to W10.

Results

Of 616 advanced therapy–naive pts at baseline, 296 had moderate (PBO, n=64; OZA [C1], n=138; OZA [C2], n=94) and 320 had severe (PBO, n=73; OZA [C1], n=149; OZA [C2], n=98) endoscopic disease. Baseline pt characteristics were similar between groups, with higher prior immunomodulator use in severe (22%–34%) vs moderate (13%–23%) pts. Significantly higher symptomatic responses with OZA vs PBO were observed by W4 in moderate pts (OZA [C1] vs PBO: 67.4% vs 42.2%; difference: 23.0% [95% CI 8.6–37.3]) and by W5 in severe pts (OZA [C1] vs PBO: 51.0% vs 32.9%; difference: 17.6% [95% CI 4.1–31.2]). Similarly, significantly higher symptomatic remission rates were observed with OZA vs PBO by W5 in moderate pts (OZA [C1] vs PBO: 39.9% vs 18.8%; difference: 19.5% [95% CI 6.9–32.2]) and by W8 in severe pts (OZA [C1] vs PBO: 32.2% vs 16.4%; difference: 15.4% [95% CI 4.0–26.8]). OZA was more effective than PBO in achieving all clinical endpoints at W10 in moderate and severe pts (Table). Treatment differences (OZA [C1] vs PBO) were greater in moderate vs severe pts for clinical remission (22.8% [95% CI 11.7–33.9]; P<0.001 vs 8.0% [95% CI 1.7–14.2]; P=0.04), clinical response (27.2% [13.1–41.3]; P<0.001 vs 21.0% [8.2–33.8]; P=0.003), endoscopic improvement (28.7% [15.7–41.7]; P<0.001 vs 13.4% [5.2–21.7]; P=0.008), and mucosal healing (18.0% [8.1–27.9]; P=0.003 vs 5.4% [0.5–10.2]; P=0.09).

Conclusion

Pts with inadequate disease control while on conventional therapies were better controlled with OZA treatment than those who continued conventional treatments. Pts with moderate disease achieved greater benefit and responded more rapidly than those with severe disease. OZA is an effective oral advanced therapy option for pts suboptimally controlled on conventional therapies, especially those with moderate disease.

Disclosure

This study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
PI: received lecture fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Ferring, Galapagos, Gilead, Janssen, MSD, Pfizer, Sandoz, Sapphire Medical, Shire, Takeda, Tillotts, and Warner Chilcott; received financial support for research from Celltrion, MSD, Pfizer, and Takeda; received advisory fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Hospira, Janssen, MSD, Pfizer, Pharmacosmos, Prometheus Biosciences, Roche, Samsung Bioepis, Sandoz, Takeda, TopiVert, VH2, Vifor, and Warner Chilcott.
MDL: received research funding from Pfizer and Takeda; consulted for AbbVie, Bristol Myers Squibb, Calibr, Eli Lilly, Genentech, Janssen, Pfizer, Prometheus, Roche, Salix, Takeda, Target RWE, and Theravance.
BS: consulted for AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Falk Pharma, Galapagos, Janssen, Lilly, Pfizer, Prometheus, and Takeda; received speaker fees from AbbVie, CED Service GmbH, Falk Pharma, Ferring, Janssen, Novartis, Pfizer, and Takeda.
GD: served as an advisor for AbbVie, Agomab Therapeutics, Alimentiv, Applied Molecular Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cytoki, Eli Lilly, Exeliom Biosciences, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Versant; and received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.
IB: received consulting fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Shire, and Takeda; received speaker fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Janssen, Mylan, Pfizer, Shire, and Takeda.
AJ, HW, and MTO: employees and/or shareholders of Bristol Myers Squibb.
DCW: received research funding from AbbVie, Bristol Myers Squibb, Genentech, Janssen, Pfizer/Arena, and Takeda; consulted for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, and Takeda; received speaker fees from AbbVie, Bristol Myers Squibb, Janssen, and Takeda.
DTR: received grant support from Takeda; consulted for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chronicles, ClostraBio, Connect BioPharma, EcoR1, Eli Lilly, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen, Kaleido Biosciences, Pfizer, Prometheus Biosciences, Reistone, Seres Therapeutics, Syneos, Takeda, Target RWE, and Trellus Health.

Introduction

Patients with moderately to severely active ulcerative colitis (UC) have debilitating symptoms that may incur substantial negative effects on health-related quality of life (HRQoL). According to the STRIDE-II consensus, restoration of HRQoL is a desirable long-term treatment goal for patients with active UC.¹ In this post-hoc analysis, we evaluated the extent to which patients treated with upadacitinib (UPA) achieved normalisation of HRQoL after induction and maintenance treatment.

Aims & Methods

Data from the multicentre, double-blind, Phase 3 trials, U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026), were analysed. During induction, patients were randomised 1:2 to oral placebo (PBO) or UPA 45 mg once daily (QD) for 8 weeks. Patients achieving a clinical response to UPA per Adapted Mayo score at Week 8 were re-randomised 1:1:1 to PBO, UPA 15 mg, or UPA 30 mg QD for 52 weeks of maintenance. The proportion of patients achieving normalisation of each individual HRQoL outcome, per literature-base normative value thresholds, was assessed at Weeks 8 and 52: FACIT-Fatigue score; IBDQ score; WPAI-UC (overall work impairment, work time missed, impairment while working, activity impairment); SF-36 PCS; SF-36 MCS; EQ-5D-5L VAS; and EQ-5D-5L index. A stringent composite score including these outcomes was also calculated to determine the proportion of patients who achieved normalisation of all individual HRQoL-related scores. Point estimates were calculated for all outcomes and treatment differences between UPA and PBO were compared using the Cochran-Mantel-Haenszel test.

Results

During induction, 660 patients were randomised to UPA 45 mg and 328 patients to PBO. In patients receiving UPA 45 mg vs PBO, more patients achieved normalisation of each individual HRQoL outcome at Week 8 of induction (p<0.001; Table 1). Improvements were also observed at Week 52 of maintenance in patients receiving UPA 15 mg (n=148) and 30 mg (n=154), with more patients achieving normalisation of each HRQoL outcome with both doses of UPA vs PBO (p<=0.01). More patients achieved normalisation of composite HRQoL scores at Weeks 8 (UPA 45 mg: 18.9%; PBO: 5.5%) and 52 (UPA 30 mg: 24.0%; UPA 15 mg: 22.3%; PBO: 8.7%) with all doses of UPA compared to PBO (p<=0.001).
Table 1. Proportion of patients with UC achieving normalisation of HRQoL outcomes after treatment

Conclusion

UPA is more efficacious than PBO at achieving normalisation of patients’ HRQoL, at induction and through Week 52 of maintenance. These results suggest that UPA may help patients with moderately to severely active UC achieve the long-term treatment goal of normalisation of HRQoL.

References

1. Turner D, et al. Gastroenterology. 2021;160:1570–83.

Disclosure

Joana Torres has received grant funding/speaker fees from and/or has participated in advisory boards for AbbVie, Galapagos, Janssen, and Pfizer.
Gareth Parkes received personal payments/honoraria/speaker fees and/or accepted travel grants or fellowships from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda, and Tillotts; and is a Director and Shareholder in Ampersand Health.
Corey Siegel has served as a consultant, advisor, speaker for CME activities, and/or received grant funding from AbbVie, BMS, Celltrion, Fresenius, Janssen, Lilly, Napo, Pfizer, Prometheus, Prometheus Labs, Roivant, and Takeda.
Julian Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman; and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.
Edward V. Loftus Jr: served as a consultant for AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota, Iterative Scopes, Janssen, Morphic Therapeutics, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Surrozen, Sun Pharma, Takeda, and UCB; and received research grants from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, and UCB.
Remo Panaccione served as a consultant for Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, UCB; and received speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and was an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
Yuri Sanchez Gonzalez, Si Xuan, Valencia Remple, Justin Klaff, Cecile Holweg, and Dolly Sharmaare full-time employees of AbbVie and may hold AbbVie stock and/or stock options.
Funding statement: Financial support for the study was provided by AbbVie. AbbVie participated in interpretation of data, review, and approval of the abstract. All authors contributed to development of the abstract and maintained control over final content. No honoraria or payments were made for authorship. Medical writing services provided by Kay Hallam, MSc, of Fishawack Facilitate, Ltd, part of Avalere Health and funded by AbbVie.