Introduction

Guselkumab (GUS), a dual-acting interleukin-23p19 subunit inhibitor, demonstrated efficacy in participants (pts) with ulcerative colitis (UC) treated with intravenous (IV) or subcutaneous (SC) induction. Here, we report the efficacy and safety of SC induction followed by SC maintenance through Week (W) 48 in ASTRO, a phase 3, randomized, double-blind, placebo (PBO)-controlled, treat-through study in pts with moderately to severely active UC.

Aims & Methods

Eligible pts had modified Mayo scores of 5 to 9, rectal bleeding subscore of ≥1, and Mayo endoscopic subscore (MES) ≥2. Pts also had documented inadequate response/intolerance to biologics, Janus kinase (JAK) inhibitors, and/or sphingosine-1-phosphate (S1P) inhibitors (BIO/JAKi/S1Pi-IR) or to corticosteroids, 6-mercaptopurine, or azathioprine. Randomization was stratified by baseline BIO/JAKi/S1Pi-IR status and MES with 418 pts allocated 1:1:1 to GUS 400 mg SC every 4 weeks (q4w) (×3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (×3)→GUS 100 mg SC every 8 weeks (q8w) (N=139), or PBO SC (N=139). PBO pts who met rescue criteria were switched to GUS at W16; GUS pts who met rescue criteria stayed on their assigned GUS dose regimen (sham rescue).

Results

At W48, greater proportions of pts in the GUS groups achieved clinical remission compared with PBO (36.7% for GUS 100 mg q8w [Δ 29.5%], 42.9% for GUS 200 mg q4w [Δ 35.6%], 7.2% for PBO) (Table). Endoscopic remission proportions were 25.9% for GUS 100 mg q8w (Δ 20.9%), 26.4% for GUS 200 mg q4w (Δ 21.4%), and 5.0% for PBO. Clinical response, symptomatic remission, endoscopic improvement, histologic improvement, and histologic remission proportions were also greater for GUS vs PBO. Consistent with the results of the overall population, efficacy was also observed for subpopulations of BIO/JAKi/S1Pi-naïve and BIO/JAKi/S1Pi-IR pts. Safety events per 100 pts-years were not greater in the GUS groups compared with the PBO group: adverse events (AE) (GUS 100 mg q8w and 200 mg q4w vs PBO: 308.3 and 310.7 vs 357.1), serious AEs (6.5 and 8.2 vs 38.4), serious infections (0.8 and 2.5 vs 3.7), and AEs leading to treatment discontinuation (4.9 and 4.1 vs 19.8).
Table. Efficacy endpoints at Week 48 in the overall population and by biologic, JAK inhibitor, and/or S1P inhibitor history

Conclusion

GUS SC induction followed by SC maintenance was efficacious through 1 year in pts with moderately to severely active UC, and the safety profile is consistent with GUS in its approved indications including UC.

Disclosure

ML reports research support from Lilly, Pfizer, and Takeda; consulting for AbbVie, Bristol Myers Squibb, Intercept, Janssen (Johnson & Johnson), Lilly, Pfizer, Prometheus, Roivant, Takeda, and Target RWE.
JRA reports grant support from Janssen, Merck, and Pfizer; consultancy fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck, Pfizer, Roivant, Celltrion, TrexBio, Shattuck Labs and Seres Therapeutics; payments for speaking from AbbVie, Bristol Myers Squibb, and Janssen; and is a steering committee member and investigator for Janssen.
SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
MG, TB, YA, KH, SJ, LJ, and HZ are employees of and may own stock in Johnson & Johnson.
TH reports research grants from AbbVie GK, Boston Scientific Corporation, EA Pharma Co. Ltd., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co. Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Lilly, Mitsubishi Tanabe Pharma Corporation, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co. Ltd.
DTR reports consulting and/or speaker fees and/or advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and membership on the Board of Directors of Cornerstones Health, Inc. and on the Crohn’s & Colitis Foundation’s Board of Trustees.
LPB reports grants or contracts from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; consulting and/or payment or honoraria and/or data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance/travel support from AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots.

Introduction

Colonoscopy as gold standard for colorectal cancer screening remains subject to subjective interpretation. Computer-aided detection (CADe) improves colorectal polyp detection and needs to be clinically tested as an objective measure.

Aims & Methods

This trial aimed to validate a novel CADe system for colorectal polyp detection versus trained endoscopists in an innovative endoscopist blinded set-up with real-time unblinding by a second observer. This study design allows to assess the performances of both CADe and endoscopists.
The CAD-ARTIPOD trial is an investigator-initiated prospective multicenter trial conducted in 9 European centers. The CADe system is unique in design combining a convolutional neural network with a recurrent neural network for detection of colorectal polyps trained in all imaging modalities. Sample size analysis for superiority in polyp detection required 2048 polyps assuming a difference in sensitivity of 2% with endoscopic diagnosis as gold standard. All participating endoscopists (adenoma detection rate (ADR) 20-50%) were blinded to the CADe output. A trained second observer assessed and classified in real time the CADe output in
(1) true positive, either detected or not detected by the endoscopist,
(2) False negative or
(3) clinically relevant or irrelevant false positive detection.
The endoscopist was the gold standard for the primary endpoint (endoscopic lesion detection) and if a CADe detected polyp was not picked-up by the endoscopist, the endoscopist was unblinded for confirmation of the finding. All polyps detected and confirmed endoscopically were resected. Histological assessment was performed by two independent histopathologists.

Results

A total number of 2141 polyps were collected in 946 patients of which 1958 (91.5%) polyps were resected and 1608 (82.1%) were histologically confirmed, with 475 hyperplastic polyps , 989 adenomas, and 119 sessile serrated lesions, 15 inflammatory pseudopolyps and 10 carcinomas.
For the primary endpoint superiority was not reached between CADe and endoscopists with a sensitivity of 0.946 and 0.961, respectively (non-inferiority margin of 5%, p = 0.0216). The CADe system detected 3.9% extra polyps, missed by the endoscopist. False positive rate was 1.8/min clean withdrawal time and 36.3% of those were deemed clinically relevant.
With histology as gold standard, CADe outperformed the endoscopists with a sensitivity of 0.9602 versus 0.9496 (p=0.03) and showed an extra detection rate of 5.0%. Remarkably, baseline polyp detection rate (PDR) increased from 0.47 to 0.70 during the trial (D0.48, OR 2.76 (95% CI: 2.26 – 3.37)). Similarly, ADR increased from 0.38 at baseline to 0.45 (D0.21, OR 1.52 (95% CI: 1.26 ; 1.85)).

Conclusion

This multiplatform CADe system, used in an innovative and competitive study design, demonstrated non-inferiority in comparison to endoscopists’ polyp detection. However, with histology as gold standard, CADe outperformed endoscopists. Our study also shows that “watching over a shoulder” in itself leads to higher PDR and ADR.

Introduction

Infectious complications of acute pancreatitis include bacteremia and infected (peri-) pancreatic necrosis (IPN). These are thought to originate from the gastro-intestinal tract due to inflammation and increased intestinal permeability. Gram-negative rod-shaped bacteria (GNRB) and Enterococcus species are most frequently cultured in IPN, and recent evidence shows that the latter is associated with increased mortality.¹ We hypothesized that these infections are preceded by an increase of abundance of pathogenic bacteria in the gastrointestinal microbiota.

Aims & Methods

Our aim was to early identify patients at risk for IPN through microbiota surveillance of the upper and lower gastrointestinal tract during the first 30 days of a first episode of acute pancreatitis. We prospectively included patients from 20 hospitals collaborating in the Dutch Pancreatitis Study Group. Saliva and rectal swabs were collected twice weekly until IPN or discharge, and the microbiota profiled using 16S rDNA sequencing. For the current study, as predefined, we first analyzed the subgroup of patients who developed (peri-) pancreatic necrosis. Further analyses including the entire cohort and focuses on other clinical endpoints will follow. Community State Type (CST) analysis was used for microbiota clustering without the input of clinical outcomes. Univariate time-to-event (survival) analyses with serial, time-dependent predictors were used for the prediction of IPN.

Results

Overall, 319 patients were included of whom 57 (17.8%) developed necrotizing pancreatitis and formed the study population of the current analysis. In this group the rate of IPN was 36.8% (21/57). CSTs associated with IPN showed at Genus-level increased abundance of Enterococcus (rectal) and Staphylococcus (saliva), but not GNRB. Clinical factors such as age, gender, biliary etiology and bacteremia, as well as alpha diversity (Inverse Simpsons Index) were not associated with IPN (see table). Enterococcus colonization in rectal swabs and Staphylococcus in saliva at optimal cut-offs were predictive for IPN (respectively, HR 4.23, 95% CI 1.61–11.10, p=0.004; HR 10.80, 95% CI 2.13-55.09, p=0.004), which occurred for the first time at median 10 (range 4 – 17) days after hospital admission and median 23 days (range 2 - 96) before IPN. Antibiotic use (>24 hours within the week before sample collection) was not associated with Enterococcus or Staphylococcus colonization. Two of five patients with Enterococcus colonization had Enterococcus species in the first pancreatic culture, as compared to one in seven patients without colonization. Initial colonization of these taxa in samples taken at the time of hospital admission did not differ, highlighting the importance of longitudinal sampling in these patients.

Conclusion

Colonization of the gut microbiota early in the course of necrotizing pancreatitis with Enterococcus or Staphylococcus was a predictive factor for IPN. The time interval between colonization and IPN appeared long enough to allow for prophylaxis. Future clinical trials should focus on prophylactic, targeted antibiotics guided by microbiota surveillance.

References

1. Timmerhuis HC, van den Berg FF, Noorda PC, et al. Over- and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: An Observational Multicenter Study. Ann Surg 2023; Publish Ahead of Print:10.1097/SLA.0000000000005790.

Disclosure

Timmerhuis HC, van den Berg FF, Noorda PC, et al. Over- and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: An Observational Multicenter Study. Ann Surg 2023; Publish Ahead of Print:10.1097/SLA.0000000000005790.