Introduction

Precision medicine aims to expand upon the summary average treatment effects reported in clinical trials by providing more refined, individualised estimates of treatment effects. The phase IIb TUSCANY-2 study (NCT04090411), which examined the efficacy and safety of afimkibart (RO7790121/RG6631; previously PF-06480605/RVT-3101), an anti-TL1A antibody, in patients (pts) with moderate to severe ulcerative colitis (UC), previously reported clinically meaningful treatment effects at UEGW 2024.¹ Here, we report post hoc analyses of the relationship between baseline clinical characteristics and Week 14 efficacy in pts enrolled in TUSCANY-2.

Aims & Methods

Pts were randomised to receive subcutaneous afimkibart 50mg, 150mg, 450mg or matched placebo (PBO) monthly during induction. In this post hoc analysis, all afimkibart doses were pooled, and the endpoint of interest was clinical remission by modified Mayo score (mMS; defined as stool frequency subscore=0 or 1; rectal bleeding subscore=0; and endoscopic subscore [ES]=0 or 1) at Week 14. Our investigation of more patient-specific treatment effects was guided by the Predictive Approaches to Treatment effect Heterogeneity (PATH) statement.² We developed a regularised logistic regression model to predict the probability of Week 14 remission and to help examine heterogeneity of treatment effects based on the following baseline characteristics: mMS, C-reactive protein (CRP), serum albumin, Robart’s Histopathology Index (RHI), number of failed advanced therapy classes, corticosteroid use, disease extent, disease duration, age and sex. Baseline faecal calprotectin (FCP) was investigated separately due to the extent of missing data.

Results

The proportion of pts achieving clinical remission by mMS at Week 14 in the afimkibart pooled dose arm was 32.5% (65/200; 90% confidence interval [CI]: 27.3 to 38.1) compared with 13.3% (6/45; 90% CI: 7.1 to 23.8) of pts in the PBO arm (treatment delta: 19.2%; 90% CI: 7.6 to 27.9). Based on calibrated predictions from the multivariate model, all of the individual TUSCANY-2 pts (both treated with PBO and afimkibart) had anywhere between a 2–76% probability of Week 14 remission at baseline. The clinical characteristics included in the model explained ~10% of the variability in the observed outcomes. There was no evidence that the clinical characteristics were associated with heterogeneous treatment effects on the relative scale (odds ratios appeared to be constant; p-value >0.5). On the clinically meaningful absolute scale, the treatment delta in the top 50% of pts with a higher baseline probability of remission (27–76%) was 28.5% (90% CI: 8 to 42; 45.2% in afimkibart pooled dose arm vs 16.7%, in PBO arm), compared with a treatment delta of 7.6% (90% CI: –7 to 18; 18.8% in afimkibart pooled dose arm vs 11.1%, in PBO arm) in pts with a lower baseline probability of remission (2–27%). Lower baseline CRP, lower RHI and higher serum albumin contributed to a greater probability of remission and absolute benefit from treatment with afimkibart.

Conclusion

Pts with inflammatory bowel disease (IBD) have diverse baseline characteristics that are associated with variability of treatment outcomes, yet clinicians rely on reported averages from clinical trials to make individual treatment decisions. This analysis demonstrates how precision medicine approaches, that account for diverse characteristics, may improve interpretation of positive IBD clinical trial results. Integrating genetic and novel biomarkers alongside clinical features could help to better predict individual outcomes for pts with IBD.

References

1. Danese S, et al. Presented at UEGW 2024 (Oral presentation OP079).
2. Kent D, et al. The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement. Ann Intern Med 2020;172:35–45.

Disclosure

This study was sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of the authors, was provided by Victoria Dagwell, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.
LP-B reports consulting or advisory role/board from AbbVie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Inc., Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion, Par' Immune, Pfizer, Prometheus, Protagonist, F. Hoffmann-La Roche Ltd, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx and Ysopia; speakers’ bureau from AbbVie, Alfasigma, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Inc., Gilead, Janssen, Kern Pharma, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots and Viatris. JRA reports consulting or advisory role/board from Janssen, Pfizer, AbbVie, Vedanta, Genentech, Inc., Seres Therapeutics, Ferring, GSK, Merck, Bristol Myers Squibb, Roivant, Celltrion, TRXBio and Shattuck Labs; speakers’ bureau from AbbVie and Janssen. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, F. Hoffmann-La Roche Ltd, Sandoz, Sublimity, Takeda, Teladoc Health, TiGenix, UCB, Vial and Vifor; lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer and Takeda. PSD reports employment at Northwestern University; consulting or advisory role/board from AbbVie, Adiso, Alimentiv, Celltrion, Genentech/Roche, Geneoscopy, Janssen, Shattuck and Takeda; research funding from Takeda and Bristol Myers Squibb. AB reports employment and stockholder from Pfizer. DEC reports employment and stock ownership from Pfizer. EP reports employment, stock or other ownership interests and patents, royalties, other intellectual property from Pfizer. SN reports employment and stock or other ownership interests from Pfizer. MSV reports employment and shareholder from Pfizer. KH reports no conflict of interest. LU reports employment at Genentech, Inc. CS reports employment, stock or other ownership interests from Genentech/Roche. DB reports employment at F. Hoffmann-La Roche Ltd. KL reports employment and stock or other ownership interests from Genentech, Inc. BES reports honoraria for consulting from AbbVie, Adiso, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen, AstraZeneca, Biolojic Design, Biora, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic, MRM Health, Nexus, Nimbus Discovery, Odyssey, OSE Immunotherapeutics, Palisade Bio, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist, Q32 Bio, Rasayana, Recludix, Reistone, Sanofi, Sorriso, Spyre, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union and Ventyx; consulting/speaking fees from Abivax; consulting/speaking fees/other support from Lilly; research grants/consulting/speaking fees/other support from Bristol Myers Squibb, Lilly, Janssen, Pfizer and Takeda; research grants/consulting fees from Janssen; stock/stock options from Ventyx.

Introduction

Most inflammatory bowel disease (IBD) randomised controlled trials (RCTs) only permit tapering of corticosteroids after initiating the maintenance period, either as adaptive or forced tapering, resulting in different corticosteroid exposure among participants.¹ These practices result in inappropriately, prolonged, and excessive exposure to corticosteroids that is not consistent with optimal clinical care and may inflate placebo response rates.^2-7

Aims & Methods

We aimed to provide comprehensive standardised recommendations on key aspects of corticosteroid use in RCTs for adults with moderately-to-severely active IBD, through a multi-phase, international expert consensus. The consensus was informed by a systematic review of MEDLINE, EMBASE, and the Cochrane CENTRAL Register of Controlled Trials which determined the corticosteroid management rules used in placebo-controlled trials of advanced therapies in IBD. Expert consensus recommendations for all aspects of corticosteroid management in RCTs were then developed using a modified Delphi process with two rounds of survey questions and a ratification meeting. For the surveys, corticosteroid management practices were divided into several domains describing the key stages of an IBD RCT and were directly reflected in clinical trial protocols: corticosteroid management during screening, induction, and maintenance; and corticosteroid-related endpoints.

Results

The international Delphi panel consisted of 45 IBD RCT experts. The recommendations propose management of corticosteroid intake during screening, induction, and maintenance phases of pharmacologic RCTs in IBD, and define corticosteroid-related endpoints. The need for minimising corticosteroid exposure through expedited tapering and shorter fixed-dosing periods that more closely reflect routine clinical care was emphasised, and recommendations for standardised definitions of corticosteroid-free remission were provided (Table). The panellists recommended a 2-week stable dosing period before screening, and favoured beginning dosage tapering at ≤2 weeks of induction. Panellists supported a unified tapering protocol of 5 mg prednisone equivalents/week, and voted that enteric- and colonic-release corticosteroids do not require tapering. A point of consensus was that both the beginning of tapering and its rate should be mandated by the trial protocol, rather than the investigators’ discretion. Consensus was not reached on the duration of corticosteroid withdrawal prior to the final study visit for defining corticosteroid-free remission. During the ratification meeting, the panellists highlighted the need for meticulous documentation of corticosteroid use during RCTs to avoid underreporting.

Conclusion

This set of internationally guided recommendations will serve to improve optimisation of RCT design and facilitate appropriate, acceptable, and standardised corticosteroid handling practices in RCTs, as well as maximise comparability between trials and minimise steroid-related harm to trial participants.

References

¹George et al. Inflamm Bowel Dis. 2020;26:515-523. DOI:10.1093/ibd/izz193
²Candy et al. Gut. 1995;37:674-678. DOI:10.1136/gut.37.5.674
³D’Haens et al. N Engl J Med. 2023;388:2444-2455. DOI:10.1056/NEJMoa2207940
⁴D’Haens et al. Lancet. 2022;399:2015-2030. DOI:10.1016/S0140-6736(22)00467-6
⁵Feagan et al. Lancet. 2021;397:2372-2384. DOI:10.1016/S0140-6736(21)00666-8
⁶Danese et al. Lancet. 2022;399:2113-2128. DOI:10.1016/S0140-6736(22)00581-5
⁷Almradi et al. J Crohns Colitis. 2022;16:717-736. DOI:10.1093/ecco-jcc/jjab194

Disclosure

JH has received consulting fees from Alimentiv Inc.
SKV has received consulting fees from Alimentiv Inc.
VS, ZR, and VA report no disclosures.
RA, MA, CNB, PB, RVB, BLC, JFC, FDA, AD, MD, RG, PF, SBH, ALH, MK, TK, PL, EL, FM, NN, RWL, TR, MR, WR, SS, AHS, RCU, CJW, TY, DTR, and PD report no disclosures related to Alimentiv Inc.
RP reports being a consultant and on the Advisory Board for Alimentiv Inc.
BES reports consulting fees from Alimentiv Inc.
LPB reports consulting for Alimentiv Inc.
SD reports consultancy fees from Alimentiv Inc.
GRDH reports advisor fees from Alimentiv Inc.
BB reports advisor/speaker fees from Alimentiv Inc.
JP has received consultancy fees/honorarium from Alimentiv Inc., and has served on a data safety monitoring board for Alimentiv Inc.
ST reports receiving consulting fees from Alimentiv Inc.
LJC and MH are employees of Alimentiv Inc.
WJS is a consultant for Alimentiv Inc.
BGF is the Senior Scientific Officer of Alimentiv Inc.
VJ has received consulting/advisory board fees from Alimentiv Inc.
CM has received consulting fees from Alimentiv Inc.

Introduction

Antiplatelets and anticoagulants significantly increase the risk of upper gastrointestinal bleeding by impairing normal clotting mechanisms. Patients on dual or combined therapy often present with more severe bleeds and poorer endoscopic control. This leads to higher rates of rebleeding, complications, and mortality compared to those not on these therapies.

Aims & Methods

To evaluate the risk and outcomes of non-variceal upper gastrointestinal bleeding (UGIB) in patients on single antiplatelet therapy, dual antiplatelet therapy, and combined antiplatelet-anticoagulant therapy, and to assess associated morbidity, mortality, and rebleeding rates.
A prospective study was conducted involving 150 patients (90 males, 60 females) aged 40–60 years, presenting with upper GI bleeding between 1st January 2023 till 1st January 2025. Patients had co-morbid conditions including hypertension, diabetes mellitus, coronary artery disease, or prior cerebrovascular events, and were on their respective medications for at least 3 months. Patients using NSAIDs, having liver disease, or known bleeding disorders were excluded. Clinical presentations included melena, hematemesis, or both. All patients underwent upper GI endoscopy, with Forrest classification used to characterize ulcers. Laboratory investigations included CBC, LFTs, renal function, PT, and APTT. Bleeding profiles and endoscopic outcomes were analyzed across three medication groups: single antiplatelet (n=60), dual antiplatelet (n=50), and combined antiplatelet-anticoagulant therapy (n=40).

Results

UGIB was reported in 6 (10%) of the single antiplatelet group, 16 (32%) of the dual antiplatelet group, and 14 (35%) of the combined therapy group. Endoscopic findings predominantly revealed Forrest class IIA ulcers. Patients on dual or combined therapy had poorer endoscopic hemostasis. Four patients experienced rebleeding refractory to standard endoscopic measures, requiring angioembolization. One mortality was recorded in the dual antiplatelet group due to massive bleeding and shock.

Conclusion

Dual antiplatelet and combined antiplatelet-anticoagulant therapies significantly increase the risk and severity of non-variceal UGIB, with higher rates of poor endoscopic hemostasis, rebleeding, and mortality. These findings underscore the importance of risk stratification and prophylactic strategies in patients requiring long-term antithrombotic therapy.

References

1. Hao, W., Liu, A., Zhu, H. et al. Risk factors and management of gastrointestinal bleeding in patients with or without antiplatelet and anticoagulation therapy: a multicenter real-world prospective study. BMC Gastroenterol 24, 155 (2024). https://doi.org/10.1186/s12876-024-03238-3
2. Risk of Gastrointestinal Bleeding Increases With Combinations of Antithrombotic Agents and Patient Age Abraham, Neena S. et al. Clinical Gastroenterology and Hepatology, Volume 18, Issue 2, 337 - 346.e19

Introduction

The optimal bowel preparation for small bowel capsule endoscopy (SBCE) has not been standardized.

Aims & Methods

Compare the rate of complete examinations, quality of bowel preparation, diagnostic yield and tolerability, using three protocols for intestinal preparation for SBCE.
A prospective, multicentre, randomized clinical trial including consecutive patients submitted to SBCE was conducted. All patients were instructed to comply with a clear liquid diet and 12-hour fasting before the exam. After ingesting water and 100 mg of simethicone and swallowing the capsule, once it reached the small bowel, patients ingested a booster, randomized into one of three protocols: 1) 1 liter of polyethylene glycol (PEG), 2) 1 liter of PEG and ascorbic acid, 3) 1 liter of water. The patients’ bowel preparation was evaluated with SB-CLEAR. Each patient responded to a questionnaire about their tolerability.

Results

A total of 261 patients were included, 96 patients (36.8%) in protocol 1, 93 (35.6%) in protocol 2 and 72 (27.6%) in protocol 3. The rate of complete examinations, adequate bowel preparation and diagnostic yield were comparable among the groups (p=0.655, p=0.193 and p=0.589, respectively). The overall SB-CLEAR score was similar among the protocols (p=0.236). Although the preparation of the third tertile had a lower score using protocol 3 (protocol 1: 2.5±0.1 vs 2: 2.6±0.1 vs 3: 2.3±0.1, p=0.021), it did not compromise the mucosal visualization, maintaining a mean score above 2 and similar diagnostic yield among the protocols (p=0.850). The patients’ reported tolerability was higher in protocol 3 (protocol 1: 2.8±0.1 vs 2: 3.0±0.2 vs 3: 0.6±0.1, p<0.001).

Conclusion

Using 1 liter of water as a booster in SBCE was better tolerated and associated with comparable rates of complete examinations, adequate bowel preparation and diagnostic yield versus PEG with or without ascorbic acid.