Introduction

Patients enrolled in randomised controlled trials (RCT) of advanced therapeutics in inflammatory bowel disease (IBD) may differ from the target population of patients given these same drugs in routine practice. Prior research from 2012 indicated that only approximately a third of patients would theoretically qualify for enrolment in an RCT (1). We aimed to re-evaluate the overlap between patients in routine practice and those in contemporary RCTs.

Aims & Methods

We evaluated all patients with active IBD at our institution who were considered for treatment with a biologic or small molecule (both de novo and switching). Their characteristics were compared against inclusion and exclusion criteria of recently completed or ongoing RCTs: ozanimod, upadacitinib, risankizumab, golimumab-guselkumab, guselkumab (Crohn’s disease [CD] only), filgotinib, mirikizumab, and etrasimod (ulcerative colitis [UC] only for the latter three drugs). We calculated the percentage of patients ineligible for all evaluated trials and identified the commonest criteria for ineligibility.

Results

We evaluated 286 patients (155 CD, 131 UC); 16 additional patients with IBD unclassified were ineligible for trial participation by default. Among patients with CD, 34.2% (53/155) would have been eligible for participation in at least one RCT; among patients with UC, 47.3% (62/131) would have been eligible for participation in at least one RCT (Table 1). Patients with CD would have been excluded mainly due to the presence of stricturing or penetrating disease, the presence of ostomies, comorbidities, including history of malignancy, and insufficient symptoms despite endoscopic activity. Patients with UC would have been excluded mainly due to insufficient symptoms despite endoscopic activity, ulcerative proctitis, newly diagnosed disease, and comorbidities, including history of malignancy.

Table 1. Number of patients (n, %) with inflammatory bowel disease eligible for participation in a randomized clinical trial.

Conclusion

Only a minority of patients with IBD from routine practice would be eligible for participation in contemporary RCTs, although the percentage has increased for patients with UC compared to past studies.

References

1. Ha C et al. Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population. Clin Gastroenterol Hepatol 2012;10:1002-7.

Disclosure

JH received speaker’s fees from Abbvie, Janssen, and Takeda; consulting fees from Alimentiv Inc.
EH declares no conflict of interest.
TK declares no conflict of interest.
TV declares no conflict of interest.
DD has served as a speaker, consultant, and/or advisory board member for MSD, Abbvie, Takeda, Pfizer, Janssen, Krka, Eli Lilly, Oktal Pharma, Roche, Novartis, Amgen, and Lek.

Introduction

Bowel urgency (BU) is a common, debilitating symptom among patients with ulcerative colitis (UC).¹ LUCENT-URGE is a Phase 3b, open-label, single-arm 28-week (W) study in adults with moderately-to-severely active UC and BU (Urgency Numeric Rating Scale [UNRS] ≥3) at baseline treated with mirikizumab (MIRI). Here, we report W28 results from LUCENT-URGE (NCT05767021).

Aims & Methods

Patients were treated with intravenous MIRI 300 mg at W0, 4 and 8, followed by 200 mg subcutaneous at W12, 16, 20, and 24. The primary objective was to assess improvement in UNRS at W12. Key secondary objectives included evaluating the improvement in UNRS at W28, the improvement in Stool Deferral Time (SDT) and Bowel Urgency Frequency (BUF) at W12 and W28, the proportion of participants achieving clinical remission and an UNRS score of ≤1 (BU remission) at W12 and W28, and the proportion of participants achieving clinical response and an improvement in UNRS score ≥3 (clinically meaningful improvement [CMI] of UNRS) at W12 and W28. UNRS and BUF was measured using a daily diary where patients recorded the number of times they experienced BU in the past 24 hours and was averaged over a 7-day period. SDT was reported in minutes (min), and the shortest weekly SDT was used. Baseline observation carried forward was used as the endpoint for the corresponding visit for all missing observations. Missing continuous data were treated as no change from baseline and binary endpoints were treated as nonresponse for participants that discontinue prior to the time point of interest.

Results

172 patients were enrolled from 8 countries. Baseline modified Mayo score (MMS; mean± standard deviation [SD]) was 6.8±1.3, and 64.0% patients had severe disease activity (MMS 7-9). Baseline mean duration of UC was 8.0 years, mean UNRS score was 6.9 and mean BUF was 6.9 times/day. Mean UNRS and BUF improved from baseline to W28 by 3.6 and 3.8, respectively. The proportion of patients with SDT defined as “≥15 min or no urgency” was 4.1% at baseline and improved to 29.7% at W28 (Table 1). At W12, 36 (20.9%) patients achieved clinical remission, 54 (31.4%) achieved endoscopic remission, and 92 (53.5%) achieved CMI of UNRS. At W28, 62 (36.1%) patients achieved clinical remission, 76 (44.2%) achieved endoscopic remission, and 100 (58.1%) achieved CMI of UNRS. 76 (44.2%) patients achieved both clinical response and CMI of UNRS at W12, and 86 (50.0%) patients at W28. At W12 and W28, 8 patients (4.7%) and 28 patients (16.3%) achieved both clinical remission and BU remission, respectively. The safety profile of MIRI observed in LUCENT-URGE was consistent with previous studies, with no death reported and similar frequency of treatment-emergent adverse events (TEAEs). Most common TEAEs were ulcerative colitis exacerbation (5.2%) and upper respiratory tract infection (5.2%).

Table 1. Change in Bowel Urgency Measures from Baseline at Week 12 and Week 28, BOCF

Conclusion

MIRI showed an early and sustained improvement on BU severity, frequency and stool deferral time through W28 in LUCENT-URGE. MIRI consistently improved clinical outcomes in patients with moderately-to-severely active UC.

References

Dubinsky M, et al. Bowel Urgency in Ulcerative Colitis: Current Perspectives and Future Directions. AJG 2023; 118(11): 1940-53.

Disclosure

SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli lilly and company, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor; lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda.
AD reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Abivax, AbbVie, Bristol Myers Squibb, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Alfasigma, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Sandoz, Stada, Takeda, Tillotts, and Vifor Pharma; payment from lectures including service on speakers bureaus from AbbVie, Alfasigma, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Streamed-Up, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Abbvie, Falk Foundation, J & J, Takeda, Thieme, and UniMed Verlag.
DL declares counselling, boards, and transport or fees from AbbVie, Amgen, Biogen, Celltrion, Ferring, Alphasigma, Janssen, Lilly, MSD, Pfizer, Prometheus, Roche, Sandoz and Takeda.
JKL has received consultancy and speaker fees from AbbVie, Abivax, Arena, AlfaSigma, Bristol Myers Squibb, Biohit, Celltrion, Eli Lilly and Company, Ferring, Galapagos, Janssen, MSD, Pfizer, Takeda and Tillotts and research grants from AbbVie, Galapagos and Takeda.
RK reports lecture fees from Aboca S.p.A. Società Agricola, Ferring, AbbVie, and Eli Lilly and Company.
JDL consulted or served on an advisory board or data monitoring committee for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, Sanofi. He has had research funding or in kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie and Eli lilly and company. He has had educational grants from Janssen. He has performed legal work on behalf of manufacturers of generic ranitidine and 3M. He owns stock in Dark Canyon Labs.
ZY has received research support from AbbVie, Axcella, Bristol Myers Squibb, CymaBay, Galectin, Intercept, Inventiva, Madrigal, NGM, Novo Nordisk, NST, Poxel, and Sagimet; has acted as a speaker for AbbVie, Intercept, and Bristol Myers Squibb; and as a consultant for Intercept and Madrigal.
EC reports advisory board and consultant for Pfizer, Takeda, and PRIME Education; speaker for AbbVie, Eli Lilly and Company, Janssen, and Takeda.
KA, WJE, TT, IR are employees and minor shareholders of Eli Lilly and Company.
DR reports grant support from Takeda and has served as a consultant for AbbVie, AltruBio, Arena Pharmaceuticals, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Gilead Sciences, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Roche, Takeda, and Techlab.
MD reports consulting fees from AbbVie, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Genentech (Roche), Gilead Sciences, Janssen, Pfizer, Prometheus Biosciences, Roche, Takeda Pharmaceuticals, and UCB; contracted research from AbbVie and Janssen; stock interest in Trellus Health; and licensing fees from Takeda Pharmaceuticals.

Introduction

In the randomized controlled LADI trial, a subset of patients with Crohn’s disease (CD) maintained clinical remission following extension of the adalimumab dose interval (1). The aim of this study was to assess long-term clinical outcomes for trial participants.

Aims & Methods

The initial LADI trial included CD patients in biochemical and corticosteroid-free clinical remission (CFCR) on adalimumab 40 mg/2 weeks. The intervention group started on a 3-week interval and increased to 4 weeks at week 24, if in clinical and biochemical remission. Controls remained on adalimumab every 2 weeks. In the current long-term study, additional data up to 3 years was collected. The primary endpoint was the proportion of patients in CFCR (Harvey Bradshaw Index (HBI) ≤4 or remission per Physician Global Assessment) without complications at year 3, while maintaining the baseline allocated adalimumab interval. Patients at an adalimumab interval >2 weeks or who discontinued for stable remission were also included in the primary endpoint. Complications were defined as IBD-related surgery or hospitalization, and new-onset or required treatment of fistulizing or penetrating disease. Secondary endpoints included CFCR and/or complications after escalation from randomized dose or discontinuation of adalimumab for reasons other than remission.

Results

Data was extracted for 143/174 initially randomized subjects (intervention: 95; control: 48). The primary endpoint was achieved in 34 of 95 patients (35.8%) in the intervention group and in 41 of 48 patients (85.4%) in the control group (p < 0.001). In the intervention group, 39/95 (41%) patients were on a de-escalated adalimumab dose at year 3: 10 (26%) 4-weekly, 25 (64%) 3-weekly, 4 (10%) stopped for stable remission. 35 (90%) patients were in CFCR, and 37 (95%) had no complications. In the control group, 44/48 (92%) were on the randomized or de-escalated dose at year 3: 30 (68%) 2-weekly, 10 (23%) 3-weekly, and 4 (9%) stopped due to remission. 42 (95%) patients were in CFCR and 42 (95%) had no complications. In the intervention group, another 39/95 (41%) patients required re-escalation of adalimumab at year 3: 33 (85%) 2-weekly, 5 (13%) weekly, and 1 (3%) every 10-days. 35 (90%) were in CFCR and 11 (28%) patients developed complications. In the control group, 2 (4%) patients required re-escalation to a weekly interval, and were in CFCR without complications at year 3. Median time to re-escalation was 6 months (Q1-Q3: 5-7) for the intervention group, and 29 (Q1-Q3: 28-30) for the control group. At year 3, 17/95 (18%) intervention and 2/48 (4%) control patients had discontinued adalimumab. 11 (65%) intervention patients and one control (50%) were in CFCR, and 4 (24%) and no complications occurred, respectively. Median time to adalimumab discontinuation was 19 (Q1-Q3: 8-29) and 24 months (Q1-Q3: 21-27) for the intervention and control patients, respectively.

Table 1. Baseline characteristics

Conclusion

Over one-third of CD patients in stable remission were on a de-escalated adalimumab dose at year 3, while maintaining CFCR without complications. Another quarter required adalimumab re-escalation but regained CFCR at year 3, without developing complications.

References

1. van Linschoten RCA, Jansen FM, Pauwels RWM, Smits LJT, Atsma F, Kievit W, et al. Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial. Lancet Gastroenterol Hepatol. 2023;8(4):343-55.

Introduction

Clinical practice guidelines recommend corticosteroids use for remission induction therapy in patients with moderate-severe ulcerative colitis (UC); however, there are limited data on their effectiveness and safety in elderly UC patients. Although comparable outcomes in elderly UC patients have been reported, these patients show higher morbidity, and mortality, than younger patients due to the lower malnutrition and immunocompromised state. It has been reported that elderly onset is associated with a lower effectiveness of intravenous corticosteroids with higher risks of surgery and adverse events in UC. Thus, the efficacy and safety of corticosteroids in elderly UC patients remains to be determined.

Aims & Methods

To compare the clinical characteristics in elderly onset UC patients treated with corticosteroid against non-elderly onset patients.
We enrolled 170 UC patients presenting at Nippon Medical School Hospital prior to March 2023. The patients were divided into two groups comprising elderly-onset and non-elderly-onset UC patients, and their clinical characteristics were determined according to medical records. We defined elderly-onset UC as UC initially diagnosed in patients at 65 years or older according to WHO criteria.

Results

Clinical characteristics of UC patients were as follows: 12 patients were categorized as elderly-onset UC including 3 males to 9 females, and 158 were non-elderly-onset UC including 91 males to 67 females. The proportion of females was higher in elderly-onset UC patients than in non-elderly onset UC patients. The rate of patients who underwent corticosteroid induction therapy was significantly higher in elderly-onset UC patients; 9 out of 12 (75%) in elderly-onset UC patients and 81 out of 158 (51%) in non-elderly-onset UC patients, although average prednisone doses were comparable. Adverse events were observed in 3 cases (33%) in elderly-onset UC patients: candidiasis in 2 cases and hyperglycemia in 1 case, and no patients required surgery. While adverse events were 21 cases (26%) in non-elderly-onset UC patients: liver disfunction (n=4), followed by hyperglycemia (n=2), depression (n=2); and one each for cytomegalovirus colitis, clostridioides difficile infection, gastric ulcer and so on. Hemoglobin values were significantly lower (P<0.01), and erythrocyte sedimentation ratio was significantly higher (P=0.04) in elderly-onset UC patients. On the other hand, no significant difference was observed between the two groups regarding; pre-treatment WBC counts, serum albumin concentrations, neutrophil-lymphocyte ratio, CRP values, the rate of patients who achieved clinical remission and steroid-free remission, rate of introduction of immunomodulators, rate of use of biologics, number of hospitalizations, and number of relapses.

Conclusion

There was no difference in responsiveness to steroid therapy between non-elderly and elderly UC patients, and no serious adverse events were observed during the period of steroid therapy in both groups. However, consideration should be given to comorbidity in elderly patients.

Disclosure

The authors declare that they have no competing interests.