Society: AGA

Background and Aims: A treat-to-target (TTT) strategy of striving for symptomatic and endoscopic remission is recommended for the management of inflammatory bowel diseases (IBD). Yet, real-world uptake of TTT strategies has been modest. We sought to assess the feasibility of implementing TTT and improve its uptake in the Crohn’s and Colitis Foundation’s learning health system (LHS), IBD Qorus.

Methods: Through encounter-level provider filled surveys, we examined an ‘intention to TTT’ for each eligible clinic visit (for patients identified as not being in endoscopic remission on most recent endoscopic evaluation) across a multi-center LHS over a 12-month period (November 2020-November 2021). ‘Intention to TTT’ (or TTT score) was defined as an affirmative response to all three of the following: (1) Was treat-to target discussed with patient, (2) Was objective assessment for inflammation (endoscopy, radiology and/or fecal calprotectin) performed within the preceding 12m, (3) Is there an intention to change treatment since target has not been reached. Over a 12-month breakthrough series (BTS) collaborative, we sought to improve implementation of TTT with monthly report cards, webinars, an active listserv and two all-Qorus learning sessions. Changes in rates of ‘intention to TTT’ were examined over 12 months, overall and at each site, with an earliest clinically meaningful signal of improvement defined a priori as 2% increase per month.

Results: Over 12 months, there were 7934 patient visits across 38 sites in the IBD Qorus collaborative; patients in 37% visits (n=2913) were not in endoscopic remission at time of visit. Overall, rates of ‘intention to TTT’ increased from 23% at the beginning of the BTS, to 49% at the end of the BTS, corresponding to a clinically significant 2.4% per month increase in rates of implementing TTT (p<0.01) (Figure 1). While rates of discussion of TTT (88% of eligible visits) and intention to adjust therapy (70% of eligible visits) were consistently high, there was a significant increase in objective evaluation for inflammation during the course of the BTS. There was considerable variability across sites in rates of ‘intention to TTT’ across sites.

Conclusions: Through a quality improvement initiative in a LHS, rates of ‘intention to TTT’ increased significantly over 12-months, though overall rates remained low. Assessing patient-, provider- and practice-level barriers and facilitators for successful implementation of a TTT strategy is warranted to improve clinical outcomes.

Rates of ‘intention to treat-to-target’ over 12 months in a learning health system

Rates of ‘intention to treat-to-target’ over 12 months in a learning health system

Background: For patients with inflammatory bowel disease (IBD) and a history of cancer, retrospective studies suggest that exposure to anti-TNF and/or immunomodulator (IMM) agents did not increase the risk of recurrent or new cancer compared to those not exposed to these medications. The SAPPHIRE Registry was developed to prospectively examine this issue.
Methods: Patients with IBD who had a confirmed first cancer (index cancer) were recruited from centers affiliated with the New York Crohn’s and Colitis Organization (NYCCO) since 2017. Patients receiving chemotherapy or radiation therapy at enrollment, a first cancer more than 10 years prior to study entry, or recurrent cancer within the last 10 years were excluded. Cancers were categorized as gastrointestinal (GI), hematologic, dermatologic, and other solid malignancies. The primary outcome was the development of recurrent or new cancer stratified by immunosuppression exposure.
Results: To date, 306 patients with IBD and an index cancer were enrolled. The average age at IBD diagnosis was 34 years and at cancer diagnosis was 52 years (Table 1). Patients were 48% male, 89% white, and 63% never smokers. Index cancers were solid (140; 46%), dermatologic (99; 32%), GI (32; 10%), and hematologic (23; 8%). The majority of index cancers were diagnosed as stage 1. Following the index cancer, patients were exposed to anti-TNF (98; 32%), vedolizumab (91; 30%), IMM (74; 24%), ustekinumab (58; 19%), and tofacitinib (9; 3%; Table 2). 103 (34%) of patients were exposed to neither immunomodulators nor biologics. During follow-up, 44 (14%) patients developed 53 subsequent cancers (25 new, 28 recurrent) comprising 18 (34%) other solid, 25 (47%) dermatologic, 5 (9%) GI, and 1 (2%) hematologic malignancy. After a mean follow up of 3.4 years (SD 1.4 years), unadjusted bivariate analysis did not reveal increased risk of new or recurrent cancer with exposure to IMM monotherapy (9.2/100 person-years; RR 1.39, 95% CI 0.41-4.37), biologic monotherapy (7.8/100 person-years; RR 1.17, 95% CI 0.52-2.87), combination therapy with an IMM and a biologic (14.0/100 person-years; RR 2.10, 95% CI 0.83-5.57), or tofacitinib (11.2/100 person-years; RR 1.70, 95% CI 0.18-8.19) compared to those not exposed to immunosuppression (6.7/100 person-years).
Conclusion: In this ongoing prospective study, exposure to immunosuppressive IBD therapies in patients with IBD and a history of cancer has so far conferred no increased risk of new or recurrent cancer. Continued prospective study is required to confirm these findings.

Background: Intestinal and perianal fistulas and fissures are associated with significant morbidity and decreased quality of life in patients with Crohn’s disease (CD). We evaluated rates of fistula and fissure improvements with upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had fistulas or fissures at baseline in phase 3 induction and maintenance trials.
Methods: In the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) phase 3 induction trials, patients with moderate-to-severe CD were randomized to UPA 45 mg once daily (QD) or placebo (PBO) for 12 weeks. Patients who achieved clinical response after 12 weeks of induction were eligible for U-ENDURE (NCT03345823) and rerandomized to UPA 30 mg QD, UPA 15 mg QD, or PBO for an additional 52 weeks of maintenance treatment. Fistula activity was assessed by presence of external openings and draining upon gentle compression. Presence of perianal fissures was also assessed. The proportion of patients with external closure of fistula openings, complete resolution of draining, and ≥ 50% reduction in draining was recorded at weeks 12 and 52. Endpoints were analyzed using non-responder imputation.
Results: Of 1021 enrolled patients, 143 patients had fistulas (124 [86.7%] perianal; 19 [13.3%] enterocutaneous) and 54 patients had perianal fissures at baseline. The proportion of patients who achieved external closure of fistula openings was higher with UPA vs PBO at week 12 (Fig 1A) and at week 52 (Fig 2A). The proportion of patients who achieved complete resolution of draining and ≥ 50% reduction in draining was higher with UPA vs PBO at week 12 (Fig 1B and 1C) and at week 52 (Fig 2B and 2C). A higher proportion of patients achieved complete resolution of fissures with UPA vs PBO at week 12 (Fig 1D) and at week 52 (Fig 2D). At weeks 12 and 52, a higher proportion of patients with fistulas treated with UPA vs PBO achieved clinical remission and endoscopic response (Fig 1E and 2E). Rates of adverse events (AEs), serious AEs, or AEs leading to study drug discontinuation were similar in UPA groups compared with PBO during the induction and maintenance periods. Rates of abscess formation were 1.8% with UPA 45 mg and 6.8% with PBO at week 12, and 3.0% with UPA 30 mg, 6.4% with UPA 15 mg, and 2.5% with PBO at week 52.
Conclusions: Among patients with CD complicated with fistulas and/or fissures at baseline, UPA treatment led to higher rates of external closure of fistula openings, resolution of draining, and healing of fissures, along with clinical remission and improvements in luminal disease compared with PBO. No new safety concerns were identified.

Background: Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P_1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The safety and efficacy of etrasimod for the treatment of moderate to severe UC has been evaluated in the OASIS phase 2 and ELEVATE phase 3 placebo (PBO)-controlled trials. Long-term safety and efficacy of etrasimod for UC are being evaluated in an ongoing, open-label extension (OLE) study. We report an integrated analysis of the cumulative safety profile observed during the clinical development program.

Methods: Safety outcomes included adverse event (AE) frequency and exposure-adjusted incidence rates (EAIRs) of AEs of interest determined based on safety data from PBO-controlled trials and OLE trials. Patients who received PBO or etrasimod (1 or 2 mg) were analyzed as two cohorts: patients who received either PBO or etrasimod as part of one phase 2 study (etrasimod 1 or 2 mg for 12 weeks; NCT02447302) or two phase 3 studies (etrasimod 2 mg for 12 or 52 weeks; NCT03945188 and NCT03996369) were reported as the PBO-controlled cohort, and all patients who received ≥1 dose of etrasimod in the all UC cohort (studies above, NCT02536404, NCT03950232, and open-label period of NCT04176588; data cut-off January 31, 2022). Patients may have participated in >1 study.

Results: Overall, 956 patients received ≥1 dose of etrasimod with 769.3 patient years (PY) of exposure with demographics for both cohorts reported in Table 1. In the PBO-controlled cohort, a total of 629 and 314 patients received etrasimod and PBO, respectively, with 288.1 and 115.1 PY of exposure. Mean (SD) exposure per patient was 23.9 (18.5) and 19.1 (15.1) weeks for etrasimod and PBO, respectively. Of the 956 patients who received etrasimod in the all UC cohort, mean (SD) exposure was 42.0 (27.5) weeks. Rates for AEs, serious AEs, and infections (including serious infections, opportunistic infections, and herpes zoster) were similar between treatment arms and between the PBO-controlled and all UC cohorts (Table 2). Eleven (1.8%) etrasimod-treated patients reported events of bradycardia (EAIR=0.04) in the PBO-controlled cohort (9 of 11 events were asymptomatic); no events were reported in PBO-treated patients. Other AEs of special interest including hypertension and macular edema were similar between treatment arms and with the all UC cohort.

Conclusion: Etrasimod in patients with moderately to severely active UC was overall well tolerated and had an acceptable safety profile that did not appear to change with longer-term treatment of up to 2.5 years. In the PBO-controlled cohort, serious infections and herpes zoster were more commonly reported among PBO patients.

<b>Table 1. </b>Patient Demographics and Treatment Exposure

Table 1. Patient Demographics and Treatment Exposure

<b>Table 2.</b> TEAEs and AEs of Special Interest

Table 2. TEAEs and AEs of Special Interest

Introduction: Patients with inflammatory bowel diseases (IBD) commonly suffer from pain that requires analgesic therapies such as tramadol and opioids. However, use of traditional opioids (TOs) has been associated with severe infections and mortality in this population. Tramadol, a partial agonist of opioid receptors, has been considered to have less abuse potential compared to TOs. It is unknown if tramadol is associated with fewer IBD-related complications compared to TOs.

Methods: This was a Danish nationwide cohort study examining adverse outcomes associated with use of tramadol vs TOs in the IBD population. Patients with IBD (International Classification of Diseases, 10^th Revision [ICD-10] codes K50 and K51) diagnosed 1995-2021 in Denmark with subsequent prescriptions for tramadol or TOs were included. For each drug exposure, two populations were defined: initial users (IUs; first prescription after IBD diagnosis) and persistent users (PUs; first 3 consecutive prescriptions within 365 days after IBD diagnosis). Outcomes included severe (hospital-diagnosed) infection, bowel obstruction or ileus, IBD surgery, and mortality within 90 days after the IU index date (i.e. date of first prescription) and within 365 days after the PU index date (i.e. date of third prescription). Multivariable logistic regression was performed to determine associations of tramadol vs TOs with outcomes while adjusting for age, sex, Charlson comorbidity index, year of IBD diagnosis, IBD type, IBD duration, and prior immunomodulator use, corticosteroid use, IBD hospitalization, severe infection, bowel obstruction or ileus, and IBD surgery within 6 months before the index date. A sensitivity analysis was performed in which patients with any diagnosis of a malignant neoplasm (ICD-10 codes C00-99) <1 year prior to the first tramadol or TO prescription were excluded.

Results: We identified 37,377 IUs and 15,237 PUs of tramadol or TOs. Baseline characteristics are presented in Table 1. IUs of tramadol had lower odds of severe infection (adjusted odds ratio [aOR] 0.80, 95% CI 0.65-0.99), bowel obstruction or ileus (aOR 0.74, 95% CI 0.53-1.03), and mortality (aOR 0.43, 95% CI 0.35-0.55), and higher odds of IBD surgery (aOR 1.27, 95% CI 1.02-1.60) compared to TOs. PUs of tramadol had lower odds of severe infection (aOR 0.69, 95% CI 0.55-0.86), bowel obstruction or ileus (aOR 0.58, 95% CI 0.39-0.85), and mortality (aOR 0.35, 95% CI 0.28-0.44) but no difference in IBD surgery (aOR 1.13, 95% CI 0.86-1.47) compared to TOs (Table 2a). Results were unchanged after excluding patients with malignancy (Table 2b).

Conclusion: Use of tramadol was associated with lower odds of severe infection, bowel obstruction/ileus, and mortality vs use of TOs among patients with IBD, however both drug classes should be used with caution. Safety comparisons of tramadol to other analgesics are needed.

Background: The phase 3, randomized True North (TN) study demonstrated the efficacy and safety of ozanimod for up to 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). The ongoing TN open-label extension (OLE) aims to assess the long-term efficacy and safety of ozanimod in UC. This analysis evaluated the cumulative long-term safety of ozanimod in these studies, which included pts with up to ~3 years of treatment exposure.

Methods: In TN, pts were randomized to once-daily ozanimod 0.92 mg or placebo, or to open-label ozanimod for a 10-week induction period. Ozanimod clinical responders were rerandomized at Week 10 to ozanimod or placebo in the maintenance period through Week 52. TN pts were eligible to enroll in the OLE and receive ozanimod if they did not achieve clinical response at the end of induction (Week 10), lost response during maintenance, or completed maintenance at Week 52. This interim analysis of the TN OLE (data cutoff: 10 January 2022) included all pts who entered the OLE from TN (n=823). Safety was monitored from the first dose of ozanimod in TN and throughout the subsequent OLE. Exposure-adjusted incidence rates per 100 patient-years (PY) were calculated.

Results: The average age of TN OLE study participants was 41.7 years (±13.6), 41% were female, 62% had left-sided UC disease, and 35% had prior exposure to tumor necrosis factor inhibitors. Total PY exposure to ozanimod was 2219 years (mean [SD] exposure = 2.7 [1.6]). The most frequent treatment-emergent adverse events (TEAEs) reported through OLE Week 94 (up to 146 weeks of continuous treatment) are listed in the Table. Most TEAEs were nonserious; TEAEs leading to discontinuation were uncommon. Bradycardia was reported in 3 pts (0.4%; EAIR 0.1/100 PY; 2 in TN and 1 in OLE; no pts were discontinued from treatment). Macular edema was reported in 2 (0.2%; EAIR 0.1/100 PY) pts. Reductions in ALC were common (470 [57.1%] had ALC < 500 cells/mm³), as previously described, but ALC reductions were not associated with the occurrence of TEAEs. Malignancies were uncommon (n=13 [1.6%]; EAIR 0.6/100 PY), and included 6 basal cell carcinomas and 3 colorectal neoplasms. Two deaths were reported: 1 due to COVID-19 and 1 sudden death. Investigators deemed both to be unrelated to treatment. Ozanimod was not associated with an increased risk of ischemic heart disease or thromboembolic events.

Conclusion: Long-term exposure to ozanimod for up to 3 years was well tolerated in pts with moderately to severely active UC. No new safety signals were observed with long-term ozanimod use in UC (2219 PY exposure). Safety findings are consistent with previous reports from the UC and multiple sclerosis development programs (>16,512 PY exposure).

James Canavan

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