BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved in the US for treating moderately to severely active ulcerative colitis (UC) and in multiple countries for treating relapsing forms of multiple sclerosis (MS). In a Phase 1 study of ozanimod in healthy participants, first-dose cardiac effects were mitigated with gradual dose escalation. Based on these results, an initial 7-day ozanimod dose escalation regimen was implemented in all Phase 2 and 3 UC and MS trials. The objective of this analysis was to evaluate the number of patients who were excluded from ozanimod treatment due to contraindications of pre-existing cardiac disorders and to evaluate the incidence of cardiac-related treatment-emergent adverse events (TEAEs) following first-dose ozanimod administration in all patients and patients with a history of non-exclusionary cardiac disorders in the UC and MS clinical trials. METHODS: For UC, the analysis included pooled data from the Phase 2 Touchstone (NCT01647516) and Phase 3 True North (NCT02435992) trials. For MS, the analysis included pooled data from the Phase 3 Radiance (NCT02047734) and Sunbeam (NCT02294058) trials. Patients with clinically relevant cardiac conditions or clinically significant electrocardiogram (ECG) disorders were excluded from the trials. On Day 1, all patients received ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg). Day 1 cardiac monitoring included collection of vital signs (including heart rate) prior to dosing and hourly for at least 6 hours after dosing, and ECG prior to dosing and at Hour 6 after dosing. RESULTS: Among patients screened, 26/2178 (1.2%) in the UC studies and 47/3351 (1.4%) in the MS studies were excluded due to protocol-defined pre-existing cardiac disorders. Of 496 patients who received ozanimod in the UC studies, 1 (0.2%) experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Of 1774 patients who received ozanimod in the MS studies, 11 (0.6%) experienced a cardiac-related TEAE on Day 1. In both the UC and MS studies, no cases of second- or third-degree AV block were observed. A decrease in mean heart rate from baseline (UC, 0.7 bpm; MS, 1.2 bpm) was observed at first-dose that reached a nadir at Hour 5 and returned to baseline by Hour 6. Among 496 patients with UC who received ozanimod, 34 (6.9%) had a known history of cardiac disorders, of whom 1 experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Among the 1774 patients with MS who received ozanimod, 96 (5.4%) had a known history of cardiac disorders, of whom 2 experienced symptomatic bradycardia on Day 1. CONCLUSION: In clinical trials of ozanimod, the number of patients with UC or MS who failed screening because of exclusionary cardiac disorders was low. Most patients with a history of cardiac disorders who were enrolled in ozanimod clinical trials did not have Day 1 cardiac events, and the events that occurred were manageable.

BACKGROUND: Urgency, the immediate need to defecate, is common in ulcerative colitis (UC). The frequently used patient reported outcome (PRO)-2 for UC includes only rectal bleeding and stool frequency. We sought to investigate the association of urgency in UC patients with 1) quality of life (QoL) domains and 2) future UC hospitalizations, steroid prescriptions, and colectomy. METHODS: We conducted a cross-sectional and then a subsequent longitudinal study within IBD Partners, a patient-powered research network. We described associations of levels of urgency in UC patients with PROMIS QoL domains (depression, anxiety, social satisfaction, fatigue, sleep, and pain). Next, a longitudinal cohort determined associations between baseline urgency and subsequent clinical outcomes including UC hospitalization, steroid prescription, or colectomy within 12 months. We used bivariate statistics and logistic regression models to describe independent associations. RESULTS: A total of 632 UC patients were included in the cross-sectional study. After adjusting for clinical variables, rectal bleeding, and stool frequency, “hurry”, “immediately” and “incontinence” increased the odds of social impairment by 2.05 [1.24-3.4] (p = 0.005), 2.76 [1.1-6.74] (p = 0.028), and 7.7 [1.66-38.3] (p = 0.009) respectively compared to “no hurry”. Urgency also significantly increased the odds of depression, anxiety, and fatigue. In the multivariate pooled logistic regression of the longitudinal cohort, Urgency was associated with a significant stepwise increase in risk of hospitalizations, steroids, and colectomy. “Hurry”, “immediately” and “incontinence” increased the odds of colectomy within 12 months by 1.41 [1.15-1.72] (p < 0001), and 3.29 [2.13-5.09] (p < 0001). CONCLUSION: We demonstrate that urgency is a PRO independently associated with compromised QoL in patients with UC. Urgency is associated with future risk of hospitalizations, steroid prescription, and colectomy. Our findings support the consideration of urgency as a UC-specific PRO and its use as an outcome in clinical trials to capture QoL and risk of clinical decompensation.

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BACKGROUND: The management of chronic antibiotic dependent pouchitis (CADP) is associated with significant morbidity and burden to patients with an ileal pouch-anal anastomosis (IPAA). When individuals fail to respond to standard antibiotic therapy for pouchitis, little guidance is available in choosing subsequent antibiotic regimens. We performed a retrospective study to evaluate specific antimicrobials as well as duration of therapy among patients treated for CADP in our multidisciplinary IBD center. METHODS: We identified patients with CADP between January 1, 2009 and December 1, 2016. Patients diagnosed with Crohn’s disease of the pouch and acute antibiotic responsive pouchitis were excluded. For each individual with CADP, we analyzed the type and duration of up to 4 antibiotic regimens. Standard descriptive statistics are presented, including medians and interquartile ranges (IQR) for duration assessments and Wilcoxon-rank sum testing for comparisons of duration of antibiotic therapy. RESULTS: A total of 288 patients were evaluated for pouch related disorders during the study period. From the initial population, 90 (31%) were excluded due to a diagnosis of Crohn's disease of the pouch and 75 (26%) were excluded due to a diagnosis of acute antibiotic responsive pouchitis. In total, there were 123 patients (53% male, mean age at time of IPAA 40.9 years) who were diagnosed with CADP. Most patients underwent a 2-stage IPAA and had pancolitis prior to colectomy. In the majority of patients (93/123; 75%), the first antibiotic regimen consisted of a fluoroquinolone alone (43%) or a fluoroquinolone in combination with either metronidazole (30%) or another antibiotic (2%). Metronidazole was used in 15%, and other antibiotics in 10% of the patients. Of the 123 patients, 93%, 76%, and 59% needed a second, third, or fourth antibiotic regimen, respectively. The use of fluoroquinolones alone or in combination decreased to 54%, 48%, and 40% of patients for the second, third, and fourth regimen. In particular, amoxicillin/clavulanate, sulfamethoxazole/trimethoprim, rifaximin and doxycycline were increasingly used in the third and fourth antibiotic approach (31% and 42%, respectively). The duration of the different antibiotic regimens varied, but fluoroquinolones alone were given for a significantly longer duration during the first 4 consecutive regimens compared to other antibiotics indicating a better persistence of therapy (regimen 1 median fluoroquinolone duration 32 weeks vs others 7.5 weeks (IQR 4–36), P < 0.001; regimen 2 median 20 weeks vs 8 weeks (IQR 4–28), P = 0.038; regimen 3 median 21 weeks vs 8 weeks (IQR 4–36), P = 0.005; regimen 4 median 20 weeks vs 10 weeks (IQR 4–20), P = 0.011). CONCLUSION(S): In a retrospective cohort of patients with CADP, we found that standard therapy with a fluoroquinolone alone or in combination was most common as the initial treatment for CADP. Although fluoroquinolones in particular demonstrated significant longevity, over time the proportion of the population treated with alternative antibiotic regimens such as amoxicillin/clavulanate, sulfamethoxazole/trimethoprim, doxycycline, and rifaximin increased presumably due to loss of response to standard therapy. Further studies are needed to individualize the therapeutic approach and determine the optimal antibiotic regimen with greatest durability and long-term response for this challenging patient population.