Pregnancy Outcomes in the Ozanimod Clinical Development Program in Patients With Ulcerative Colitis, Crohn's Disease, and Relapsing Multiple Sclerosis.

This study evaluated pregnancy outcomes in patients with ulcerative colitis, Crohn's disease, or multiple sclerosis and in healthy volunteers treated with ozanimod. There was no increased incidence of fetal abnormalities or adverse pregnancy outcomes with ozanimod exposure during early pregnancy.

Efficacy and Safety of Approximately 3 Years of Continuous Ozanimod in Moderately to Severely Active Ulcerative Colitis: Interim Analysis of the True North Open-label Extension.

BACKGROUNDS AND AIMS: This interim analysis from the True North open-label extension [OLE] study examines efficacy and safety of approximately 3 years of continuous ozanimod treatment in patients with moderately to severely active ulcerative colitis. METHODS: Clinical responders after 52 weeks of ozanimod during the phase 3 True North study, who continued treatment in the OLE, were evaluated. Efficacy, including endoscopic and histological endpoints, was assessed during the OLE for approximately 2 additional years through OLE Week 94, using observed case [OC] and nonresponder imputation [NRI] analyses. Adverse events were monitored from True North baseline through OLE data cutoff and expressed as exposure-adjusted incidence rates. RESULTS: This analysis included 131 patients; 54% had achieved corticosteroid-free remission at True North Week 52. In OC analyses, clinical response, clinical remission, and corticosteroid-free remission were achieved by 91.4%, 69.1%, and 67.9% of patients, respectively, at OLE Week 94 [146 weeks of total treatment]. Similarly, endoscopic improvement, histological remission, and mucosal healing were achieved by 73.3%, 67.3%, and 56.3% of patients, respectively, at OLE Week 94. Efficacy rates were lower using NRI analyses, but maintenance of efficacy was demonstrated through OLE Week 94. No new safety signals emerged from this analysis. Serious infections, malignancy, cardiovascular events, and hepatic events occurred infrequently. CONCLUSIONS: Among patients who achieved clinical response after 1 year of ozanimod treatment during True North, a high percentage sustained clinical and mucosal efficacy over 2 additional years in the OLE. No new safety signals were observed with long-term ozanimod use.

Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses.

BACKGROUND & AIMS: Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE). METHODS: All patients who received ozanimod in TN (n = 796) and all eligible TN patients who entered the OLE (n = 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN. RESULTS: On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low. CONCLUSIONS: No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126.

Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed. RESULTS: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod. CONCLUSIONS: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).

Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study.

BACKGROUND AND AIMS: This analysis examined the long-term safety and efficacy of ozanimod in patients with moderately to severely active ulcerative colitis [UC] with ≥ 4 years of follow-up in the phase 2 TOUCHSTONE open-label extension [OLE]. METHODS: Patients receiving placebo or ozanimod HCl 0.5 mg or 1 mg during the double-blind period could enter the OLE [ozanimod HCl 1 mg daily]. Partial Mayo score [pMS] clinical response and remission were assessed through OLE week 200 and summarized descriptively using observed cases [OC] and non-responder imputation [NRI]. Endoscopy was required at OLE week 56 and the end of treatment. Parameters associated with endoscopy were summarized at weeks 56 and 104 [OC], and week 56 [NRI]. C-reactive protein and faecal calprotectin were assessed. Adverse events were monitored throughout the study. RESULTS: Of 197 patients receiving double-blind treatment, 170 entered the OLE. Discontinuation rates were 28% at year 1 and 15-18% annually through year 4. Partial Mayo measures indicated clinical response and remission rates at OLE week 200 of 93.3% and 82.7%, respectively, using OC and 41% and 37% with the more conservative NRI analysis. At weeks 56 and 104, respectively, histological remission rates were 46.3% and 38.5%, and endoscopic improvement rates were 46.4% and 46.5% [OC]. No new safety signals were identified during ≥ 4 years of follow-up. CONCLUSIONS: There was a high rate of continued study participation and long-term benefit with ozanimod HCl 1 mg daily based on clinical, histological and biomarker measures in patients with moderately to severely active UC in the TOUCHSTONE OLE. [NCT02531126].

P037 Effect of Ozanimod Treatment and Discontinuation on Absolute Lymphocyte Count in Moderate-to-Severe Ulcerative Colitis: Results from a Phase 3 Trial.

BACKGROUND: Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, which reduces migration of lymphocytes involved in adaptive immunity from lymphoid tissues to blood and inflamed tissues while preserving components of the innate immune response. Ozanimod is approved in multiple countries for the treatment of relapsing forms of multiple sclerosis and in the US for the treatment of moderately-to-severely active ulcerative colitis (UC). The reduction of circulating lymphocytes is expected based on the mechanism of action of ozanimod and thought to be an important driver of efficacy. METHODS: We assessed absolute lymphocyte count (ALC) during ozanimod induction and maintenance, and after ozanimod discontinuation, per protocol, in adults with moderately-to-severely active UC to characterize the time course of ALC reduction and recovery. The analysis included patients who received ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo once daily in True North, a phase 3 randomized trial (NCT02435992). During a 10-week induction period, patients were randomized 2:1 to double-blind treatment with ozanimod or placebo (Cohort 1) or received open-label ozanimod (Cohort 2). Patients from either cohort with a clinical response to ozanimod at week 10 were re-randomized 1:1 to double-blind treatment with ozanimod or placebo during maintenance through week 52. Placebo-treated patients with a clinical response at week 10 continued placebo during maintenance. ALC was assessed at baseline and at visits throughout induction and maintenance. RESULTS: A total of 69 patients received continuous placebo treatment, 230 received continuous ozanimod treatment, and 227 received ozanimod during induction and placebo during maintenance. In patients who received continuous placebo, mean ALC remained stable between 1.8‒2.1 x 109/L over time (normal range: 1.02‒3.36 x 109/L). In ozanimod-treated patients, mean ALC was reduced to 43%‒45% of baseline and 70%‒73% of patients had ALC shifts from normal at baseline to low (9/L) at week 10. In patients who continued ozanimod, mean ALC reductions were sustained at approximately the same level and ALC shifts from normal at baseline to low were maintained in 73%‒89% of patients during maintenance. In patients who received ozanimod induction therapy and then were re-randomized to placebo for maintenance, mean ALC recovered within 8 weeks to levels similar to baseline at induction and the proportion of patients with ALC shifts from normal at baseline to low decreased from 73% at week 10 to 6% at week 52. Fewer than 2% of ozanimod-treated patients had ALC 9/L during either induction or maintenance and ALC generally returned to ≥ 0.2 x 109/L while patients remained on ozanimod. Among those who switched from ozanimod induction to placebo maintenance, there were no occurrences of ALC 9/L at the end of maintenance. No patients with a serious/opportunistic infection had concurrent ALC 9/L. CONCLUSION: Consistent with the mechanism of action of ozanimod, ALC reductions occurred during ozanimod induction and were sustained during maintenance. Incidence of ALC 9/L was low. ALC recovered after switching to placebo and most patients did not require treatment discontinuation because of changes in ALC.

P038 Ozanimod First-Dose Cardiac Effects in Patients with Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis.

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.

Epidemiology and Management Trends of Patients With Sepsis and Septic Shock in the Intensive Care Unit: A Prospective Trial in the Caribbean.

Objectives To investigate the epidemiology, management, and predictors of mortality in severe sepsis and septic shock in the intensive care units (ICUs) of Trinidad, Trinidad & Tobago. Methods A prospective observational study in four ICUs over a one-year period (August 2017-August 2018) was conducted. Physiologic variables, treatment data, and outcomes were collected on admission to ICU and daily until 28 days. The 28-day mortality and ICU mortality were recorded. Subgroup analysis was performed based on survival, and predictors of mortality were determined through logistic regression. Results Outcome data were available for 163 patients. The 28-day mortality rates for sepsis and septic shock were 42% and 47%, respectively. ICU mortality rate for sepsis was 34%. The most common suspected source of infection was pneumonia (33%). Acute kidney injury (AKI) was common and present in 71% of patients, with renal replacement therapy only being used in 30% of cases. Mechanical ventilation was required in 84% of cases. Moderate-to-severe acute respiratory distress syndrome (ARDS) (OR: 4; 95% CI: 1.9-8.8; p < 0.001) and the development of AKI (all stages) (OR: 10; 95% CI: 3.9-30.2; p < 0.001) were found to be predictive of mortality. Incidence of mechanical ventilation, moderate-to-severe ARDS, stage 3 AKI, septic shock, and failure to achieve a mean arterial pressure of > 60 mmHg within the first 24 hours of admission were higher in patients who did not survive (p < 0.05). Conclusions Sepsis and septic shock are associated with a high 28-day mortality. Organ dysfunction with renal and pulmonary involvement was an important factor in predicting a higher mortality.

Long-term Safety of Sunitinib in Metastatic Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr. OBJECTIVE: To analyze long-term safety with sunitinib in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g., cytokine refractory or treatment-naïve). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment. RESULTS AND LIMITATIONS: Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients. CONCLUSIONS: Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative. PATIENT SUMMARY: More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk.

Patient perception of the role of anesthesiologists: a perspective from the Caribbean.

STUDY OBJECTIVE: To assess patients' perception of the role of an anesthesiologist in a Caribbean country. DESIGN: Self-administered structured questionnaire evaluation. SETTING: Preoperative waiting rooms of three tertiary-care teaching hospitals: Port of Spain General Hospital, Eric Williams Medical Sciences Complex, and San Fernando General Hospital, Trinidad. PATIENTS: 424 adult surgical patients awaiting elective surgery. INTERVENTIONS: None. MEASUREMENTS: A questionnaire was devised to test the knowledge of the respondents regarding the job description, attitudes, and various roles of anesthesiologists in the hospital. MAIN RESULTS: 371 completed responses were obtained for analysis. One tenth of the respondents did not know who an anesthesiologist was and 59% of them knew that an anesthesiologist was a doctor; there was a statistically significant association of the educational level of the respondent and this response. Of the respondents, 70% felt that the anesthesiologists were easy to talk to and pleasant by the bedside; 46% responded that the anesthesiologists did not discuss the complications and side effects of drugs before the procedure; 5% considered the anesthesiologists as more important than the surgeon, and 59% considered both equally important. Only 19% responded that they knew that the anesthesiologists had a role in the intensive care unit. CONCLUSIONS: Patients still have inadequate knowledge regarding anesthesiologists and their different roles in hospitals.

Evaluation of the utilization of the preanaesthetic clinics in a university teaching hospital.

BACKGROUND: Dedicated out-patient preanaesthetic clinics are relatively recent phenomenon and information is sparse from developing world. This study attempted to evaluate the utilization of adult and paediatric preanaesthetic clinics and its impact on the cancellations of surgery in Trinidad. METHODS: All patients scheduled to have elective surgery during the period of twelve weeks were enrolled for prospective collection of data including demographics, the admitting diagnoses, surgical procedure, category of surgery and specialty, and the patients' attendance to preanaesthetic clinics. Cancellations on the day of surgery along with reasons were recorded. The difference between patients who attended and did not attend the clinic was analysed. RESULTS: Of 424 patients scheduled for procedures during the study period, 213 were adults and 211 were children. Overall 39% of adults and 46% of the children scheduled for surgery had previously attended the preanaesthetic clinic. Among adults, general surgery patients were the largest majority to attend the preanaesthetic clinic. The paediatric preanaesthetic clinic was mostly utilized by paediatric general surgery. Overall 30% of procedures in adults and 26% of those in children were cancelled. There was a statistically significant difference in cancellations between patients who attended and did not attend the preanaesthetic clinic (p = 0.004). There was a 52% more chance of the procedure getting cancelled if the patient did not attend the clinic. CONCLUSION: The study highlights the inadequate use of the preanaesthetic clinics and the impact of the clinics on last-minute cancellations.

Performance of a pediatric ambulatory anesthesia program--a developing country experience.

BACKGROUND: The aim of this study was to evaluate the performance of a pediatric ambulatory anesthesia program in a tertiary care teaching hospital in a developing country. METHODS: Data on all pediatric patients (<16 years of age) scheduled to have elective day-care surgery during a 1 year period from January 1999 to December 1999 were collected retrospectively. An audit form was used to determine the specialty of the procedures, anesthesia techniques, postoperative analgesia, perioperative complications, unplanned admissions and outcomes with respect to morbidity and mortality. RESULTS: A total of 763 pediatric ambulatory surgical procedures were performed during the year of 1999. The procedures included general surgery, ENT, orthopedic and plastic surgery. The most common procedure was inguinal hernia repair followed by umbilical hernia repair, adenotonsillectomy and circumcision and 96% of the patients had general anesthesia. There were only three unplanned admissions (0.4%); one for a surgical reason and two for anesthetic reasons. There was no serious morbidity or mortality in any patient. CONCLUSIONS: Performance of pediatric day-care anesthesia has been good in our day-care unit and we have a successful ambulatory surgery program, despite the limitations of a developing country.