A 24 Milligram Bimodal Release Ondansetron Pill (RHB-102) Shows No Evidence of QT Interval Prolongation

Background: Ondansetron is first line treatment for vomiting and one of the most common medications in the ED setting. Concerns over the 32mg IV dose association with prolonged corrected QT interval (QTc) and torsades de pointes prompted an FDA warning in 2011. Still, there is a paucity of prospective data evaluating lower dose ondansetron in the acute care setting. As part of a double blind, placebo-controlled trial of a 24 mg bimodal release ondansetron (BRO) pill, we tested the safety of BRO compared to placebo on QTc change. The safety outcomes included either an increase in mean QTc or an increase in the proportion of patients with QTc change \u3e 30 msec. Methods: This was a planned safety outcome analysis within a multi-center, double blind, placebo-controlled trial. The trial compared the effects of BRO among patients â%o¥ 12 years, who presented to 19 EDs and 2 urgent-care centers with symptoms of acute gastroenteritis. The BRO provides early serum levels similar to an 8mg immediate release ondansetron tablet with sustained levels over 24 hours. Exclusion criteria were CHF, uncontrolled diabetes, recent surgery, alcohol and substance abuse, and a baseline EKG QTc\u3e 450ms. The safety endpoint for this analysis was the change in QTc interval at 4 hours following administration of study drug compared to baseline QTc. We calculated each QTc using both Bazett’s (QTcB) and Fredericia’s (QTcF) formulas. Statistical analyses included Chi Square and student’s t-test methods. Results: There were 156 patients who had ECG testing within the overall trial. The mean baseline QTcB in the BRO and placebo arms were 429.9 and 423.5 msec respectively. There was no difference in the change in QTcB at 4 hours post-study drug administration between the BRO (+1.1, 95% CI -2.9 to 5.2 msec) and placebo group (+4.4, 95% CI -0.2 to 9.0 msec). There was similarly no difference using the QTcF calculation. There were 4 (4.4%) patients in the BRO arm with a QTcB change \u3e 30 msec vs. 4 (7.1%) in the placebo arm (p=0.48). No patients in either arm had a QTcB change \u3e 60 msec after study drug administration. Conclusion: In patients with normal baseline QTc, bimodal extended release ondansetron caused no QTc prolongation in comparison to placebo. This supports previous post-marketing safety data for the currently available single dose short-acting oral formulation among patients without risk factors

Treatment of Acute Gastroenteritis-Related Emesis with Bimodal Release Ondansetron

Background: There are 179 million cases of acute gastroenteritis (AGI) annually in the USA. In this study we tested a long-acting experimental 24 mg bimodal release ondansetron (BRO) pill which provides early serum levels similar to an 8mg immediate release tablet but sustains levels over 24 hours. We studied whether oral BRO improves 24 hour emesis related outcomes without the use of intravenous (IV) therapy among emergency department (ED) and urgent-care patients with AGI. Methods: This was a placebo-controlled double-blind randomized trial comparing the effects of BRO with a like-appearing placebo among patients \u3e12 years presenting to 19 EDs and 2 urgent-care centers with symptoms of AGI. Among inclusion criteria were \u3e2 episodes of emesis 4 hours prior to ED arrival, and duration of symptoms ≤ 36 hours. Among exclusion criteria were pregnancy, recent surgery, alcohol abuse, and an EKG QTC\u3e 450ms. The primary endpoint of treatment failure was defined as IV fluids given, vomiting, or rescue anti-emetics 30 minutes-24 hours after the first dose of study medication. Randomization was performed in a 3:2 treatment/placebo ratio after obtaining written consent and before any intervention. Patients with ED treatment success were discharged with a home diary and 3 additional study pills to use as needed. Statistical analyses included the Cochran Mantel Haenszel test and supporting logistic regression analyses. Odds ratios (OR) included 95% confidence intervals. Results: 321 patients were randomized with a mean age of 29.0 years. The intention to treat (ITT) analysis indicated treatment success of 66% (126/192) in the BRO group vs 54% (70/129) in the placebo group (OR 1.6 (1.02, 2.54) p=0.04). A per-protocol analysis found treatment success of 70% (123/177) vs 55% (67/122) in placebo (OR 1.87 (1.16, 3.02) p=0.01). Baseline nausea was a predictor of outcome (p=0.01) and was more severe in the treatment group. The ITT nausea-adjusted OR in favor of treatment was (1.78 (1.11, 2.86), p=0.02). Finally, the OR for treatment effect in ITT outcomes at 4 days after ED treatment was 1.47 (0.92, 2.35, p=0.10). Conclusion: This is the first study of AGI-related emesis showing benefit from any ondansetron preparation in adolescents and adults. Further, the study suggests AGI can be treated with a long-acting bimodal release tablet, potentially avoiding the need for IV access and repeat oral dosing