Chemotherapy-induced nausea and vomiting is ranked among the worst side effects of chemotherapy. NEPA is an oral fixed-dose combination antiemetic under development, consisting of netupitant 300 mg, a highly selective NK1 receptor antagonist (RA), and palonosetron 0.5 mg, a pharmacologically and clinically distinct 5-HT3 RA. Although palonosetron is not associated with relevant ECG effects, this study evaluated cardiovascular safety of netupitant in combination with palonosetron, as well as its tolerability.This randomised, placebo- and positively controlled study in 197 subjects included 4 treatment groups: placebo, 200 mg netupitant + 0.5 mg palonosetron (NEPA200/0.5), 600 mg netupitant + 1.5 mg palonosetron (NEPA600/1.5, a supratherapeutic dose), and 400 mg moxifloxacin. Assessments included a 24-h baseline ECG recording, followed by a single dose of treatment and ECG measurements for 2 days.Mean placebo-corrected time-averaged changes from baseline were similar in NEPA200/0.5 and NEPA600/1.5 groups primarily for individually heart rate-corrected QT interval (QTcI: +4.7 and +3.6 ms, respectively) and for heart rate (HR: –3.3 bpm and –3.0 bpm), PR interval (–0.4 ms and 0.2 ms), and QRS interval (1 ms and 0.5 ms). The time-matched analysis showed no upper confidence interval >10 ms, with no suggestion of a QTc effect by pharmacokinetic-pharmacodynamic modeling for parent/metabolites. Moxifloxacin showed the expected placebo-corrected change from baseline (+8.4 ms time average) and the expected profile to establish assay sensitivity. No new morphologic changes of clinical relevance were observed. Treatment-related adverse events were comparable among groups.This study showed that NEPA treatments produced no significant effects on QTcI, HR, PR interval, QRS interval, and cardiac morphology relative to placebo, even at supratherapeutic doses.

No abstract

Purpose The use of serotonin type 3 (5-HT 3 ) receptor antagonists (RAs) in the prevention of nausea and vomiting caused by emetogenic chemotherapy is part of a comprehensive management strategy for patients undergoing chemotherapy. Electrocardiographic effects have been reported in patients after intravenous administration of 5-HT 3 RAs. The present study investigated the electrocardiogram (ECG) profile of the 5-HT 3

e20538 Background: Despite advances in supportive cancer care, chemotherapy-induced nausea and vomiting (CINV) is ranked by patients among the worst side effects of chemotherapy. NEPA is a new antiemetic under development composed of a unique fixed-dose combination of netupitant (NETU, 300 mg), a new, highly selective NK1 receptor antagonist (RA), and palonosetron (PALO, 0.5 mg), a pharmacologically and clinically distinct 5-HT3RA. NEPA targets the 2 most important emetic pathways with a single oral dose. Although PALO is not associated with cardiovascular issues, this study aimed to evaluate the tolerability and cardiovascular safety of different doses of NETU + PALO. Methods: This randomized, double-blind, parallel-group, placebo- and open-label positive-controlled study in 197 volunteers (106 men) included 4 treatment groups: placebo, 200 mg NETU + 0.5 mg PALO (NEPA 200/0.5), 600 mg NETU + 1.5 mg PALO (NEPA 600/1.5), and 400 mg moxifloxacin. Assessments, based on ICH E14 Guidelines, included a 24-h baseline ECG after which volunteers received a single dose of treatment, followed by ECG measurements for 2 days. The primary objective was to determine the individual heart rate-corrected QT interval (QTcI) (n=196). Safety and tolerability of NEPA groups were also assessed (n=197). Results: Mean placebo-corrected QTcI change from baseline was +5 and +4 ms for NEPA200/0.5 and NEPA600/1.5, respectively. Mean placebo-corrected change from baseline for heart rate (HR) was -3 bpm for the 2 NEPA groups. Placebo-corrected changes in pulse rate (PR) and QRS durations were similar in both NEPA groups (0 to 1 ms) and not clinically different from placebo. These data show no signs of an effect of NEPA groups on QTcI. In comparison, the moxifloxacin showed the expected increase in QTcI vs placebo (+8/9 ms). The frequency of all treatment-related AEs (TRAEs) for NEPA200/0.5 was lower than placebo but slightly higher in volunteers treated with NEPA600/1.5. The most commonly reported TRAEs in the NEPA groups were constipation, upper abdominal pain, and headache. Conclusions: NEPA treatments produced no significant effects on QTcI, HR, PR, QRS interval, or cardiac morphology relative to placebo.

SUMMARYThis double‐blind one‐year study compares the long‐term efficacy and safety of nimesulide with naproxen in patients with osteoarthritis (OA) of the knee or hip. Patients were randomised to nimesulide 100 mg twice daily (n=183) or naproxen 250 mg morning, 500 mg evening (n=187). The primary efficacy variable was change in pain intensity (WOMAC A scale) at 6 months. Nimesulide tablets showed at least equivalent efficacy to naproxen tablets in reducing pain intensity at 6 and 12 months (nimesulide ‐22.5% at 6 and 12 months; naproxen ‐22.4% at 6 months, ‐19.9% at 12 months; non‐inferiority proven). At 6 months the investigator assessed efficacy as ‘good’ or ‘excellent’ in 59.3% of nimesulide and 56.4% of naproxen‐treated patients, with corresponding values for patient assessment of 57% and 52.7%. Both treatments were well tolerated, with fewer related gastrointestinal adverse events reported with nimesulide (77 cases, 47.5%) than with naproxen (96 cases, 54.5%). This study shows nimesulide to be as effective as naproxen in the long‐term treatment of OA and to be associated with fewer gastrointestinal side‐effects.