title: Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial.
abstract: 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.
authors.affiliation: Helsinn Healthcare SA, Via Pian Scairolo 9, 6912 Lugano/Pazzallo, Switzerland.
authors.forename: Tulla
authors.initials: T
authors.lastname: Spinelli
authors.affiliation: Helsinn Healthcare SA, Via Pian Scairolo 9, 6912 Lugano/Pazzallo, Switzerland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Moresino
authors.affiliation: CRS Clinical Research Services Mannheim GmbH, Grenadierstrasse 1, 68167 Mannheim, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Baumann
authors.affiliation: CRS Clinical Research Services Mannheim GmbH, Grenadierstrasse 1, 68167 Mannheim, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Timmer
authors.affiliation: CRS Clinical Research Services Mannheim GmbH, Grenadierstrasse 1, 68167 Mannheim, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Schultz
keywords: Chemotherapy-induced nausea and vomiting; ECG; NEPA; Netupitant; Palonosetron; QTc
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