Amisulpride prevents nausea and vomiting associated with highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled, dose-ranging trial
Chemotherapy-induced nausea and vomiting (CINV) remain significant clinical problems, especially in the delayed phase (24–120 h after chemotherapy). Amisulpride is a dopamine D2/D3-receptor antagonist previously shown to be an effective intravenous antiemetic. We conducted a randomised, double-blind study to characterise the dose response of oral amisulpride in delayed phase CINV.
Chemotherapy-naïve patients receiving cisplatin ≥ 70 mg/m2 or an anthracycline-cyclophosphamide regimen for breast cancer received, on day 1, 20 mg amisulpride and 8–16 mg ondansetron intravenously followed, once daily on days 2–4, by 10, 20 or 40 mg oral amisulpride or placebo. A control group receiving standard three-drug prophylaxis was enrolled for assay sensitivity purposes. The primary endpoint was complete response (CR), defined as no emesis or rescue medication use, in the delayed phase.
Three hundred eighteen subjects were evaluable per protocol. CR rate (24–120 h) was 20% with placebo and 46% with 10 mg amisulpride (p = 0.006 after multiplicity adjustment); in the three-drug control group, it was 59%. Emesis, nausea and 0–120-h CR rate were significantly improved with 10 mg amisulpride compared to placebo. Higher doses of amisulpride were not more effective than 10 mg. In patients with acute phase CR, delayed phase CR rate was 44% for placebo, 75% for 10 mg amisulpride (p = 0.022) and 70% for the 3-drug control. No significant differences were seen between groups in safety parameters.
Amisulpride 10 mg orally is safe and superior to placebo at preventing delayed CINV caused by highly emetogenic chemotherapy.
KeywordsAmisulpride Nausea Vomiting Chemotherapy Cisplatin Anthracycline-cyclophosphamide
Editorial assistance was provided by Peter Bates of Cambridge Medical Writing Services, UK.
The protocol was drafted by Gabriel Fox and Jørn Herrstedt and all authors contributed to the final version. All other authors included patients in the study. A draft manuscript was prepared by Jørn Herrstedt and Gabriel Fox and finally reviewed and approved by all authors.
This study was financially funded by Acacia Pharma Ltd., Cambridge, UK.
Compliance with ethical standards
The protocol was approved by independent ethics committees at each site/country (25 sites and 3 countries) and the study was conducted in accordance with Good Clinical Practice and with the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all individual participants included in the study.
Conflict of interest
Gabriel Fox is an employee and stockholder of Acacia Pharma Ltd.
Karin Jordan has received honoraria for advisory board meetings and/or presentations for Merck, MSD, Helsinn, Tesaro, Amgen, Hexal and Pfizer.
No other potential conflicts are disclosed.
- 1.Roila F, Molassiotis A, Herrstedt J, Aapro M, Gralla RJ, Bruera E, Clark-Snow RA, Dupuis LL, Einhorn LH, Feyer P, Hesketh PJ, Jordan K, Olver I, Rapoport BL, Roscoe J, Ruhlmann CH, Walsh D, Warr D, van der Wetering M, participants of the MASCC/ESMO Consensus Conference Copenhagen 2015 (2016) 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol 27:v119–v133CrossRefGoogle Scholar
- 7.Kranke P, Eberhart L, Motsch J, Chassard D, Wallenborn J, Diemunsch P, Liu N, Keh D, Bouaziz H, Bergis M, Fox G, Gan TJ (2013) I.V. APD421 (amisulpride) prevents postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled, multicentre trial. Br J Anaesth 111:938–945CrossRefGoogle Scholar
- 8.Gan TJ, Kranke P, Minkowitz HS, Bergese SD, Motsch J, Eberhart L, Leiman DG, Melson TI, Chassard D, Kovac AL, Candiotti KA, Fox G, Diemunsch P (2017) Intravenous amisulpride for the prevention of postoperative nausea and vomiting: two concurrent, randomized, double-blind, placebo-controlled trials. Anesthesiology 126:268–275CrossRefGoogle Scholar
- 10.Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 280:83–97PubMedGoogle Scholar
- 12.Aapro M, Rugo H, Rossi G, Rizzi G, Borroni ME, Bondarenko I, Sarosiek T, Oprean C, Cardona-Huerta S, Lorusso V, Karthaus M, Schwartzberg L, Grunberg S (2014) A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 25:1328–1333CrossRefGoogle Scholar
- 13.Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, Chawla SP, Carides AD, Ianus J, Elmer ME, Evans JK, Beck K, Reines S, Horgan KJ (2003) The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin Oncol 21:4112–4119CrossRefGoogle Scholar
- 14.Warr DG, Hesketh PJ, Gralla RJ, Muss HB, Herrstedt J, Eisenberg PD, Raftopoulos H, Grunberg SM, Gabriel M, Rodgers A, Bohidar N, Klinger G, Hustad CM, Horgan KJ, Skobieranda F (2005) Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23:2822–2830CrossRefGoogle Scholar
- 16.Herrstedt J, Sigsgaard T, Handberg J, Schousboe BMB, Hansen M, Dombernowsky P (1997) Randomized, double-blind comparison of ondansetron versus ondansetron plus metopimazine as antiemetic prophylaxis during platinum-based chemotherapy in patients with cancer. J Clin Oncol 15:1690–1696CrossRefGoogle Scholar
- 17.Sigsgaard T, Herrstedt J, Handberg J, Kjær M, Dombernowsky P (2001) Ondansetron plus metopimazine compared with ondansetron plus metopimazine plus prednisolone as antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy. J Clin Oncol 19:2091–2097CrossRefGoogle Scholar
- 19.Besser GM, Delitala G, Grossman A, Stubbs WA, Yeo T (1980) Chlorpromazine, haloperidol, metoclopramide and domperidone release prolactin through dopamine antagonism at low concentrations but paradoxically inhibit prolactin release at high concentrations. Br J Pharmacol 71:569–573CrossRefGoogle Scholar