Amisulpride for the Rescue Treatment of Postoperative Nausea or Vomiting in Patients Failing Prophylaxis

A Randomized, Placebo-controlled Phase III Trial

Ashraf S. Habib, M.B., B.Ch.; Peter Kranke, M.D.; Sergio D. Bergese, M.D.; Frances Chung, M.D.; Sabry Ayad, M.D.; Naveed Siddiqui, M.D.; Johann Motsch, M.D.; David G. Leiman, M.D.; Timothy I. Melson, M.D.; Pierre Diemunsch, M.D., Ph.D.; Gabriel M. Fox, M.B.; B.Chir.; Keith A. Candiotti, M.D.

Disclosures

Anesthesiology. 2019;130(2):203-212. 

In This Article

Materials and Methods

Study Design

This randomized, double-blind, parallel-group study (chief investigator: A.S.H.) was conducted at 23 centers in the United States, Germany, Canada, and France between March 2016 and January 2017. An independent ethics committee approved the study at each center. Written informed consent was obtained from all patients before enrollment. The study was sponsored and fully funded by Acacia Pharma, Ltd. (United Kingdom). Data were collected and analyzed by the sponsor; all authors had access to the data. The study was overseen by a data monitoring committee and was registered on ClinicalTrials.gov (reference NCT02646566) in January 2016.

Patient Population

Patients of either sex could be considered for inclusion if they were at least 18 yr of age, had freely given written informed consent, were scheduled to undergo open or laparoscopic elective surgery under general inhalational anesthesia expected to last at least 1 hr, and were judged by the investigator to have a moderate or high risk of experiencing postoperative nausea or vomiting, based on established postoperative nausea or vomiting risk factors such as those included in the Apfel risk score.[20] Women of childbearing potential had to be able and willing to use a highly effective form of contraception. Patients were ineligible if they were scheduled to undergo transplant surgery or any surgery where postoperative emesis would pose a significant danger to them; were planning to receive only a local anesthetic or regional neuraxial (intrathecal or epidural) block; had received amisulpride for any indication in the 2 weeks before screening; were allergic to amisulpride or any of the excipients of the study medication; had significant ongoing vestibular disease or dizziness; had a known prolactin-dependent tumor or pheochromocytoma; had documented or suspected alcohol or substance abuse within the previous 6 months; had direct or indirect evidence of clinically significant hypokalemia, such as serum potassium less than 3.0 mM; had received postoperatively, and before receiving study drug, any medication with a substantial risk of inducing torsades de pointes; had a documented, clinically significant cardiac arrhythmia or congenital long QT syndrome; were pregnant or breastfeeding; had a history of epilepsy or Parkinson's disease or were being treated with levodopa; or had received emetogenic anticancer chemotherapy in the previous 4 weeks.

Procedures, Randomization, and Masking

Patients were screened for enrollment up to 28 days before surgery. With respect to the surgical procedure, institutions followed their standard practice in terms of anesthetic technique and agents and peri-/postoperative management. Although patients should only have been enrolled if inhalational anesthesia was planned, it was permitted to randomize a patient with postoperative nausea or vomiting who had received total intravenous anesthesia.

To be randomized into a treatment arm, enrolled patients had to have received pre- or perioperative nausea or vomiting prophylaxis, involving the investigator's choice of one or more antiemetics, as long as no dopamine-antagonist antiemetic was included; and experienced a "qualifying postoperative nausea or vomiting episode," defined as a first episode of emesis (retching or vomiting) or request or obvious requirement for antiemetic medication to treat nausea, not more than 24 h after wound closure and before hospital discharge, for which they had not already received an antiemetic. A dopamine-antagonist with antiemetic potential was not to be given for any purpose from 24 h before surgery up to the time of the qualifying postoperative nausea or vomiting episode. Antiemetic rescue medication was to be given immediately on patient request or when there were signs of patient distress attributable to nausea or emesis; or, once 30 min had elapsed after treatment with the study drug, when symptoms were not improving. The choice of rescue antiemetic was according to standard practice in each institution.

A master randomization list was generated by a specialist contractor before study start using Prisym software (Prisym ID, Ltd., United Kingdom), to allocate patients on a 1:1:1 basis to receive 5 mg amisulpride, 10 mg amisulpride, or placebo, with a block size of nine and stratification by study center. Study medication was manufactured by the sponsor and provided in individual patient kits, each prelabeled with a unique patient identification number from the randomization list. Each kit contained a pair of identical 2-ml vials containing a clear, colorless solution. For the 5-mg treatment, both vials contained 2.5 mg amisulpride; for the 10-mg treatment, both contained 5 mg amisulpride; and for the placebo, both contained the same excipients as the active drug but no amisulpride. All study staff and patients were blinded as to the contents of the vials. To randomize an eligible patient, study staff selected the next available kit from their stock held in pharmacy or PACU and drew up 4 ml of study medication from the two vials. Study drug was administered intravenously over approximately 2 min.

To assess clinical effect, all episodes of emesis (vomiting or retching), nausea (scored using a self-reported 11-point verbal scale, where 0 represented no nausea and 10 represented the worst nausea possible), and rescue medication use were recorded during the 24 h after study drug administration. Nausea was further assessed by direct questioning immediately before and at 5, 15, 30, and 120 min after dosing and at any time the patients spontaneously reported nausea afterward. Patients could be discharged as soon as the investigator was satisfied that it was medically acceptable for them to go home, subject to a minimum 2-h stay postdosing if the criteria for failure had not been met. Patients discharged before 24 h, who had not already met the criteria for failure or were withdrawn from the study, were given a diary card to complete at home and were followed up for the data by telephone as soon as possible after 24 h.

Blood samples were taken for hematology and biochemistry analysis before dosing and at 24 h, or within an hour of discharge if that occurred sooner. Adverse events were recorded for 7 days after treatment, except for nausea and emesis in the first 24 h, which were already captured as part of the efficacy assessment.

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