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Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Amisulpride as Treatment of Established Postoperative Nausea and Vomiting in Patients Who Have Had No Prior Prophylaxis

Candiotti, Keith A. MD*; Kranke, Peter MD, MBA; Bergese, Sergio D. MD; Melson, Timothy I. MD§; Motsch, Johann MD; Siddiqui, Naveed MD, MSc; Chung, Frances MD#; Rodriguez, Yiliam MD*; Minkowitz, Harold S. MD**; Ayad, Sabry S. MD††; Diemunsch, Pierre MD, PhD‡‡; Fox, Gabriel MB, BChir§§

doi: 10.1213/ANE.0000000000003733
Ambulatory Anesthesiology: Original Clinical Research Report
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BACKGROUND: Postoperative nausea and vomiting (PONV) occurs commonly in surgical patients despite widespread prophylactic antiemetic use. Rescue options are currently limited. 5HT3 antagonists are most frequently used for prophylaxis, but if they fail, additional doses are not effective as rescue medication. Intravenous (IV) amisulpride, a well-studied D2/D3 antagonist, has been shown in trials to prevent PONV. This study was designed to determine if amisulpride could be used to treat established PONV in patients at low-to-moderate risk of PONV who had not received any prior prophylaxis.

METHODS: Men and women aged over 18 years were permitted to enroll if they were to undergo general inhalational anesthesia, expected to last at least 1 hour, for an outpatient or inpatient surgical procedure. Patients who then suffered PONV were randomized equally to 1 of 3 single-dose IV regimens: placebo or 5 or 10 mg amisulpride. The primary end point was complete response, defined as no emesis in the period 30 minutes to 24 hours after study drug treatment and no use of rescue medication in the entire 24-hour period.

RESULTS: One thousand nine hundred eighty-eight patients were enrolled preoperatively, of whom 560 were randomized to a treatment arm. Complete response occurred in 39 of 181 patients (21.5%) in the placebo group compared to 60 of 191 patients (31.4%; P = .016) and 59 of 188 patients (31.4%; P = .016) in the amisulpride 5 and 10 mg groups, respectively. The adverse event profile of amisulpride at either dose was similar to placebo.

CONCLUSIONS: IV amisulpride at 5 and 10 mg was safe and efficacious in the treatment of established PONV in surgical patients undergoing general anesthesia with no prior PONV prophylaxis.

From the *Department of Anesthesiology, Jackson Memorial Hospital, Miami, Florida

Department of Anaesthesia and Critical Care, University Hospitals of Würzburg, Würzburg, Germany

Department of Anesthesiology, Wexner Medical Center at The Ohio State University, Columbus, Ohio

§Department of Anesthesia, Helen Keller Hospital, Sheffield, Alabama

Department of Anesthesiology, Universitätsklinikum Heidelberg, Heidelberg, Germany

Department of Anesthesia, Mount Sinai Hospital, Toronto, Ontario, Canada

#Department of Anesthesia, Toronto Western Hospital, Toronto, Ontario, Canada

**Department of Anesthesia, Memorial Hermann Hospital, Houston, Texas

††Anesthesiology Institute, Outcomes Research, Fairview Hospital, Cleveland Clinic Health System, Cleveland, Ohio

‡‡Service d’Anesthésie-Réanimation Chirurgicale, Centre Hospitalier Universitaire de Hautepierre, Strasbourg, France

§§Department of Clinical Development, Acacia Pharma, Cambridge, United Kingdom.

Published ahead of print 16 July 2018.

Accepted for publication July 3, 2018.

Funding: This work was supported by Acacia Pharma Ltd, Cambridge, United Kingdom.

Conflicts of Interest: See Disclosures at the end of the article.

Clinical trial registry number: ClinicalTrials.gov NCT2449291.

Reprints will not be available from the authors.

Address correspondence to Keith A. Candiotti, MD, Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami, Jackson Memorial Hospital, (C-302), 1611 NW 12th Ave, Miami, FL 33136. Address e-mail to kcandiotti@miami.edu.

See Editorial, p

Postoperative nausea and vomiting (PONV) has remained a problem for surgical patients for many years, with an occurrence rate of approximately 30%1 in the general population and predicted to be up to 80% in patients at very high risk.2 While prophylaxis for PONV has been well studied and clearly shown to reduce the incidence of PONV,3 the area of rescue for patients who develop PONV, with or without prophylaxis, has been studied to a much lesser extent. There are multiple reasons for this. First, rescue trials require far more patients to be screened and are difficult to execute. Second, it is generally more desirable to prevent rather than rescue a patient from PONV, making the studies harder to justify and to enroll.

Although the intention of most practitioners is to prevent PONV, they often fail to give guideline-recommended prophylaxis4,5; in 1 observational study, 8% of patients at high risk for PONV received no antiemetic prophylaxis at all.6 In addition, even when patients are given appropriate prophylaxis, they often still develop PONV.6 For these reasons, the study of PONV rescue is important.

Another issue complicating PONV rescue is the fact that the agent used for prophylaxis, should it fail, cannot be used effectively for rescue, usually giving results no better than placebo.7 Rescue for patients developing PONV appears to be most effective with a drug from a different class from the one previously used for prophylaxis.8,9 In current practice, the most commonly used class of antiemetics for prophylaxis is the 5HT3 antagonists,10 ruling out this class as a rescue option for many patients. Dexamethasone, another commonly used antiemetic, is a suboptimal rescue choice, as it is slow to take effect and there are no prospective trial data to support its use. Other rescue options are limited due to lack of proven efficacy or due to the side effects associated with many of the other agents available for treatment. Historically, droperidol (a dopamine D2 receptor antagonist) was frequently used for PONV prophylaxis11 and treatment12 even though evidence from prospective, randomized trials of its efficacy in treatment is lacking. However, in 2001, a Food and Drug Administration boxed warning related to the risk of torsade de pointes caused its use to fall off considerably.10 It is, therefore, important to investigate new agents that could be used to treat established PONV.

Amisulpride is a dopamine (D2 and D3) antagonist that has been used in oral form since the 1980s for the treatment of psychosis.13 It has a highly favorable safety profile,14 with a very low incidence of extrapyramidal, cardiac, central nervous system, and gastrointestinal side effects, and has been shown in recent trials to be effective for the prevention of PONV.15,16 Amisulpride has the additional benefit of showing minimal QT prolongation when dosed in the therapeutic range for PONV,17 obviating a major concern related to droperidol.

The objective of this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was to determine if a single dose of either 5 or 10 mg amisulpride was superior to placebo in terms of complete response (CR) for the treatment of established PONV in surgical patients who had not received prior antiemetic prophylaxis.

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METHODS

This study was conducted at 21 sites in Canada, France, Germany, and the United States between August 2015 and July 2016. Prior to patient enrollment, the study was registered on ClinicalTrials.gov on 20 May 2015 (number NCT02449291; Chief Investigator: Dr K.A.C.). An independent ethics committee approved the study at each institution. Written informed consent was obtained from all patients before enrollment. The study was designed with the intention of generating data to meet the requirements of drug regulatory agencies for a new drug application. This article adheres to the applicable CONSORT guidelines.

Male and female subjects were eligible to be included in the study if they were at least 18 years of age; scheduled to undergo an elective, ambulatory or in-patient surgery (open or laparoscopic technique), excluding transplant surgery or any surgery where postoperative emesis could pose a significant danger to the patient and receive general, inhalational anesthesia expected to last at least 1 hour; and had a low-to-moderate risk of PONV based on a validated risk factor scoring system.18 Patients were ineligible if they were scheduled to receive only a local anesthetic and/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 amisulpride; had a significant history of ongoing vestibular disease or dizziness; were receiving regular antiemetic therapy (dosed at least 3 times per week), still ongoing within 1 week before surgery; had a known prolactin-dependent tumor (eg, pituitary gland prolactinoma or breast cancer) or pheochromocytoma; were pregnant or breastfeeding; had documented or suspected alcohol or substance abuse within the previous 6 months; had a documented, clinically significant cardiac arrhythmia or congenital long QT syndrome; had a history of epilepsy or Parkinson’s disease or were being treated with levodopa; or had received emetogenic anticancer chemotherapy in the 4 weeks before screening. To be randomized into a treatment arm, enrolled patients had to meet the following 3 criteria: (1) they had undergone a nonexcluded surgical procedure; (2) they experienced a first (“qualifying”) episode of PONV (an episode of vomiting or retching or an episode of nausea for which they requested antiemetic medication) in the 24-hour period after the end of surgery and before hospital discharge; and (3) they had not received any antiemetic agents for PONV prophylaxis or as treatment for the qualifying PONV episode. Patients could not be randomized if they had received postoperatively any medication with a substantial risk of inducing torsade de pointes or if they had direct or indirect evidence of clinically significant hypokalemia, such as a serum potassium level <3.0 mmol/L.

Screening took place in the 28 days before the operation. The primary study period was the period beginning with the qualifying PONV episode and ending 24 hours after administration of study medication. Safety follow-up occurred, by telephone if necessary, at day 7. (See Figure 1 for study design schema.) Patients were randomized to receive amisulpride, at a dose of 5 or 10 mg, or matching placebo in the following manner. Study medication was provided to centers in subject kits, each with a unique identification number. Each kit comprised 2 identical 2-mL vials, with 3 possible configurations: both vials could contain 2.5 mg amisulpride solution for a 5-mg treatment; both vials could contain 5 mg amisulpride for a 10-mg treatment; or both vials could contain placebo, which was identically formulated except for the absence of amisulpride. All vials were indistinguishable as to their contents. Kits were packed in multikit containers in numerical order, based on a master randomization list generated by a consultant statistician using Prisym software (Prisym ID Ltd, Wokingham, UK) before the study start to deliver a 1:1:1 randomization stratified according to study center. As soon as an enrolled patient had a qualifying PONV episode and met other criteria for randomization, the next kit was removed from the container and 4 mL of study medication was drawn up from the 2 vials. This effected randomization of the patient into the study. Study medication was administered over approximately 2 minutes into a peripheral or central venous cannula.

Figure 1.

Figure 1.

As far as possible, normal institutional practice was followed in terms of anesthetic technique, agents, and perioperative/postoperative management. Total intravenous anesthesia with propofol was to be avoided although propofol could be used for induction. Particular care was taken to avoid using any drugs with antiemetic potential even for another indication, eg, diphenhydramine for itching or metoclopramide as a prokinetic.

Efficacy was assessed during the 24 hours after administration of study drug. Episodes of emesis (vomiting or retching) and use of rescue medication were recorded. Nausea (scored using a self-reported 11-point verbal scale, where 0 represented no nausea and 10 the worst nausea possible) was assessed predose and at 5, 15, and 30 minutes and 2 hours after administration of study medication. Any nausea episodes spontaneously reported by the patient in the 24-hour period were also scored and recorded. Patients could be discharged as soon as the investigator or delegate was satisfied that it was medically acceptable for them to go home, subject to a minimum stay of 2 hours after study drug administration for those patients who had been randomized but not yet met the criteria for treatment failure. Treated patients discharged before 24 hours were given a diary card to complete at home, unless they had already received rescue therapy or withdrawn from the study; a follow-up telephone call was conducted as soon as possible after the end of the primary study period to obtain diary data.

Blood samples were drawn for hematology and biochemistry analysis before study drug dosing and at 24 hours or within an hour of discharge if that occurred sooner. Adverse events occurring during the 7 days after treatment were recorded, except for nausea and emesis events in the first 24 hours, which were already captured as efficacy variables.

The primary efficacy end point was CR, defined as no emetic episode or use of antiemetic rescue medication in the 24-hour period after administration of study medication, excluding any emesis in the first 30 minutes after dosing, intended to give time for the study medication to work. Secondary end points included the incidence of vomiting, rescue medication, and nausea separately; area under the curve (AUC) of nausea scores against time in the first 30 minutes; and time to failure of initial PONV treatment.

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Statistics

The primary efficacy analysis was a comparison, in the modified intent-to-treat population (all subjects who signed the informed consent form and received a dose of amisulpride or placebo study medication), of the incidence of CR between each amisulpride group and the placebo group using Pearson’s χ2 test, with a global 2-sided 5% significance level, after applying Hommel’s method to control the family-wise error rate, given a significance level of 2.5% for the comparison of each dose with placebo.

Secondary efficacy analyses included logistic modeling of the incidence of the primary efficacy variable to investigate the effects of adjustment for country, center, number and type of PONV risk factors, and type of operation. Secondary efficacy variables assessed by incidence (eg, nausea, vomiting, rescue medication use) were compared between the groups using Pearson’s χ2 test (without adjustment for multiplicity). Time-to-event secondary efficacy variables (eg, time to failure of rescue) were compared between the groups using the log-rank test. Ordinal secondary efficacy variables (eg, severity of nausea) were compared between the groups using a Mann-Whitney U test.

A sample size of 558 subjects (average of 186 per arm) had a power of 89.3% at an overall 1-sided α of .0125 (adjusting for multiplicity) to detect a difference of 0.175 between the response rate in the placebo group, assumed to be 0.30, and the response rate in either amisulpride dose group, assumed to be 0.475. Approximately 2500 patients were expected to be needed to give informed consent to yield the required number of evaluable, randomized subjects. There was no age distribution plan.

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RESULTS

A total of 1988 patients signed informed consent before surgery, of whom 568 were ultimately randomized for treatment (Figure 2).

Figure 2.

Figure 2.

Eight randomized patients did not receive treatment and discontinued the study because they withdrew consent before dosing or for other reasons. The 3 study groups were well balanced at baseline, with no material differences in respect of age, sex, race, country of enrolment, baseline PONV risk, or surgical/anesthetic details (Table 1).

Table 1.

Table 1.

In the modified intent-to-treat population, CR occurred in 39 of 181 patients (21.5%; 95% confidence interval [CI], 15.56–27.54) in the placebo group; 60 of 191 patients (31.4%; 95% CI, 24.83–38.00; P = .015; after Hommel adjustment: P = .016) in the amisulpride 5 mg group; and 59 of 188 patients (31.4%; 95% CI, 24.75–38.02; P = .016; adjusted P = .016) in the amisulpride 10 mg group (Table 2).

Table 2.

Table 2.

A logistic regression model with treatment, number of baseline risk factors, type of operation (abdominal surgery versus other surgery), and center as factors showed a benefit for both 5 mg amisulpride (adjusted odds ratio, 1.76; 95% CI, 1.09–2.86; P = .014) and 10 mg amisulpride (adjusted odds ratio, 1.72; 95% CI, 1.06–2.80; P = .014) over placebo.

The benefit was more marked in the first 2 hours after treatment, with a statistically significant difference of 12–15 percentage-points between the amisulpride groups and placebo. A post hoc analysis of CR at later time points indicated that a benefit of around 15 percentage-points was maintained for the 0–4 and 0–6 hour periods. Time to treatment failure was significantly longer for both doses of amisulpride than placebo (hazard ratio, 0.66, P < .001 for amisulpride 5 mg; hazard ratio, 0.71, P = .003 for amisulpride 10 mg; Figure 3).

Figure 3.

Figure 3.

The preplanned definition of CR excluded emesis events that occurred in the first 30 minutes after treatment. An exploratory sensitivity analysis in which those events were included showed CR rates of 20.4% for placebo, 31.4% for amisulpride 5 mg (P = .008), and 30.9% for amisulpride 10 mg (P = .011).

The use of rescue medication in the 24-hour posttreatment period was more frequent in the placebo group (74.6%) than the amisulpride 5 mg group (63.4%; P = .010) or 10 mg group (63.3%; P = .010). The incidences of emesis, any nausea, and significant nausea in the 24-hour posttreatment period were not significantly different among the 3 groups. The AUC of nausea scores was not significantly lower for either the 5 or the 10 mg dose of amisulpride than for placebo. However, in a post hoc analysis of the nausea AUC over the first 1, 2, and 3 hours after treatment, significant reductions were seen with both doses of amisulpride compared to placebo (Table 2).

The mean duration of stay in the postanesthesia care unit was 200 minutes (SD, 271) in the placebo group, 191 minutes (SD, 205) in the 5 mg amisulpride group, and 191 minutes (SD 191) in the 10 mg amisulpride group.

Table 3.

Table 3.

A higher proportion of patients reported at least 1 treatment-emergent adverse event in the placebo group (53.0%) than in the amisulpride 5 mg group (39.8%) or 10 mg group (42.0%; Table 3). There were very few serious adverse events and no deaths or withdrawals due to adverse events. There was 1 life-threatening event, renal hemorrhage, which occurred in the placebo group. The only adverse events to occur in 5% or more of any treatment group were flatulence, nausea occurring >24 hours after study drug administration, constipation, and infusion site pain. There were no meaningful differences between the amisulpride 5 mg and 10 mg and placebo groups in terms of the incidence of any adverse event or abnormal hematology or clinical chemistry value.

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DISCUSSION

A single intravenous dose of amisulpride, at both 5 and 10 mg, was significantly superior to placebo at treating established PONV, as determined by CR in the 24-hour period after study drug administration, thereby meeting the primary end point of the study. There were no material differences in terms of efficacy between the 5 and 10 mg doses of amisulpride. Although the preplanned definition of CR excluded emesis events in the first 30 minutes after treatment, intended to allow time for the treatment to take effect, this did not have a material effect on the overall results: in fact, when all emesis events from dosing were included in the CR definition, the benefit of amisulpride was slightly greater. The effect of amisulpride appeared to be rapid, with immediate separation of the amisulpride and placebo Kaplan–Meier curves for treatment failure. The benefit was somewhat more pronounced in the first 6 hours, where it amounted to about 15 percentage-points.

The incidence of CR in the placebo group was consistent with the few previously reported trials in treatment of established PONV. In 2 ondansetron treatment studies, each of which included a placebo group of slightly >100 patients, the incidence of treatment failure (defined, somewhat less strictly, as >1 emetic episode or use of any rescue medication) was 71%–76%19—similar to the 78.5% rate seen in this trial—while the failure rate in the ondansetron groups ranged from 41% to 53%. In a dose-ranging dolasetron study, which used an identical CR definition to this study, the placebo CR rate was 11%, while the CR rate in the different dolasetron dose groups ranged from 28% to 35%.20

Of the efficacy variables making up CR, the use of rescue medication—a key indicator of clinically relevant nausea—was significantly less frequent with both doses of amisulpride than placebo, whereas emesis was not significantly different between the groups. This may be entirely attributable to the low overall incidence of emesis (around 30%); however, it might also suggest that amisulpride may be more effective against nausea than emesis in the treatment setting. Such a pattern was reported for droperidol, another dopamine antagonist antiemetic21 though a subsequent investigation cast doubt on that.22 In terms of nausea, no difference was seen in the simple count of patients with any or significant nausea after treatment, but since most patients were randomized into the study with marked nausea at baseline (averaging between 6 and 7 on a 0–10 scale in each group), it is perhaps to be expected that most patients would still report nausea at some level after treatment. To overcome this limitation, it was preplanned to evaluate the evolution of nausea after treatment by comparing the AUC of the nausea scores reported by patients on direct questioning at 5, 15, and 30 minutes after treatment. Although this was not a validated measure, AUC is commonly used to compare pain scores in clinical trials and has been proposed as a suitable metric in general for patient subjective responses in episodic conditions.23 For the prespecified analysis period of the first 30 minutes after treatment, the reduction in nausea AUC for both doses versus placebo was not statistically significant. However, there was evidence, from a post hoc analysis, of superiority for both doses at 1, 2, and 3 hours after treatment.

It was of note that the 2 dose levels of amisulpride performed more or less identically. This contrasts with an earlier study in PONV prophylaxis in which a 20 mg dose appeared less effective than a 5 mg dose.15 It is unclear whether the antiemetic activity of amisulpride tapers off at doses above 10 mg but below 20 mg or whether a different dose–response profile exists for prevention and treatment.

Fewer adverse events were reported, and fewer patients experienced at least 1 AE in both amisulpride groups than in the placebo group, even with events of nausea and vomiting in the 24-hour posttreatment period excluded. This suggests that amisulpride is very well tolerated and also that effective management of PONV is associated with a general improvement in patient well-being. Of particular note, amisulpride showed no evidence of the toxicities associated with other commonly used antiemetics, notably cardiac and extrapyramidal events (droperidol, haloperidol, metoclopramide, and other dopamine antagonists), constipation (5HT3-antagonists), sedation (promethazine), and infection and diabetogenesis (dexamethasone), all of which are potential concerns in the early postoperative period. This benign safety profile is consistent with previous reports in both the perioperative setting15,16 and, at much higher doses, in psychiatric practice14 and suggests that amisulpride could be compatible with modern protocols for enhanced recovery after surgery.24

The major limitation of this study is that it involved only patients who had not received prophylaxis. Many patients undergoing general anesthesia have multiple PONV risk factors and receive 1 or more prophylactic antiemetics preoperatively or perioperatively. However, there remains an appreciable population of patients at low-to-moderate risk of PONV who are not routinely given prophylaxis, and a proportion of these patients still suffer with PONV. Therefore, it is worthwhile to study the effectiveness of an antiemetic in this setting and provides a useful proof of principle. Studies involving patients who have failed PONV prophylaxis are essential to establish substantial clinical utility for amisulpride. Another limitation is that only adult patients were included in this study. The drug’s utility for treating PONV in children remains to be determined.

PONV remains a persistent problem even many years after it was first addressed. Many patients still do not receive adequate PONV prophylaxis and many patients who do nevertheless go on to develop PONV. Agents approved for rescue that are reliable, effective, and safe to use in the demanding postanesthesia setting are lacking. Amisulpride may help to fill this need though further studies are required to determine its optimal role in the clinical management of PONV.

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DISCLOSURES

Name: Keith A. Candiotti, MD.

Contribution: This authorserved as the global chief investigator for the study and helped design the study, develop the protocol, enroll patients, review final data, and draft the manuscript.

Conflicts of Interest: None.

Name: Peter Kranke, MD, MBA.

Contribution: This authorhelped design the study, develop the protocol, enroll patients, and critically review the manuscript.

Conflicts of Interest: P. Kranke received consulting fees from Acacia Pharma Ltd.

Name: Sergio D. Bergese, MD.

Contribution: This authorcontributed to the protocol and helped enroll patients and critically review the manuscript.

Conflicts of Interest: None.

Name: Timothy I. Melson, MD.

Contribution: This authorcontributed to the protocol and helped enroll patients and critically review the manuscript.

Conflicts of Interest: None.

Name: Johann Motsch, MD.

Contribution: This authorserved as the coordinating investigator for Germany and helped design the study, develop the protocol, enroll patients, and critically review the manuscript.

Conflicts of Interest: None.

Name: Naveed Siddiqui, MD, MSc.

Contribution: This authorcontributed to the protocol and helped enroll patients and critically review the manuscript.

Conflicts of Interest: None.

Name: Frances Chung, MD.

Contribution: This authorserved as the coordinating investigator for Canada and helped design the study, develop the protocol, enroll patients, and critically review the manuscript.

Conflicts of Interest: None.

Name: Yiliam Rodriguez, MD.

Contribution: This authorcontributed to the protocol and the manuscript and helped enroll patients.

Conflicts of Interest: None.

Name: Harold S. Minkowitz, MD.

Contribution: This authorcontributed to the protocol and helped enroll patients and critically review the manuscript.

Conflicts of Interest: None.

Name: Sabry S. Ayad, MD.

Contribution: This authorcontributed to the protocol and helped enroll patients and critically review the manuscript.

Conflicts of Interest: None.

Name: Pierre Diemunsch, MD, PhD.

Contribution: This authorserved as the coordinating investigator for France and helped design the study, develop the protocol, enroll patients, and critically review the manuscript.

Conflicts of Interest: None.

Name: Gabriel Fox, MB, BChir.

Contribution: This authorserved as the study director and helped design the study, develop the protocol, oversee study operational activities, review final data, and draft the manuscript.

Conflicts of Interest: G. Fox is an employee and stockholder of Acacia Pharma Ltd.

This manuscript was handled by: Tong J. Gan, MD.

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