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

Outcomes

The primary efficacy variable was the dichotomous variable success or failure of initial postoperative nausea or vomiting treatment, where success (also termed complete response) was defined as no emetic episodes (vomiting or retching) or administration of antiemetic rescue medication in the 24-h period after dosing, excluding any emesis events in the first 30 min. The purpose of the 30-min exclusion was to allow time for the study medication to work. A sensitivity analysis was prespecified to assess whether the exclusion period had any impact on the results.

Secondary endpoints included the incidence of vomiting, nausea, significant nausea (defined as a nausea score at or above 4 on an 11-point verbal rating scale[21]), and rescue medication use; severity of nausea; evolution of nausea, defined as area under the curve of nausea scores against time after treatment; time to treatment failure; time spent in PACU after dosing; and overall hospital length of stay after dosing.

Statistical Analysis

A sample size of 690 subjects (average 230 per arm) delivered a power of at least 90% at an overall two-sided α of 0.025 of detecting a difference of 0.16 between the success rate in the placebo group, assumed to be 0.30, based on Kovac et al.,[13] and the success rate in either amisulpride dose group, set pragmatically at 0.46 as a realistic and clinically relevant rate, after adjusting for multiplicity from making two pairwise comparisons with placebo, achieving a global two-sided α of 0.05. Because 25 to 30% of enrolled patients were expected to experience postoperative nausea or vomiting, it was planned to enroll about 2,500 patients.

All statistical analyses were specified a priori in a Statistical Analysis Plan, signed before study unblinding, and were conducted in SAS version 9.4 (SAS Institute, USA). Baseline characteristic, efficacy, and safety variables were summarized using standard descriptive 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 complete response between each amisulpride group and the placebo group using Pearson's χ 2 test, with a 5% significance level, after applying Hommel's method to control the family-wise error rate. This technique adjusts the P value to take account of multiple comparisons (two active groups) against the single placebo group. To test the robustness of the primary analysis, a Cochran-Mantel-Haenszel test of complete response, stratified by center, and a logistic regression analysis, with treatment, number of risk factors, type of surgery (open vs. laparoscopic), and center included as factors in the model, were conducted.

Secondary efficacy variables assessed by incidence (e.g., nausea, vomiting, rescue medication use) were compared between the groups using Pearson's χ 2 test. Time-to-event secondary efficacy variables were compared using the log-rank test. Continuous secondary efficacy variables (e.g., nausea evolution) were compared using a Mann–Whitney test. No statistical testing was prespecified for PACU or hospital length of stay or for adverse event rates.

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