Casopitant and Ondansetron for Postoperative Nausea and Vomiting Prevention in Women at High Risk for Emesis a Phase 3 Study

ORIGINAL ARTICLE Casopitant and Ondansetron for Postoperative Nausea and Vomiting Prevention in Women at High Risk for Emesis A Phase 3 Study A´ ron Altorjay, MD, PhD; Timothy Melson, MD; Thitima Chinachoit, MD; Attila Kett, MD; Keith Aqua, MD; Jeremey Levin, MD, PhD; Linda M. Blackburn, MS, RN; Steve Lane, MSc; Joseph V. Pergolizzi Jr, MD Hypothesis: Postoperative nausea and vomiting (PONV) sponse, defined as no vomiting, retching, or rescue are associated with a variety of complications. Neuroki- therapy. Patients received a balanced anesthetic nin subtype 1 receptor antagonists have antiemetic ac- regimen. tivity in the postoperative setting, and the neurokinin subtype 1 receptor antagonist casopitant mesylate Results: Between March 20 and August 31, 2006, 484 (GW679769) was well tolerated and effective at reduc- patients were enrolled in the study. Patients in the ca- ing the incidence of PONV in phase 1 and phase 2 trials. sopitant plus ondansetron group had a 68.7% rate of complete response during the first 24 hours after surgery com- Design: A multicenter, randomized, double-blind, par- pared with 58.7% in the ondansetron-only group (P=.03). allel-group, phase 3 analysis was designed to evaluate the The difference between groups in complete response from safety and efficacy of casopitant in combination with a 24 to 48 hours (63.4% with ondansetron only vs 70.0% single intravenous dose of the serotonin subtype 3 re- with ondansetron plus casopitant) was not significant. ceptor antagonist ondansetron hydrochloride for the pre- No vomiting for 0 to 24 hours was observed in 89.7% of vention of PONV in the perioperative setting. the casopitant plus ondansetron group compared with 74.9% of the ondansetron-only group (PϽ.001). Oral ca- Setting: Forty-three centers in 11 countries. sopitant administered in combination with ondanse- Patients: We studied 484 women at high risk for de- tron was well tolerated. veloping PONV scheduled to undergo operations associated with high emetogenic risk. Conclusions: The results of this pivotal phase 3 study demonstrate that the combination of casopitant and on- Interventions: The women were randomized to re- dansetron was superior to ondansetron only in patients ceive a single dose of intravenous ondansetron, 4 mg, or at high risk for PONV. oral casopitant, 50 mg, in combination with intravenous ondansetron, 4 mg. Trial Registration: clinicaltrials.gov Identifier: NCT00326248 Main Outcome Measures: The primary end point was the proportion of patients who achieved a complete re- Arch Surg. 2011;146(2):201-206 OSTOPERATIVE NAUSEA AND postsurgical administration of opioids of- vomiting (PONV) can oc- ten leads to emesis.3 Risk stratification cur after local, regional, or analyses have identified female sex, a his- general anesthesia and is as- tory of motion sickness or PONV, non- sociated with a variety of smoking status, and the use of postopera- Ppostsurgical complications that can ad- tive opioids as independent risk factors for versely affect patient recovery and dis- PONV.4,5 In higher-risk patients, PONV charge.1 Examples of common surgical can occur at rates of 70% to 80%.6,7 Be- procedures associated with increased risk cause multiple receptors appear to be in- of emesis include laparoscopic cholecys- volved in the etiology of PONV, there is a tectomy and abdominal surgery for all pa- growing consensus that prophylaxis against tients, gynecologic procedures and breast PONV, especially in high-risk popula- surgery for women, and shoulder sur- tions, may be better achieved by using a gery for men. Volatile anesthetics have combination of antiemetic agents that act Author Affiliations are listed at been reported to be associated with higher on the different neurotransmitter recep- the end of this article. rates of PONV,2 and intraoperative and tors involved in the emetic pathway.8 (REPRINTED) ARCH SURG/ VOL 146 (NO. 2), FEB 2011 WWW.ARCHSURG.COM 201 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Human studies have demonstrated that neurokinin sub- nasogastric or oral-gastric tube with intermittent or continu- type 1 receptor antagonists have antiemetic activity in the ous suctioning postoperatively were excluded from this study. postoperative setting for prevention and treatment.9,10 The Patients who had received medication with potential anti- neurokinin subtype 1 receptor antagonist aprepitant was emetic activity in the 24-hour period before surgery or were found to be superior to the intravenous (IV) serotonin sub- scheduled to receive antiemetics not included in the study dos- ing scheme during the evaluation period were also excluded. type 3 receptor antagonist ondansetron hydrochloride for The first dose of rescue antiemetic medication could be ad- the prevention of vomiting in the first 24 to 48 hours and ministered when medically indicated, at physician discretion, comparable with ondansetron for nausea control, use of or at any time on the patient’s request. During the 48-hour as- rescue therapy, and complete response.11 sessment phase, episodes of nausea or emesis that resulted in Casopitant mesylate (GW679769) is a potent and se- the administration of rescue medication were considered treat- lective neurokinin subtype 1 receptor antagonist that is ment failures rather than adverse events (AEs) or serious ad- readily absorbed after oral administration with a mean verse events (SAEs) and were captured in the assessments of absolute bioavailability of 57.0% and a median (range) emesis and nausea in the patient diary unless the severity was time to maximal plasma concentration of 1.75 hours (1.0- greater than expected. The institutional review board or eth- 4.0 hours). Casopitant is extensively metabolized, and ics committee at each institution approved the protocol, and written informed consent was obtained from each patient be- nonclinical data suggest this occurs primarily via CYP3A4. fore the performance of any study-specific procedures. The terminal plasma elimination half-lives of casopitant after single-dose administration of 150 mg of oral casopitant or 90 mg of IV casopitant were 17.0 and 15.6 hours, STUDY DESIGN respectively. A major circulating metabolite, GSK525060 (M13), has a similar half-life.12 Patients were randomized to 1 of 2 treatment arms. Patients in Casopitant has been investigated for the prevention cohort A received an oral placebo for casopitant approxi- and treatment of PONV and chemotherapy-induced nau- mately 60 minutes before and standard IV ondansetron, 4 mg sea and vomiting. In previous phase 1 and 2 trials, ca- (for 2-5 minutes), immediately before the induction of anes- sopitant at a 50-mg oral dose was well tolerated and re- thesia. Patients in cohort B received oral casopitant, 50 mg, ap- duced the incidence rate of PONV. In a repeat-dose proximately 60 minutes before and IV ondansetron, 4 mg (for pharmacokinetic interaction study13 in healthy pa- 2-5 minutes), immediately before the induction of anesthesia. The primary objective of this study was to determine the tients, no relevant effect on ondansetron kinetics was proportion of patients who achieved a complete response (de- found after coadministration with single doses of caso- fined as no vomiting, retching, or rescue therapy during the pitant, 30 and 90 mg. first 24 hours after the placement of the last suture or last staple). On the basis of these results, this phase 3 study On the basis of phase 2 data, assuming a 40.0% complete re- (NKT102553) was designed to evaluate the safety and sponse rate for cohort A (IV ondansetron, 4 mg, only) at 24 efficacy of casopitant in combination with ondansetron hours, 231 patients per arm were expected to be required to for the prevention of PONV. The primary objective was show a 15.0% absolute difference in complete response rates to demonstrate the superiority of oral casopitant in com- between the 2 treatment arms with 90.0% power and a 2-sided bination with a single IV dose of ondansetron compared level of significance of .05. with a single IV dose of ondansetron only in the control Secondary objectives included analyzing the following: (1) the severity of nausea experienced by patients, as assessed by of emesis during the first 24 hours after surgery in women a 0- to 10-point Likert scale and a categorical scale (none, mild, who were predicted to have a high risk of emesis. moderate, or severe) analyzed using a nonzero correlation test; (2) time to first emetic event, defined as the time from place- METHODS ment of the last suture or staple to the first emetic episode and summarized using Kaplan-Meier estimates; (3) time to first antiemetic rescue medication, defined as the time from place- PATIENT POPULATION ment of the last suture or staple to the first use of antiemetic rescue medication and summarized using Kaplan-Meier esti- This multicenter, randomized, double-blind, parallel-group, mates; (4) patient satisfaction with the prophylactic anti- phase 3 study (NCT00326248) enrolled only patients 18 years emetic regimens and their willingness to use the same treat- or older with American Society of Anesthesiologists Physical ment regimen for future surgical procedures, as assessed by the Status Classification of P1 or P2 (healthy or mild systemic dis- patient satisfaction assessment in the patient diary; (5) safety ease, respectively) who had all 4 Apfel risk factors4 for PONV and tolerability of the antiemetic regimens and AE reporting; (female sex, history of

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