ORIGINAL ARTICLE Casopitant and 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 ac- regimen. tivity in the postoperative setting, and the neurokinin sub- type 1 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 com- plete 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 asso- ciated 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 intrave- nous 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- postsurgicalP 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 with potential anti- neurokinin subtype 1 receptor antagonist 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 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 caso- pitant 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 an- tiemetic 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 PONV and/or motion sickness, non- (6) proportion of patients experiencing complete protection, smoker status, and anticipated to receive opioids postopera- defined as no vomiting, retching, or rescue therapy, and maxi- tively) and were scheduled to undergo 1 of the following sur- mum nausea score less than 3 on the Likert scale; (7) propor- gical procedures: breast surgery, orthopedic shoulder surgery, tion of patients experiencing total control, defined as no vom- or thyroid surgery and laparoscopic or laparotomic proce- iting, retching, or rescue therapy, and a maximum nausea score dures for cholecystectomy, hysterectomy, or other gyneco- less than 1 on the Likert scale; (8) proportion of patients ex- logic surgery. periencing no vomiting, where vomiting was defined as vomit All operations were anticipated to involve general anesthe- or retch, but including patients who received rescue therapy; sia of at least 1 hour. Anesthetic regimens were not specified, (9) proportion of patients experiencing significant nausea, de- but investigators were required to adhere to a balanced gen- fined as a maximum nausea score of 3 or higher on the Likert eral anesthetic regimen as per their institutional guidelines and scale for nausea from all nausea assessments; (10) proportion common practice. was permitted for induction of, but of patients experiencing nausea, defined as a maximum nau- not maintenance of, anesthesia. Total IV anesthesia was not al- sea score of 1 or higher on the Likert scale for nausea from all lowed in this study. Patients who were anticipated to require a nausea assessments, with maximum nausea score analyzed using

(REPRINTED) ARCH SURG/ VOL 146 (NO. 2), FEB 2011 WWW.ARCHSURG.COM 202

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 1. Demographics of Study Patientsa

Cohort A Cohort B (Ondansetron (Casopitant Mesylate Hydrochloride Only) Plus Ondansetron) Demographic (n=229) (n=227) Total Age, y Mean (SD) 44.8 (12.44) 44.4 (12.19) 44.6 (12.30) Median (range) 44 (18-79) 44 (18-83) 44 (18-83) Height, cm Mean (SD) 161.3 (8.74) 162.8 (9.98) 162.0 (9.40) Median (range) 161 (79-183) 162 (65-194) 162 (65-194) Weight, kg Mean (SD) 70.6 (17.05) 72.3 (17.55) 71.5 (17.30) Median (range) 67 (37-154) 69 (41-128) 68 (37-154) Race, No. (%) African American or African 20/236 (8.5) 19/233 (8.2) 39/469 (8.3) American Indian or Alaskan Native and white 1/236 (0.4) 1/233 (0.4) 2/469 (0.4) Asian 50/236 (21.2) 46/233 (19.7) 96/469 (20.5) Central or South Asian 5/236 (2.1) 7/233 (3.0) 12/469 (2.6) Japanese, East Asian, or Southeast Asian 45/236 (19.1) 39/233 (16.7) 84/469 (17.9) Native Hawaiian or other Pacific Islander 0 1/233 (0.4) 1/469 (0.2) White 165/236 (69.9) 166/233 (71.2) 331/469 (70.6) American Society of Anesthesiologists Physical Status Classification, No. (%) P1 (healthy) 94/242 (38.8) 87/242 (36.0) 181/484 (37.4) P2 (mild systemic disease) 145/242 (59.9) 152/242 (62.8) 297/484 (61.4) P3 (severe systemic disease) 2/242 (0.8) 1/242 (0.4) 3/484 (0.6) Total surgery time, min Mean (SD) 92.1 (56.96) 87.7 (50.39) NA Median (range) 77 (10-414) 77 (14-270) NA

Abbreviation: NA, not applicable. a Percentages do not total 100 because of rounding.

a Wilcoxon rank sum test; and (11) proportion of patients re- RESULTS ceiving rescue medication. If a patient withdrew prematurely during the first 48 hours and did not have an emetic event or take rescue medication, the time of withdrawal was consid- STUDY POPULATION ered to be the time to first emetic episode or the time to first use of antiemetic rescue medication, and the patient’s data were Forty-three centers in 11 countries participated in this censored from that time point. global study. Between March 20 and August 31, 2006, For the primary analysis, testing was conducted at a .05 level of significance. The Cochran-Mantel-Haenszel test was 484 patients were enrolled. Demographic characteris- used to make comparisons. The odds ratios (ORs) are pre- tics were well balanced among the treatment groups sented along with the associated 95% confidence intervals (Table 1). The most frequently reported surgery types (CIs). Complete response in the 24- to 48-hour and 0- to 48- were hysterectomy (119 patients; 24.6%), cholecystec- hour periods was analyzed as described for the primary effi- tomy (77 patients; 15.9%), breast operation (44 pa- cacy analysis. If the primary objective was deemed significant, tients; 9.1%), thyroid operation (34 patients; 7.0%), and the following secondary objectives were tested hierarchically: bilateral salpingo-oophorectomy (12 patients; 2.5%). no vomiting, complete protection (defined as complete re- In total, 456 patients (94.2%) completed the study: 229 sponse with no significant nausea), maximum nausea score, (94.6%) in cohort A and 227 (93.8%) in cohort B. The rea- and total control (defined as complete response with no nau- sons for the premature withdrawal of the 28 patients were sea). Each secondary objective used the prespecified hierar- chy at the .05 level of significance with 95% CI. as follows: 7 were lost to follow-up (3 [1.3%] in cohort A All objectives (except safety, health outcomes, and time- and4[1.8%]incohortB),3hadprotocolviolations(2[0.9%] to-event end points) were assessed in the following time win- in cohort A and 1 [0.4%] in cohort B), 5 decided to with- dows: 0 to 24 hours, 24 to 48 hours, and 0 to 48 hours after draw (1 [0.4%] in cohort A and 4 [1.8%] in cohort B), and placement of the last suture or staple. Health outcomes were 13 withdrew because of other reasons (7 [3.1%] in cohort assessed at 48 hours only. Nausea was also assessed in the fol- A and 6 [2.6%] in cohort B), including canceled surgery (4 lowing time windows: 0 to 2 hours and 0 to 6 hours. Safety was in cohort A and 3 in cohort B), closed to recruitment (1 in also assessed at days 6 to 10. each group), and treatment failure (1 in cohort A). The primary population of interest was the modified intent-to- treat (ITT) population, which was used to perform the efficacy analysis. This population was the subset of the ITT population that PRIMARY EFFICACY DATA received any investigational product and underwent surgery. The safety population was a subset of the ITT population that received A significantly greater proportion of patients in the caso- an investigational product (casopitant or placebo). pitant plus ondansetron group achieved the primary ob-

(REPRINTED) ARCH SURG/ VOL 146 (NO. 2), FEB 2011 WWW.ARCHSURG.COM 203

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 significant. There was a statistically significant treatment A difference in favor of the casopitant plus ondansetron group 1.0 for patients with no vomiting during 0 to 24 hours (209/ 0.9 233 [89.7%] in the casopitant plus ondansetron group vs 0.8 176/235 [74.9%] in the ondansetron-only group; OR,0.34; 0.7 95% CI, 0.20-0.57; PϽ.001). No statistically significant 0.6 treatment difference was observed between the ondansetron- 0.5 only group (102/235 [43.4%]) and the casopitant plus on- 0.4 dansetron group (120/233 [51.5%]) for complete protec- 0.3 tion during 0 to 24 hours (OR, 1.39; 95% CI, 0.96-2.01;

Proportion With No Emesis 0.2 P=.08). As a result, the third and fourth hypotheses, for 0.1 maximum nausea score and total control, were not tested. 0.0 Although no statistically significant treatment difference was observed between the ondansetron-only group and the casopitant plus ondansetron group for severity of nausea B as measured by the Likert or categorical scales during 0 to 1.0 24 hours, there appeared to be a smaller proportion of pa- 0.9 tients in the casopitant plus ondansetron group (8.6%) re- 0.8 porting severe nausea compared with the ondansetron- 0.7 only group (16.2%). 0.6 Time to first emetic episode was different between the 0.5 ondansetron-only group and the casopitant plus on- 0.4 dansetron group, with the first emetic episode occur- 0.3 ring later in the casopitant plus ondansetron group. The 0.2 hazard ratio for the risk of emesis at any given time, rela-

Proportion With No Rescue Therapy 0.1 tive to the risk of the patients who received only on- 0.0 dansetron, was 0.414 (95% CI, 0.265-0.646) (Figure, A). Rescue medication use was reported by 31.0% of pa- tients in the ondansetron-only group and 26.0% in the ca- C 1.0 sopitant plus ondansetron group during 0 to 24 hours, by 0.9 6.0% in both groups during 24 to 48 hours, and by 33.0% 0.8 in the ondansetron-only group and 29.0% in the casopi- 0.7 tant plus ondansetron group during 0 to 48 hours. No dif- 0.6 ference was observed in the time to first rescue medica- 0.5 tion use. The hazard ratio for the risk of rescue medication 0.4 at any given time, relative to the risk of the patients who received only ondansetron rescue, was 0.841 (95% CI,

Proportion With CR 0.3 Casopitant Mesylate 0.606-1.167) (Figure, B). In a post hoc analysis, Kaplan- 0.2 0 mg Meier curves were produced for time to first complete re- 0.1 50 mg sponse failure (Figure, C). The trend was as expected and 0.0 0 12 24 36 48 was consistent with the overall clinical conclusion of ben- Time, h efit of casopitant plus ondansetron over ondansetron alone.

Figure. Kaplan-Meier curves. A, Time from last suture or staple to first SAFETY AND HEALTH OUTCOMES DATA emetic episode; B, time from last suture or staple to first rescue medication; and C, time from last suture or staple to first complete response (CR) failure. Of the 472 patients in the safety population, 237 pa- tients were randomized in the ondansetron-only group jective of complete response (no vomiting, retching, or res- and 235 patients in the casopitant plus ondansetron group. cue therapy) during 0 to 24 hours (160/233 [68.7%]) Three patients in the ondansetron-only group and 2 in compared with the ondansetron-only group (138/235 the casopitant plus ondansetron group received an in- [58.7%]; OR, 1.54; 95% CI, 1.05-2.25; P=.03). In the sup- vestigational product but were not recorded as having portive analysis of the ITT population, there was also a treat- received ondansetron study medication. ment difference between the casopitant plus ondansetron At least 1 AE was reported during the study by 182 group (66.0%) and the ondansetron-only group (57.0%) patients (38.6%). The most frequently reported AE irre- for complete response during 0 to 24 hours (P=.04). spective of causality was constipation, which occurred in 25 patients overall (5.3%). The AE profiles were simi- SECONDARY EFFICACY DATA lar in the 2 treatment groups (Table 2). However, con- stipation and hypotension were reported in a greater pro- The difference between groups in complete response from portion of patients in the casopitant group than in the 24 to 48 hours (163/233 [70.0%] in the casopitant plus on- ondansetron-only group. Twenty-seven patients (5.7%) dansetron group vs 149/235 [63.4%] in the ondansetron- had hypotension or procedural hypotension reported as only group; OR, 1.34; 95% CI, 0.91-1.98; P=.14) was not an AE: 10 patients in the ondansetron-only group and

(REPRINTED) ARCH SURG/ VOL 146 (NO. 2), FEB 2011 WWW.ARCHSURG.COM 204

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 17 in the casopitant plus ondansetron group. None of these was classed as an SAE. Twenty-seven patients (5.7%) Table 2. Adverse Events Irrespective of Causality Reported had at least 1 AE that was considered possibly related to in More Than 1% of Patients in Either Treatment Group (Safety Population) the investigational product by the investigator, with simi- lar profiles in both treatment groups. No. (%) of Patients Most AEs were of mild or moderate intensity, and the treatment groups were balanced with regard to AE pro- Cohort A Cohort B file by intensity. Twelve patients in the study (2.5%) ex- (Ondansetron (Casopitant Hydrochloride Mesylate Plus perienced at least 1 AE of severe intensity, 6 patients in Only) Ondansetron) each group. The most frequently reported AEs of severe Adverse Event (n=237) (n=235) intensity were constipation, occurring in 2 patients (0.4%) Any event 87 (36.7) 95 (40.4) in the casopitant plus ondansetron group, and muscu- Constipation 8 (3.4) 17 (7.2) loskeletal pain, occurring in 1 patient (0.2%) in each Flatulence 12 (5.1) 11 (4.7) group. Eleven patients (2.3%) had at least 1 SAE re- Hypotension 8 (3.4) 15 (6.4) ported in this study, but none of the SAEs were fatal or Headache 11 (4.6) 8 (3.4) considered to be related to the investigational product Anemia 5 (2.1) 6 (2.6) by the investigator. Cough 5 (2.1) 5 (2.1) Insomnia 4 (1.7) 6 (2.6) Patient satisfaction during 0 to 48 hours appeared to Nausea 4 (1.7) 6 (2.6) be similar in the 2 treatment groups. This also appeared Pruritus 5 (2.1) 4 (1.7) to be true regarding patient willingness to use the same Urinary retention 3 (1.3) 5 (2.1) regimens for future surgical procedures. Hypertension 5 (2.1) 2 (0.8) Diarrhea 4 (1.7) 2 (0.8) Procedural hypotensiona 2 (0.8) 2 (0.8) COMMENT Liver function test result abnormalb 7 (3.0) 8 (3.4)

a Included herein to present a more complete picture of hypotension. In this phase 3 study, the primary end point of complete b Indicates an increased alanine aminotransferase level, an increased response during the first 24 hours after surgery under aspartate aminotransferase level, an increased transaminase level and/or abnormal blood or liver function test results. Patients for whom more than 1 general anesthesia was achieved in a significantly greater adverse event was reported (eg, increased alanine aminotransferase level proportion of patients in the casopitant plus ondanse- and increased aspartate aminotransferase level reported as separate events) tron group compared with the ondansetron-only group are counted once. During the 48-hour assessment phase, episodes of nausea for the primary efficacy (modified ITT) population or emesis that resulted in the administration of rescue medication were considered treatment failures rather than adverse events or serious adverse (P=.03), with a similar difference noted in the support- events and were captured in the assessments of emesis and nausea in the ive analysis of the ITT population. The benefit of caso- patient diary, unless the severity was greater than expected. pitant treatment appeared to persist during the 48 hours, although it was statistically significant only for the first 24-hour period. surgery has been shown to correlate with PONV risk.4 In addition, a statistically significant decrease was noted Analyses of the efficacy results categorized by duration of in the proportion of patients reporting vomiting in the ca- anesthesia are not available for this study. However, the sopitant plus ondansetron group compared with the on- time of dosing 1 hour before anesthesia, the relatively short dansetron-only group. The effect of casopitant on the end time to maximal concentration of casopitant after oral ad- point of no vomiting appears more robust than the effect ministration (Ͻ2 hours), the duration of anesthesia, and on complete response. A possible explanation for this out- the time to first event suggest that most patients will have come is that complete response required the patient to have the opportunity to fully benefit from casopitant treat- no vomiting, retching, or rescue medication. It is possible ment even with short durations of anesthesia. In addi- that some patients required rescue medication for severe tion, the entry criteria in the phase 2 studies were changed nausea, thus affecting the results for complete response be- for the current analysis so that there was no upper age limit, cause casopitant is an antiemetic drug and is therefore ex- patients were not required to be premenopausal or peri- pected to be less effective against nausea. Formal hypoth- menopausal (a possible risk factor), the definition of non- esis testing was not performed on the nausea end points smoker was relaxed to include those who had not smoked because of the lack of benefit of casopitant for complete for 6 months and patients were permitted 2 or fewer ciga- protection (no vomiting, retching, or rescue medication and rettes per week, and anesthetic regimens were not speci- no significant nausea) in this study. fied but rather only were required to be “balanced- The demonstrated superiority of casopitant in combi- general” according to institutional practices. All these nation with ondansetron compared with ondansetron only factors would tend to increase the proportion of patients was particularly noteworthy, considering the proportion achieving complete response.4,14 of patients achieving a complete response (68.7% vs 58.7%, The significant protection against PONV noted in pa- respectively) was higher than anticipated in the sample- tients receiving casopitant in combination with ondanse- size calculations (which had assumed a 40.0% complete tron observed in this study is additionally notable for oc- response rate for the ondansetron-only group at 24 hours). curring in a high-risk population in whom PONV is A possible explanation for this is that many of the opera- anticipated in up to 80.0% of cases in the absence of ef- tions were shorter than expected and anesthesia times were fective antiemetic therapy.4 In addition, eligible opera- less than the 1 hour required by the protocol. Duration of tions were restricted to those with a high risk of PONV.4

(REPRINTED) ARCH SURG/ VOL 146 (NO. 2), FEB 2011 WWW.ARCHSURG.COM 205

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 The selection of the 50-mg oral dose of casopitant was content:Altorjay,Melson,Chinachoit,Kett,Aqua,Levin,Black- based on the results of a phase 2 study,15 which showed burn, Lane, and Pergolizzi. Statistical analysis: Lane. Admin- that oral casopitant in combination with ondansetron was istrative, technical, and material support: Kett and Blackburn. clinically effective and well tolerated. In the current analy- Study supervision: Altorjay, Levin, and Pergolizzi. sis, casopitant mesylate at 50 mg was also determined to Financial Disclosure: Ms Blackburn, Dr Levin, and Mr Lane be well tolerated. The AE profiles were similar in the 2 are employed by GlaxoSmithKline plc. Dr Pergolizzi is a treatment groups, but hypotension or procedural hypo- past speaker and consultant for GlaxoSmithKline plc and tension was reported in a smaller proportion of patients a consultant for Baxter Healthcare Corporation and Eisai in the ondansetron-only group (4.2%) than in the caso- Pharmaceuticals Inc. pitant plus ondansetron group (7.2%). Because peri- Funding/Support: Funding for this study was provided operative events may have occurred before, during, or by GlaxoSmithKline plc. after surgery and the exact time of hypotension was not Additional Contributions: Editorial support in the form recorded, it was thought more appropriate to look at the of development of the draft outline, development of the hypotension and procedural hypotension events in com- first draft of the manuscript, editorial suggestions to draft bination rather than considering them as distinct events. versions of the manuscript, assembling tables and fig- There were no notable differences in clinical labora- ures, collating author comments, copyediting, fact check- tory hematology and biochemistry results or in vital signs ing, and referencing was provided by John Watson, BA, and electrocardiography results among treatment groups. and Kara Quick, ELS, of Publication CONNEXION and There were no deaths in this study, and none of the SAEs funded by GlaxoSmithKline plc. observed were considered by the investigator to be re- lated to the investigational product or study medica- tion. There were no AEs that led to premature discon- REFERENCES tinuation from the study. 1. Marcus JR, Tyrone JW, Few JW, Fine NA, Mustoe TA. Optimization of conscious A limitation of the study was that there was no placebo sedation in plastic surgery. Plast Reconstr Surg. 1999;104(5):1338-1345. arm in which no emetogenic medication was adminis- 2. Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted? tered. Because nausea and vomiting are highly likely to oc- Anesthesiology. 1999;91(1):109-118. cur in this high-risk patient population and perioperative 3. Kovac AL. Prevention and treatment of postoperative nausea and vomiting. Drugs. 2000;59(2):213-243. antiemetic prophylaxis is the standard of care, a placebo 4. Apfel CC, Kranke P, Eberhart LH, Roos A, Roewer N. Comparison of predictive mod- arm would not have been acceptable or appropriate. els for postoperative nausea and vomiting. Br J Anaesth. 2002;88(2):234- In conclusion, the results of this pivotal phase 3 study 240. demonstrate the efficacy and tolerability of the 50-mg oral 5. Pierre S, Benais H, Pouymayou J. Apfel’s simplified score may favourably pre- dict the risk of postoperative nausea and vomiting. Can J Anaesth. 2002;49 casopitant dose, in combination with IV ondansetron, 4 (3):237-242. mg, in patients at high risk for PONV. The combined treat- 6. Apfel CC, Läärä E, Koivuranta M, Greim CA, Roewer N. A simplified risk score ment was superior to ondansetron alone. for predicting postoperative nausea and vomiting: conclusions from cross- validations between two centers. Anesthesiology. 1999;91(3):693-700. Accepted for Publication: January 25, 2010. 7. Gan TJ, Meyer T, Apfel CC, et al; Department of Anesthesiology, Duke University Medical Center. Consensus guidelines for managing postoperative nausea and Author Affiliations: Department of Surgery, St. George Uni- vomiting. Anesth Analg. 2003;97(1):62-71. versity Teaching Hospital, Sze´kesfehe´rva´r, Hungary (Dr Al- 8. Gan TJ, Meyer TA, Apfel CC, et al; Society for Ambulatory Anesthesia. Society torjay); Department of Anesthesia, Helen Keller Hospi- for Ambulatory Anesthesia guidelines for the management of postoperative nau- tal, Sheffield, Alabama (Dr Melson); Faculty of Medicine, sea and vomiting. Anesth Analg. 2007;105(6):1615-1628. 9. Gesztesi Z, Scuderi PE, White PF, et al. (Neurokinin-1) antagonist Siriraj Hospital, Mahidol University, Bangkok, Thailand prevents postoperative vomiting after abdominal hysterectomy procedures. (Dr Chinachoit); Department of Anesthesiology, Saint Pe- Anesthesiology. 2000;93(4):931-937.

ter’s University Hospital, New Brunswick, New Jersey 10. Diemunsch P, Schoeffler P, Bryssine B, et al. Antiemetic activity of the NK1 re- (Dr Kett); Visions Clinical Research, Boynton Beach, Florida ceptor antagonist GR205171 in the treatment of established postoperative nau- (Dr Aqua); Oncology Medicines Development, sea and vomiting after major gynaecological surgery. Br J Anaesth. 1999;82 (2):274-276. GlaxoSmithKline plc, Collegeville, Pennsylvania (Dr Levin, 11. Gan TJ, Apfel CC, Kovac A, et al; Aprepitant-PONV Study Group. A randomized,

Ms Blackburn, and Mr Lane); and Department of Medi- double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron cine, The Johns Hopkins University School of Medicine, for the prevention of postoperative nausea and vomiting. Anesth Analg. 2007; Baltimore, Maryland, and Department of Anesthesiology 104(5):1082-1089. 12. Pellegatti M, Bordini E, Fizzotti P, Roberts A, Johnson BM. Disposition and me- and Pain Medicine, Georgetown University School of Medi- tabolism of radiolabeled casopitant in humans. Drug Metab Dispos. 2009;37 cine, Washington, DC (Dr Pergolizzi). (8):1635-1645. Correspondence: Joseph Pergolizzi Jr, MD, Depart- 13. Lates C, Adams L, Lu E, Johnson B, Zhang K, Lebowitz P. Effect of casopitant, a ment of Medicine, The Johns Hopkins University, 1830 novel NK-1 receptor antagonist, on the pharmacokinetics of co-administered on- E Monument St, Ninth Fl, Baltimore, MD 21205 (jpjmd dansetron and . Paper presented at: 2008 Multinational Asso- ciation of Supportive Care of Cancer (MASCC)/International Society of Oral On- @msn.com). cology (ISOO) Symposium; June 27, 2008; Houston, TX. Abstract 01-012. Author Contributions: Study concept and design: Levin and 14. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treat- Blackburn. Acquisition of data: Melson, Chinachoit, Kett, ment, and prevention. Anesthesiology. 1992;77(1):162-184. Aqua, Levin, and Blackburn. Analysis and interpretation of 15. Singla N, Chung F, Singla S, et al. Efficacy of oral casopitant mesylate, a novel neurokinin-1 receptor antagonist, with intravenous ondansetron HCl in the pre- data: Altorjay, Melson, Levin, Blackburn, Lane, and Per- vention of postoperative nausea and vomiting (PONV) in high-risk patients. Pre- golizzi. Drafting of the manuscript: Chinachoit and Levin. sented at: Euroanaesthesia 2006; June 5, 2006; Madrid, Spain. Abstract Critical revision of the manuscript for important intellectual A-614.

(REPRINTED) ARCH SURG/ VOL 146 (NO. 2), FEB 2011 WWW.ARCHSURG.COM 206

©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021