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Anesth Analg 2008; 107:445-451 © 2008 International Anesthesia Research Society doi: 10.1213/ane.0b013e31817b5ebb
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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BACKGROUND: In this randomized, double-blind study we assessed the efficacy and safety of three different doses of the 5-HT3 receptor antagonist palonosetron, compared with placebo, on the incidence and severity of postoperative nausea and vomiting (PONV) for 72 h postsurgery.
METHODS: Five hundred seventy-four patients undergoing either outpatient abdominal or gynecological laparoscopic surgery were stratified according to gender, history of PONV or motion sickness, and nonsmoking status. Patients with 
2 PONV risk factors were eligible and randomized to receive one of three doses of IV palonosetron (0.025 mg, 0.050 mg, or 0.075 mg) or placebo immediately prior to induction of anesthesia. Co-primary efficacy end-points included complete response (CR: no emetic episodes and no rescue medication) during the 0 to 24 h and 24 to 72 h postoperative time intervals.
RESULTS: A dose-response trend in the proportion of patients with a CR was observed with increasing doses of palonosetron in the first 24 hrs. CR rates for placebo and palonosetron 0.075 mg were 26% and 43%, respectively, for the 0 to 24 h postoperative interval (P = 0.004), and 41% and 49%, respectively, for the 24 to 72 h interval (P = 0.188). Compared with placebo, palonosetron 0.075 mg was associated with a significant downward shift toward less intense nausea (P = 0.042) and with significant reduction in the impact of PONV on patient functioning (P = 0.004) during the 0 to 24 h interval.
CONCLUSIONS: A single 0.075-mg IV dose of palonosetron significantly increased the CR rate (no emetic episodes and no rescue medication) from 0 to 24 h, decreased nausea severity and patients experienced significantly less interference in their postoperative function due to PONV.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Palonosetron is a unique 5-HT3 receptor antagonist approved for use in the prevention of chemotherapy-induced nausea and vomiting. In a phase three head-to-head comparative trial in patients receiving moderately emetogenic chemotherapy, palonosetron was clinically and statistically superior to ondansetron in reducing the incidence of emesis and the impact of nausea and vomiting on patient function during the acute (0–24 h) and delayed (24–120 h) phase after chemotherapy.1,2
Palonosetron can be distinguished from older 5-HT3 receptor antagonists (ondansetron, dolasetron, and granisetron) by its unique chemical structure, greater binding affinity (pKi = 10.45), and substantially longer half-life (approximately 40 h).3–6 Recent differential binding studies compared the molecular interactions of palonosetron, granisetron, and ondansetron at the 5-HT3 receptor. The findings demonstrated that palonosetron has allosteric binding and positive cooperativity that, in contrast with the older drugs, confers a long-lasting functional effect which inhibits serotonin-mediated Ca2+ influx. These and other characteristics of palonosetron's binding are discussed in greater detail in the article by Rojas et al. in this issue of the journal.7
These pharmacologic differences, combined with the previously mentioned efficacy of palonosetron against chemotherapy-induced nausea and vomiting,1,8 prompted the investigation of palonosetron for the prevention of postoperative nausea and vomiting (PONV). An earlier dose-ranging study provided the rationale for the selection of the three doses used in this study.9,10 The current study was conducted to evaluate the hypothesis that IV palonosetron provides safe and effective prevention of PONV and explore its duration of action across multiple dose levels for up to 3 days in patients undergoing laparoscopic surgery who were expected to be discharged on the same day as their surgical procedure.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Prior to any subject enrollment, all sites obtained IRB approval. Eligible patients were at least 18-yrs-of-age with an ASA physical status of one to three and scheduled to undergo elective laparoscopic abdominal or gynecological surgery of at least 1 h duration. All patients had at least two risk factors for PONV: female gender, a history of PONV and/or motion sickness, or nonsmoking status (never smoked or quit
12 mo ago). All patients were expected to go home on the same day as surgery. Excluded from the study were patients who had received cancer chemotherapy within 4 wks or emetogenic radiotherapy within 8 wks prior to study entry. Signed informed consent was obtained from all patients before being randomized. Patients were randomized to one of three active treatment groups or placebo. To achieve a homogeneous risk of PONV in each of the four groups, randomization to treatment was stratified by gender, history of PONV and/or motion sickness, and smoking status. A dynamic adaptive stratification type of randomization method was used to balance the four groups across the entire study and not within each individual site.
At each study site, palonosetron and placebo were prepared for administration to patients by an unblinded research pharmacist or designee who was otherwise not involved in the conduct of the study. A single IV dose of palonosetron (0.025 mg, 0.050 mg, or 0.075 mg), with an adequate volume of saline solution added to bring the total injectable volume to 2 mL, was administered as a 10-s IV bolus immediately (no more than 5 minutes) before induction of anesthesia. The assigned randomization number was associated with sealed cartons containing the study drug which were provided to the unblinded research pharmacist at each site. Subjects in the placebo group received a single IV dose of normal saline as a 2-mL bolus in a similar manner. Because rescue medication for relief of PONV was permitted, withholding active treatment was not considered detrimental to patients randomized to placebo.
Premedication with midazolam or fentanyl was permitted. Induction was performed with propofol, barbiturates, or methohexital. Anesthetic maintenance consisted of any inhaled drugs combined with nitrous oxide (concentration 50%–70%). Neuromuscular blocking drugs were used at the discretion of the anesthesiologist with reversal by neostigmine and glycopyrrolate. Medication for the prevention of nausea and vomiting or any other medication with antiemetic properties (propofol was only allowed for induction) was prohibited in the 24 h prior to the induction of anesthesia. Rescue medication for the treatment of PONV, with the exception of palonosetron or droperidol, was permitted at the discretion of the investigator.
Emetic episodes, intensity of nausea, and interference with daily life activities were measured at the time points of 2, 6, 24, 48, and 72 h in reference to symptom occurrence during the prior observation period. Complete response (CR), defined as no emetic episodes and no rescue medication, was evaluated by co-primary efficacy end-points during the 0 to 24 h and 24 to 72 h postoperative time intervals. The assessment of secondary end-points for CR included the postoperative intervals of 0 to 6 h, 6 to 72 h (not a prespecified endpoint), and 0 to 72 h. Also assessed as a secondary endpoint was time to treatment failure, defined as time to first emetic episode or time to first administration of rescue medication, whichever occurred first. The primary analysis population for all variables, except safety variables, included all patients who received study drug, anesthesia and underwent the surgical procedure.
The primary efficacy hypotheses were that at least one dose of palonosetron was superior to placebo, for the CR rate, in the 0 to 24 h and 24 to 72 h time periods. To account for multiple comparisons of treatments (placebo vs 0.025 mg, 0.050 mg, and 0.075 mg), the multiple type-I error level was guaranteed by the Holm-Bonferroni method. In order to claim a significant difference, the smallest of the 3 2-sided P values could not exceed 0.0166 (0.05/3). If this was achieved, the second smallest P value could not exceed 0.025 (0.05/2) in order to be significant and, if this was also achieved, the significance threshold for the third P value was 0.05. This sequential procedure was to be stopped if the respective threshold was exceeded. The procedure guarantees the multiple type I error level of 0.05. Analysis of secondary end-points did not adjust for multiple comparisons of treatments. All differences in secondary end-points compared with placebo were considered significant if the P value was <0.05.
Comparisons of CR, incidence of emesis and use of rescue medications were made between individual palonosetron groups and placebo using logistic regression analysis, adjusting for stratification parameters. Differences in the distribution of nausea severity were assessed using the Cochran-Mantel-Haenszel test for pairwise comparison with placebo. Time to event was analyzed using the Kaplan-Meier methods with results reported by the log-rank test. Each of the modified Osoba module questionnaire items (Appendix)11 and the total score were analyzed by the Kruskal-Wallis test for overall comparison and the Mann-Whitney test for pairwise comparisons.
The sample size was calculated based on a responder rate of 60% in the palonosetron group and 40% in the placebo group. For a two-sided test of difference, using 
= 0.0166 (obtained as error type I/number of comparisons = 0.05/3) and β = 0.2 for each comparison, the sample size was estimated at 131 evaluable patients per group, rounded up to 136 patients per group.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Patient Enrollment and Disposition
Six hundred thirty-nine patients were screened for this study, of which 65 were screening failures. Of the 574 remaining patients, 489 were randomized at 36 centers in the United States, and 85 were randomized at seven centers in Romania. Five hundred forty-seven patients were treated: palonosetron 0.025 mg (n = 136), 0.050 mg (n = 137), 0.075 mg (n = 138), and placebo (n = 136); 27 patients were not treated. The 48 patients who were randomized but did not complete the study were distributed across the three treatment groups and placebo group as follows: placebo (n = 7), palonosetron 0.025 mg (n = 18), palonoestron 0.050 mg (n = 9), and palonosetron 0.075 mg (n = 14).
There were no statistically significant differences in age, height, weight, Body Mass Index, PONV risk factors, type of surgery or ASA status in patients across all treatment groups. Additional baseline characteristics for patients are shown in Table 1. Of the 574 randomized patients, 5% (n = 27) were not treated and 8% (n = 48) did not complete the study for the following reasons: patient lost to follow-up (n = 16), violation of inclusion and/or exclusion criteria (n = 7), patient choice (n = 4), decision of investigator (n = 3), non-serious adverse event (n = 1) and other reasons (n = 17).
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Efficacy
Complete Response (CR)
Compared with placebo, a dose-response trend for CR was observed with increasing doses of palonosetron. In the 0 to 24 h postoperative time interval, CR rates were: placebo, 26%; palonosetron 0.025 mg, 33% (P = 0.187); palonosetron 0.050 mg, 39% (P = 0.017); and palonosetron 0.075 mg, 43% (P = 0.004). For the 24 to 72 h interval after surgery, CR rates were: placebo, 41%; palonosetron 0.025 mg, 44% (P = 0.638); palonosetron 0.050 mg, 47% (P = 0.249); and palonosetron 0.075 mg, 49% (P = 0.188) (all P values are versus placebo). Overall, the greatest effect was noted in the 0–24 h period with a clear dose-response trend. In the 24–72 h range, no dose reached statistical significance compared to placebo.
Since a dose-response relationship for CR rates was observed for palonosetron versus placebo for the primary CR interval for 0 to 24h and the 0 to 6 h and 0 to 72 h intervals, the following discussion of the results of the secondary end-points over the five key time intervals will focus on the 0.075-mg dose of palonosetron. Compared with placebo, during the 0 to 6 h, 6 to 72 h, and 0 to 72 h time intervals, patients who received palonosetron 0.075 mg had CR rates of 49% (P = 0.042), 45% (P = 0.064) and 39% (P = 0.010) respectively (Fig. 1).
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Time to Treatment Failure and Use of Rescue Therapy
A dose-response trend was observed for the median time to treatment failure. Patients who received any dose of palonosetron, compared with placebo, had a significant delay in this variable (P = 0.024) (Fig. 2). Over the entire 0 to 72 h time course of observation, 70 of the 135 patients (52%) who received placebo required rescue therapy, compared with 60 of the 138 patients (44%) who received palonosetron 0.075 mg (P = 0.184).
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Emetic Episodes
The proportion of patients in the placebo group who experienced vomiting was smaller than expected in a population at increased risk for PONV, particularly during the 24 to 72 h time interval.12 During the 0 to 24 h interval (Table 2), the percentage of patients with emetic episodes was 44% in the placebo group and was 33% for patients who received palonosetron 0.075 mg (P = 0.075). The percentage of patients with emetic episodes in the placebo versus palonosetron 0.075-mg group, respectively, were 9% and 9% for 24 to 72 h (P = 1.0), 34% and 26% for 0 to 6 h (P = 0.180), 24% and 19% for 6 to 72 h (P = 0.298), and 46% and 36% for 0 to 72 h (P = 0.100).
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Nausea
On the day of surgery (0–24 h), a larger proportion of patients who received palonosetron 0.075 mg had no nausea (P = 0.033) and also a significantly less intense distribution of nausea over a four-point categorical scale ("none" to "severe") (P = 0.042), compared with patients who received placebo. However, no significant difference (P = 0.504) was noted in the distribution of nausea intensity during the 24 to 72 h interval for palonosetron 0.075 mg and placebo. Patients who received palonosetron 0.075 mg had a significantly less intense distribution of nausea compared with patients who received placebo during the immediate postoperative interval, 0 to 6 h (P = 0.028), 6 to 72 h (P = 0.036), and overall time course 0 to 72 h (P = 0.040) (Fig. 3). These findings indicate that palonosetron 0.075 mg appears to be associated with an overall downward shift toward less intense nausea (e.g., toward "mild" to "none") especially in the first 24 hrs.
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Interference of PONV with Patient Function
During the 0 to 24 h time period, palonosetron 0.075 mg was statistically superior to placebo in reducing the impact of PONV on patient function (based on the modified Osoba questionnaire, Appendix)11 for the total score (P = 0.004) and for the following key subdomains: appetite (P = 0.018), social life (P = 0.013), and enjoyment of life (P = 0.030) (Fig. 4) but not significantly different for the subdomains of sleep (P = 0.066) and physical activity (P = 0.096).
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Safety
In this study, all doses of palonosetron were well tolerated; the majority of adverse events were of mild or moderate intensity, and adverse events did not show a dose relationship. The percentage of patients experiencing any treatment-related adverse event was 7% in the palonosetron 0.075 mg group and 10% in the placebo group. The rates of the most frequently occurring treatment-related adverse events for the four treatment groups (placebo, palonosetron 0.025 mg, 0.050 mg, 0.075 mg) were headache (4%, 4%, 7%, 3%, respectively) and constipation (3%, 2%, 4%, 3%, respectively).
No patients withdrew due to serious adverse events, and only one serious adverse event, a prolonged QTc interval in a patient receiving placebo, was noted. Electrocardiogram intervals (including QTc by Bazett and Fridericia) at all time points (15 minutes and 3 to 6 h post-dose) were similar between placebo and all palonosetron groups.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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This randomized, double-blind, multicenter, stratified phase three study evaluated the dose response of three different, single IV doses of palonosetron compared with placebo for the prevention of PONV and its consequences on perioperative functioning in patients at risk for nausea and or vomiting. Dose selection was based on findings of an earlier study that evaluated IV doses of palonosetron ranging from 0.1 to 30 µg/kg.10 In the current study, a linear trend in efficacy with increasing doses was observed, with only the highest dose (0.075 mg) of palonosetron demonstrating a statistically significant treatment effect compared with placebo over the first 24 hrs.
The marked shift in the 1990s toward outpatient treatment has heightened the awareness of postdischarge nausea and vomiting (PDNV) as a concern.13,14 Despite the widespread use of different classes of prophylactic antiemetics for PONV, including older 5-HT3 receptor antagonists, a significant percentage of patients still suffer from PONV either in the postanesthesia care unit or after discharge to either the hospital ward or home.12,15–18 PDNV can be a major problem for patients and their caregivers and often goes unrecognized by the perioperative anesthesia care team since symptoms, when they do occur at home and are reported, are usually communicated to the surgeon.
The treatment effect of palonosetron in this trial is most pronounced during the first 24 h. The duration of effect of palonosetron over placebo, which can be inferred from the time to treatment failure curves in Figure 2, suggests a long-lasting mechanism of action of at least 24 hrs.
The benefits of palonosetron 0.075 mg compared with placebo seen in this trial are complemented by the results of a second, multicenter, inpatient study evaluating the efficacy and safety of the same three doses of palonosetron (0.025 mg, 0.050 mg, 0.075 mg), compared with placebo for prevention of PONV for up to 72 h in women undergoing general anesthesia for elective gynecological or breast surgery.19 Larger trials with an active comparator will be required to determine the relevance of these observations.
The antinausea properties of palonosetron warrant further attention from both a clinical perspective and research view. Palonosetron 0.075 mg, compared with placebo, produced a larger proportion of patients with no nausea and also a significantly less intense distribution of nausea over a four-point categorical scale. Palonosetron is the first 5-HT3 antagonist to be shown to have this property. This benefit in symptom control, combined with the drug's antiemetic effect, translated into less interference with patient functioning.
Study Limitations
One possible limitation of this study was the modest population size for a dose-response trial, with perhaps too few patients in each treatment arm for a robust evaluation of the treatment effect on all end-points and all time intervals for the purposes of statistical analyses. An example of this limitation was the low rate of vomiting (approximately 9%) noted in this trial during the 24 to 72 h interval after surgery. Although there was an 11% reduction in the incidence of vomiting during the 0–24 h interval, it did not prove to be statistically significant (P = 0.075). It would have required a two-arm study of approximately 1800 patients per treatment group to detect a 25% reduction in the rate of vomiting between palonosetron 0.075 mg and placebo. Due to the overall low rate of vomiting, it is difficult to make conclusions about the drug's efficacy in this respect.
Although this study was placebo-controlled, the lack of an active comparator limits the ability to directly compare the results for palonosetron with published placebo-controlled trials of older members of the 5-HT3 receptor antagonist class. The study also evaluated a dose range in which the two lowest doses did not demonstrate statistical significance versus placebo in most end-points. The dose selection in this study was based on a prior dose-ranging study10 and it is not anticipated that doses higher than 0.075 mg would have demonstrated increased efficacy due to a noted ceiling effect; prior dose-ranging results are also described in the accompanying paper by Kovac et al. in this issue of the journal.19
In patients undergoing elective gynecological or abdominal laparoscopic surgery, a single 0.075 mg IV dose of palonosetron significantly improved the CR rate, decreased nausea severity and reduced the interference with patients' postoperative functioning due to PONV. These benefits may distinguish palonosetron as unique among 5-HT3 receptor antagonists and potentially address important needs such as protection against nausea in patients at risk for PONV and PDNV. Although additional comparator studies are required, the recent Food and Drug Administration approval of palonosetron 0.075 mg for the prevention of PONV up to 24 hrs after surgery will give practitioners the opportunity to gain clinical experience with this new drug.
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ACKNOWLEDGMENTS |
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The authors thank Rebecca Gerber, Susan Weidner, Tim DeGroot, and Don Tessier for their help in the preparation and review of the manuscript.
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Footnotes |
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Sponsored by Helsinn Healthcare SA and supported by MGI PHARMA INC.
Participating primary investigators in the Palonosetron 04–06 Study Group were Valerie Armstead, MD; Lucien Baila, MD; Alex Bekker, MD, PhD; Keith Allen Candiotti, MD; Jacques Chelly, MD, PhD; Paul Cook, MD; Victor Culman, MD; Paul Diehl, MD; Helene Finegold, MD; Tong Joo Gan, MB; Timothy Gilbert, MD; Flaviu Narcis Gliga, MD; Jeffrey Grass, MD; Scott Groudine, MD; Lily Hsu, MD; Gary Haynes, MD, PhD; Christopher Hutchinson, MD; Hatim Hyderally, MD; Daniel Katz, MB; Brian Kirshon, MD; Piotr Janicki, MD, PhD; Kevin Jones, MD; Girish Joshi, MD; Anthony Kovac, MD; Nicholas Lam, MD; John Leslie, MD; Bogdan Marinescu, MD, PhD; Timothy Melson, MD; John Miklos, MD; Harold Minkowitz, MD; Scott Nicolson, MD; Peter Pan, MD; Gheorghe Peltecu, MD, PhD; Joseph Pergolizzi, MD; Alex Pue, MD; Charles Richard Robertson, MD; Jon Samuels, MD; Dorel Sandesc, MD; Denise Scaringe, MD; Samuel Simha, MD; Neil Singla, MD; Daneshvari Solanki, MD; Yung-Fong Sung, MD; Suzanne Trupin, MD; Radu Vladareanu, MD, PhD; Mark Wallace, MD; and Steven Wininger, MD.
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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- Kovac AL, Eberhart L, Kotarski J, Clerici G, Apfel CC, Palonosetron 04–07 Study Group. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg 2008;107:439–44
[Abstract/Free Full Text]
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