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Keith Candiotti, MD Departments of Anesthesiology, Perioperative Medicine and Pain Management

Efficacy and Safety of 3 Different IV Doses of Palonosetron for the Prevention of PONV in the Outpatient (Study 1) and Inpatient (Study 2) Settings. Keith Candiotti, MD Departments of Anesthesiology, Perioperative Medicine and Pain Management University of Miami Miami, Florida

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Keith Candiotti, MD Departments of Anesthesiology, Perioperative Medicine and Pain Management

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  1. Efficacy and Safety of3 Different IV Doses of Palonosetron for the Prevention of PONV in the Outpatient (Study 1) and Inpatient (Study 2) Settings Keith Candiotti, MD Departments of Anesthesiology, Perioperative Medicine and Pain Management University of MiamiMiami, Florida American Society of Anesthesiologists Annual Meeting October 20, 2008 Study 1 (Outpatients—US): Candiotti KA, et al. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo for preventing postoperative nausea and vomiting. Anesth Analg. 2008;107:445-451. Study 2 (Inpatients—Europe): Kovac A, et al. 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;107:439-444.

  2. Palonosetron PONV Trials • Study funded by MGI/Eisai • Study presented on behalf of all investigators involved in both trials.

  3. Phase 3 Study Designs Two Randomized, Stratified, Double-blind, Parallel-group, Balanced, Placebo-controlled Multicenter Studies Study 1: Outpatients (US) Study 2: Inpatients (Europe) M/F pts undergoing elective laparoscopic abdominal or gynecological surgery Female pts undergoing elective gynecological or breast surgery Patients Randomization Stratification Placebo vs PALO dosage Interactive voice response system • Hx of PONV/motion sickness • Non-smoking status • Gender • Hx of PONV/motion sickness • Non-smoking status • Type of surgery

  4. Patient Demographics

  5. There were no statistically significant differences in PONV risk factors in patients across all treatment groups. Stratification: PONV Risk Factors

  6. Anesthesia • Premeds • Midazolam 1-2 mg IV or fentanyl 50-100 g IV as needed • Induction • Propofol 2.0-2.5 mg/kg IV or thiopental 2.5-5.0 mg/kg IV; methohexital 1.5-3.0 mg/kg IV • Succinylcholine 1-1.5 mg/kg IV; rocuronium 0.4-0.6 mg/kg IV, cisatracuronium 0.15-0.3 mg/kg IV, vecuronium 0.05-0.1 mg/kg IV, or mivacurium 0.015-0.25 mg/kg • Maintenance • N2O 50-70% end tidal concentration, O2 30-50% end tidal concentration • Rocuronium, cisatracuronium or vecuronium titrated as needed for muscle relaxation • Inhalation agent • Isoflurane 0.4-3%, desflurane 2-6% or sevoflurane 1-3% end tidal concentration, titrated as needed • Intraoperative opioid • Fentanyl 2-10 g/kg IV or sufentanil 0.2-0.6 g/kg, titrated as needed • Muscle relaxant reversal • Neostigmine <or= 2.5 mg IV and glycopyrrolate 0.4-0.8 mg IV as per usual clinical practice

  7. Study Endpoints Primary endpoint for both studies • Complete response* (CR) at 0-24 h and 24-72 h (no emetic episodes and no rescue medication) Secondary endpoints for both studies† • CR at additional time intervals • Complete control (CR plus no more than mild nausea) • Percentage of pts experiencing emesis • Number of emetic episodes • Severity of nausea • Time to treatment failure • Patient functional interference (Study 1 only) * P value adjusted for 3-dose comparison vs placebo [P=0.05/3=0.0166] † Measured at 2, 6, 24, 48, and 72 h (all tested at P<0.05)

  8. Complete Response(No Emesis, No Use of Rescue Medication) Study 2 Study 1 * * † † * † * % of Patients Primary endpoints Primary endpoints * Statistically significant at P <0.0166 (for primary analyses); analysis by logistic regression. †Statistically significant at P <0.05 (for secondary analyses); analysis by logistic regression.

  9. 0 20 40 60 80 Hours Percentage of Patients With No Treatment Failure Study 2: Inpatients (Europe) Study 1: Outpatients (US) 100 100 80 80 60 PALO 0.075 mg 60 % of Patients With No Treatment Failure PALO 0.075 mg Placebo 40 40 Placebo 20 20 0 0 0 20 40 60 80 Hours P = 0.0035 for palonosetron 0.075 mg vs placebo. P = 0.0185 for palonosetron 0.075 mg vs placebo. Time to treatment failure: time to first emetic episode and/or to first use of rescue meds. Patients who did not have treatment failure were censored at 72 hours.

  10. Nausea Severity Study 1 Study 2 * * * * 100 80 Severe Moderate 60 Mild None % of Patients Evaluable for Nausea 40 20 0 PALO PALO PALO Placebo Placebo Placebo Placebo PALO 0.075 mg 0.075 mg 0.075 mg 0.075 mg 0-24 h 0-72 h 0-24 h 0-72 h * Statistically significant vs placebo at P<0.05 (Cochran-Mantel-Haenszel).

  11. Percentage of Patients Without Functional Interference* (Study 1 Only) Placebo PALO 0.075 mg 100 † † 73 80 † 73 65 66 64 62 59 57 57 60 44 % of Patients Without Interference 40 20 0 Appetite Sleep Physical activities Social life Enjoyment of life 0-24 h * Functional interference due to nausea and vomiting was measured utilizing a Modified Osoba Nausea and Emesis Module. Measurements were based on a 4-point Likert scale: 1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much. The percentages provided above represent those patients with a score of 1 on any individual subscale. †P<0.05 (Mann-Whitney test for pair-wise comparisons of palonosetron vs placebo).

  12. There were no statistically significant differences among treatment groups. Most Frequent Treatment-related Adverse Events

  13. Changes in QTc ECGs: In triplicate at baseline (screening) and as a single recording at 15 minutes and at 3-6 hours (Study 1) and 6 hours (Study 2) post-study drug administration. Independent blinded cardiologist reading with manual QT interval measurement. Results: At 15 minutes post-dose, QT prolongation was consistent across all treatment groups. At 3 to 6 hours post-dose (Study 1) and at 6 hours post-dose (Study 2), QTc intervals remained slightly increased from baseline values; however, they tended to normalize compared with the 15-minute results.

  14. Overall Summary • Dose-response trend observed with increasing doses of PALO • A single IV dose of PALO (0.075 mg) : • was effective in reducing PONV in both the inpatient and outpatient settings • was superior to placebo (0-24 hours) for the primary endpoint (CR) • reduced the severity of nausea compared with placebo • Adverse events: no dose relationship, no differences vs placebo, consistent with those expected for the 5-HT3 receptor antagonist class • These benefits may: • distinguish PALO as unique among the 5-HT3receptor antagonists • address important unmet needs, including nausea control

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