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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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slide1

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.

palonosetron ponv trials
Palonosetron PONV Trials
  • Study funded by MGI/Eisai
  • Study presented on behalf of all investigators involved in both trials.
phase 3 study designs
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
anesthesia
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
study endpoints
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)

slide8

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.

percentage of patients with no treatment failure

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.

nausea severity
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).

slide11

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).

changes in qtc
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.

slide14

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