Transcript Document

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
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.
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Palonosetron PONV Trials
• Study funded by MGI/Eisai
• Study presented on behalf of all investigators involved in both
trials.
2
Phase 3 Study Designs
Two Randomized, Stratified, Double-blind, Parallel-group, Balanced, Placebo-controlled Multicenter Studies
Patients
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
Randomization
Stratification
Placebo vs PALO
dosage
Interactive voice response system
 Hx of PONV/motion sickness
 Non-smoking status
 Gender
Placebo
(1) n = 135
(2) n = 136
 Hx of PONV/motion sickness
 Non-smoking status
 Type of surgery
PALO
0.025 mg/kg IV
PALO
0.050 mg/kg IV
PALO
0.075 mg/kg IV
(1) n = 136
(2) n = 136
(1) n = 137
(2) n = 137
(1) n = 138
(2) n = 135
Patient Demographics
Study 1: Outpatients (US)
Study 2: Inpatients (Europe)
Palonosetron (IV)
Palonosetron (IV)
Placebo
0.025 mg/kg
0.050
mg/kg
0.075 mg/kg
Placebo
0.025
mg/kg
0.050
mg/kg
0.075
mg/kg
(n=135)
(n=136)
(n=137)
(n=138)
(n=136)
(n=136)
(n=137)
(n=135)
Gender (female)
96
96
96
96
100
100
100
100
Mean age (years)
37
39
37
38
50
48
48
50
Hx of PONV/motion
sickness
64
63
66
66
46
47
47
47
Smoking status (nonsmoker)
86
85
85
85
85
86
85
84
Alcohol consumption
(no)
50
54
58
57
38
33
35
33
Gynecologic
laparoscopy
78
75
77
69
--
--
--
--
Abdominal
laparoscopy
22
25
23
31
--
--
--
--
Gynecologic surgery
--
--
--
--
84
81
84
84
Breast surgery
--
--
--
--
16
19
16
16
ASA status I
42
52
50
52
36
48
45
50
ASA status II
53
43
45
45
61
49
52
48
ASA status III
5
5
4
3
3
3
3
2
4
Stratification: PONV Risk Factors
(% of Patients)
Placebo
PALO
0.025 mg IV
PALO
0.050 mg IV
PALO
0.075 mg IV
Study 1: Outpatients (US)
Male + hx PONV + non-smoker
4
4
4
4
Female + hx PONV + non-smoker
47
44
47
46
Female + hx PONV + smoker
13
15
15
15
Female + no hx PONV + non-smoker
36
37
34
34
Hx no PONV/motion sickness + non-smoker
54
53
53
53
Hx PONV/motion sickness + non-smoker
32
33
33
31
Hx PONV/motion sickness + smoker
15
14
15
16
Study 2: Inpatients (Europe)
There were no statistically significant differences in PONV risk factors in patients across all treatment groups.
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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
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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)
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Complete Response
(No Emesis, No Use of Rescue Medication)
Study 2
Study 1
100
90
*
% of Patients
80
70
70
*
60
*
* 43
50
40
30
33
39
41
44
† †
47 49
26
56
24
32
37 39
46 47
52
56
†
61
44 45
36
52
36
20
10
0
0-24 h
24-72 h
0-72 h
Primary endpoints
* Statistically
significant at P <0.0166 (for primary analyses); analysis by logistic regression.
at P <0.05 (for secondary analyses); analysis by logistic regression.
†Statistically significant
0-24 h
24-72 h
0-72 h
Primary endpoints
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Percentage of Patients With No Treatment Failure
Study 2: Inpatients (Europe)
% of Patients With No Treatment Failure
Study 1: Outpatients (US)
100
100
80
80
60
60
PALO 0.075 mg
40
Placebo
PALO 0.075 mg
40
Placebo
20
20
0
0
0
20
40
60
80
0
20
40
60
Hours
Hours
P = 0.0185 for palonosetron 0.075 mg vs placebo.
P = 0.0035 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.
80
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Nausea Severity
Study 1
*
100
% of Patients Evaluable for Nausea
Study 2
*
*
*
80
Severe
Moderate
Mild
None
60
40
20
0
Placebo
PALO
0.075 mg
0-24 h
Placebo
PALO
0.075 mg
0-72 h
* Statistically significant vs placebo at P<0.05 (Cochran-Mantel-Haenszel).
Placebo
PALO
0.075 mg
0-24 h
Placebo
PALO
0.075 mg
0-72 h
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Percentage of Patients Without
Functional Interference* (Study 1 Only)
Placebo
% of Patients Without Interference
100
PALO 0.075 mg
†
80
60
†
57
64
73
59
65
†
73
66
62
57
44
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).
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Most Frequent Treatment-related
Adverse Events
Study 1: Outpatients (US)
Adverse Events: n, %
Placebo
(n=137)
PALO
0.025 mg IV
(n=136)
PALO
0.050 mg IV
(n=138)
PALO
0.075 mg IV
(n=136)
Total treatment-related AEs
13 (10%)
12 (9%)
15 (11%)
9 (7%)
Headache
6 (4%)
5 (4%)
9 (7%)
4 (3%)
Constipation
4 (3%)
2 (2%)
6 (4%)
4 (3%)
Study 2: Inpatients (Europe)
Adverse Events: n, %
(n=136)
(n=136)
(n=137)
(n=135)
Total treatment-related AEs
45 (27%)
48 (29%)
49 (29%)
48 (29%)
Bradycardia
15 (9%)
16 (10%)
14 (8%)
13 (8%)
ECG QTc prolonged
11 (7%)
10 (6%)
14 (8%)
15 (9%)
There were no statistically significant differences among treatment groups.
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Changes in QTc
Placebo
(n=137)
PALO
0.025 mg IV
(n=136)
PALO
0.050 mg IV
(n=138)
PALO
0.075 mg IV
(n=136)
15 minutes
18
15
13
16
6 hours
9
10
11
11
(n=168)
(n=168)
(n=169)
(n=168)
15 minutes
20
24
22
21
6 hours
10
11
13
11
Study 1: Outpatients (US)
Mean change from baseline
in QTc by Fridericia, msec
Study 2: Inpatients (Europe)
Mean change from baseline
in QTc by Fridericia, msec
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 15minute results.
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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-HT3 receptor antagonists
• address important unmet needs, including nausea control
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