S3820642
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Study No.: S3820642
Title: A Pharmacokinetic Evaluation of Nicotine Patches in Smokers
Rationale: This study was planned to establish the pharmacokinetic (PK) profile of a 21 mg
patch as compared to a 25 patch, specifically, the primary PK parameter, AUC0-∞.
Phase: I
Study Period: May 26, 2009 through June 5, 2009
Study Design: PK, single-center, randomized, single-dose, and two-way crossover in design
Centres: Single center, USA
Indication: Nicotine Replacement Therapy/smoking cessation
Treatment: 21mg/24 hour nicotine transdermal system and 25mg/16hour nicotine transdermal
system
Objectives: The primary objective was to demonstrate that 21 mg patch was superior to the 25
mg patch with respect to AUC0-∞; this parameter is considered equivalent to the 24-hour AUC in
steady state.
Primary Outcome/Efficacy Variable: Plasma nicotine AUC 0-∞ (area under the plasma nicotine
concentration through time curve from zero and extrapolated to infinity)
Secondary Outcome/Efficacy Variable(s): Plasma nicotine AUC0-t, Cmax, tmax, C24, Kel, t1/2
Statistical Methods: A linear mixed effects model was fit to log AUC(0-∞) (as the dependent
variable), with treatment and period as fixed factors, and subject as a random effect. Least
squares estimates of treatment means were calculated and a 90% CI for the treatment difference
was computed. The treatment difference and its 90% confidence interval (CI) were exponentiated
to obtain the ratio of the geometric means between the test and reference products and its CI.
The same procedure was used for analysis of the secondary parameters, Cmax, AUCo-t, and C24.
The 21 mg patch was accepted as superior to the 25 mg patch if the lower limit of the 90% 2sided (or equivalently 95% one-sided) CI (based on the log transformed data and back
transformed) for the ratio of the geometric means for these PK parameters was above 1.0. The
secondary parameters (tmax, Kel, and t1/2) were summarized and analyzed using nonparametric
signed rank tests on the within-subject differences to compare treatments (21mg vs. 25mg)
Study Population: Male and female subjects, aged 19 to 55 years (inclusive), who were
generally healthy, smoked more than 10 cigarettes per day for a minimum of six months, had a
body mass index ranging from 19-27 kg/m2, and provided written informed consent.
21mg25mgTotal
25mg
21mg
Number of Subjects:
Planned, N
Randomised, N
Completed, n (%)
Total Number Subjects Withdrawn, N (%)
Withdrawn due to Adverse Events n (%)
Withdrawn due to Lack of Efficacy n (%)
Withdrawn for other reasons n (%)
Demographics
25
25
25
24 (96%)
1 (4%)
0 (0%)
0 (0%)
1 (4%)
21mg25mg
25
N (ITT)
1
25
25
25
23 (92%)
2 (8%)
1 (4%)
0 (0%)
1 (4%)
25mg21mg
25
50
50
50
47 (94%)
3 (6%)
1 (2%)
0 (0%)
2 (4%)
Total
50
S3820642
Females: Males
Mean Age, years (SD)
Caucasian, n (%)
BMI
10:15
11:14
21:29
30.9 (9.39)
23 (92%)
32.1 (9.91)
24 (96%)
31.5 (9.57)
47 (94%)
23.18
(2.02)
23.69
(2.57)
23.44
(2.30)
Primary Efficacy Results:mean AUC0-∞
AUC0-∞
Geometric mean
21mg
25mg
382.36
243.69
156.90%
Ratio Geometric means (21mg/25mg)
90% Confidence Interval for the ratio of the geometric
(148.10%, 166.23%)
means
p-value
<0.0001
Secondary Outcome Variable(s): mean AUC0-t and Cmax and median tmax, C24, Kel, t1/2
21mg
25mg
Cmax
18.34
16.56
Geometric mean
110.72%
Ratio Geometric means (21mg/25mg)
90% Confidence Interval for the ratio of the geometric
(104.82%, 116.94%)
means
AUC0-t
370.91
238.51
Geometric mean
Ratio Geometric means (21mg/25mg)
155.51%
90% Confidence Interval for the ratio of the geometric
(146.79%, 164.75%)
means
C24
11.09
3.05
Geometric mean
363.62%
Ratio Geometric means (21mg/25mg)
90% Confidence Interval for the ratio of the geometric
(308.16%, 429.07%)
means
tmax
6.00
12.00
Median
Median of difference (21mg-25mg)
-5.001
t1/2
2.90
3.29
Median
Median of difference (21mg-25mg)
-0.409
Kel
0.24
0.21
Median
Median of difference (21mg-25mg)
0.030
Safety Results: An adverse event (AE) was an AE encountered or spontaneously reported by
the subject following administration of any investigational product, which did not necessarily have
a casual relationship with the treatment. AEs were categorized as serious or non-serious.
Treatment Emergent AEs reported by > 1 subject
Most Frequent Adverse Events – On-Therapy
Subjects with any AE(s), n(%)
Application site erythema
Application site pruritus
2
21mg
25mg
n (%)
36 (75.0%)
24 (50.0%)
29 (60.4%)
n (%)
44 (89.8%)
38 (77.6%)
16 (32.7%)
S3820642
Application site irritation
2 (4.2%)
4 (8.2%)
Dizziness
6 (12.5%)
2 (4.1%)
Headache
5 (10.4%)
4 (8.2%)
Back pain
2 (4.2%)
0 (0%)
Nausea
1 (2.1%)
2 (4.1%)
Serious Adverse Events - On-Therapy
n (%) [n considered by the investigator to be related to study medication]
21mg
25mg
Subjects with non-fatal SAEs, n (%)
0 (0%)
0 (0%)
Subjects with fatal SAEs, n (%)
0 (0%)
0 (0%)
Conclusion: Pending publication
Publications: DeVeaugh-Geiss AM, Chen LH, Kotler MK, Ramsay LR, Durcan MJ.
Pharmacokinetic Comparison of Two Nicotine Transdermal Systems, a 21mg/24-Hour Patch and
a 25-mg/16-Hour Patch: A Randomized, Open-Label, Single-Dose, Two-Way Crossover Study in
Adult Smokers. Clinical Therapeutics. (in press).
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