Clinical trial NCT03229759
Conditions: Preoperative Skin Preparation
Sponsor: Becton, Dickinson and Company
Start date: 2017-06-21; Completion date: 2017-08-04
Enrollment: 99 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Healthy volunteers will receive treatment to two body locations with the investigational product and placebo and the antimicrobial effectiveness of each treatment will be measured.

Detailed description:

Arms: arm 1: Polyester cloth impregnated with investigational product arm 2: Polyester cloth impregnated with the vehicle control arm 3: Saline applied wtih polyester cloth
Interventions: intervention 1: Octenidine Dihydrocloride in aqueous solution intervention 2: Vehicle Control intervention 3: Saline Control
Intervention descriptions: intervention 1: application of investigational product intervention 2: application of vehicle control intervention 3: application of placebo

Protocol documents:
SAP_002.pdf: 
Corporate Clinical Development
Template CCD-6230.T01
Revision 01
Statistical Analysis Plan
Protocol Number/version
MPS-17IPVAW10
Protocol Title
Statistical Analysis Plan for MPS-17IPVAW10: A Randomized, Single-Center,
Blinded, Clinical Evaluation of the Antimicrobial Eﬀectiveness of an Antimi-
crobial Cloth Compared to Vehicle and 0.9% Saline
SAP Date
June 23, 2017
Version History
Action
June 23, 2017
Original Release
This report is proprietary to Becton Dickinson. No part of it may be distributed or shared with persons
other than BD associates without written permission from Corporate Clinical Development (CCD).
Approval
Signature below indicates approval of the statistical analysis plan as written.
Function
Name
Signature
Statistician
(Author)
Lingzhi Li
This document is signed electronically in the
eTMF system.
Clinical Trial
Manager
Carole Schatz
This document is signed electronically in the
eTMF system.
Statistics
Manager
Julie B´erub´e
This document is signed electronically in the
eTMF system.
MPS-17IPVAW10 Statistical Analysis Plan


Contents
1
List of Abbreviations and Deﬁnitions
3
2
Executive Summary
3
3
Overall Study Description
4
3.1
Study Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
3.2
Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
3.2.1
Primary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
3.2.2
Secondary Objectives
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
3.3
Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
3.4
Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
3.5
Acceptance Criteria
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
4
Sample Size
6
5
Intended Statistical Software
6
6
Data
7
6.1
Data Sets Analyzed
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
6.2
Analysis Population Set(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
7
Statistical Analysis/Calculations
9
7.1
Derived Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
7.1.1
Log CFU/cm2 of skin
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
7.1.2
Log Reduction
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
7.1.3
Product Expression Volumes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
7.2
Handling of Missing Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
7.3
Summary Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
7.4
Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
7.4.1
Primary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
7.4.2
Secondary Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
7.4.3
Exploratory Analyses
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
7.4.3.1
Log Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
7.4.3.2
Product Expression Volumes/Weight
. . . . . . . . . . . . . . . . . . . .
14
7.5
Graphs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
7.5.1
Average Treatment Eﬀect Per Primary Analysis
. . . . . . . . . . . . . . . . . . .
15
8
Appendix
17
9
References
17
MPS-17IPVAW10 Statistical Analysis Plan
Page 2 of 17


1
List of Abbreviations and Deﬁnitions
AE
Adverse Events
ASTM
American Society for Testing And Materials
BD
Becton Dickinson and Company
CFU
Colony Forming Units
CI
Conﬁdence Interval
cm2
Square Centimeter
Conf Int
Conﬁdence Interval
FDA
Food and Drug Administration
IP
Investigational Product
ITT
Intent to Treat
LSMean
Least Squares Mean
mITT
Modiﬁed Intent to Treat
mL
Milliliter
OCT
Octenidine Dihydrochloride
SC
Saline Control
SD
Standard Deviation
TFM
Tentative Final Monograph
VC
Vehicle Control
2
Executive Summary
For the average treatment eﬀect correcting for pre-treatment log10 bacterial counts, the per-protocol data
may be diﬀerent from the modiﬁed intent to treat (mITT) data and analysis will be made separately
based on both the per-protocol data and the modiﬁed intent to treat (mITT) data if two data sets are
diﬀerent. Summary statements will be made for each analysis to show whether superiority of the Investi-
gational Product as compared to the Vehicle Control and the Saline Control is satisﬁed. Links to tables
showing analysis results will be provided.
MPS-17IPVAW10 Statistical Analysis Plan
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3
Overall Study Description
3.1
Study Background
A Phase 2 study MPS-16IPVAW01 evaluated the antimicrobial eﬃcacy of thermally treated polyester
cloths impregnated with 0.4% w/v octenidine dihydrochloride in aqueous formulation as compared to
the thermally treated polyester cloth impregnated with vehicle formulation and the FDA-approved active
comparator SAGE 2% CHG cloth. Activity was assessed relative to a 70% response rate target based
on the log reduction standards in the 1994 FDA TFM. The current study will evaluate the immediate
antimicrobial eﬃcacy of thermally treated polyester cloths impregnated with 0.4% w/v octenidine dihy-
drochloride in aqueous formulation as compared to two negative controls, the thermally treated polyester
cloth impregnated with vehicle formulation and a polyester cloth containing 0.9% normal saline, according
to the revised statistical analyses and expected performance criteria published by the FDA on January
19, 2017.
3.2
Objectives
3.2.1
Primary Objectives
The primary objective of this study is to compare the immediate antimicrobial activities of a thermally
treated polyester cloth impregnated with 0.4% w/v octenidine dihydrochloride in aqueous solution to
thermally treated polyester cloths impregnated with vehicle formulation and a polyester cloth containing
0.9% saline. In agreement with the Food and Drug Administration Tentative Final Monograph (TFM)
for Eﬀectiveness Testing of a Patient Preoperative Skin Preparation, a log reduction study will be used
to determine antimicrobial eﬃcacy based on the statistical analyses outlined in published letters from
the FDA on January 19, 2017. Testing will be performed according to the procedures outlined in the
Food and Drug Administration Tentative Final Monograph (TFM) for Eﬀectiveness Testing of a Patient
Preoperative Skin Preparation (FR 59:116, 17 June 94, pp. 31450-31452). The test methods for this
evaluation will be based on ASTM Standard Test Method E1173-15, Evaluation of Preoperative, Pre-
catheterization, or Preinjection Skin Preparations and the test criteria from the deferal letters published
by the FDA on January 19, 2017.
At 10 minutes post-prep, the mean treatment eﬀect of the test article vs. negative controls should be >
1.2 log10 on both the abdomen and the groin with 95% conﬁdence. In this protocol two negative controls
will be used, the Vehicle Control and the Saline Control.
3.2.2
Secondary Objectives
Safety will be evaluated using skin irritation scores and the incidence of adverse events.
3.3
Study Design
This single site study is a randomized, blinded design employing a minimum of 36 healthy volunteers,
where each subject receives two of the planned treatments on the abdomen and groin.
Treatment materials for the following treatment groups will be blinded with treatment codes A or B:
 Thermally treated cloth impregnated with 0.4% w/v octenidine dihydrochloride aqueous solution
(IP: Investigational Product).
MPS-17IPVAW10 Statistical Analysis Plan
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 Thermally treated cloth impregnated with vehicle formulation (VC: Vehicle Control).
The 0.9% Saline Control (SC) cannot be blinded due to product application requirements and will be
assigned to treatment code C.
Out of the minimum 36 evaluable subjects, 12 subjects will receive treatments from both A and B, 12
subjects will receive treatments from both A and C, and 12 subjects will receive treatments from both B
and C to achieve 24 test sites from A, B and C for groin and abdominal regions. The application will be
randomized so that each treatment is applied on an equal number of left and right sides of the body. Due
to baseline requirements the ﬁnal data set may be imbalanced with regard to right and left sides upon
achieving the minimum number of qualifying body sites.
Subjects will be sampled for treatment day baseline microbial populations on randomly assigned sites of
the abdominal and inguinal areas on both sides. Subjects will have samples collected at baseline and 10
minutes (± 30 seconds) on both abdomen and inguinal sites. All sampling times will be calculated from
the completion of the dry time of each product following application.
There is a neutralization test before the main treatment study. Note: this statistical analysis plan is
only for the Main Treatment study and does not include the analysis for the Neutralization study. The
analysis for the Neutralization study will be conducted by the clinical site and included in the ﬁnal clinical
report.
The group treatments and number of treatment sites planned for each group for the main treatment
study are shown in Table 1.
Table 1: Group treatments and number of treatment sites planned
Arm
Treatment
Number of evaluable
treatment sites per
anatomical site
Investigational Product (IP)
Thermally treated polyester cloth impregnated
with 0.4% w/v octenidine dihydrochloride
24
Vehicle Control (VC)
Thermally treated polyester cloth impregnated
with vehicle formulation
24
Saline Control (SC)
0.9% normal saline applied with polyester cloth
24
3.4
Endpoints
 Primary Endpoints: The primary endpoints are the microbial counts for each product at baseline
and 10 minutes post-application time point for both the abdomen and groin.
Log10 CFU/cm2
calculated based on the microbial counts will be used for primary analysis.
 Secondary Endpoints: The secondary endpoints are safety data including evaluations for skin re-
actions using the modiﬁed Berger Bowman irritation assessment scale and the incidence of adverse
events reported during the study for all randomized subjects (the full Intent-to-Treat data set).
Post treatment skin irritation scores of 3 on those scales are also considered adverse events.
 Exploratory Endpoints: The exploratory endpoints are log10 CFU/cm2 reductions from baseline for
each treatment per body site per post-application time point.
MPS-17IPVAW10 Statistical Analysis Plan
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 Informational Endpoints: The informational endpoints are product expression volumes. The weight
of the treatment applied to a test site will be estimated by subtracting the weight measurement (g)
of the treatment after the application from the weight of the treatment (g) before application.
3.5
Acceptance Criteria
The following table summarizes the minimum baseline criteria for each of the test sites and the expected
minimum eﬃcacy standards (superiority criteria).
Table 2: Minimum Treatment Baseline and Expected Mean Log10 Reduction per Anatomical Site
Anatomical Site
Treatmen Day Baseline Criteria
Expected Eﬃcacy Standards
Abdomen
3.00 to 5.50 log10 CFU/cm2
At 10 minutes, the lower two-sided 95% conﬁdence bound
of the average treatment eﬀect of IP vs. VC and IP vs. SC
should be greater than 1.2 log10
Groin
5.00 to 7.50 log10 CFU/cm2
At 10 minutes, the lower two-sided 95% conﬁdence bound
of the average treatment eﬀect of IP vs. VC and IP vs. SC
should be greater than 1.2 log10
4
Sample Size
This is a phase 2 study to assess the immediate antimicrobial eﬀect of the Investigational Products relative
to the two negative controls using a log reduction study according to the procedures outlined in the
Food and Drug Administration Tentative Final Monograph (TFM) for Eﬀectiveness Testing of a Patient
Preoperative Skin Preparation (FR 59:116, 17 June 94, pp. 31450-31452) and the test criteria outlined
in the deferal letters from the FDA published on January 19, 2017. The purpose is to inform design
of future eﬃcacy studies. Therefore, no sample size calculation was performed to provide statistically-
powered evidence of eﬃcacy as part of this study. The sample size is deemed adequate for these purposes.
5
Intended Statistical Software
R 3.2.0 (2015-04-16) or later version if updated.
MPS-17IPVAW10 Statistical Analysis Plan
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6
Data
6.1
Data Sets Analyzed
Descriptions of the modiﬁed intent to treat (mITT) data, per-protocol data and intent to treat (ITT)
data are shown below. Inclusion for the per-protocol data / mITT data set is evaluated for each body
area (left and right for the groin and abdomen).
 Modiﬁed Intent to Treat (mITT) data: data collected will be included if the treatment-day baseline
counts are within the acceptable range (≥3.00 - ≤5.50 log10 CFU/cm2 on abdominal area, and ≥
5.00 - ≤7.50 log10 CFU/cm2 on inguinal area). Data collected will be excluded from mITT data if
the treatment-day baseline counts are outside the acceptable range.
 Per-Protocol data: data collected will be included if the treatment-day baseline counts are within
the acceptable range (≥3.00 - ≤5.50 log10 CFU/cm2 on abdominal area, and ≥5.00 - ≤7.50
log10 CFU/cm2 on inguinal area). Data collected will be excluded from per-protocol data if the
treatment-day baseline counts are outside the acceptable range.
 Intent to Treat (ITT) data: all randomized subjects with available data will be included and used
for the ITT analysis. The full intent to treat (ITT) data set (all randomized subjects) will be used
for the secondary analysis.
For log10 CFU/cm2 determinations, missing data will not be imputed for either mITT data or Per Pro-
tocol data and will be excluded from analysis. For data points excluded from per-protocol analysis due
to protocol deviations, those data points may be included in mITT analysis.
For primary analysis (average treatment eﬀect correcting for pre-treatment log10 bacterial counts) and
exploratory analysis (log reduction), eﬃcacy analyses will be ﬁrst made on the modiﬁed intent to treat
(mITT) data set. Eﬃcacy analyses will be also conducted on the per-protocol data set as supportive
analyses when per-protocol data are diﬀerent from mITT data.
For informational analysis (product expression volumes), inclusion of data points will be based on whether
the matching data point is included for eﬃcacy for primary analysis. Analysis will be performed based
on the per-protocol data as supportive analyses when per-protocol data are diﬀerent from mITT data for
product expression volumes.
MPS-17IPVAW10 Statistical Analysis Plan
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6.2
Analysis Population Set(s)
For each treatment per body site, the number of subjects randomized with treatments received, the num-
ber of subjects available for mITT analysis and / or for per-protocol analysis at 10 minutes post-treatment
time point will be provided in tables below (cf. Table 3, Table 4 and Table 5).
Table 3: Number of Subjects Randomized with Treatment Received
Treatment
Body Site
N Subjects Randomized with Treatment Received
A
Abdomen
B
Abdomen
C
Abdomen
A
Groin
B
Groin
C
Groin
Table 4: Number of subjects available for mITT analysis
Treatment
Body Site
N Subjects for
mITT
Treatment
Eﬀect
N Subjects for
mITT log10
CFU Reduction
N Subjects for
mITT Product
Expression
Volumes
A
Abdomen
B
Abdomen
C
Abdomen
A
Groin
B
Groin
C
Groin
Table 5: Number of subjects available for Per-protocol analysis
Treatment
Body Site
N Subjects for
Per-protocol
Treatment
Eﬀect
N Subjects for
Per-protocol
log10 CFU
Reduction
N Subjects for
Per-protocol
Product
Expression
Volumes
A
Abdomen
B
Abdomen
C
Abdomen
A
Groin
B
Groin
C
Groin
MPS-17IPVAW10 Statistical Analysis Plan
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7
Statistical Analysis/Calculations
7.1
Derived Variables
7.1.1
Log CFU/cm2 of skin
The estimated log10 number of viable microorganisms per cm2 recovered from each sample site will be
designated the “R-value”. To convert the volumetric measure of the sample into the number of colony-
forming units per square centimeter (cm2), the following formula will be employed:
R = log10
"F
 P2
i=1 Ci
n

10-D
A
#
(1)
Where:
R = the average colony-forming unit count in log10 scale per cm2 of sampling surface
F = Total number of mL of sampling solution (SS) added to the sampling cylinder (in this study, F = 6
mL for all samples)
P2
i=1 Ci
n
= average of the duplicate colony counts used for each sample collected (n = 2)
D = Dilution factor of the plates counted
A = Inside area of the sampling cylinder (A= 3.46 cm2 in this study)
Note: The reason that a log10 transformation will be performed on the collected data is to obtain a linear
scale. A linear scale, more appropriately a log10 linear scale, is a basic requirement of the statistical
models used in this study.
If colonies on one of the plates are uncountable, the count from the remaining plate will be used.
In order to avoid potential calculation problems due to taking the logarithm of zero, counts of less than
1 CFU/cm2 are treated as 1 CFU/cm2, such that the log10 transformation is no less than zero.
7.1.2
Log Reduction
Log10 CFU/cm2 reductions from baseline will be calculated separately for each subject, each post-
application time point, and each of the treated anatomical sites by taking the baseline log10 CFU/cm2
values and then subtracting the log10 CFU/cm2 values for the samples taken after the baseline.
7.1.3
Product Expression Volumes
The weight of drug product applied to a test site will be estimated by subtracting the weight measurement
of the test material after the application from the weight of the test material before application.
7.2
Handling of Missing Data
For log10 CFU/cm2 determinations, missing data will not be imputed for either mITT data or Per Pro-
tocol data and will be excluded from analysis.
MPS-17IPVAW10 Statistical Analysis Plan
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7.3
Summary Statistics
Summary statistics will be provided for log10 CFU/cm2 of skin, log10 CFU/cm2 reduction and product
expression volumes based on mITT data and/or per-protocol data. For continuous variables, data will be
summarized with the following descriptive statistics: number of observations, mean (LSMean), median,
standard deviation and range (minimum - maximum). See examples for summary statistics Tables 6 and
7 below for log10 CFU/cm2 and log10 CFU/cm2 reduction.
Table 6: Example: summary statistics for log10 CFU/cm2 for Groin
log10 CFU/cm2
Treatment
Time Point
N
Mean
LSMean
Median
SD
Range
log10 CFU/cm2
A
Baseline
24
5.92
5.92
5.82
0.53
5.01 - 7.23
log10 CFU/cm2
A
10 Minutes
24
3.29
3.29
3.44
1.10
0.89 - 5.89
log10 CFU/cm2
B
Baseline
24
5.78
5.78
5.66
0.54
5.05 - 7.04
log10 CFU/cm2
B
10 Minutes
24
3.27
3.27
3.43
1.09
0.00 - 4.95
log10 CFU/cm2
C
Baseline
24
5.92
5.92
5.82
0.53
5.01 - 7.23
log10 CFU/cm2
C
10 Minutes
24
3.05
3.05
3.09
0.72
1.22 - 4.09
Table 7: Example: summary statistics for log10 CFU/cm2 reduction for Groin
log10 CFU/cm2 reduction
Treatment
N
Mean
LSMean
Median
SD
Range
log10 CFU/cm2 reduction
A Baseline - 10 Minutes
24
2.63
2.63
2.57
1.18
0.20 - 4.80
log10 CFU/cm2 reduction
B Baseline - 10 Minutes
24
2.83
2.83
2.83
0.89
1.24 - 4.86
log10 CFU/cm2 reduction
C Baseline - 10 Minutes
24
2.52
2.52
2.33
1.09
0.83 - 5.50
7.4
Analysis Methods
For each body site, when per-protocol data are diﬀerent from mITT data for log10 CFU/cm2, log reduc-
tion, or product expression volumes, per-protocol analysis and mITT analysis will be performed separately
using the same statistical methods. The following analysis methods will be applied to both per-protocol
analysis and mITT analysis, both abdomen and groin.
An alpha level of 5% (two-sided) is used for all analyses.
7.4.1
Primary Analysis
An analysis of variance (ANOVA) of the baseline log10 CFU/cm2 values will be performed separately
for abdomen and groin. In each model, there will be a random subject eﬀect, a ﬁxed treatment eﬀect,
a ﬁxed body side eﬀect and the interaction between treatment and body side. Pairwise comparisons
with Tukey’s method will be made for log10 CFU/cm2 to determine if there is any signiﬁcant diﬀerence
between treatments at baseline after adjusting body side (e.g., randomization has produced treatment
arms with similar baseline CFU values) for each body site.
The primary purpose of the study is to compare the immediate antimicrobial activity of the Investiga-
tional Products to the Negative Control according to the methods described in the FDA TFM with the
statistical analyses outlined in a deferral letter published January 19, 2017 for superiority.
Evaluate the treatment eﬀect at 10 minutes for Investigational Product (IP) vs. Vehicle Control (VC) /
Saline Control (SC) for abdomen and groin by comparing to a superiority margin of 1.2 log10.
MPS-17IPVAW10 Statistical Analysis Plan
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 Ho: treatment eﬀect of IP vs. VC/SC correcting for pre-treatment log 10 bacterial counts ≤1.2
log10
 Ha: treatment eﬀect of IP vs. VC/SC correcting for pre-treatment log 10 bacterial counts > 1.2
log10
Ho is the null hypothesis and Ha is the alternative hypothesis.
A linear regression model for each body site will be used for primary analyses. In the model, the response
is the post-treatment log10 bacterial counts and predictors are the treatment eﬀect as a ﬁxed eﬀect and the
pre-treatment log10 bacterial counts as a covariate. The two-way interaction between the treatment and
pre-treatment log10 bacterial counts will also be explored. If there is no signiﬁcant interaction detected,
the interaction term will be removed from the model and the average diﬀerence between treatments cor-
recting for pre-treatment bacterial loads will be estimated from the linear regression model. If there is a
signiﬁcant interaction detected between treatment and pre-treatment log10 bacterial counts, the average
diﬀerence between treatments will be estimated from the linear regression model at the average of the
covariate.
The average treatment eﬀect along with 95% conﬁdence interval between IP and VC/SC will be estimated
from the model above for each body site and compared to a superiority margin of 1.2. If the two-sided
95% lower conﬁdence bound > 1.2 log10, the null hypothesis for superiority is rejected and it is concluded
that IP is superior to VC/SC by passing the superiority margin of 1.2 log10. Otherwise the superiority
criteria cannot be passed.
The primary analysis will be based on the modiﬁed Intent to Treat (mITT) data set and the supportive
analysis may be conducted using the per-protocol data set, as described in Section 6.
Since the study will declare success when and only when superiority is demonstrated for both IP vs. VC
and IP vs. SC for both abdomen and groin, no multiplicity adjustment for multiple primary objectives
is required[1].
An example for results of comparisons above can be found in Table 8. All results that do not meet the
targets are highlighted.
Table 8: Example: results for for IP vs. VC and SC for Groin
Comparison
N Pairs
Average Treatment Eﬀect
Conf Int
Meet Superiority Criteria
IP vs. VC
24
1.23
0.90, 1.50
No
IP vs. SC
24
1.65
1.31, 1.99
Yes
MPS-17IPVAW10 Statistical Analysis Plan
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7.4.2
Secondary Analysis
The ITT data set (all randomized subjects) will be considered evaluable for safety. Skin irritation scores
will be reported for any subject who is scored with a 1 or more at any observation (baseline treatment
day or the 10 minute post-application time point) in any category for any site.
Based on the protocol, subjects who receive an irritation score of 1 or greater (any redness, swelling, rash,
or dryness present at any treatment area) for any individual skin condition prior to the treatment Day
baseline sample collection will be excluded from the study and will not be randomized.
Adverse Events (including post treatment skin irritation scores of 3), will also be summarized. Summary
tables will present incidence rates of adverse events by treatment group for all subjects who enter the
treatment period. Listings of Adverse Events will be provided.
The statistical signiﬁcance of diﬀerences in skin irritation between the Investigational Product, Vehicle
Control and Saline Control will be evaluated using Fisher’s exact test on skin irritation data summarized
as follows: any reaction above zero (no reaction) on the skin irritation rating scale for any category
(erythema, edema, rash, and dryness) will be considered a positive signal for that substance. If Fisher’s
exact test shows there is an overall signiﬁcant treatment eﬀect, Fisher’s exact test or two-proportion test
with Score method with multiplicity adjustment on the alpha level may be used for multiple sub-group
comparisons to ﬁnd out which comparisons show the diﬀerence. Odds ratio (odds of having positive
signals for one treatment / odds of having positive signals for the other treatment) using Fisher’s exact
test or the diﬀerence in percentage of positive signals between treatments using a two-proportion test
may be calculated along with the conﬁdence interval for each category at the certain time interval.
Examples for Fisher’s exact test and two-proportion test with Score method are shown below.
MPS-17IPVAW10 Statistical Analysis Plan
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> # overall treatment effect
> irr_tab <- matrix(c(2, 1, 3, 22, 23, 21),
+
nrow = 3,
+
dimnames =
+
list(c("A", "B", "C"),
+
c("Positive (Score > 0)", "Non-positive (Score = 0)")))
> irr_tab
Positive (Score > 0) Non-positive (Score = 0)
A
2
22
B
1
23
C
3
21
> irr <- fisher.test(irr_tab, alternative = "two.sided",
+
conf.level = 0.95)
> print(irr)
Fisher's Exact Test for Count Data
data:
irr_tab
p-value = 0.8654
alternative hypothesis: two.sided
> # subgroup comparisons
> library(PropCIs)
> print(diffscoreci(2, 22, 1, 23, conf.level = 0.984))
data:
98.4 percent confidence interval:
-0.1934747
0.3014313
MPS-17IPVAW10 Statistical Analysis Plan
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7.4.3
Exploratory Analyses
7.4.3.1
Log Reduction
Log10 reductions will be compared between test materials by an Analysis of Variance (ANOVA) for each
body site based on mITT data and/or per-protocol data. In the ANOVA model, the response is the log10
reduction and the predictor is the treatment as a ﬁxed eﬀect. The average diﬀerence in log reduction
between treatments at 10 minutes post-treatment time point will be estimated. However, all conclusions
for the average treatment eﬀect will be based on the primary analysis only.
An example for results of comparisons above can be found in Tables 9.
Table 9: Example: Log reduction comparisons for Groin
Comparison
N Pairs
Diﬀerence
Conf Int
IP Baseline-IP 10 min vs. VC Baseline-VC 10 min
24
0.13
-0.44, 0.70
IP Baseline-IP 10 min vs. SC Baseline-SC 10 min
24
0.11
-0.65, 0.87
7.4.3.2
Product Expression Volumes/Weight
An analysis of variance (ANOVA) of the applied volumes/weight will be performed separately for each
body site based on mITT data and/or per-protocol data. In the model, there will be a random subject
eﬀect, a ﬁxed body side (left or right) eﬀect, a ﬁxed treatment eﬀect and the interaction between ﬁxed
eﬀects. ANOVA table will be checked to see whether the treatment has a signiﬁcant eﬀect on product
expression volumes as well as the interaction. If a signiﬁcant diﬀerence is found, subgroup comparisons
with Tukey’s method will be made to determine which pair of comparisons shows signiﬁcant diﬀerence.
MPS-17IPVAW10 Statistical Analysis Plan
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7.5
Graphs
7.5.1
Average Treatment Eﬀect Per Primary Analysis
Graphs for least squares means with 95% intervals estimated from the regression model for each treatment
will be provided (see an examples in Figure 1).
Graphs for the average treatment eﬀect between IP vs. VC/SC with 95% intervals (as in Table 8) will
be provided (see an example in Figure 2).
Groin
G
G
G
−2
0
2
4
6
IP
VC
SC
Treatment
Least Squares Means for Log CFU with 95% CI
Example: Least Squares Means for Log CFU per Treatment 
 Correcting for Pre−treatment Log Bacterial counts  for Groin
Figure 1: Mean with conﬁdence interval plots for log reduction for Groin
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G
G
0.9
1.2
1.5
1.8
IP vs. VC
IP vs. SC
Treatment
Average Treatment Effect with 95% CI
Example:  Average Treatment Effect for IP vs. VC and SC for Groin
Figure 2: Average diﬀerence between products in log reduction from baseline for Groin
MPS-17IPVAW10 Statistical Analysis Plan
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8
Appendix
Subjects not passing the treatment-day baseline criteria will be listed.
Subjects included in mITT analysis, but excluded from per-protocol analysis, if any, will be listed.
9
References
References
[1] Alex Dmitrienko, Ajit C.Tamhane, Frank Bretz Multiple Testing Problems in Pharmaceutical Statis-
tics
MPS-17IPVAW10 Statistical Analysis Plan
Page 17 of 17


Signature Page for MPS-17IPVAW10_Statistical_Analysis_Plan 
Signature Page for MPS-17IPVAW10_Statistical_Analysis_Plan - System Version No. 
Approved
Lingzhi Li Statistician, Corporate/Shared Services
Statistician
23-Jun-2017 13:40:59 GMT+0000
Approved
Julie Berube Manager Statistics, Corporate/Shared
Services
Functional Management
26-Jun-2017 12:56:35 GMT+0000
Approved
Carole Schatz
Study Manager
29-Jun-2017 22:17:31 GMT+0000

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