Clinical trial NCT04143945
Conditions: Healthy Volunteers Diabetes Mellitus, Type 2 Healthy Volunteers Overweight Healthy Volunteers Obesity
Sponsor: Novo Nordisk A/S
Start date: 2019-10-28; Completion date: 2020-01-04
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study in healthy men and women looks at the injection site experience of the DV3396 pen to that of the PDS290 pens when both pens are used to deliver 0.25 mg semaglutide subcutaneously (s.c., under the skin). Participants will receive 2 single doses of semaglutide 0.25 mg on 1 day. The 2 injections will be given at least 30 minutes apart, one in each side of the stomach. Participants will be in the clinic research center for 1 day. A follow-up phone call will take place between 4 and 5 weeks after the injections were given.

Detailed description:

Arms: arm 1: The 2 treatments will be administered at least 30 minutes apart, one in each side of the stomach arm 2: The 2 treatments will be administered at least 30 minutes apart, one in each side of the stomach
Interventions: intervention 1: Semaglutide (administered by DV3396 pen) intervention 2: Semaglutide (administered by PDS290 pen)
Intervention descriptions: intervention 1: Subjects will receive 1 single dose of semaglutide 0.25 mg on 1 day intervention 2: Subjects will receive 1 single dose of semaglutide 0.25 mg on 1 day

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04143945 
Sponsor trial ID: 
INS-4603 
Official title of study: 
A trial to compare the injection site pain experience of 0.25 mg 
semaglutide B and semaglutide D administered sc 
Document date 
26 August 2020 
 
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CLINICAL STUDY PROTOCOL, INS-4603 VERSION 2.0, 18 OCTOBER 2019 .................
CONFIDENTIAL 
Date: 
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Novo Nordisk 
Version: 
1.0 
Status: 
Final 
Semaglutide
Trial ID: INS-4603
Clinical Trial Report 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04143945 
Sponsor trial ID: 
INS-4603 
Official title of study: 
A trial to compare the injection site pain experience of 0.25 mg 
semaglutide B and semaglutide D administered sc 
Document date 
26 August 2020 
 
VV-CLIN-110330
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'RFXPHQWDWLRQRI6WDWLVWLFDO0HWKRGV
Statistical Analysis Plan, 10 December 2019 .......................................................................
STATISTICAL METHODS AND ANALYSIS OUTPUT, 09Mar20 ......................................

2
/LVWRIFRQWHQWV
CONFIDENTIAL 
Date: 
2$XJ2020
Novo Nordisk 
Version: 
1.0 
Status: 
Final 
Semaglutide
Trial ID: INS-4603
Clinical Trial Report 
$SSHQGL[
Page: 
1 of 36
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 
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Statistical Analysis Plan
Protocol: INS-4603
Version Date: 10-Dec-2019
Page 2 of 27
2.0 Table of Contents
1.0 Approvals ................................................................................................................................................1 
2.0 Table of Contents....................................................................................................................................2 
3.0 Introduction .............................................................................................................................................4 
4.0 Changes from Previous Version of Approved SAP ................................................................................4 
5.0 Study Objectives .....................................................................................................................................4 
5.1 Primary................................................................................................................................................4 
5.1.1 Primary Endpoint..........................................................................................................................4 
5.2 Exploratory ..........................................................................................................................................4 
5.2.1 Exploratory Endpoint....................................................................................................................5 
5.3 Study Hypothesis ................................................................................................................................6 
6.0 Study Design...........................................................................................................................................6 
6.1 Sample Size Considerations...............................................................................................................7 
6.2 Randomization ....................................................................................................................................7 
7.0 Overview of Planned Analysis ................................................................................................................7 
7.1 Changes from Protocol .......................................................................................................................7 
7.2 Interim Analysis and Key Results .......................................................................................................7 
7.3 Final Analysis ......................................................................................................................................7 
8.0 Data Review............................................................................................................................................7 
8.1 Data Management...............................................................................................................................7 
8.2 Acceptance of Data for Summarization ..............................................................................................7 
9.0 Definitions and General Analysis Methods .............................................................................................8 
9.1 Analysis Data Presentation.................................................................................................................8 
9.1.1 Rounding......................................................................................................................................8 
9.1.2 Imputation ....................................................................................................................................8 
9.1.3 Descriptive Statistics....................................................................................................................8 
9.1.4 Pooling .........................................................................................................................................8 
9.1.5 Unscheduled Measurements .......................................................................................................8 
9.2 Analysis Data Definitions ....................................................................................................................8 
9.2.1 Baseline Definition .......................................................................................................................8 
9.2.2 Treatment/Subject Grouping........................................................................................................9 
9.2.3 Common Variable Derivations .....................................................................................................9 
9.2.4 QC................................................................................................................................................9 
9.2.5 ADaM Datasets and Metadata.....................................................................................................9 
9.3 Software ..............................................................................................................................................9 
9.4 Statistical Methods..............................................................................................................................9 
9.4.1 Statistical Outlier Determination...................................................................................................9 
9.4.2 Predetermined Covariates and Prognostic Factors .....................................................................9 
9.4.3 Hypothesis Testing.......................................................................................................................9 
9.5 TFL Layout ........................................................................................................................................10 
10.0 Analysis Sets.......................................................................................................................................10 
10.1 Safety Set........................................................................................................................................10 
10.2 Full Analysis Set (FAS) ...................................................................................................................10 
10.3 Per-Protocol Set..............................................................................................................................11 
11.0 Subject Disposition..............................................................................................................................11 
12.0 Protocol Deviations and Violations .....................................................................................................11 
13.0 Demographic and Baseline Characteristics........................................................................................11 
13.1 Demographics .................................................................................................................................11 
13.2 Medical History................................................................................................................................11 
13.3 Other Baseline Characteristics .......................................................................................................11 
14.0 Concomitant Medications....................................................................................................................11 
15.0 Treatment Compliance and Exposure ................................................................................................12 
16.0 Safety Analyses ..................................................................................................................................12 
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Statistical Analysis Plan
Protocol: INS-4603
Version Date: 10-Dec-2019
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16.1 Safety Variables..............................................................................................................................12 
16.1.1 Injection Site Pain Experience .................................................................................................12 
16.1.2 Adverse Events ........................................................................................................................15 
16.1.3 Deaths and Serious Adverse Events .......................................................................................16 
16.1.4 Laboratory Data .......................................................................................................................16 
16.1.5 Vital Signs ................................................................................................................................16 
16.1.6 Electrocardiograms ..................................................................................................................16 
16.1.7 Other Observations Related to Safety .....................................................................................16 
17.0 References..........................................................................................................................................17 
Appendix 1: Glossary of Abbreviations .......................................................................................................18 
Appendix 2: Schedule of Assessments.......................................................................................................20 
Appendix 3: List of In-Text Tables ..............................................................................................................22 
Appendix 4: List of End of Text Outputs .....................................................................................................23 
Document History........................................................................................................................................27 
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Statistical Analysis Plan
Protocol: INS-4603
Version Date: 10-Dec-2019
Page 4 of 27
3.0 Introduction
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under Novo Nordisk Protocol Version 2.0.
This SAP should be read in conjunction with the study protocol and electronic case report form (eCRF). 
This version of the SAP has been developed using the protocol dated 18-Oct-2019 (including all 
amendments up to this protocol date) and the final eCRF(s) dated 24-Oct-2019.
An approved and signed SAP is a requirement for database lock. An approved SAP is also required for 
unblinding of the study treatments.
This SAP only covers the results that will be processed by the
Early Development Services (EDS) 
Biostatistics Department.
EDS will evaluate the safety and tolerability analysis with focus on the injection site pain experience 
of two different pen-injectors.
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant 
changes from the planned analysis in this SAP performed to provide results for inclusion in the clinical 
study report (CSR) but not included in this SAP, will be clearly identified in Section 9.8.2 of the CSR. 
Changes to planned analyses after unblinding do not require an updated SAP but should be included in 
the CSR if significant.
4.0 Changes from Previous Version of Approved SAP
This is the first version of the SAP.
5.0 Study Objectives
5.1 Primary
The primary objective is to compare, in healthy subjects, the injection site pain experience of a single 
dose of 0.25 mg semaglutide subcutaneously (sc), given as the DV3396 product, to that of the PDS290 
product
5.1.1 Primary Endpoint
Endpoint Title
Time Frame
Unit
Intensity of injection site pain
1 min after each injection (Day 
1)
Millimeter (mm) on a 100-mm 
horizontal visual-analogue scale 
[VAS] (where 0 mm= no pain, 
100 mm = unbearable pain)
5.2 Exploratory
Comparison of injection site pain experience of the two products will be further explored by:
x
Categorial assessments by means of a 6-point scale, and a derived dichotomous scale; 
x
Quality of pain;
x
Duration of pain;
x
Comparative pain experience by means of a 5-point scale, and a derived dichotomous scale; 
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Protocol: INS-4603
Version Date: 10-Dec-2019
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5.2.1 Exploratory Endpoint
Endpoint Title
Time Frame
Unit
Categorical 
assessment 
of 
injection site pain intensity
Immediately after rating of 
intensity of injection site pain, 
ie, after 1 min plus the time it 
takes to complete the rating of 
intensity of injection site pain 
by visual analogue scale (Day 
1)
6-point scale (none – very mild 
– mild – moderate – severe –
very severe)
Moderate or more injection site 
pain
Dichotomous variable based 
on categorical assessment of
intensity of injection site pain 
(Day 1) (item above)
Yes = moderate, severe, very 
severe
No = none, very mild, mild
Quality of pain
Immediately after categorical 
assessment 
of 
intensity 
of 
injection site pain, ie, after 1 
min plus the time it takes to 
complete the rating of intensity 
of injection site pain and the 
categorical rating of intensity of 
injection site pain (Day 1)
Pain quality items on short-form 
McGill 
Pain 
Questionnaire 
[modified SF-MPQ-2 inventory]
(select all that apply):
Throbbing pain տ
Shooting pain տ
Stabbing pain տ
Sharp pain տ
Cramping pain տ
Gnawing pain տ
Hot-burning pain տ
Aching pain տ
Heavy pain տ
Tender տ
Splitting pain տ
Tiring-exhausting տ
Sickening տ
Fearful տ
Punishing-cruel տ
Electric-shock pain տ
Cold-freezing pain տ
Piercing տ
Duration of pain
From time of injection until 
cessation of pain (Day 1)
min and sec
Comparative pain experience
After pain has ended after the 
last injection (Day 1)
5-point scale (the last injection 
hurt much more than the first 
injection – the last injection hurt 
more than the first injection –
they 
hurt 
about 
the 
same 
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Version Date: 10-Dec-2019
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Endpoint Title
Time Frame
Unit
[includes: none of the injections 
hurt] – the last injection hurt 
less than the first injection – the 
last injection hurt much less 
than the first injection)
The DV3396 product hurt less 
than or about the same as the 
PDS290 product
Dichotomous variable based 
on 
“Comparative 
pain 
experience” 
variable 
above 
(Day 1)
Yes 
= 
“about 
the 
same” 
(includes “none of the products 
hurt” or “the DV3396 product 
hurt less than the PDS290 
product” or “the DV3396 product 
hurt much less than the PDS290 
product”)
No = “The DV3396 product hurt 
much more than the PDS290 
product” 
or 
“The 
DV3396 
product hurt more than the 
PDS290 product”
5.3 Study Hypothesis
Not applicable.
6.0 Study Design
This is a single-center, cross-over, randomized, double-blind study in healthy men and women comparing 
the injection site pain experience of the DV3396 product to that of the PDS290 product when both 
products are used to deliver 0.25 mg semaglutide sc. A total of 104 subjects are planned to be 
randomized to achieve at least 100 completed subjects. The aim is to have an even distribution of males 
and females in the study; at least 30% of the same sex should be randomized in the study. Subjects will 
be randomized in a 2×2 scheme evenly to 4 sequences A,B,C or D of product and injection side as in
Table 1.
Table 1 Product and site of injection on abdomen per treatment
Sequence 
Sequence Description
Ratio Required
First injection on right side, Second injection on left side
A
DV3396 (Right) followed by PDS290 (Left)
1
C
PDS290 (Right) followed by DV3396 (Left)
1
First injection on left side, Second injection on right side
B
DV3396 (Left) followed by PDS290 (Right)
1
D
PDS290 (Left) followed by DV3396 (Right)
1
Subjects will receive 1 dose of semaglutide 0.25 mg with the DV3396 product and 1 dose of semaglutide 
0.25 mg with the PDS290 product. The 2 products will be administered at least 30 minutes apart, in the 
anterior aspect of the abdominal wall on opposite sides of the midline. If pain experience still exists after 
60 minutes, the second injection will not be administered. A follow-up phone call (last subject last visit) 
will take place between 4 and 5 weeks after drug administrations on Day 1.
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6.1 Sample Size Considerations
The sample size calculation considers both the primary endpoint and the dichotomous endpoints. 
With 100 subjects, a conservative standard deviation of 30 mm on the VAS, and 90% power, it is possible 
to detect a difference smaller than 10 mm. Hence a sample size of 100 subjects is considered sufficient to 
detect a clinically important difference. Allowing for 4% dropouts or missing data, a total of 104 subjects 
will need to be randomized.
Considering precision on the proportion of the dichotomous endpoints, a sample size of 100 subjects 
results in a confidence interval (CI) with a width of 10% on each side, e.g. for a proportion of 60%, the CI 
is 60% (50%-70%).
6.2 Randomization
Subjects who have met all eligibility criteria will receive a subject number upon inclusion in the study. 
They receive the subject number just prior to dosing. The subject number will ensure identification 
throughout the study. The subject number will be the same as the randomization number given on the 
randomization list provided by Novo Nordisk.
The randomization list will be transferred to the
Pharmacy and kept in a restricted area to which only 
the
Pharmacy has access.
7.0 Overview of Planned Analysis
7.1 Changes from Protocol
Additional statistical analyses will be performed on the exploratory endpoints. See Sections 16.1.1.2,
16.1.1.4, and 16.1.1.5 for more details on these analyses.
7.2 Interim Analysis and Key Results
A set of topline tables, figures and listings (TFLs) will be provided after Database (DB) lock-1 (without 
follow up data). The study will be unblinded after this DB lock-1. These TFLs are indicated with a * in 
Appendix 4: List of End of Text Outputs .
7.3 Final Analysis
All TFLs will be provided after DB lock-2 (all data included).
8.0 Data Review
8.1 Data Management
Data handling and transfer will take place under the
Data Management Plan for the study. Two DB 
locks are planned: 
DB lock-1 : includes all data except follow up data. These data will be used for topline TFLs.
DB lock-2 : includes all data. These data will be used for draft and final TFLs.
8.2 Acceptance of Data for Summarization
Programming of analysis datasets and TFLs may be ongoing during the data management of the study. 
However, programming of analysis datasets and TFLs will be completed and quality controlled (QC’d) 
after each DB lock. Only quality assured (QA’d) results released by the Safety Laboratory will be used for 
the programming of analysis datasets and TFLs for the final report. Any data values requiring 
investigation or corrections that are identified while programming the analysis datasets and TFLs will be 
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sent to the project Data Manager. If the issue affects the TFLs the Programmer or Statistician who 
identified the issue will follow it to resolution.
9.0 Definitions and General Analysis Methods
9.1 Analysis Data Presentation
9.1.1 Rounding
In listings, data will be presented with the same precision as the original data.  Derived data will be 
rounded for presentation purposes.
For all summaries, the mean, standard deviation (SD) and median will be presented to one decimal place 
greater than the data, and the minimum (min) and maximum (max) will be presented to the same number 
of decimal places as the data. Frequency percentages will be presented with one decimal.
The above rule can be applied directly to collected data. For derived data rounding will occur prior to 
summarization so a specific number of decimal places will have to be assumed to apply the above 
rounding rules for summary statistics.
P-values will be reported to four decimal places; p-value less than 0.0001 will be reported as p <0.0001.
9.1.2 Imputation
Unless otherwise noted, data will not be imputed.
9.1.3 Descriptive Statistics
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: n (number of observations), (arithmetic) mean, SD, min, median and max.
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of subjects exposed within a treatment.
For categorical data the categories will be presented in the tables exactly as they appear in the CRF / 
Database, unless otherwise indicated. For injection pain experience categories, categories will be 
combined to create dichotomic categories in addition to the original scale.
9.1.4 Pooling
Not applicable.
9.1.5 Unscheduled Measurements
Unscheduled measurements will be included in the listings. With the exception of unscheduled 
measurements used for baseline, unscheduled measurements will be excluded from the descriptive 
statistics and statistical analysis.
9.2 Analysis Data Definitions
9.2.1 Baseline Definition
Unless otherwise stated, baseline for post-dose evaluations is defined as the last observation recorded 
before the first study drug administration. The last observation can be an unscheduled / repeated 
measurement.
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9.2.2 Treatment/Subject Grouping 
Label
Grouping
Study Treatment 
0.25 mg semaglutide D sc - DV3396 product
0.25 mg semaglutide B sc - PDS290 product 
Treatment
DV3396, PDS290
Dose Level
0.25 mg
9.2.3 Common Variable Derivations
Variable
Data Type
Definition/Calculation
Note
Analysis Study Day 
(Post Dose)
All
Date of Measurement 
minus Dose Date +1
9.2.4 QC
The analysis datasets and the TFLs will be QC’d according to the
EDS QC plan.
9.2.4.1 Critical Data
The QC plan requires datasets to be classified as critical or non-critical. As the primary objective is to 
compare the injection site pain experience, the datasets considered critical are subject level analysis data 
(ADSL), adverse events analysis data (ADAE), and questionnaire analysis data (ADQS) [containing all 
injection site pain experience data]. As these are related to the primary objectives these datasets will be 
double programmed per the QC Plan.
9.2.5 ADaM Datasets and Metadata
The analysis datasets will be generated in accordance with Clinical Data Interchange Standard 
Consortium (CDISC) Analysis Data Model (ADaM) Version 2.1. 
ADaM compliant datasets will be delivered to the sponsor. A define.xml file version 2 with the 
corresponding metadata will be included. Analysis results metadata are excluded.
9.3 Software
The statistical analysis and reporting will be done using SAS® for WindowsTM Version 9.4 or higher (SAS 
Institute, Inc.).
9.4 Statistical Methods
9.4.1 Statistical Outlier Determination
No statistical outlier analysis is planned.
9.4.2 Predetermined Covariates and Prognostic Factors
There are no predetermined covariates or prognostic factors.
9.4.3 Hypothesis Testing
No formal hypothesis testing will be done.
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9.5 TFL Layout
Report layout will be according to the
EDS – ICH E3 compliant – CSR Template. The layout of TFLs 
will be according to the
EDS standards.
No table shells will be provided. The TFLs will be provided in Adobe PDF format.
Format:
x
Page size: A4
x
Data in listings will be sorted by subject number and number of injection. Side and treatment 
(product) will be added to the listings.
x
For presentation of  the tables, please refer to the sections in this SAP.
x
Column titles will be in title case letters.
x
All tables and listings will be in landscape format.
x
The following headers and labels will be used in the TFLs:
Treatment:
Injection Number
Injection Site 
o
DV3396 
o
Inj. 1
o
Left
o
PDS290
o
Inj. 2
o
Right
10.0 Analysis Sets
Analyses
All
Subjects
Safety Set
Full Analysis Set
Per Protocol Set
Disposition
Summaries
3
Safety Assessments
3
Baseline 
Characteristics
3
3
Endpoint Analyses

3
Both the full analysis set and the per protocol set will be used for summaries. All analyses will be based 
on the per protocol analysis set except if it is specifically stated otherwise. Since the safety set and the full 
analysis set are the same, only the safety set will be used for the safety summaries.
The analysis sets are established before DB hardlock-1.
10.1 Safety Set
All subjects who have received at least 1 injection of semaglutide (includes any skin contact with study 
product whether the injection was completed or not).
10.2 Full Analysis Set (FAS)
All randomized subjects who have received at least 1 injection of semaglutide (includes any skin contact 
with trial product whether the injection was completed or not). In exceptional cases, subjects from the 
FAS may be excluded. In such cases the exclusion will be justified and documented before DB hard lock.
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10.3 Per-Protocol Set
All subjects who have received both injections of semaglutide and have completed both intensity of 
injection site pain assessments of the primary endpoint.
11.0 Subject Disposition
The number and percentage of subjects randomized, dosed, and members of each analysis set will be 
presented. The number and percentage of subjects who withdrew from the study prematurely and a 
breakdown of the corresponding reasons for withdrawal will also be presented.
Individual data on randomization, dosing and completion will be listed. 
12.0 Protocol Deviations and Violations
Protocol deviations/violations are collected throughout the study. Protocol deviations for the analysis sets 
will be described in the CSR.
13.0 Demographic and Baseline Characteristics
13.1 Demographics
Individual demographic data will be listed.
Subject demographics at screening will be summarized descriptively for all subjects. All data in this 
summary will be collected at screening and will include the subjects’ age (in years), gender, race, 
ethnicity, weight (in kg), height (in cm), body mass index (BMI) [in kg/m2].
Demographics will be summarized for the safety, FAS, and per protocol sets (if different  from the safety 
set).
13.2 Medical History
Medical history (including coding according to Medical Dictionary for Regulatory Activities [MedDRA], 
version 22.0, will be listed.
13.3 Other Baseline Characteristics
Previous medications (i.e., any recorded medications that start and end before administration of the study 
drug) will be listed.
Previous injection experience as recalled by the subject to the best of their ability will be listed: product 
name, dose, type [vial/syringe, prefilled syringe, autoinjector, other], indication, frequency of use, injection 
site, chronological period used.
Previous medications and previous injection experience will be coded by using the World Health 
Organisation (WHO) Drug Dictionary Enhanced (DDE). The version described in the Coding Conventions
will be used (version 2019MAR01 B3).
Non-compliance to inclusion or exclusion criteria (if any) will be listed.
14.0 Concomitant Medications
Concomitant medication will be listed including coding (WHO-DDE version 2019MAR01 B3).
Concomitant medications are defined as those taken by the patient at any time between the date of study 
drug administration and study completion/discontinuation. Medication with start date being partially or 
completely missing will be assumed to be concomitant if it cannot be definitively shown that the 
medication did not occur during treatment.
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In addition, non-drug treatments will be listed.
15.0 Treatment Compliance and Exposure
Study drug administration data including location of the injection will be listed by subject.
16.0 Safety Analyses
16.1 Safety Variables
The following safety variables will be summarized:
x
Injection site pain experience:
o
Intensity of injection site pain VAS
o
Categorical assessment of injection site pain intensity (6-point scale; dichotomous scale)
o
Quality of pain modified SF-MPQ-2 inventory;
o
Duration of pain assessment
o
Comparative pain assessment (5-point scale, dichotomous scale);
x
Adverse Events (AEs) 
The following safety variables will be listed:
x
Vital Signs (supine systolic and diastolic blood pressure and pulse rate)
x
Electrocardiograms (ECG) (if post dose assessments are deemed relevant by the investigator)
o
Heart Rate
o
PR Interval
o
QRS-Duration
o
QT Interval
o
QTc (Fridericia’s) Interval
x
Clinical Laboratory Evaluations (if post dose assessments are deemed relevant by the 
investigator)
o
Clinical Chemistry 
o
Hematology
o
Hormones
x
Physical Examination (if post dose assessments are deemed relevant by the investigator)
16.1.1 Injection Site Pain Experience
Summaries will be presented for the full analysis set, and in addition for the per protocol set if the sets are 
different from each other. 
16.1.1.1 Intensity of injection Site Pain – VAS
The pain score will be measured on a visual analogue scale, from ‘no pain’ (0 mm) to ’unbearable pain’ 
(100 mm). VAS score will be listed by subject and injection number, side and treatment will be added to 
the listing.
The following descriptive statistics will be presented: number of subjects, arithmetic mean, SD, coefficient 
of variation (CV), median, min and max. The results will be summarized by treatment, by injection 
number, by side, by treatment and injection number, and by treatment and side.
Ping pong plots with individual VAS scores will be presented for each treatment sequence (i.e. by 
treatment and side).
In addition, the primary endpoint will be analyzed for the per protocol population by a fixed analysis of 
variance model with VAS score as the dependent variable, and product, injection side (right side, left 
side), injection number (first injection, second injection), and subject as fixed effects. 
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From the model, the difference in VAS score between the 2 products is estimated and presented with a 
95% CI and a p-value.
Model in SAS:
PROC MIXED data=VAS; /*for per protocol population*/ 
class product inj_number inj_side subject;
/*inj_number: first or second injection*/
/*inj_side: left or right*/
model VAS = product inj_number inj_side subject / ddfm=satterthwaite;
lsmeans product/ diff cl;
RUN;
The interpretation of the difference in VAS pain scores will be supported and contextualized by the results 
of the analyses of the exploratory endpoints.
16.1.1.2 Intensity of Injection Site Pain – Categorial Assessments
Categorical assessment of injection site pain intensity
The categorial pain score will be measured by a 6-point scale in which the pain intensity is rated by the 
subjects as follows: none - very mild – mild - moderate – severe – very severe. 
Individual results will be listed by subject and injection number, side and treatment will be added to the 
listing.
The results will be summarized descriptively, by counting the number (and percentage) of subjects in 
each category. Missing scores will be a separate category. The results will be summarized by treatment.
Moderate or more injection site pain
The 6-point scale will be dichotomized in two categories to evaluate the experience of ‘moderate or more 
injection site pain’. The two categories are:
x
No: none - very mild - mild
x
Yes: moderate – severe – very severe.
The results will be summarized descriptively by counting the number (and percentage) of subjects in each 
category. Missing scores will be a separate category. The results will be summarized by treatment, by 
injection number, by side, by treatment and injection number, and by treatment and side.
In addition, a statistical analysis will be conducted using a McNemar mid-p test (Fagerland et al. 2013) 
with Bonett-Price hybrid score (Fagerland et al. 2014) 95% confidence intervals comparing the two 
products on the moderate or more pain score (No vs Yes).
Model in SAS:
PROC FREQ data=Pain score;
tables DV3396* PDS290 / alpha=0.05;
exact mcnem / midp ;
RUN;
16.1.1.3 Quality of Pain - Modified SF-MPQ-2 Inventory
The quality of pain will be assessed using the modified SF-MPQ-2 inventory.
Individual results will be listed by subject and injection number, side and treatment will be added to the 
listing.
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The results will be summarized descriptively by counting the number (and percentage) of subjects for 
each description of pain quality. Missing scores will be a separate category. The results will be 
summarized by treatment.
16.1.1.4 Duration of Pain Assessment
The duration of pain as indicated by the subject will be recorded from time of injection until cessation of 
pain in seconds.
Individual results will be listed by subject and injection number, side and treatment will be added to the 
listing.
The results will be summarized with the following descriptive statistics: number of subjects, arithmetic 
mean, SD, CV, median, min and max. The results will be summarized by treatment, by injection number, 
by side, by treatment and injection number, and by treatment and side.
In addition, the conditional duration of pain, given there is pain, will be analyzed for subjects in the per 
protocol set who has a non-missing and non-zero duration of pain on both injections, by a fixed analysis 
of variance model with duration of pain as the dependent variable, and product, injection side (right side, 
left side), injection number (first injection, second injection), and subject as fixed effects. 
From the model, the difference in VAS score between the 2 products is estimated and presented with a 
95% CI and a p-value.
Model in SAS:
PROC MIXED data=Duration of pain; /*for per protocol population*/ 
class product inj_number inj_side subject;
/*inj_number: first or second injection*/
/*inj_side: left or right*/
model  duration = product inj_number inj_side subject / ddfm=satterthwaite;
lsmeans product/ diff cl;
RUN;
16.1.1.5 Comparative Pain Assessment 
Comparative pain experience
The comparative pain assessment is a 5-point scale in which the subjects will compare the pain between 
the first and second injection to preserve blinding. After unblinding the scoring will be translated into the 
following 5-point scale:
-
The DV3396 product hurt much more than the PDS290 product.
-
The DV3396 product hurt more than the PDS290 product.
-
The DV3396 and PDS290 products hurt about the same (includes: none of the products hurt).
-
The DV3396 product hurt less than the PDS290 product.
-
The DV3396 product hurt much less than the PDS290 product.
Individual results will be listed by subject.
The results will be summarized descriptively by counting the number (and percentage) of subjects in each 
category. Missing scores will be a separate category.
The DV3396 product hurt less than or about the same as the PDS290 product
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The 5-point scale will be translated in two categories to evaluate if the DV3396 product hurt less than or 
about the same as the PDS290 product. The two categories are:
x
Yes: This includes “none of the products hurt” or “the DV3396 product hurt less than the PDS290 
product” or “the DV3396 product hurt much less than the PDS290 product”.
x
No: This includes “the DV3396 product hurt much more than the PDS290 product” or “the 
DV3396 product hurt more than the PDS290 product”.
The results will be summarized descriptively by counting the number (and percentage) of subjects in each 
category. Missing scores will be a separate category.
In addition, a statistical analysis will be conducted presenting the proportion with Clopper Pearson 95% 
confidence interval of “DV3396 product hurt less than or about the same as the PDS290 product”.
Model in SAS:
PROC FREQ data=comparative_pain;
tables score / binomial(exact) alpha=.05;
RUN;
16.1.2 Adverse Events
A treatment-emergent AE (TEAE) is defined as an event that has onset date on or after the day of the first 
injection and no later than 28 days after the day of the last injection (both injections are scheduled on 
Day 1), or has onset date before the day of the first injection and increases in severity in the period up to 
28 days after the last injection. If the time is missing for an AE on a dosing day, the AE will be categorized 
as TEAE.
In general, TEAEs will not be assigned to one of the products (PDS290 or DV3396) because time 
between dosing is 30-60 minutes. Local tolerability TEAEs will be categorized by product (PDS290 or 
DV3396), based on the location of the injection site which is indicated for these TEAEs.
AE summaries will include TEAEs only, one table will present all TEAEs (all TEAEs), and one table will 
present TEAEs related to local tolerability only (categorized by product).
A breakdown of the number of events and number and percentage of subjects reporting each AE,
categorized by body system and preferred term coded according to the (MedDRA, version 22.0), will be 
presented for all local tolerability TEAEs, categorized by product (PDS290 or DV3396). Subjects will only 
be counted once within each body system or preferred term per product. A similar table will be provided 
for all TEAEs, subject will only be counted once within each body system or preferred term.
The summary tables will present the counts in descending order by system organ class and preferred 
term (within a system organ class) based on the number of subjects experiencing the event. 
Additional tables for all TEAEs and for local tolerability TEAEs (number of events and number and 
percentage of subjects) by severity (mild/moderate/severe) will be provided.
All AEs (including non-treatment-emergent events) recorded on the eCRF will be listed.
A listing of AEs leading to study discontinuation will be provided.
The following missing data will be imputed as defined (for calculations only / will not be presented):
x
Missing AE start and / or end times for the calculation of onset and duration will be assumed to be 
at 00:01 for a start time and 23:59 for end times.
x
Missing AE severity or relationship will be classified as missing severity or missing relationship.
x
Missing AE start times for the determination of treatment emergence will be assumed to occur 
after treatment unless partial date documents the AE as happening prior to treatment.
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x
Missing AE start date will be assumed to be after treatment for the determination of TEAE and on 
treatment for single treatment studies but will not be attributed to treatment in studies with 
multiple treatments.
16.1.3 Deaths and Serious Adverse Events
A listing of deaths and other serious adverse events (SAE) will be provided by subject.
16.1.4 Laboratory Data
Clinical laboratory data will be presented using Système International (SI) units (also used in the Study 
data tabulation model [SDTM] Controlled Terminology).
All laboratory data will be listed by subject and scheduled time. Normal ranges (with units corresponding 
to the reported SI units) will be used directly from the clinical laboratory and will be included in the listings. 
Clinical laboratory results outside the reference range will be flagged. In case the out of reference range 
values were considered clinically significant by the investigator, this will also be indicated in the listings as 
well as in the AE. Comments with regard to the laboratory test results will be shown in a separate listing.
A summary listing with all out-of-range values will also be provided. 
16.1.5 Vital Signs
All vital signs measurements will be listed by subject and timepoint. 
16.1.6 Electrocardiograms
All ECG measurements will be listed by subject and timepoint. The physician’s interpretation and the 
specification of any abnormalities will be provided in a separate listing by subject and timepoint.
16.1.7 Other Observations Related to Safety
17.1.6.1 Physical Examination 
Findings at screening and changes from screening (if applicable) for the physical examination will be 
listed.
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17.0 References
SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC.
Clinical Study Protocol. A TRIAL TO COMPARE THE INJECTION SITE PAIN EXPERIENCE OF 0.25 MG 
SEMAGLUTIDE B AND SEMAGLUTIDE D ADMINISTERED SC. Version 2.0, Final, 18 October 2019.
Clinical Data Interchange Standards Consortium, Inc. , Analysis Data Model (ADaM), Version 2.1, 2009.
Clinical Data Interchange Standards Consortium, Inc., Analysis Data Model (ADaM) Implementation 
Guide, Version 1.1, 2016
Fagerland MW, Lydersen S, Laake P. The McNemar test for binary matched-pairs data: mid-p and 
asymptotic are better than exact conditional. BMC Medical Research Methodology 2013; 13:91.
Fagerland MW, Lydersen S, Laake P. Recommended tests and confidence intervals for paired binomial 
proportions. Statistics in Medicine 2014; 33:2850–2875.
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Appendix 1: Glossary of Abbreviations
ADaM
Analysis data model
ADAE
Subject level analysis dataset
ADSL
Adverse events analysis dataset
AE
Adverse event
ADQS
Questionnaires analysis dataset
BMI
Body mass index
CDISC
Clinical Data Interchange Standard Consortium
CSR
Clinical study report
CI
Confidence interval
CV
Coefficient of variation
DB
Database
ECG
Electrocardiogram
eCRF
Electronic case report form
EDS
Early Development Services
FAS
Full analysis set
HBA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
ICH
The International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum 
mm
millimeter
N
Number of observations
PDF
Portable Document Format
QA’d
Quality assured
QC’d
Quality controlled
SAE
Serious adverse event
SAP
Statistical analysis plan
sc
Subcutaneous(ly)
SD
Standard deviation
SDTM
Study data tabulation model
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SI
Système International
TEAE
Treatment-emergent adverse event
TFLs
Tables, figures and listings
VAS
Visual analogue scale
WHO-DDE
World Health Organization – Drug Dictionary Enhanced
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Appendix 2: Schedule of Assessments
Visit
Screening
Pretreatment
Treatment
Follow-up Phone 
Call
Study Day
Days
-21 to -1
Day 1
Day 29 to Day 36
Predose
Dosing and 
After
Ambulatory
X
X
X
X
Admission
X
Discharge
X
Informed Consent
X
Medical History
X
Previous Injection Experiencea
X
Demographics
X
Hand out of subject ID card
X
Physical Examination
X
Xb
Body Height, Body Weight and BMI Calculation
X
Serology (HBsAg, anti-HCV, anti-HIV-1 and -2)
X
Urine Drug and Alcohol Screen
X
X
Urine Pregnancy Test (Females of Childbearing Potential 
Only)
X
X
Xc
Clinical Laboratoryd
X
Xd
HbA1c
X
12-lead ECGe
X
Xe
Vital Signsf
X
X
Eligibility Check
X
Xg
Randomization and Stratificationh
X
Study Drug Administrationh
X
Intensity of Injection Site Pain VASi
X
Categorical Assessment of Injection Site Pain Intensityj
X
Quality of Pain Modified SF-MPQ-2 Inventoryk
X
Duration of Painl
X
Comparative Pain Assessmentm
X
Previous and Concomitant Medication
X
X
X
X
AE Monitoring
X
X
X
X
Technical Complaintsn
X
X
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Drug Accountability
X
AE=adverse event; BMI=body mass index; ECG=electrocardiogram; HbA1c=glycosylated hemoglobin; HBsAg=hepatitis B surface antigen;
HCV=hepatitis C virus; HIV=human immunodeficiency virus; SF-MPQ-2=short-form McGill Pain Questionnaire 2; VAS=visual-analogue scale
a
Previous injection experience as recalled by the subject to the best of their ability: product used (name, dose, type [vial/syringe, prefilled 
syringe, autoinjector, other], indication, frequency of use, injection site, chronological period used).
b
Physical examination: this will be a focused examination only done if deemed relevant by the Investigator.
c
For the check on pregnancy at the follow-up phone call, female subjects of childbearing potential will be handed out a urine pregnancy test 
on Day 1. They will have to do the pregnancy test at the earliest in the morning of Day 29 and at the latest in the morning of the follow-up
phone call.
d
Clinical laboratory tests (including clinical chemistry and hematology): at screening (non-fasting).
The same tests may be done after the second study drug administration on Day 1 prior to discharge, if deemed relevant by the Investigator.
e
12-lead ECG: at screening.
12-lead ECG may be done after the second study drug administration on Day 1 prior to discharge, if deemed relevant by the Investigator. 
f
Vital signs (supine systolic and diastolic blood pressure, and pulse): at screening and after the second study drug administration on Day 1 
prior to discharge.
g
Eligibility check on Day 1 before dosing concerns the urine pregnancy test (female subjects of childbearing potential only), urine drug and 
alcohol screen, and concomitant medication only.
h
Subjects will be randomized in a 2×2 scheme evenly to 4 sequences of product and injection side as in the table below:
Treatment Short 
Identifier
Treatment Long Identifier
Ratio Required
First injection on right side, Second injection on left side
A
DV3396 (Right) followed by PDS290 (Left)
1
C
PDS290 (Right) followed by DV3396 (Left)
1
First injection on left side, Second injection on right side
B
DV3396 (Left) followed by PDS290 (Right)
1
D
PDS290 (Left) followed by DV3396 (Right)
1
Subjects will receive 1 dose of semaglutide 0.25 mg with the DV3396 product and 1 dose of semaglutide 0.25 mg with the PDS290 product
within the same day. The 2 products will be administered at least 30 minutes apart, in the anterior aspect of the abdominal wall on opposite 
sides of the midline.
i
One minute after each injection, the VAS to rate the intensity of injection site pain will be administered.
j
The categorical assessment of injection site pain intensity (6-point scale) will be started after the VAS to rate the intensity of injection site pain 
has been completed after each injection.
k
The quality of pain modified SF-MPQ-2 inventory will be started after the categorical assessment of injection site pain intensity (6-point scale) 
has been completed after each injection.
l
Subjects have to indicate after each injection when the pain, if any, is gone.
m
The comparative pain assessment (5-point scale) comparing pain between the 2 injections will be completed after the last injection.
n
All technical complaints that occur, from the time of receipt of the product at the site until the time of the last usage of the product, must be 
collected and reported to Novo Nordisk. 
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Appendix 3: List of In-Text Tables
List of In-Text Tables and  Figures:
Output
Title 
Analysis Set
Table
Summary of Subject Disposition
All Subjects
Table 
Summary of Demographics
Safety
Table
Summary of Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term - Local Tolerability
Safety
Table
Summary of Treatment Emergent Adverse Events by Severity for 
Treatment Emergent Adverse Events - Local Tolerability
Safety
Table
Summary of Intensity of Injection Site Pain - VAS
Per Protocol
Figure
Ping-Pong Plots of Individual VAS scores by treatment sequence
Per Protocol
Table
Statistical Analysis on Injection Site Pain - VAS
Per Protocol
Table
Summary of Intensity of Injection Site Pain - Moderate or more 
injection site pain
Per Protocol
Table
Statistical Analysis on Intensity of Injection Site Pain - Moderate or 
more injection site pain
Per Protocol
Table
Summary of Quality of Pain - Modified SF-MPQ-2 Inventory
FAS
Table
Summary of Duration of Pain
Per Protocol
Table
Statistical Analysis on Duration of Pain
Per Protocol
Table
Summary of Comparative Pain - 5-Point Scale
FAS
Table
Summary of Comparative Pain - DV3396 product hurt less than or 
about the same as the PDS290 product
Per Protocol
Table
Statistical Analysis on Comparative Pain - DV3396 product hurt less 
than or about the same as the PDS290 product
Per Protocol
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Appendix 4: List of End of Text Outputs
TFLs indicated with a * will be presented in Topline results.
List of End of Text Tables and Figures:
Output
Title 
Population 
Set
Section 14.1 – Disposition and Demographic Data
Table 14.1.1
Summary of Subject Disposition
All subjects
Table 14.1.2 *
Summary of Demographics
Safety
Extended with 
FAS, Per 
Protocol if 
different from 
Safety 
Table 14.1.3
Summary of Dosing
Safety
Section 14.2 – Pharmacokinetic Data - Not Applicable
Section 14.3 – Safety Data
Table 14.3.1.1  
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term – all TEAEs
Safety
Table 14.3.1.2
Summary of Treatment Emergent Adverse Events by Severity 
for Treatment Emergent Adverse Events – all TEAEs
Safety
Table 14.3.1.3
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term - Local Tolerability
Safety
Table 14.3.1.4
Summary of Treatment Emergent Adverse Events by Severity
for Treatment Emergent Adverse Events - Local Tolerability
Safety
Table 14.3.2
Listing of Deaths and Other Serious Adverse Events 
All Subjects
Table 14.3.3
Not part of TFL – Reserved for Narratives in CSR
Table 14.3.4
Listing of Abnormal Laboratory Values
Safety
Table 14.3.5 *
Summary of Intensity of Injection Site Pain - VAS
Per Protocol, 
FAS
Figure 14.3.6 *
Ping-Pong Plots of Individual VAS Scores by Treatment 
sequence
Per Protocol
Table 14.3.7 *
Statistical Analysis on Injection Site Pain - VAS
Per Protocol
Table 14.3.8 *
Summary of Intensity of Injection Site Pain - 6-Point Categorial 
Scale
Per Protocol, 
FAS
Table 14.3.9 *
Summary of Intensity of Injection Site Pain - Moderate or more 
injection site pain
Per Protocol, 
FAS
Table 14.3.10 *
Statistical Analysis on Intensity of Injection Site Pain -
Moderate or more injection site pain
Per Protocol
Table 14.3.11 *
Summary of Quality of Pain - Modified SF-MPQ-2 Inventory
Per Protocol, 
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FAS
Table 14.3.12*
Summary of Duration of Pain
Per Protocol, 
FAS
Table 14.3.13 *
Statistical Analysis on Duration of Pain
Per Protocol
Table 14.3.14 *
Summary of Comparative Pain - 5-Point Scale
Per Protocol, 
FAS
Table 14.3.15 *
Summary of Comparative Pain - DV3396 product hurt less 
than or about the same as the PDS290 product
Per Protocol, 
FAS
Table 14.3.16 *
Statistical Analysis on Comparative Pain - DV3396 product 
hurt less than or about the same as the PDS290 product
Per Protocol
For the Topline results, additional plots might be created to support visualization of pain scores and /or 
consistency between the results on the different pain scales.
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List of End of Text Listings:
Output
Title 
Section 16.2.1  Disposition
Listing 16.2.1.1
Subject Disposition
Listing 16.2.1.2
Deviation from Eligibility Criteria
Section 16.2.2  Protocol Deviations
Listing 16.2.2.1 
Reference to CSR
Section 16.2.3 Allocation to Analysis Sets
Listing 16.2.3.1 *
Overview Analysis Sets
Section 16.2.4  Demographics Data and Other Baseline Characteristics
Listing 16.2.4.1 *
Subject Demographics
Listing 16.2.4.2
Medical History
Listing 16.2.4.3
Previous Medications and Previous Injection Experience
Section 16.2.5 Compliance and/or Drug Concentration Data
Listing 16.2.5.1
Study Dates
Listing 16.2.5.2 *
Study Drug Administration
Section 16.2.6  Injection Pain Experience Data
Listing 16.2.6.1 *
Intensity of Injection Site Pain – VAS
Listing 16.2.6.2 *
Intensity of Injection Site Pain – Categorial Scale
Listing 16.2.6.3 *
Quality of Pain - Modified SF-MPQ-2 Inventory
Listing 16.2.6.4 *
Duration of Pain 
Listing 16.2.6.5 *
Comparative Pain Assessment
Section 16.2.7 Adverse Events Data
Listing 16.2.7.1
Adverse Events
Listing 16.2.7.2
Adverse Events Leading to Study Drug Discontinuation
Listing 16.2.7.3
Concomitant Medications and Non Drug Therapies 
Section 16.2.8 Laboratory Data
Listing 16.2.8.1
Clinical Laboratory Results – Chemistry
Listing 16.2.8.2
Clinical Laboratory Results – Hematology
Listing 16.2.8.3
Clinical Laboratory Results – Comments
Section 16.2.9 Other Safety Data
Listing 16.2.9.1
Vital Signs
Listing 16.2.9.2
12-Lead Electrocardiogram Results – Individual Parameters
Listing 16.2.9.3
12-Lead Electrocardiogram Results – Investigator’s Interpretation and 
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Specification of ECG Abnormalities
Listing 16.2.9.4
Physical Examination Findings
Other Appendix Outputs:
Output
Title 
Appendix 16.1.7
Randomization
Appendix 16.1.9.2
Statistical Appendices
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Document History
Version Date
Modified/Reviewed 
By
Brief Summary of Changes (if created from a 
template, include template code)
02-Dec-2019
Draft for internal review
05-Dec-2019
First Draft to Novo Nordisk
10-Dec-2019
Final
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Statistical Methods
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STATISTICAL METHODS AND ANALYSIS OUTPUT
A TRIAL TO COMPARE THE INJECTION SITE PAIN EXPERIENCE OF 0.25 MG 
SEMAGLUTIDE B AND SEMAGLUTIDE D ADMINISTERED SC 
CONFIDENTIAL
code:
Sponsor code: INS-4603
SPONSOR
Novo Nordisk A/S
AUTHOR
MSc, Biostatistician
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TABLE OF CONTENTS
1. DEVIATIONS FROM THE SAP .................................................................................... 3 
2. ANALYSIS POPULATIONS ......................................................................................... 3 
3. STATISTICAL ANALYSIS OUTPUT ............................................................................ 3 
3.1 
Statistical Analysis VAS ............................................................................................................... 3 
3.2 
Statistical Analysis Duration of Pain........................................................................................... 4 
3.3 
Statistical Analysis on Intensity of Injection Pain - Moderate or more injection site pain .... 5 
3.4 
Statistical Analysis on Comparative Pain - DV3396 versus PDS290 ....................................... 7 
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1.
Deviations from the SAP
None.
2.
Analysis Populations
All 104 subjects were in the safety set, full analysis set and in the per protocol set.
 
3.
Statistical Analysis Output  
3.1
Statistical Analysis VAS  
analysis primary VAS - fix: trtp aperiod side - ran: subject 
The Mixed Procedure 
          Number of Observations 
Number of Observations Read             208 
Number of Observations Used             208 
Number of Observations Not Used           0 
Covariance Parameter 
      Estimates 
Cov Parm     Estimate 
Residual      80.5244 
        Type 3 Tests of Fixed Effects 
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
TRTA            1     101       4.35    0.0395 
APERIOD         1     101       7.74    0.0065 
EXLAT           1     101       0.01    0.9386 
SUBJID        103     101       2.09    0.0001 
                                               Estimates 
                           Standard 
Label           Estimate   Error      DF    t Value    Pr > |t|     Alpha   Lower    Upper 
DV3396 - PDS290   2.5962   1.2444     101       2.09      0.0395      0.05  0.1276   5.0647 
                                        Least Squares Means 
           Actual                                     Standard 
Effect   Treatment    Laterality Period    Estimate    Error      DF    t Value    Pr > |t| 
TRTA     DV3396                              8.2788   0.8799     101       9.41      <.0001 
TRTA     PDS290                              5.6827   0.8799     101       6.46      <.0001 
APERIOD                          1           5.2500   0.8799     101       5.97      <.0001 
APERIOD                          2           8.7115   0.8799     101       9.90      <.0001 
EXLAT                 LEFT                   7.0288   0.8799     101       7.99      <.0001 
EXLAT                 RIGHT                  6.9327   0.8799     101       7.88      <.0001 
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Statistical Analysis on Injection Site Pain - VAS 
Per Protocol Set 
_________________________________________________________________________________________
                              ______LSmeans______ _Difference Test/Reference_
Treatment Comparison          ________  _________                ___95% CI___  _p value__ 
(Test vs. Reference) ParameterTest      Reference  Estimate      Lower  Upper     product 
_________________________________________________________________________________________
DV3396 - PDS290      VAS (mm)    8.28      5.68      2.6         0.1    5.1      0.0395 
_______________________________________________________________________________________
Model: ANOVA with a fixed effect for product (DV33 and PDS290), injection number (1st 2nd), 
injection side (left and right), and subject.
3.2
Statistical Analysis Duration of Pain
analysis Conditional Duration Pain - fix: trtp aperiod side - ran: subject 
The Mixed Procedure 
          Number of Observations 
Number of Observations Read              90 
Number of Observations Used              90 
Number of Observations Not Used           0 
Covariance Parameter 
      Estimates 
Cov Parm     Estimate 
Residual       213.59 
        Type 3 Tests of Fixed Effects 
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
TRTA            1      42       0.87    0.3553 
APERIOD         1      42       1.58    0.2162 
EXLAT           1      42       2.85    0.0985 
SUBJID         44      42       7.47    <.0001 
                                               Estimates 
                             Standard 
Label            Estimate    Error      DF    t Value    Pr > |t|  Alpha   Lower   Upper 
DV3396 - PDS290   3.0168     3.2277     42     0.93      0.3553    0.05   -3.4970  9.5305 
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                                        Least Squares Means 
        Actual                                        Standard 
Effect  Treatment  Laterality  Period    Estimate      Error      DF    t Value    Pr > |t| 
TRTA    DV3396                            26.1084      2.2311      42      11.70      <.0001 
TRTA    PDS290                            23.0916      2.2311      42      10.35      <.0001 
APERIOD                        1          22.5777      2.2288      42      10.13      <.0001 
APERIOD                        2          26.6223      2.2288      42      11.94      <.0001 
EXLAT              LEFT                   21.9890      2.1821      42      10.08      <.0001 
EXLAT              RIGHT                  27.2110      2.1821      42      12.47      <.0001 
Table XXX  Statistical Analysis on Duration of Pain 
Per Protocol Set (conditional dataset) 
____________________________________________________________________________________________
                                      ______LSmeans______ _Difference Test/Reference_
Treatment Comparison                  ________  _________            ___95% CI___ _p value__ 
(Test vs. Reference) Parameter          Test    Reference  Estimate  Lower  Upper
product
_________________________________________________________________________________________
DV3396 - PDS290     Pain Duration (sec)  26.1   23.1       3.0    -3.5    9.5      0.3553 
____________________________________________________________________________________________
Model: ANOVA with a fed effect for product (DV3396 and PDS290), injection number (1st 2nd), 
injection side (left and right), and subject.
Note: The conditional duration of pain, given there is pain, is analyzed for subjects in the 
per protocol set who have a non-missing and non-zero duration of pain on both injections. 
3.3
Statistical Analysis on Intensity of Injection Pain - Moderate or more injection site 
pain
analysis moderate or more injection site pain 
McNemar paired exact mid-p test 
The FREQ Procedure 
Table of _11 by _22 
_11(DV3396)     _22(PDS290) 
Frequency‚
Percent  ‚ 
Row Pct  ‚ 
Col Pct  ‚Yes     ‚No      ‚  Total 
_________ˆ________ˆ________ˆ
Yes      ‚      1 ‚      7 ‚      8 
         ‚   0.96 ‚   6.73 ‚   7.69 
         ‚  12.50 ‚  87.50 ‚ 
         ‚  50.00 ‚   6.86 ‚ 
_________ˆ________ˆ________ˆ
No       ‚      1 ‚     95 ‚     96 
         ‚   0.96 ‚  91.35 ‚  92.31 
         ‚   1.04 ‚  98.96 ‚ 
         ‚  50.00 ‚  93.14 ‚ 
_________ˆ________ˆ________ˆ
Total           2      102      104 
             1.92    98.08   100.00 
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Statistics for Table of _11 by _22 
                         McNemar's Test 
                                      -----------Exact---------- 
Chi-Square        DF    Pr > ChiSq    Pr >= ChiSq    Mid p-Value 
    4.5000         1        0.0339         0.0703         0.0391 
           Simple Kappa Coefficient 
            Standard 
Estimate       Error    95% Confidence Limits 
  0.1746      0.1668     -0.1524       0.5016 
Sample Size = 104 
_analysis moderate or more injection site pain 
relative risk 
The FREQ Procedure 
Table of TRTA by AVALCAT1 
TRTA(Actual Treatment) 
          AVALCAT1(Analysis Value Category 1) 
Frequency‚
Percent  ‚ 
Row Pct  ‚ 
Col Pct  ‚No      ‚Yes     ‚  Total 
_________ˆ________ˆ________ˆ
DV3396   ‚     96 ‚      8 ‚    104 
         ‚  46.15 ‚   3.85 ‚  50.00 
         ‚  92.31 ‚   7.69 ‚ 
         ‚  48.48 ‚  80.00 ‚ 
_________ˆ________ˆ________ˆ
PDS290   ‚    102 ‚      2 ‚    104 
         ‚  49.04 ‚   0.96 ‚  50.00 
         ‚  98.08 ‚   1.92 ‚ 
         ‚  51.52 ‚  20.00 ‚ 
_________ˆ________ˆ________ˆ
Total         198       10      208 
            95.19     4.81   100.00 
Statistics for Table of TRTA by AVALCAT1 
                  Odds Ratio and Relative Risks 
Statistic                        Value       95% Confidence Limits 
__________________________________________________________________
Odds Ratio                      0.2353        0.0487        1.1359 
Relative Risk (Column 1)        0.9412        0.8849        1.0010 
Relative Risk (Column 2)        4.0000        0.8701       18.3891 
Sample Size = 208 
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Table Statistical Analysis on Intensity of Injection Pain - Moderate or more injection site 
pain
Study Population: per protocol 
_______________________________________________________________________________
                     Moderate or more Pain
______________________________________________________________________________
Crosstabulation of categories for DV3396 (rows) versus PDS290 (cols)
Yes                    No
Yes                    1                     7
No                     1                    95
McNemar mid-p test and relative ratio with Bonett-Price hybrid score 95% CI
McNemar mid-p value   0.0391
Ratio and 95% CI *    4.00                  1.08 - 14.8
_______________________________________________________________________________
*: Relative incidence ratio of moderate or more pain for DV3396 over DPS290
No: none - very mild - mild    Yes: moderate - severe - very severe.
3.4
Statistical Analysis on Comparative Pain - DV3396 versus PDS290
analysis proportion DV3396 hurt less/same as PDS290 with Clopper Pearson 95% CI 
The FREQ Procedure 
                  Analysis Value Category 1 
                                     Cumulative    Cumulative 
AVALCAT1    Frequency     Percent     Frequency      Percent 
_____________________________________________________________
Yes               65       62.50            65        62.50
No                39       37.50           104       100.00
 Binomial Proportion 
    AVALCAT1 = Yes 
Proportion      0.6250 
ASE             0.0475 
 Confidence Limits for the Binomial Proportion 
              Proportion = 0.6250 
Type                       95% Confidence Limits 
Clopper-Pearson (Exact)    0.5247         0.7180 
  Test of H0: Proportion = 0.5 
ASE under H0              0.0490 
Z                         2.5495 
One-sided Pr >  Z         0.0054 
Two-sided Pr > |Z|        0.0108 
Sample Size = 104 
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Table Statistical Analysis on Comparative Pain - DV3396 versus PDS290 
Per Protocol Set 
________________________________________________________________
_______________DV3396 hurts less/same as PDS290 *_______________ 
                                Proportion
 Yes           No               #
  n   (%)     n   (%)             Yes          95% CI
________________________________________________________________
 65 (62.5)   39 (37.5)           0.63       0.52 - 0.72
________________________________________________________________
*: DV3396 product hurt less than or about the same as the PDS290 product.
#: Proportion "Yes" and Clopper-Pearson (Exact) 95% CI.
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