A Trial to Complare the Injection Site Pain Experience of Semaglutide 0.25 mg and Dulaglutide 0.75 mg Administered sc
Phase: PHASE4
Conditions: Healthy Volunteers, Diabetes Mellitus, Type 2, Overweight, Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04189848 
Sponsor trial ID: 
NN9535-4648 
Official title of study: 
A Trial to Compare the Injection Site Pain Experience of 
Semaglutide 0.25 mg and Dulaglutide 0.75 mg Administered 
SC 
Document date: 
06 Oct 2020 
 

CLINICAL STUDY PROTOCOL NN9535-4648/
 Version 2.0 – 22 NOV 2019 ............................... 2
&OLQLFDO6WXG\3URWRFROB1RY
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CONFIDENTIAL
Date:
06 Oct 2020
Novo Nordisk
Version:
1.0
Status:
Final
Semaglutide and Dulaglutide
Trial ID: NN9535-4648
Clinical Trial Report 
$SSHQGL[
Page:
1 of 
CONFIDENTIAL
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 

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CLINICAL STUDY PROTOCOL
A TRIAL TO COMPARE THE INJECTION SITE PAIN EXPERIENCE OF SEMAGLUTIDE 
0.25 MG AND DULAGLUTIDE 0.75 MG ADMINISTERED SC
CONFIDENTIAL
Sponsor code: NN9535-4648
PRA code:
EudraCT number: 2019-83003844-57
Universal Trial Number: U1111-1241-0348
Comparison of injection site pain experience for semaglutide and dulaglutide sc 
Investigational product: 
Semaglutide and dulaglutide
Clinical phase: 
Phase 4 trial
Indication to be studied: 
Not applicable
Sponsor:
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsvaerd
Denmark
Contract Research
Organisation and
Clinical Site:
Principal Investigator:
, MD
Phone:
Fax:
E-mail:
Version 2.0 – 22 Nov 2019
This trial will be performed in compliance with the principles of Good Clinical Practice.
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AUTHORISATION OF CLINICAL STUDY PROTOCOL BY CONTRACT
RESEARCH ORGANISATION
The Sponsor and the Contract Research Organisation agree to conduct the trial as outlined in this 
clinical study protocol. Any modification of the clinical study protocol must be agreed upon by the 
Sponsor and the Contract Research Organisation and must be documented in writing.
Name/Position:
Date:
Signature:
Contract Research Organisation:
Principal Investigator
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CONTACT INFORMATION
Sponsor
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsvaerd
Denmark
Sponsor's Contact
Trial Start-up Manager
Trial Operations, Insulin & Devices
Phone:
E-mail:
Sponsor’s Medical Specialist
International Medical Director
Medical & Science, Devices & Titration
Phone:
E-mail:
Contract Research Organisation and Clinical Site
Clinical Site Contacts
 MD
Principal Investigator
Phone:
Fax:
E-mail:
PharmD, PhD
Project Manager
Phone:
Fax:
E-mail:
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Clinical Laboratory
Medical Screening Centre
Study Monitor
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SYNOPSIS
Trial Title
A TRIAL TO COMPARE THE INJECTION SITE PAIN EXPERIENCE OF SEMAGLUTIDE 0.25 MG AND 
DULAGLUTIDE 0.75 MG ADMINISTERED SC
Short Trial Title
Comparison of injection site pain experience for semaglutide and dulaglutide sc
Trial Codes
Sponsor code
: NN9535-4648
PRA code
:
EudraCT number
: 2019-83003844-57
Universal Trial Number
: U1111-1241-0348
Sponsor
Novo Nordisk A/S, Novo Allé, DK-2880 Bagsvaerd, Denmark
Sponsor’s contact
:
, Trial Start-up Manager
Contract Research Organisation and Clinical Site
Principal Investigator
, MD
Clinical Phase
4
Objectives
The primary objective is to compare, in healthy subjects with overweight or obesity, the injection site pain 
experience of a single dose of semaglutide 0.25 mg sc using the semaglutide product compared to a single 
dose of dulaglutide 0.75 mg sc using the dulaglutide product.
Endpoints
Primary Endpoint
Endpoint title
Time frame
Unit
Intensity of injection site pain
1 min after each injection 
(Day 1)
mm on a 100 mm horizontal visual-analogue 
scale (where 0 mm = no pain, 100 mm = 
unbearable pain)
Exploratory Endpoints
Endpoint title
Time frame
Unit
Categorical assessment of 
intensity of injection site pain
Immediately after rating of 
intensity of injection site pain, 
i.e. 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)
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Endpoint title
Time frame
Unit
Moderate or more injection 
site pain
Dichotomous variable based 
on categorical assessment of 
intensity of injection site pain
(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, i.e. 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 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 painտ
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 s
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 – about the same 
(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 semaglutide product hurt 
less than or about the same 
as the dulaglutide product
Dichotomous variable based 
on “Comparative pain 
experience” variable above
Yes = “about the same (includes none of the 
products hurt)” or “the semaglutide product hurt 
less than the dulaglutide product” or “the 
semaglutide product hurt much less than the 
dulaglutide product”
No = “the semaglutide product hurt much more 
than the dulaglutide product” or “the semaglutide 
product hurt more than the dulaglutide product”
Design and Treatments
This is a single centre, crossover, randomised, double-blind trial in healthy, overweight or obese, men and 
women comparing the injection site pain experience of the semaglutide product to the dulaglutide product. 
Enrolment will be carried out to include no more than 70% of each gender. Subjects will receive 1 dose of 
semaglutide 0.25 mg and 1 dose of dulaglutide 0.75 mg on 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.
Subjects will be randomised in a 2×2 scheme evenly to 4 sequences of product and injection side as 
described in the table below:
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Treatment Short 
Identifier
Treatment Long Identifier
Ratio Required
First injection on right side, Second injection on left side
A
Semaglutide product (Right) followed by Dulaglutide 
product (Left)
1
C
Dulaglutide product (Right) followed by Semaglutide 
product (Left)
1
First injection on left side, Second injection on right side
B
Semaglutide product (Left) followed by Dulaglutide product 
(Right)
1
D
Dulaglutide product (Left) followed by Semaglutide product 
(Right)
1
The present trial compares the injection site pain experience after a single use of each product, both given 
on the same day. To minimise gastrointestinal adverse events inherent to glucagon-like petide-1 (GLP-1)
receptor agonist (RA)s the lowest marketed dose of each drug will be used, i.e. semaglutide 0.25 mg and 
dulaglutide 0.75 mg. Based on pharmacokinetic modelling1, the single dose of dulaglutide 0.75 mg given on
the same day as semaglutide 0.25 mg sc is expected to provide a similar effect to semaglutide 0.5 mg, which 
is the highest single dose of emaglutide tolerated without dose excatlation due to risk of GI AEs. Also, as 
per its summary of product characteristics, dulaglutide may be initiated at the 1.5 mg dose.
The length of the crossover interval is set to be as short as possible to minimise the impact of systemic 
effects of both semaglutide and dulaglutide, especially nausea, between the first and the last injection, while 
being long enough to minimise residual pain and emotional carry-over from the first injection. See figure 
below for an overview of the trial design.
CRO=contract research organisation
Trial Schedule
Screening
: Between Day -21 and Day -1
Confinement period
: One day in the clinic: Day 1
Follow-up
: A follow-up phone call will take place between 4 and 5 weeks after drug 
administration on Day 1
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Subjects
A total of 104 subjects are planned to be randomised to achieve at least 100 completed subjects. The aim is 
to have an even distribution of male and female subjects in the trial; at least 30% of the same sex should be 
randomised in the trial.
Key Inclusion Criteria
x
Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent.
x
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x
Considered to be generally healthy based on the medical history, physical examination, and the results 
of vital signs, electrocardiogram and clinical laboratory tests performed during the screening visit, as 
judged by the Investigator.
Key Exclusion Criteria
x
Female who is pregnant, breast-feeding or intends to become pregnant within 4 weeks of Day 1 or is of 
childbearing potential and not using highly effective contraceptive methods.
x
Any disorder which in the Investigator’s opinion might jeopardise subject’s safety, evaluation of results, 
or compliance with the protocol.
x
Glycosylated haHPRJORELQ+E$FPPROPRODWVFUHHQLQJ
x
Use of prescription medicinal products or non-prescription drugs or herbal products, except routine 
vitamins, topical medication, contraceptives and occasional use of paracetamol (not allowed within 
24 hours prior to drug administration), within 14 days prior to Day 1.
x
Average intake of more than 21 units of alcohol per week for male subjects and more than 14 units per 
week for female subjects: 1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 
35 mL of spirits).
x
Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], 
cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol) at screening and 
admission to the clinical research centre.
x
Use of tobacco and nicotine products, defined as any of the below:
o
Smoking more than 1 cigarette or the equivalent per day on average.
o
Not able or willing to refrain from smoking and use of nicotine substitute products during the 
in-house period.
x
Subject is not able to understand and read English or Dutch, or subject is not able to understand and 
comply with the trial requirements.
Trial Drug
Name
Name of Intervention Product
Semaglutide 1.34 mg/mL PDS290 pre-filled pen-injector
Semaglutide product
Trulicity 0.75 mg solution for injection in pre-filled pen 
(dulaglutide)
Dulaglutide product
Variables
Safety
: Intensity of injection site pain on a visual-analogue scale (VAS), categorical 
assessment of injection site pain intensity (6-point scale), quality of pain
modified short-form McGill Pain Questionnaire 2 (SF-MPQ-2) inventory,
duration of pain assessment, comparative pain assessment (5-point scale),
adverse events, clinical laboratory (if postdose assessments are deemed 
relevant by the Investigator), physical examination (if postdose assessments
are deemed relevant by the Investigator),
12-lead
ECG (if postdose 
assessments are deemed relevant by the Investigator), and vital signs
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Statistical Methods
Sample size calculation
: The sample size calculation considers both the primary endpoint and the 
dichotomous endpoints. 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, eg, for a proportion of 60%, the 
CI is 60% (50%-70%).
A standard deviation (SD) of within-pair differences in VAS pain score between 
2 SC injections was obtained from Novo Nordisk clinical trial INS-4011. The 
within-subject variance (adjusting for the effects of speed, volume, and injection 
region) was estimated to 348, corresponding to an SD of the within-pair 
GLIIHUHQFHRI¥Â = 26 mm. A prospective study of acute pain found that 
the minimum clinically important difference (MCID) for worsening of pain, ie, the 
difference on a VAS associated with the selection of “a little more pain” rather 
than “about the same”, had a mean value of 10 mm.5
With 100 subjects, a conservative SD of 30 mm, 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 randomised.
Analysis of endpoints
: The primary endpoint will be analysed 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. From the model, the difference in VAS score between the 2 products 
will be estimated and presented with a 95% confidence interval (CI) and a 
p-value. The interpretation of the difference in VAS pain scores will be 
supported and contextualised by the results of the analyses of the exploratory 
endpoints. Descriptive statistics only will be applied for other safety parameters
and secondary endpoints.
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Table 1
Schedule of Assessments
Visit
Screening
Pretreatment
Treatment
Follow-up Phone Call
Trial 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
Randomisation and Stratificationh
X
Trial 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
Drug Accountability
X
AE=adverse event; BMI=body mass index; ECG=electrocardiogram; HbA1c=glycosylated haemoglobin; 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, pre-filled syringe, autoinjector, 
other], indication, frequency of use, injection site pain, chronological period used).
b
Physical examination: this will be a focused examination only done if deemed relevant by the Investigator.
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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 haematology): at screening (non-fasting).
The same tests may be done after the second trial 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 trial 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 trial 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 randomised 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
Semaglutide product (Right) followed by Dulaglutide product (Left)
1
C
Dulaglutide product (Right) followed by Semaglutide product (Left)
1
First injection on left side, Second injection on right side
B
Semaglutide product (Left) followed by Dulaglutide product (Right)
1
D
Dulaglutide product (Left) followed by Semaglutide product (Right)
1
Subjects will receive 1 single dose of semaglutide 0.25 mg and 1 single dose of dulaglutide 0.75 mg on 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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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................................1
SPONSOR AUTHORISATION OF CLINICAL STUDY PROTOCOL..................................2 
AUTHORISATION OF CLINICAL STUDY PROTOCOL BY CONTRACT RESEARCH 
ORGANISATION..........................................................................................................3 
CONTACT INFORMATION ................................................................................................4 
SYNOPSIS..........................................................................................................................6 
TABLE OF CONTENTS.................................................................................................... 13 
TABLE OF TABLES......................................................................................................... 15 
TABLE OF FIGURES ....................................................................................................... 16 
LIST OF ABBREVIATIONS.............................................................................................. 17 
1. INTRODUCTION ........................................................................................................ 18 
1.1 
Background.................................................................................................................18 
1.2 
Risk-Benefit Assessment and Risk Mitigation..........................................................18 
1.2.1 Anticipated Clinical Benefits...............................................................................18 
1.2.2 Risks Related to Semaglutide............................................................................19 
1.2.2.1 
Description of selected side effects....................................................19 
1.2.2.2 
Potential risks ....................................................................................19 
1.2.2.3 
Other safety considerations ...............................................................20 
1.2.3 Risks Related to Dulaglutide..............................................................................20 
1.2.4 Risks Associated with Participation in the Clinical Trial......................................21 
1.2.5 Possible Interactions with Concomitant Medical Treatments..............................21 
1.2.6 Risk Mitigation ...................................................................................................21 
1.2.7 Risk-Benefit Rationale .......................................................................................21 
1.3 
Trial Rationale .............................................................................................................21 
2. OBJECTIVES ............................................................................................................. 22 
3.
ENDPOINTS............................................................................................................... 22
4. INVESTIGATIONAL PLAN ........................................................................................ 24 
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4.1 
Overall Trial Design and Plan.....................................................................................24 
4.1.1 Type of Trial.......................................................................................................24 
4.1.2 Screening Period ...............................................................................................25 
4.1.3 Treatment Period...............................................................................................25 
4.1.4 Follow-up...........................................................................................................26 
4.2 
Discussion of Trial Design .........................................................................................26 
4.3 
Selection of Trial Population......................................................................................26 
4.3.1 Inclusion Criteria................................................................................................26 
4.3.2 Exclusion Criteria...............................................................................................27 
4.3.3 Removal of Subjects from Assessment..............................................................28 
4.4 
Treatments...................................................................................................................29 
4.4.1 Treatments Administered...................................................................................29 
4.4.2 Identity of Investigational Products ....................................................................29 
4.4.3 Method of Assigning Subjects to Treatment Groups ..........................................30 
4.4.4 Selection of Doses in the Trial ...........................................................................30 
4.4.5 Timing of Doses in the Trial ...............................................................................31 
4.4.6 Meals During the Trial........................................................................................31 
4.4.7 Blinding..............................................................................................................32 
4.4.8 Concomitant Medication and Other Restrictions During the Trial .......................32 
4.4.9 Treatment Compliance.......................................................................................33 
4.5 
Safety Measurements and Variables .........................................................................33 
4.5.1 Safety Measurements Assessed and Schedule of Assessments .......................33 
4.5.1.1 
Safety and Tolerability Measurements ...............................................33 
4.5.1.1.1 
Intensity of Injection Site Pain Visual-Analogue Scale .....34 
4.5.1.1.2 
Categorical Assessment of Injection Site Pain Intensity...34 
4.5.1.1.3 
Quality of Pain Modified SF-MPQ-2 Inventory .................35 
4.5.1.1.4 
Duration of Pain...............................................................35 
4.5.1.1.5 
Comparative Pain Assessment (5-point Scale)................35 
4.5.1.1.6 
Adverse Events ...............................................................36 
4.5.1.1.7 
Technical Complaints ......................................................39 
4.5.1.1.8 
Clinical Laboratory...........................................................40 
4.5.1.1.9 
Vital Signs .......................................................................41 
4.5.1.1.10 Electrocardiogram ...........................................................41 
4.5.1.1.11 Physical Examination ......................................................41 
4.5.1.2 
Total Blood Volume............................................................................41 
4.5.2 Appropriateness of Measurements ....................................................................41 
4.5.3 Safety Variables ................................................................................................42 
4.6 
Statistical Procedures and Determination of Sample Size.......................................42 
4.6.1 Analysis Sets.....................................................................................................42 
4.6.1.1 
Safety Set..........................................................................................42 
4.6.1.2 
Full Analysis Set ................................................................................42 
4.6.1.3 
Per-Protocol Set ................................................................................42 
4.6.2 Statistical and Analytical Plan for Safety Evaluation...........................................42 
4.6.2.1 
Evaluation of Safety and Tolerability ..................................................43 
4.6.2.1.1 
Intensity of Injection Site Pain Visual-Analogue Scale .....43 
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4.6.2.1.2 
Categorical Assessment of Injection Site Pain Intensity, 
Quality of Pain Modified SF-MPQ-2 Inventory, Duration of 
Pain, and Comparative Pain Assessment........................43 
4.6.2.1.3 
Adverse Events ...............................................................44 
4.6.2.1.4 
Technical Complaints ......................................................45 
4.6.2.1.5 
Clinical Laboratory...........................................................45 
4.6.2.1.6 
Vital Signs and Electrocardiograms.................................45 
4.6.2.1.7 
Physical Examination ......................................................45 
4.6.3 Determination of Sample Size............................................................................45 
4.6.4 Interim Analysis .................................................................................................46 
4.7 
Data Quality Assurance..............................................................................................46 
5. ETHICS....................................................................................................................... 47 
5.1 
Independent Ethics Committee..................................................................................47 
5.2 
Ethical Conduct of the Trial........................................................................................47 
5.3 
Subject Information and Consent ..............................................................................48 
5.4 
Privacy.........................................................................................................................48 
6. TRIAL ADMINISTRATIVE STRUCTURE................................................................... 49 
6.1 
Distribution of Activities.............................................................................................49 
6.2 
Documentation............................................................................................................49 
6.2.1 Archiving............................................................................................................49 
6.2.2 Recording of Data in Source Documents and eCRFs ........................................50 
7. CONFIDENTIALITY AND PUBLICATION POLICY ................................................... 51 
7.1 
Publication Policy .......................................................................................................51 
7.2 
Dissemination of Clinical Trial Data...........................................................................51 
8. REFERENCES ........................................................................................................... 52 
9. APPENDICES............................................................................................................. 53 
9.1 
Drug Accountability....................................................................................................53 
9.2 
Adverse Events: Definitions and Procedures for Recording, Evaluation, Follow-up,
and Reporting to Sponsor ..........................................................................................53 
TABLE OF TABLES
Table 1 
Schedule of Assessments.............................................................................................11 
Table 2 
Primary Endpoint...........................................................................................................22 
Table 3 
Exploratory Endpoints...................................................................................................22 
Table 4 
Product and Side of Injection on Abdomen per Treatment ............................................24 
Table 5 
Products Supplied by Novo Nordisk A/S .......................................................................29 
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Table 6 
Visual Appearance and Function of the semaglutide product and the dulaglutide product
......................................................................................................................................30 
Table 7 
Number and Volume of Blood Samples and Total Blood Volume Collected per Subject41 
Table 8 
Primary Endpoint...........................................................................................................43 
Table 9 
Exploratory Endpoints...................................................................................................43 
Table 10 Detectable Difference with a Sample Size of 100 Subjects for Different Combinations of
Power, and Standard Deviation.....................................................................................46 
TABLE OF FIGURES
Figure 1 Overview of the Trial Design .........................................................................................25 
Figure 2 Decision Tree for Determining the Event Type and the Respective Forms to Complete
with Associated Timelines.............................................................................................37 
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LIST OF ABBREVIATIONS
AE
adverse event 
ALAT (ALT)
alanine aminotransferase
ASAT (AST)
aspartate aminotransferase
ASCVD
arteriosclerotic cardiovascular disease
BMI
body mass index
CA
Competent Authority
CI
confidence interval
CHMP
Committee for Medicinal Products for Human Use (formerly: Committee for 
Proprietary Medicinal Products [CPMP])
CRF
case report form
CSP
clinical study protocol
CSR
clinical study report
CTD
Clinical Trial Directive
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GI
gastrointestinal
GLP
glucagon-like peptide
HbA1c
glycosylated haemoglobin
HBsAg
Hepatitis B surface antigen
HCV
hepatitis C virus
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation (formerly: International Conference on 
Harmonisation)
IEC
Independent Ethics Committee
LSFT
last subject first treatment
MCID
minimum clinically important difference
PCD
primary completion date
PK
pharmacokinetic(s)
RA
receptor agonist
SAE
serious adverse event
SAP
statistical analysis plan
sc
subcutaneous
SD
standard deviation
SF-MPQ-2
Short-form McGill Pain Questionnaire 2
SmPC
summary of product characteristics
SOP
standard operating procedure
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent adverse event
TMM
trial materials manual
ULN
upper limit of normal
VAS
visual-analogue scale
WMA
World Medical Association
WMO
Wet medisch-wetenschappelijk onderzoek met mensen (Medical Research 
Involving Human Subjects Act)
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1.
INTRODUCTION
1.1
Background
Type 2 diabetes mellitus (T2DM) is a debilitating, chronic disease associated with 
increased morbidity and mortality. According to current treatment guidelines, first-line 
treatment consists of lifestyle management and metformin. If further glycaemic control is 
needed, for patients with established arteriosclerotic cardiovascular disease (ASCVD), 
and for patients with no ASCVD for whom there is a need to minimise hypoglycaemia, 
and/or compelling need to minimise weight gain or promote weight loss, glucagon-like 
peptide-1 receptor agonists (GLP-1 RAs) are recommended as second in line treatment. 
Unfortunately, despite their demonstrated clinical efficacy, a barrier to the adoption of 
injectables may exist, among other factors, in the form of fear of injection site pain.
The purpose of the current trial is to compare the injection site pain experience of 
2 subcutaneous GLP-1 RAs for once-weekly administration, approved and widely used, 
for the treatment of T2DM in major markets: semaglutide (Ozempic®) and dulaglutide 
(Trulicity®).
Both semaglutide and dulaglutide are marketed in a pen-injector. Whereas the 
dulaglutide pen-injector for single use has an integrated needle, a needle must be 
attached to the semaglutide pen-injector for multiple use before each injection. The 
semaglutide pen-injector will be used with the NovoFine Plus® 4 mm x 32 G needle with 
which it is normally co-packed; together, they will be referred to as the semaglutide 
product. The pre-filled dulaglutide pen-injector will be referred to as the dulaglutide 
product.
The present trial compares the injection site pain experience after single use of each 
product, both given on the same day. Due to the risk of gastrointestinal adverse events 
such as nausea and vomiting inherent to GLP-1 RAs, the lowest marketed dose of each 
drug will be used, i.e semaglutide 0.25 mg and dulaglutide 0.75 mg.
Detailed information about semaglutide sc and the 1.5 ml PDS290 pre-filled pen is 
available in the investigator’s brochure (IB)2. Detailed information about dulaglutide sc,
and the dulaglutide pre-filled pen is available in the summary of product characteristics
(SmPC)3.
1.2
Risk-Benefit Assessment and Risk Mitigation
1.2.1
Anticipated Clinical Benefits
The subjects will not benefit from the treatment because there are no know benefits to 
receiving a single dose of semaglutide and a single dose of dulaglutide, regardless of 
health status.
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1.2.2
Risks Related to Semaglutide
Subjects enrolled in the present trial do not have T2DM and are only exposed to a single 
dose of semaglutide and thus, may not have the same risks as the patients included in 
the clinical development programme. Detailed information about the semaglutide risks, 
precautions and mitigation actions for patients with T2DM are described in the correct 
edition of the IB2 or any updates hereof. The known side effects (adverse drugreactions) 
associated with semaglutide are mainly gastrointestinal (nausea, diarrhoea, vomiting, 
abdominal 
pain, 
abdominal 
distension, 
constipation, 
dyspepsia, 
gastritis, 
gasto-oesophageal reflux disease, eructation, flatulence), but also include cholelithiasis, 
decreased appetite, dizziness, dysgeusia, fatigue, increased heart rate, increased lipase 
and amylase, injection site reactions and weight decrease, diabetic retinopathy 
complications, hypoglycaemia and anaphylactic reactions.
1.2.2.1
Description of selected side effects
Gastrointestinal disorders
Consistent with other GLP-1 RAs, the most frequentadverse reactions with semaglutide 
are gastrointestinal (GI, nausea, diarrhoea, vomiting). In general, these reactions are 
mild or moderate in severity, of short duration and dose dependent. Clinical trials have 
shown that a low starting dose and gradual dose escalation mitigates the risk of 
developing gastrointestinal symptoms.
In patients treated with GLP-1 RAs, nausea, vomiting and diarrhoea may lead to 
significant dehydration. This should be considered when treating patients with impaired 
renal function as it may cause a deterioration of renal function. Patients with 
gastrointestinal symptoms are recommended to drink plenty of fluids to avoid volume 
depletion.
Hypoglycaemia
There is a low risk of hypoglycaemic episodes when semaglutide is used as 
monotherapy.
1.2.2.2
Potential risks
For the risks below there is some basis for suspicion of an association to semaglutide 
but the association has not been confirmed.
Allergic reactions
As with all protein-based pharmaceuticals, treatment with semaglutide may evoke 
allergic reactions, including serious allergic reactions such as anaphylactic reactions.
Acute pancreatitis
Acute pancreatitis has been observed with the use of GLP-1 RAs. Subjects should be 
informed of the characteristic symptoms of acute pancreatitis and if pancreatitis is 
suspected, semaglutide should be discontinued. If confirmed, semaglutide should not be 
restarted.
As a precaution, subjects with a history of chronic pancreatitis or recent acute 
pancreatitis will not be enrolled in the trial.
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Pancreatic cancer
Pancreatic cancer has been classified as a potential class risk for all marketed 
GLP-1 RAs by regulatory agencies. However, in the clinical development programme, 
rates of pancreatic cancer were low and do not support a causal association with 
semaglutide, and no safety concerns related to the pancreas were identified in the 
nonclinical programme.
Medullary thyroid cancer
This is a potential class risk for long acting GLP-1 RAs. Thyroid C-cell tumours were 
seen in mice and rat carcinogenicity studies after daily exposure to semaglutide for 
2 years. The rodent C-cell tumours are caused by a non-genotoxic, specific 
GLP-1 receptor mediated mechanism to which rodents are particularly sensitive. No 
C-cell tumours were observed in monkeys after 52 weeks exposure up to 27-fold above 
the clinical plasma exposure at 1.0 mg/week.
The GLP-1 receptor is not expressed in the normal human thyroid and the risk of GLP-1
receptor mediated C-cell changes in humans is considered to be low.
1.2.2.3
Other safety considerations
Drug interactions
Semaglutide delays gastric emptying and has the potential to impact the rate of 
absorption of concomitantly administered oral medicinal products. The potential effect of 
semaglutide on the absorption of co-administered oral medications was studied in trials 
at semaglutide 1 mg/week steady state exposure. No clinically relevant drug-drug 
interactions with semaglutide were observed based on the evaluated medications.
Pregnancy, lactation and fertility
Studies in animals have shown reproductive toxicity. There are limited data from the use 
of semaglutide in pregnant women. Therefore, semaglutide should not be used during 
pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, semaglutide 
should be discontinued immediately. In lactating rats, semaglutide was excreted in milk. 
As a risk to a breast-fed child cannot be excluded, semaglutide should not be used during 
breast-feeding.
The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect 
male fertility in rats. In female rats, an increase in oestrous length and a small reduction 
in number of ovulations were observed at doses associated with maternal body weight 
loss.
1.2.3
Risks Related to Dulaglutide
Dulaglutide belongs to the same class of drugs as semaglutide and as such they share 
many of the same efficacy and safety characteristics. As dulaglutide is a marketed drug 
its characteristics are described in the EU SmPC3.
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1.2.4
Risks Associated with Participation in the Clinical Trial
In the current trial, risks related with venous blood sampling are minimal as no 
pharmacokinetic (PK) samples will be collected; only a few blood samples will be taken 
for clinical laboratory evaluations.
1.2.5
Possible Interactions with Concomitant Medical Treatments
Semaglutide delays gastric emptying and has the potential to impact the rate of 
absorption of concomitantly administered oral medicinal products. The potential effect of 
semaglutide on the absorption of co-administered oral medications was studied in trials
(for semaglutide 1 mg/week steady state exposure ). No clinically relevant drug-drug 
interactions with semaglutide were observed based on the evaluated medications.
1.2.6
Risk Mitigation
All subjects in this trial will have a thorough medical check before entering the trial.
During the trial, they will be followed closely and carefully by qualified medical staff. This 
will mitigate the known and potential risks.
1.2.7
Risk-Benefit Rationale
The healthy subjects enrolled in the trial will not have immediate health benefits from 
participating in this trial. Data from this trial might, however, benefit future treatment of 
subjects with T2DM based on knowledge about the injection experience. The safety 
profiles of semaglutide and dulaglutide are well documented; AEs were mostly 
predictable based on the known effects of GLP-1 RAs. Thus, based on the large 
nonclinical and clinical studies with semaglutide
(1.34 mg/mL) and dulaglutide 
(1.5 mg/mL and 3 mg/mL) and on the usablility evaluation of both dose devices, it is 
concluded that there are no safety issues that would prohibit administration of 
semaglutide and dulaglutide in accordance with the planned clinical trial.
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of semaglutide and dulaglutide sc, the 1.5 mL PDS290
pre-filled pen, and the dulaglutide pre-filled pen are available in the IB2 and the SmPC3.
1.3
Trial Rationale
The purpose of the current trial is to compare the injection site pain experience of 
2 subcutaneous GLP-1 RAs for once-weekly administration, approved and widely used, 
for the treatment of T2DM in major markets: semaglutide (Ozempic®) and dulaglutide 
(Trulicity®).
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2.
OBJECTIVES
The primary objective is to compare, in healthy, overweight or obese subjects, the 
injection site pain experience of a single dose of semaglutide 0.25 mg sc using the 
semaglutide product compared to a single dose of dulaglutide 0.75 mg sc using the 
dulaglutide product.
3.
ENDPOINTS
Table 2
Primary Endpoint
Endpoint title
Time frame
Unit
Intensity of injection site pain
1 min after each injection 
(Day 1)
mm on a 100 mm horizontal visual-
analogue scale (where 0 mm = no pain, 
100 mm = unbearable pain)
Table 3
Exploratory Endpoints
Endpoint title
Time frame
Unit
Categorical assessment of 
intensity of injection site pain
Immediately after rating of 
intensity of injection site 
pain, i.e. 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 (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, i.e. 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 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 painտ
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
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Endpoint title
Time frame
Unit
Duration of pain
From time of injection until 
cessation of pain (Day 1)
min and s
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 – about the same 
(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 
semaglutide 
product 
hurt less than or about the 
same as the dulaglutide 
product
Dichotomous variable based 
on “Comparative pain 
experience” variable above
Yes = “about the same (includes none 
of 
the 
products 
hurt)” 
or 
“the 
semaglutide product hurt less than the 
dulaglutide 
product” 
or 
“the 
semaglutide product hurt much less 
than the dulaglutide product”
No = “the semaglutide product hurt 
much more than the dulaglutide 
product” or “the semaglutide product 
hurt more than the dulaglutide 
product”
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4.
INVESTIGATIONAL PLAN
4.1
Overall Trial Design and Plan
4.1.1
Type of Trial
This is a single centre, crossover, randomised, double-blind trial in healthy, overweight 
or obese, men and women comparing the injection site pain experience of the 
semaglutide product to the dulaglutide product. Enrolment will be carried out to include 
no more than 70% of each gender. Subjects will receive 1 dose of semaglutide 0.25 mg 
and 1 dose of dulaglutide 0.75 mg on 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.
Subjects will be randomised in a 2×2 scheme evenly to 4 sequences of product and 
injection side as described in Table 4:
Table 4
Product and Side of Injection on Abdomen per Treatment
Treatment Short 
Identifier
Treatment Long Identifier
Ratio Required
First injection on right side, Second injection on left side
A
Semaglutide product (Right) followed by 
Dulaglutide product (Left)
1
C
Dulaglutide product (Right) followed by 
Semaglutide product (Left)
1
First injection on left side, Second injection on right side
B
Semaglutide product (Left) followed by 
Dulaglutide product (Right)
1
D
Dulaglutide product (Left) followed by 
Semaglutide product (Right)
1
The present trial compares the injection site pain experience after a single use of each 
product, both given on the same day. To minimise GI AEs inherent to GLP-1 RAs the 
lowest marketed dose of each drug will be used i.e. semaglutide 0.25 mg and dulaglutide 
0.75 mg. Based on pharmacokinetic modelling1, the single dose dulaglutide 0.75 mg 
given on the same day as semaglutide 0.25 mg sc is expected to provide a similar effect 
to semaglutide 0.5 mg, which is the highest single dose of semaglutide tolerated without 
dose excalation due to risk of GI AEs. Also, as per its SmPC, dulaglutide may be initiated 
at the 1.5 mg dose.
The length of the crossover interval is set to be as short as possible to minimise the 
impact of systemic effects of both semaglutide and dulaglutide, especially nausea, 
between the first and the last injection, while being long enough to minimise residual 
pain and emotional carry-over from the first injection.
An overview of the trial design is given in Figure 1.
The follow-up period is 4-5 weeks (28 days with a +7 days window).
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Figure 1 Overview of the Trial Design
CRO=contract research organisation
4.1.2
Screening Period
Subjects will report to the medical screening facility for the eligibility screening (see 
Section 4.3
for inclusion and exclusion criteria) within 3 weeks prior to drug 
administration.
Subjects will sign the trial-specific informed consent form (ICF) prior to any trial-specific 
screening procedures being performed. The written informed consent will be obtained 
for all subjects, regardless of their eligibility for the trial; the signed ICFs will be retained 
and archived at 
 and a copy will be provided to the subject.
Eligibility screening will consist of the assessments as presented in the schedule of 
assessments (Table 1).
4.1.3
Treatment Period
Subjects will be in the clinical research centre for 1 day, on Day 1. On this day, the 
subjects will be admitted, the drug will be administered twice, and the subjects will be 
discharged after all assessments have been performed. During this day subjects will be 
provided with a card stating that they are participating in a trial and given contact details 
of relevant trial site staff.
If the subject admits to bodily pain (eg, headache) at admission (Day 1), then Day 1
should be rescheduled within the visit window as the existing pain could impact the 
injection site pain assessment.
Assessments during the treatment period will be performed as presented in the schedule 
of assessments (Table 1).
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4.1.4
Follow-up
A follow-up phone call will take place between 4 and 5 weeks after drug administration 
on Day 1. In this phone call, the females of childbearing potential will be asked if they
are pregnant.
4.2
Discussion of Trial Design
A total of 104 subjects are planned to be randomised to achieve at least 100 completed 
subjects. The aim is to have an even distribution of males and females in the trial; at 
least 30% of the same sex should be randomised in the trial.
Subjects with a body mass index (BMI)  kg/m2 but generally healthy will be included 
to minimise inter-subject variability due to frequent comorbidities in the target users of 
semaglutide and dulaglutide (T2DM). It is assumed that the ability to detect differences 
between the 2 products does not differ between healthy subjects and target users. Only 
subjects with a BMI  25 kg/m2 will be included to reduce the risk of intramuscular 
injection. Both male and female subjects will be included to ensure generalizability to the 
intended users of both genders. Only individuals 18 years of age or older are eligible 
because semaglutide sc and dulaglutide sc are only approved for use in adults with 
T2DM. The upper age limit of 75 years is justified by the cognitive demands of the 
subjects when completing the inventories used in this trial.
The length of the cross-over interval is set to be as short as possible to minimise
systemic effects of semaglutide and dulaglutide, especially nausea, between the first 
and the last injection, while being long enough to minimise residual pain and emotional 
carry-over from the first injection.
4.3
Selection of Trial Population
4.3.1
Inclusion Criteria
Note: Restrictions that apply to the period after admission are described in Section 4.4.8,
except when they concern a statement of willingness.
The following inclusion criteria must be met for a subject to be eligible for inclusion in the 
trial:
1.
Informed consent obtained before any trial-related activities. Trial-related activities 
are any procedures that are carried out as part of the trial, including activities to 
determine suitability for the trial.
2.
Male or female, aged 18-75 years (both inclusive) at the time of signing informed 
consent.
3.
%RG\PDVVLQGH[ kg/m2.
4.
Considered to be generally healthy based on the medical history, physical 
examination, and the results of vital signs, electrocardiogram and clinical laboratory 
tests performed during the screening visit, as judged by the Investigator.
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4.3.2
Exclusion Criteria
Note: Restrictions that apply to the period after admission are described in Section 4.4.8,
except when they concern a statement of willingness.
A subject who meets any of the following exclusion criteria will not be eligible for inclusion 
in the trial:
1.
Known or suspected hypersensitivity to trial product(s) or related products.
2.
Previous participation in trial INS-4603, INS-4582 or NN9535-4648. Participation is 
defined as having received investigational product.
3.
Female who is pregnant, breast-feeding or intends to become pregnant within 
4 weeks of Day 1 or is of childbearing potential and not using highly effective 
contraceptive methods.
4.
Participation in a drug study within 60 days prior to drug administration in the current 
trial OR participation in more than 4 other drug studies in the 12 months prior to drug 
administration in the current trial.
5.
Any disorder which in the Investigator’s opinion might jeopardise subject’s safety, 
evaluation of results, or compliance with the protocol.
6.
Glycosylated haemoglobin +E$FPPROPRODWVFUHHQLQJ
7.
Supine blood pressure at VFUHHQLQJDIWHUUHVWLQJIRUPLQRXWVLGHWKHUDQJHRI
90-160 mmHg for systolic or 45-89 mmHg for diastolic.
8.
6XSLQHSXOVHUDWHDVSDUWRIYLWDOVLJQVRXWVLGHWKHUDQJHRIíEHDWVPLQDIWHU
UHVWLQJIRUPLQXWHVDWVFUHHQLQJ
9.
Use of prescription medicinal products or non-prescription drugs or herbal products, 
except routine vitamins, topical medication, contraceptives (see Section 4.4.8) and
occasional use of paracetamol (not allowed within 24 hours prior to drug 
administration), within 14 days prior to Day 1.
10. Diagnostic test results positive for HIV-1 or HIV-2 infection.
11. Diagnostic test results positive for active hepatitis B or hepatitis C infection.
12. Mental incapacity, language barriers,
or unwillingness to comply with the 
requirements of the protocol, which may preclude adequate understanding or co-
operation during the trial as judged by the Investigator.
13. Average intake of more than 21 units of alcohol per week for male subjects and more 
than 14 units per week for female subjects: 1 unit of alcohol equals approximately 
250 mL of beer, 100 mL of wine, or 35 mL of spirits).
14. Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines 
[including 
ecstasy], 
cannabinoids, 
barbiturates, 
benzodiazepines, 
tricyclic 
antidepressants, and alcohol) at screening and admission to the clinical research
centre.
15. Use of tobacco and nicotine products, defined as any of the below:
x Smoking more than 1 cigarette or the equivalent per day on average.
x Not able or willing to refrain from smoking and use of nicotine substitute 
products during the in-house period.
16. Blood donation, plasma donation, or blood draw
x In excess of 400 mL within the past 90 days prior to the day of screening
x In excess of 50 mL within the past 30 days prior to the day of screening
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17. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or 
medullary thyroid carcinoma.
18. Subjects with a history of malignant neoplasms within the past 5 years prior to 
screening will be excluded from the trial.
19. Presence or history of pancreatitis (acute or chronic; as declared by the subject or 
reported in the medical records).
20. Subject is not able to understand and read English or Dutch, or subject is not able 
to understand and comply with the trial requirements.
21. Subject depends on the Sponsor, the Investigator, or the study centre, or subject is 
the Investigator or any sub-investigator, research assistant, pharmacist, study 
coordinator, other staff, or relative thereof directly involved in the conduct of the trial.
22. Vulnerable subject (e.g. person kept in detention) who may have an increased 
likelihood of being wronged or of incurring additional harm.
Please note that subjects should refrain from consumption of any foods containing poppy 
seeds and alcohol within 48 hours (2 days) prior to screening and admission to the 
clinical research centre to avoid false-positive drug screen results. In addition, they 
should refrain from strenuous exercise within 96 hours (4 days) prior to screening and 
admission as this could result in abnormal clinical laboratory values.
4.3.3
Removal of Subjects from Assessment
Participation in the trial is strictly voluntary. A subject has the right to withdraw from the 
trial at any time for any reason.
The subject may be discontinued at any time during the trial at the discretion of the 
Investigator for safety, behavioural, compliance, or administrative reasons.
If a subject is withdrawn from the trial, the Sponsor will be informed immediately. If there 
is a medical reason for withdrawal, the subject will remain under the supervision of the 
Investigator until satisfactory health has returned.
Subjects who drop out or withdraw for any reason without completing all screening 
evaluations successfully will be considered screening failures.
A subject who is withdrawn or voluntarily withdraws from the trial for any reason, whether 
related to the trial product or not, after having received a subject number, will be 
considered an early-termination subject. Early-termination subjects will not be replaced.
 will make every effort to ensure that early-termination subjects who have received 
trial drug complete the safety follow-up assessments.
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4.4
Treatments
4.4.1
Treatments Administered
Subjects will be randomised in a 2×2 scheme evenly to 4 sequences of product and 
injection side as shown in Table 4 in Section 4.1.1. Subjects will receive 1 dose of 
semaglutide 0.25 mg and 1 dose of dulaglutide 0.75 mg on 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.
Unblinded members of the 
 staff not otherwise involved in the trial procedures will 
be responsible for trial drug administration. In each subject, the 2 injections should be 
performed by the same staff member.
The 
 staff member will be instructed to select an injection site on the assigned side 
of the midline, that, according to their judgement based on visual inspection and 
palpation, has the maximal thickness of subcutaneous fat. The injection with the 
semaglutide product will be performed as described in the 1.5 mL PDS290 pre-filled pen
directions for use and the NovoFine® Plus 4 mm x 32 G needle instructions for use. The 
injection with the dulaglutide product will be performed as described in the dulaglutide 
pre-filled pen (Trulicity®) instructions for use.
Using a lifed skin fold with either product (the semaglutide product or the dulaglutide 
product) will not be an option.
The unblinded 
 staff will instruct the subject to avoid discussing the administration 
of the trial drug with other study staff including the Investigator.
4.4.2
Identity of Investigational Products
Novo Nordisk A/S Denmark will supply the following products, see Table 5:
Table 5
Products Supplied by Novo Nordisk A/S
Name
Name of Intervention Product
Semaglutide 1.34 mg/mL PDS290 pre-filled
pen-injector
Semaglutide product
Trulicity 0.75 mg solution for injection in 
pre-filled pen (dulaglutide)
Dulaglutide product
This NovoFine® Plus 4 mm x 32 G needle will be sourced directly by 
.
For details concerning drug storage and drug accountability see Appendix 9.1.
The characteristics of the 2 products are shown in Table 6.
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Table 6
Visual Appearance and Function of the semaglutide product and the 
dulaglutide product
All dose administrations will be performed by trained, unblinded staff at the study site.
Directions for use of all products provided by Novo Nordisk are provided in the Trial 
Materials Manual (TMM) also provided by Novo Nordisk.
4.4.3
Method of Assigning Subjects to Treatment Groups
After obtaining informed consent, subjects will be screened according to the inclusion 
and exclusion criteria. Subjects who have met all eligibility criteria will receive a subject 
number upon inclusion in the trial. They will receive the subject number just prior to 
dosing. The subject number will ensure identification throughout the trial.
The subject number will be the same as the randomisation number given on the 
randomisation list provided by Novo Nordisk. The randomisation list will be transferred 
to the 
 Pharmacy and kept in a restricted area to which only the 
 Pharmacy 
has access.
Subjects will receive a randomisation number based on the randomisation list provided 
to the site. The randomisation number encodes the assignment to one of the 
4 sequences as described in Section 4.1.1.
Subjects who drop out or withdraw for any reason without completing all screening 
evaluations successfully will be considered screening failures. Such subjects, and also 
subjects who are eligible for inclusion in the trial but do not receive the trial drug, will not 
receive a subject number, and only applicable data will be entered in the electronic case 
report forms (eCRFs).
4.4.4
Selection of Doses in the Trial
Due to the risk of gastrointestinal adverse events such as nausea and vomiting inherent 
to GLP-1 RAs, the lowest marketed dose of each drug will be used, i.e. semaglutide 
0.25 mg and dulaglutide 0.75 mg. Based on pharmacokinetic modelling1 the single dose 
of dulaglutide 0.75 mg given on the same day as semaglutide 0.25 mg sc is expected to 
provide similar effect to semaglutide 0.5 mg, which is the highest single dose of 
semaglutide tolerated withou dose escalation due to risk of GI AEs. Also, as per its 
SmPC, dulaglutide may be initiated at the 1.5 mg dose.
Uses
Dose volume 
Needle
Semaglutide product
Dulaglutide product
Single
Multiple
0.5 mL for 0.75 mg dose
Selectable: 0.19 mL for 0.25 mg dose
Must be attached before injection:        
NovoFine® Plus 4 mm x 32 G
Integrated and hidden, 5 mm, 29 G
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4.4.5
Timing of Doses in the Trial
The first dose will be administered as follows. An unblinded 
 staff member who is 
present in the study room will start a timer when the other unblinded staff member starts 
the injection. The timer will be placed such that it is not visible to the subject. The subject 
will be instructed by an unblinded staff member to indicate when all pain is gone. If no 
pain is experienced, “00 min, 00 s (sec)” will be recorded. The blinded staff member will 
not be present in the room when the dosing is given. As soon as possible after dosing 
and before the 1 minute after injection timepoint, the blinded staff member takes over.
One minute after the injection, the blinded staff member will administer the visual-
analogue scale (VAS) to rate the intensity of injection site pain (not the momentary pain 
at the time of VAS completion) (see Section 4.5.1.1.1).
When the subject has completed the intensity of injection site pain VAS after the first 
injection of the trial drug, the subject will complete a categorical assessment of injection 
site pain intensity (6-point scale) (see Section 4.5.1.1.2) and then a quality of pain 
modified
short-form McGill Pain Questionnaire 2 (SF-MPQ-2)
inventory (see 
Section 4.5.1.1.3).
Because the completion of the inventories may distract the subject, they will be reminded 
at regular intervals to indicate when the pain, if any, is gone, if they have not already 
done so.
At least 30 minutes after the first injection, after confirmation from the subject that the 
pain is entirely gone (to not contaminate the rating of the last injection), the timer will be 
reset, and the last injection will be given. If the pain is not gone at 30 minutes, another 
attempt will be made at 60 minutes. If pain is still present at that time, no further attempts 
will be made.
Following the last injection, the same measurements will be performed as after the first 
injection, as described above. Subjects will not be allowed to consult their own prior 
ratings. After confirmation from the subject that the pain is entirely gone, the subjects will 
complete a comparative pain assessment (5-point scale) comparing pain between 
injections (see Section 4.5.1.1.4).
During the 30 minutes after each administration of the trial drug the subjects should stay 
in bed or should be seated in a chair, and not walk around.
4.4.6
Meals During the Trial
There are no requirements with regard to fed or fasting conditions prior to or after trial
drug administration. Further, no fasting is required before obtaining clinical laboratory 
samples.
With the exception of the restrictions with respect to the use of alcohol, methylxanthine-
containing beverages or food, as described in Section 4.4.8, there are no special 
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requirements related to food and beverage intake. Meals and snacks (such as 
decaffeinated coffee, herbal tea, fruit, biscuits) will be provided according to 
 
standard operating procedures (SOPs).
4.4.7
Blinding
This is a double-blind trial.
Investigators will remain blinded to each subject's assigned product throughout the 
course of the trial. Also, all 
 staff not participating in unblinded tasks will be blinded 
to treatment. To maintain this blind, qualified, unblinded members of the 
 staff not 
otherwise involved in the trial procedures will be responsible for trial drug administration 
according to the randomisation list. Technical complaints will also be collected by 
unblinded site staff. The unblinded 
 staff will not be involved in any other 
assessments or safety reporting.
Subjects will be blinded to treatment as well. To maintain blinding of subjects, a visual 
blind will be in place during dose administration.
Individual code break envelopes will be provided for all subjects by Novo Nordisk. Each 
sealed envelope containing the sequence will be kept in a medication storage room, 
which is locked with restricted access. To manage the subject’s condition in case of a 
medical emergency, the Investigator is allowed to break the code to know which 
sequence of product and injection side the subject was randomised to. The date when 
and reason why the blind was broken must be recorded in the source documentation. 
The Sponsor (Global Safety department) and unblinded monitor will be informed in case 
of unblinding.
4.4.8
Concomitant Medication and Other Restrictions During the Trial
Note: Restrictions that apply to the period before admission are described in 
Section 4.3.1 and Section 4.3.2.
The use of all prescription medicinal products or non-prescription drugs or herbal 
products is not allowed from admission to the clinical research centre until discharge. An 
exception is made for routine vitamins, topical medication, and contraceptives, which are 
allowed throughout the trial. During the stay in the clinical research centre, the 
Investigator may permit a limited amount of paracetamol for the treatment of headache 
or any other pain, but this is only allowed after all pain assessments have been 
completed. Other medication to treat AEs during the stay in the clinical research centre
may only be prescribed if deemed necessary by the Investigator. If medication is used
during the stay in the clinical research centre, the name of the drug, the dose, and 
dosage regimen will be recorded in the eCRF. Any medication taken between discharge 
and the follow-up phone call will be documented in a similar fashion.
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The use of alcohol, methylxanthine-containing beverages or food (coffee, tea, cola,
chocolate, energy drinks), grapefruit (juice), and tobacco products is not allowed during 
the stay in the clinical research centre.
No contraception measures are required for male subjects as the risk of 
teratogenicity/fetotoxicity caused by transfer of semaglutide in seminal fluid is unlikely.
Female subjects of childbearing potential who have a fertile male sexual partner must 
agree to use highly effective contraception from screening up to 4 weeks after drug 
administration. Highly effective contraception is defined as:
x
Use of combined (oestrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal [patch]), or
x
Use of progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral or injectable).
The above requirements on contraception do not apply if:
x
The male partner of the female subject is vasectomised and has a confirmed 
post-vasectomy semen analysis.
x
The female subject practises sexual abstinence during the period mentioned above.
4.4.9
Treatment Compliance
Each of the single doses will be administered by trained unblinded staff at the clinical 
research centre. The exact times of trial drug administration will be recorded in the eCRF.
4.5
Safety Measurements and Variables
Only safety parameters will be assessed in this trial; the trial does not comprise efficacy, 
PK, or pharmacodynamic measurements.
4.5.1
Safety Measurements Assessed and Schedule of Assessments
A schedule of assessments is presented in Table 1.
4.5.1.1
Safety and Tolerability Measurements
Safety and tolerability assessments will consist of intensity of injection site pain VAS, 
categorical assessment of injection site pain intensity (6-point scale), quality of pain 
modified SF-MPQ-2 inventory, duration of pain
assessment, comparative pain 
assessment (5-point scale), AEs, clinical laboratory, vital signs, 12-lead ECG, and 
physical examination. In addition, some assessments will only be performed at screening 
or predose for the assessment of eligibility and are also described in this section.
All assessments will be performed in accordance with the schedule of assessments
(Table 1).
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4.5.1.1.1
Intensity of Injection Site Pain Visual-Analogue Scale
The intensity of injection site pain VAS will be filled in by the subjects starting 1 minute 
after each injection of the trial drug to report the pain intensity experienced in the first 
minute after the injection.
Subjects will be instructed to make a vertical line on the VAS (100 mm); the endpoints 
are “no pain” and “unbearable pain.” The distance (mm) between the endpoint “no pain” 
and the vertical line on the VAS will be recorded in the eCRF.
First injection
English version:
Indicate the intensity of pain you felt during the injection. For this, make a vertical line 
somewhere through the line below, where the endpoints are “no pain” and “unbearable 
pain”.
Last injection
English version:
Indicate the intensity of pain you felt during the last injection only. For this, make a 
vertical line somewhere through the line below, where the endpoints are “no pain” and 
“unbearable pain”.
4.5.1.1.2
Categorical Assessment of Injection Site Pain Intensity
The categorical assessment of injection site pain intensity is a 6-point scale in which the 
pain intensity is rated by the subjects as follows:
Please tick one box describing the pain intensity during the injection:
none
Ƒ
very mild
Ƒ
mild 
Ƒ
moderate 
Ƒ
severe
Ƒ
very severe
Ƒ
Please tick one box describing the pain intensity during the last injection only:
No pain
Unbearable pain
100 mm
No pain
Unbearable pain
100 mm
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none
Ƒ
very mild
Ƒ
mild 
Ƒ
moderate 
Ƒ
severe
Ƒ
very severe
Ƒ
4.5.1.1.3
Quality of Pain Modified SF-MPQ-2 Inventory
The quality of pain will be assessed using the modified SF-MPQ-2 inventory4, to be filled 
in by the subjects as follows:
This questionnaire provides you with a list of words that describe some of the different 
qualities of pain and related symptoms. Please put an X in all boxes that apply:
Throbbing pain
Ƒ
Shooting pain
Ƒ
Stabbing pain
Ƒ
Sharp pain
Ƒ
Cramping pain
Ƒ
Gnawing pain 
Ƒ
Hot-burning pain
Ƒ
Aching pain
Ƒ
Heavy pain
Ƒ
Tender
Ƒ
Splitting pain
Ƒ
Tiring-exhausting
Ƒ
Sickening
Ƒ
Fearful
Ƒ
Punishing-cruel
Ƒ
Electric-shock pain
Ƒ
Cold-freezing pain
Ƒ
Piercing
Ƒ
4.5.1.1.4
Duration of Pain
The duration of pain as indicated by the subject will be recorded from time of injection 
until cessation of pain in minutes and seconds.
4.5.1.1.5
Comparative Pain Assessment (5-point Scale)
The comparative pain assessment is a 5-point scale in which the subjects will compare 
the pain between the 2 injections.
The subjects will be asked to answer the following question:
Please choose the statement below that best describes your experience:
x
The last injection hurt much more than the first injection.
x
The last injection hurt more than the first injection.
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x
They hurt about the same (includes: neither of the injections hurt).
x
The last injection hurt less than the first injection.
x
The last injection hurt much less than the first injection.
4.5.1.1.6
Adverse Events
The definitions of AEs and serious AEs (SAEs) can be found in Appendix 9.2.
The Investigator is responsible for detecting, documenting, recording, and following up 
on events that meet the definition of an AE or SAE.
Time period and frequency for collecting AE and SAE information
All AEs will be collected from the first trial-related activity after obtaining informed 
consent and until the follow-up visit at the time points specified in the schedule of 
assessments (Table 1).
All SAEs will be recorded and reported to Novo Nordisk or designee within 24 hours, as 
indicated in Figure 2 and Appendix 9.2. The Investigator must submit any updated SAE 
data to Novo Nordisk within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former trial subjects. 
However, if the Investigator learns of any SAE, including a death, at any time after a 
subject has been discontinued from/completed the trial, and the Investigator considers 
the event to be possibly/probably related to the investigational trial product or trial
participation, the Investigator must promptly notify Novo Nordisk.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the
procedures for completing and transmitting SAE reports are provided in Appendix 9.2.
Medication error AEs require additional data collection via a specific event form. For 
definition of medication errors, see Appendix 9.2.
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo 
Nordisk might ask the Investigator to complete a technical complaint form. For reporting 
of technical complaints, see Section 4.5.1.1.7.
The reporting timelines are specified in Figure 2.
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Figure 2 Decision Tree for Determining the Event Type and the Respective 
Forms to Complete with Associated Timelines
Method of detecting AEs and SAEs
Care should be taken not to introduce bias when detecting AEs and/or SAEs. 
Open-ended and non-leading verbal questioning of the subject is the preferred method 
to inquire about events.
Follow-up on AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilisation, or if the event is otherwise explained (eg, chronic condition), or the subject 
is lost to follow-up. Further information on follow-up procedures is given in Appendix 9.2.
Regulatory reporting requirements for SAEs
Prompt notification by the Investigator to Novo Nordisk of an SAE (according to Figure 2
and Appendix 9.2) is essential so that legal obligations and ethical responsibilities 
towards the safety of subjects and the safety of a trial product under clinical investigation 
are met.
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a trial product under clinical investigation. 
Novo Nordisk will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, the Independent Ethics Committee (IEC), and 
investigators.
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Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Novo Nordisk policy and 
forwarded to regulatory authorities, the IEC, and investigators as locally required.
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from Novo Nordisk will 
review and then file it along with the IB and will notify the IEC, if appropriate, according 
to local requirements.
Pregnancies and associated adverse events
Details of pregnancies in female subjects will be collected after the first trial-related 
activity after obtaining informed consent and until pregnancy outcome.
If a pregnancy is reported in a female subject, the Investigator should inform Novo 
Nordisk within 14 calendar days of learning of the pregnancy and should follow the 
procedures outlined below:
x
The Investigator will collect pregnancy information on any female subject who 
becomes pregnant while participating in this trial.
x
Information will be recorded on the appropriate form and submitted to Novo Nordisk 
within 14 calendar days of learning of a subject's pregnancy.
x
Subject will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the subject and neonate, which will be forwarded 
to Novo Nordisk. Generally, follow-up will not be required for longer than 1 month 
beyond the delivery date.
x
Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.
x
Although pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE.
x
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.
x
Any SAE occurring as a result of a post-trial pregnancy that is considered 
possibly/probably related to the trial product by the Investigator will be reported to 
Novo Nordisk as described in Appendix 9.2. Although the Investigator is not 
obligated to actively seek this information in former subjects, he or she may learn of 
an SAE through spontaneous reporting.
Pregnancy outcome should be documented in the subject's medical record. An abnormal 
pregnancy outcome (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomaly, and ectopic pregnancy) is considered an SAE.
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4.5.1.1.7
Technical Complaints
The unblinded 
 staff are responsible for the detection and documentation of 
technical complaints that occur when using the pen-injectors used in this trial.
Definition of technical complaint:
x
A technical complaint is any written, electronic, or oral communication that alleges 
medical product defects and device product defects. The technical complaint may 
be associated with an AE, but does not concern the AE itself.
Examples of technical complaints are as follows:
x
Problems with the physical or chemical appearance of trial products (eg, 
discolouration, particles, or contamination).
x
Problems with packaging material including labelling.
x
Problems related to pen-injectors (eg, to the injection mechanism, dose setting 
mechanism, push button, or interface between the pen-injector and the needle).
The Investigator must assess whether a technical complaint is related to an AE.
Time period for detecting technical complaints
All technical complaints that occur from the time of receipt of the product at 
 until 
the time of the last usage of the product must be collected for products predefined on 
the technical complaint form.
Reporting of technical complaints to Novo Nordisk
Technical complaints must be reported on a separate technical complaint form:
x
One technical complaint form must be completed for each affected dispensing unit 
number (DUN).
x
If a DUN is not available, a technical complaint form for each batch, code, or lot
number must be completed.
Timelines for reporting of technical complaints to Novo Nordisk
The Investigator must complete as much information on the form as possible and hand 
it over to the unblinded 
 staff. The unblinded 
 staff must fill in the unblinded 
information on the form (such as the DUN and batch, code, or lot number) and forward 
the technical complaint form to the Customer Complaint Center, Novo Nordisk, within 
the timelines specified below:
x
Technical complaints related to SAEs, within 24 hours
x
All other technical complaints, within 5 calendar days
The technical complaint form must be kept inaccessible to blinded site staff.
Follow-up of technical complaints
The Investigator is responsible for ensuring that new or updated information is recorded 
on the originally completed form.
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Collection, storage, and shipment of technical complaint samples
The unblinded 
 staff must collect the technical complaint sample and all associated 
parts that were packed in the same DUN. The unblinded 
 staff collect the sample 
and notify the unblinded monitor within 5 calendar days of obtaining the sample at 
. 
The sample and all associated parts must be sent as soon as possible to the Customer 
Complaint Center, Novo Nordisk, together with a copy of the completed technical 
complaint form.
The technical complaint sample should contain the batch, code, or lot number and, if 
available, the DUN. If the technical complaint sample is unobtainable, the reason must 
be stated on the technical complaint form.
If several samples are shipped in one shipment, the sample and the corresponding 
technical complaint form should be kept together.
Storage for the technical complaint sample must be done in accordance with the 
conditions prescribed for the product.
Reporting of technical complaints for Novo Nordisk products not included in technical 
complaint form
Technical complaints about Novo Nordisk products not included in the technical 
complaint form should be reported to local Novo Nordisk affiliate with a reference to 
trial ID.
4.5.1.1.8
Clinical Laboratory
Blood and urine samples for clinical laboratory assessments will be collected according 
to 
 SOPs. No fasting is required prior to collecting these samples.
The following parameters will be measured:
x
Clinical chemistry (serum quantitatively):
total bilirubin, alkaline phosphatase, aspartate aminotransferase (ASAT), alanine 
aminotransferase (ALAT), creatinine, albumin, sodium, potassium, and calcium.
x
Haematology (blood quantitatively):
leukocytes, haemoglobin, and thrombocytes.
HbA1c at screening only.
x
Serology:
hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), and anti HIV-1
and -2.
x
Drug and alcohol screen:
opiates, methadone, cocaine, amphetamines (including ecstasy), cannabinoids, 
barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol in urine.
x
Hormones (serum quantitatively):
thyroid-stimulating hormone.
x
Pregnancy test (female subjects of childbearing potential only):
ȕ-human chorionic gonadotropin in urine.
In case of unexplained or unexpected clinical laboratory test values, the tests will be 
repeated as soon as possible and followed up until the results have returned to the 
normal range and/or an adequate explanation for the abnormality is found. The clinical 
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laboratory will clearly mark all laboratory test values that are outside the normal range, 
and the Investigator will indicate which of these deviations are clinically significant. 
Clinically significant laboratory result deviations after trial drug administration will be 
recorded as AEs, and the relationship to the treatment will be indicated (see also 
Appendix 9.2). Clinically significant laboratory results at screening will not be reported 
as AE as this is considered part of medical history.
4.5.1.1.9
Vital Signs
Systolic and diastolic blood pressure and pulse will be recorded after the subject has 
been resting for at least 5 minutes in the supine position. These assessments will be 
made using an automated device.
4.5.1.1.10 Electrocardiogram
A standard 12-lead ECG will be recorded after the subject has been resting for at least 
5 minutes in the supine position. The ECG will be recorded using an ECG machine 
equipped with computer-based interval measurements. The following ECG parameters 
will be recorded: heart rate, PR-interval, QRS-duration, QT-interval, QTc-interval 
(Fridericia's), and the interpretation of the ECG profile by the Investigator.
4.5.1.1.11 Physical Examination
Physical examination will be performed according to 
 SOPs. In addition, body weight 
and height will be measured according to 
 SOPs.
4.5.1.2
Total Blood Volume
Table 7 presents the number and volume of blood samples and the total volume of blood 
that will be collected throughout the trial per subject.
If deemed necessary by the Investigator or the Sponsor, the number and/or volume of 
blood samples per assessment may be increased as long as the total volume of blood 
drawn for a subject does not surpass 500 mL.
Table 7
Number and Volume of Blood Samples and Total Blood Volume 
Collected per Subject
Assessment
Maximum # 
Samples
Volume of Blood per 
Sample (mL)
Total Volume of 
Blood (mL)
Clinical Chemistry
2
3.5
7
Haematology 
2
3
6
Serology
1
5
5
Total Volume of Blood Drawn
18
4.5.2
Appropriateness of Measurements
The assessments that will be made in this trial are standard and generally recognised
as reliable, accurate, and relevant.
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4.5.3
Safety Variables
The safety variables to be measured include but are not limited to the variables as given 
below. A complete list of safety variables will be provided in the statistical analysis plan
(SAP).
x
Intensity of injection site pain VAS
x
Categorical assessment of injection site pain intensity (6-point scale)
x
Quality of pain modified SF-MPQ-2 inventory
x
Duration of pain
x
Comparative pain assessment (5-point scale)
x
AEs
x
Clinical laboratory
(if postdose assessments
are deemed relevant by the 
Investigator)
x
Vital signs
x
ECG (if postdose assessments are deemed relevant by the Investigator)
x
Physical examination (if postdose assessments are deemed relevant by the 
Investigator)
4.6
Statistical Procedures and Determination of Sample Size
4.6.1
Analysis Sets
4.6.1.1
Safety Set
All subjects who have received at least 1 injection of semaglutide or dulaglutide (includes 
any skin contact with trial product, whether the injection was completed or not).
4.6.1.2
Full Analysis Set
All randomised subjects who have received at least 1 injection of semaglutide or 
dulaglutide (includes any skin contact with trial product, whether the injection was 
completed or not). In exceptional cases, subjects from the full analysis set may be 
excluded. In such cases the exclusion will be justified and documented.
4.6.1.3
Per-Protocol Set
All subjects who have received both injections of semaglutide and dulaglutide and have 
completed both intensity of injection site pain assessments.
4.6.2
Statistical and Analytical Plan for Safety Evaluation
A SAP will be generated by the Biostatistics Department of 
; the SAP will be finalised
prior to database lock. Full details of the analysis to be performed will be included in the 
SAP.
Any deviation from the SAP will be reported in the section “Changes in Planned Analysis” 
in the clinical study report (CSR).
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4.6.2.1
Evaluation of Safety and Tolerability
Safety and tolerability will be assessed through intensity of injection site pain VAS,
categorical assessment of injection site pain intensity, quality of pain modified 
SF-MPQ-2 inventory, duration of pain assessment, comparative pain assessment, AEs, 
clinical laboratory, vital signs, ECGs, and physical examination findings (if results are 
available after dosing), and any other parameter that is relevant for safety assessment.
4.6.2.1.1
Intensity of Injection Site Pain Visual-Analogue Scale
The primary endpoint is given in Table 8.
Table 8
Primary Endpoint
Endpoint title
Time frame
Unit
Intensity of injection site pain
1 min after each injection 
(Day 1)
mm on a 100 mm horizontal 
visual-analogue scale (where 
0 mm = no pain, 100 mm = 
unbearable pain)
The primary endpoint will be analysed 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. From the 
model, the difference in VAS score between the 2 products will be estimated and 
presented with a 95% confidence interval (CI) and a p-value. The interpretation of the 
difference in VAS pain scores will be supported and contextualised by the results of the 
analyses of the exploratory endpoints.
4.6.2.1.2
Categorical Assessment of Injection Site Pain Intensity, Quality of Pain Modified 
SF-MPQ-2 Inventory, Duration of Pain, and Comparative Pain Assessment
The exploratory endpoints are given in Table 9.
Table 9
Exploratory Endpoints
Endpoint title
Time frame
Unit
Categorical assessment of 
intensity of injection site pain
Immediately after rating of 
intensity of injection site pain, 
i.e. 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
(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, i.e. 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 modified SF-
MPQ-2 inventory (select all that 
apply):
Throbbing pain տ
Shooting pain տ
Stabbing pain տ
Sharp pain տ
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Endpoint title
Time frame
Unit
Cramping pain տ
Gnawing pain տ
Hot-burning pain տ
Aching pain տ
Heavy painտ
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 s
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 –
about the same (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 semaglutide product hurt 
less than or about the same 
as the dulaglutide product
Dichotomous variable based 
on “Comparative pain 
experience” variable above
Yes = “about the same (includes 
none of the products hurt)” or “the
semaglutide product hurt less than 
the dulaglutide product” or “the 
semaglutide product hurt much 
less than the dulaglutide product”
No = “the semaglutide product 
hurt 
much 
more 
than 
the 
dulaglutide 
product” 
or 
“the
semaglutide product hurt more 
than the dulaglutide product”
The results will be listed, and they will be presented descriptively, where applicable.
4.6.2.1.3
Adverse Events
A listing of all individual AEs will be provided. Summary tables of treatment-emergent 
adverse events (TEAEs) will be presented by system organ class based on the Medical 
Dictionary for Regulatory Activities terminology list (preferred terms): one containing the 
number of TEAEs (frequency of occurrence, number of subjects experiencing the event) 
by treatment and one containing the number of drug-related TEAEs (frequency of 
occurrence, number of subjects experiencing the event) per treatment. Additional tables 
of total counts by treatment and relationship and by treatment and severity will be given.
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4.6.2.1.4
Technical Complaints
A listing of all technical complaints will be provided.
4.6.2.1.5
Clinical Laboratory
Clinical laboratory data will be listed accompanied by an indication if the parameter is 
outside the reference range. A summary of all data outside the reference range of the 
clinical laboratory will be provided. Clinical laboratory data will be presented 
descriptively, where applicable.
4.6.2.1.6
Vital Signs and Electrocardiograms
Vital signs and ECG parameters will be listed, and they will be presented descriptively, 
where applicable.
4.6.2.1.7
Physical Examination
Changes from baseline for physical examination (if available after dosing) will be 
described and listed.
4.6.3
Determination of Sample Size
The sample size calculation considers both the primary endpoint and the dichotomous 
endpoints.
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, eg, 
for a proportion of 60%, the CI is 60% (50%-70%).
A standard deviation (SD) of within-pair differences in VAS pain score between 2 SC
injections was obtained from Novo Nordisk clinical trial INS-4011. The within-subject 
variance (adjusting for the effects of speed, volume, and injection region) was estimated 
to 348, corresponding to an SD of the within-SDLUGLIIHUHQFHRI¥Â  mm. A
prospective study of acute pain found that the minimum clinically important difference 
(MCID) for worsening of pain, ie, the difference on a VAS associated with the selection 
of “a little more pain” rather than “about the same”, had a mean value of 10 mm.5
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With 100 subjects, a conservative SD of 30 mm, and 90% power, it is possible to detect 
a difference smaller than 10 mm (Table 10). 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 randomised.
Table 10
Detectable Difference with a Sample Size of 100 Subjects for Different 
Combinations of Power, and Standard Deviation
Number of 
Subjects
Power
Standard
Deviation
Difference
100
0.8
25 mm
7.1 mm
100
0.8
30 mm
8.5 mm
100
0.9
25 mm
8.2 mm
100
0.9
30 mm
9.8 mm
4.6.4
Interim Analysis
After the last subject has completed Day 1, all data collected will be released unblinded 
for analysis notwithstanding that the subjects have not completed the safety follow-up 
phone call.
4.7
Data Quality Assurance
The trial may be audited by the Quality Assurance Department at 
 to assess 
adherence to the clinical study protocol (CSP) and Quality System. During the conduct 
of the trial, process-related audits may be performed. An audit certificate will be provided 
in the appendices of the final CSR outlining any audits and other related activities 
performed.
The clinical research site will be monitored by the study blinded monitor and unblinded 
monitor to ensure correct performance of the trial procedures and assure that the trial is 
conducted according to the relevant regulatory requirements. The eCRF entries will be 
verified with the source documentation, if applicable (in some cases there are no source 
pages, therefore verification is not necessary).
Regulatory authorities, the IEC, and/or the Sponsor’s clinical quality assurance group 
may request access to all source documents, eCRFs, and other trial documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities.
Quality control principles will be applied throughout the performance of this trial. Review 
procedures will be followed at 
 for all documents that are generated in relation to 
the trial.
An explanation will be given for all missing, unused, and spurious data in the relevant 
sections of the CSR.
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5.
ETHICS
5.1
Independent Ethics Committee
The CSP and the ICFs will be submitted for review and approval by the IEC of the 
foundation “Beoordeling Ethiek Biomedisch Onderzoek” (English translation: “Evaluation 
of Ethics in Biomedical Research”) (Dr. 
) prior to the eligibility screening. The composition of the IEC is in 
accordance with the recommendations of the World Health Organization, the 
International Council for Harmonisation (ICH) E6 Guideline for Good Clinical Practice 
(GCP) (EMA/Committee for Medicinal Products for Human Use [CHMP]/ICH/135/1995)6,
and the EU Clinical Trial Directive (CTD) (Directive 2001/20/EC)7.
will keep the IEC informed about the progress of the trial. All changes in research 
activities and all unanticipated problems involving risks to human subjects will be
immediately reported to the IEC. In accordance with Section 10, Subsection 1, of the 
Dutch law on Medical Research in Human Subjects (WMO, revised December 2015)8,
will inform the subjects and the IEC if anything occurs on the basis of which it 
appears that the disadvantages of participation may be significantly greater than was 
foreseen in the research proposal, or if further recruitment of subjects in the trial has
been put on hold for that reason, whichever occurs first. The trial may be suspended 
pending further review by the IEC, except insofar as suspension would jeopardise the 
subjects’ health. 
will take care that all subjects are kept informed.
No changes will be made in the trial without IEC approval, except when required to 
eliminate apparent immediate hazards to human subjects.
Notification of the end of the trial will be sent by 
 to the Competent Authority (CA) in 
The Netherlands and to the IEC within 90 days after completion of follow-up for the last 
subject. In case a trial is temporarily halted, 
 will notify the IEC immediately, 
including the reason for this. In case a trial is ended prematurely, 
 will notify the IEC 
and the CA in The Netherlands within 15 days, including the reasons for the premature 
termination. A summary of the results of the trial will be sent by 
 to the CA and the 
IEC within 1 year after the end of the trial.
5.2
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origin 
in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 18th
WMA General Assembly, Helsinki, Finland, June 1964, and subsequent amendments.9
This trial is also designed to comply with ICH E6 Guideline for GCP (EMA/Committee 
for Medicinal Products for Human Use [CHMP]/ICH/135/1995)6 and the EU CTD 
Directive 2001/20/EC7, as incorporated into Dutch Law.8
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Guidelines adopted by the ICH and other relevant international guidelines, 
recommendations, and requirements will be taken into account as comprehensively as 
possible, as long as they do not violate local law.
Whenever the term “Investigator” is noted in the CSP text, it may refer to either the 
Investigator at the site or an appropriately qualified, trained, and delegated individual of 
the investigational site.
5.3
Subject Information and Consent
All subjects will be informed verbally and in writing regarding the objectives, procedures,
and risks of trial participation. The subjects will have to sign the Dutch or English version 
of the ICF before any trial-related procedures are started. The ICF contains information 
about the objectives of the trial, the procedures followed during the trial, and the risks 
and restrictions of the trial, with special reference to possible side effects of the 
medication and potential interactions. In addition, insurance coverage provided during 
the trial is explained. The elements addressed in the ICF are according to the ICH E6 
Guideline for GCP (EMA/CHMP/ICH/135/1995).6
5.4
Privacy
All personal details will be treated as confidential by the Investigator and staff at 
,
and the handling of personal data will be in compliance with the EU General Data 
Protection Regulation (GDPR).10
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6.
TRIAL ADMINISTRATIVE STRUCTURE
6.1
Distribution of Activities
Supply of Trial Drug
Novo Nordisk A/S Denmark will supply the semaglutide products and the 
dulaglutide products for use in the trial.
Laboratory Assessments
The analysis of clinical laboratory samples will be performed at the 
 Clinical 
Laboratory.
eCRF Design
The eCRF design will be performed with the computer program 
 by the Database Programming Department 
of 
.
Data Management
Data management will be performed with the computer programs
, a technology subsidiary of 
) by the Data Management Department of 
.
Statistics
A SAP will be generated by the Biostatistics Department of 
. The safety analysis will 
be conducted by the Biostatistics Department of 
. Statistical analysis will be 
performed with the computer program 
.
CSR Writing
The CSR, structured in accordance with the guideline “Structure and Content of Clinical 
Study Reports - ICH E3”,11 will be written by 
.
6.2
Documentation
6.2.1
Archiving
All documents concerning the trial will be kept on file in the Central Archives of 
 for 
at least 15 years after conduct of the trial. The Sponsor will receive the completed eCRFs 
(upon request, as PDF file).
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6.2.2
Recording of Data in Source Documents and eCRFs
Wherever possible, all data will be entered directly into the eCRFs. Source documents 
will be used in some cases.
A data management plan will be written by the Data Management Department of 
 
which will be finalised prior to performing any data validation. An appendix to the data 
management plan (Origin of Source Data List for Data Entry) will identify any data to be 
recorded directly in the eCRF (ie, no prior written or electronic record of data) and which 
data should be considered source data.
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7.
CONFIDENTIALITY AND PUBLICATION POLICY
By signing this CSP, the Investigator reaffirms to the Sponsor that he will maintain in 
confidence all information furnished to him or resulting from this trial. The Investigator
will only divulge such information as may be necessary to the IEC, the members of the 
staff, and the subjects who are involved in this trial.
The primary completion date (PCD) is the last assessment of the primary endpoint, and 
is for this trial Last Subject First Treatment (LSFT) corresponding to Day 1. If the last 
subject is withdrawn early, the PCD is considered the date when the last subject would 
have completed Day 1. The PCD determines the deadline for results disclosure at 
clinicaltrials.gov according to the Food and Drug Administration Amendments Act.
7.1
Publication Policy
Novo Nordisk commits to communicate and disclose results of trials regardless of 
outcome. Disclosure includes publication of a manuscript in a peer-reviewed scientific 
journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means. The results of this trial will be subject to public disclosure on 
external web-sites according to international and national regulations. Novo Nordisk 
reserves the right to defer the release of data until specified milestones are reached, for 
example when the clinical trial report is available. This includes the right not to release 
the results of interim analyses, because the release of such information may influence 
the results of the entire trial. At the end of the trial, one or more scientific publications 
may be prepared collaboratively by the Investigator(s) and Novo Nordisk. Novo Nordisk 
reserves the right to postpone publication and/or communication for up to 60 days to 
protect intellectual property. In all cases the trial results will be reported in an objective, 
accurate, balanced, and complete manner, with a discussion of the strengths and 
limitations. In the event of any disagreement on the content of any publication, both the 
investigators’ and Novo Nordisk opinions will be fairly and sufficiently represented in the 
publication.
7.2
Dissemination of Clinical Trial Data
Information on the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. 
It will also be disclosed according to other applicable requirements such as those of the 
International Committee of Medical Journal Editors, the Food and Drug Administration 
Amendments Act, European Commission Requirements, and other relevant 
recommendations or regulations. If a subject requests to be included in the trial via the 
Novo Nordisk e-mail contact at these websites, Novo Nordisk may disclose the 
Investigator’s contact details to the subject. As a result of increasing requirements for 
transparency, some countries require public disclosure of Investigator names and their 
affiliations.
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8.
REFERENCES
1.
Overgaard RV, Lindberg SO, Thielke D. Impact on HbA1c and body weight of 
switching from other GLP-1 receptor agonists to semaglutide: A model-based 
approach. Diabetes Obes Metab 2019, 21: 43-51
2.
Novo 
Nordisk 
A/S. 
Investigator's 
Brochure, 
Ozempic®
Semalgutide 
(subcutaneous administration), project NN9535 Type 2 Diabetes (edition 15)
3.
Eli Lilly and Company. Trulicity, EU Summary of Product Characterisitcs, 2017
4.
Dworkin RH, Turk DC, Revicki DA, et al. Development and initial validation of an 
expanded and revised version of the Short-form McGill Pain Questionnaire (SF-
MPQ-2). Pain. 2009;144:35-42.
5.
Todd KH, Funk KG, Funk JP, et al. Clinical significance of reported changes in 
pain severity. Ann Emerg Med.1996;27:485-89.
6.
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, 
E6 
(R2): 
Guideline 
for 
Good 
Clinical 
Practice 
(EMA/CHMP/ICH/135/1995), 15 December 2016.
7.
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 
2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in 
the conduct of clinical trials on medicinal products for human use.
8.
Medical 
Research 
Involving 
Human 
Subjects 
Act 
(WMO, 
Wet 
Medisch-Wetenschappelijk Onderzoek met Mensen), revision December 2015.
9.
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 
64th World Medical Association General Assembly, Fortaleza, Brazil, October 
2013.
10.
The General Data Protection Regulation (GDPR). Regulation (EU) 2016/679 of 
the European Parliament and the Council of the European Union, 27 April 2016.
11.
International Council
for
Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, 
E3: 
Structure 
and 
Content 
of 
Clinical 
Study 
Reports 
(CPMP/ICH/137/95), November 1995.
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9.
APPENDICES
9.1
Drug Accountability
x
Trial product storage, in-use conditions, and in-use time will be available on the label 
and in the TMM. The Investigator must confirm that appropriate temperature 
conditions have been maintained during transit for all trial products received and any 
discrepancies are reported and resolved before use of the trial products.
x
All trial products must be stored in a secure, controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access 
limited to the pharmacist and pharmacy assistant.
x
The Investigator must inform Novo Nordisk immediately if any trial product has been 
stored outside specified conditions. Additional details regarding handling of 
temperature deviations can be found in the TMM.
x
Trial product that has been stored improperly must not be dispensed to any subject 
before it has been evaluated and approved for further use by Novo Nordisk.
x
The Investigator is responsible for drug accountability and record maintenance (ie,
receipt, accountability, and final disposition records).
x
For trial products packed unblinded in a blinded trial: Drug accountability will be 
performed by an unblinded person who will ensure that unblinding information such 
as batch numbers is not revealed to personnel that should remain blinded).
x
Drug accountability should be performed at dose level unless this is not possible (eg,
products in pen-injectors), then describe and explain the actual level of 
accountability.
9.2
Adverse Events: Definitions and Procedures for Recording, Evaluation, 
Follow-up, and Reporting to Sponsor
AE definition
x
An AE is any untoward occurrence in a clinical trial subject that is temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal 
product.
x
An AE can be any unfavourable and unintended sign, including an abnormal laboratory 
finding, symptom, or disease (new or exacerbated) temporally associated with the use of 
a medicinal product. 
Events meeting the AE definition
x
Any abnormal laboratory test results or safety assessments, including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgement of 
the Investigator.
x
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
x
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
x
Signs, symptoms, or the clinical sequelae of a suspected overdose of trial product 
regardless of intent.
Events NOT meeting the AE definition 
x
Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, 
including those identified during screening or other trial procedures performed before 
exposure to trial product.
Note: Pre-existing conditions should be recorded as medical history/concomitant illness.
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x
Pre-planned procedures, unless the condition for which the procedure was planned has 
worsened from the first trial-related activity after the subject has signed the informed 
consent.
x
Pain: Non-serious pain will be collected on specific pain-rating schemes. If the event of 
pain fulfils the criteria for a serious adverse event then in addition to the above, an 
adverse event form and a safety information form must also be filled in. All other injection 
site reactions besides pain will be reported as an adverse event (Table 1) and Section 
4.5.
If the event of pain fulfils the criteria for an SAE then in addition to the above, an AE form 
and a safety information form must also be filled in.
Definition of an SAE
An SAE is an AE that fulfils at least one of the following criteria:
x
Results in death
x
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death, if it were more severe
x
Requires inpatient hospitalization or prolongation of existing hospitalization
x
Hospitalization signifies that the subject has been detained at the hospital or 
emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.
x
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
Note:
x
Hospitalizations for administrative, trial-related, and social purposes do not constitute 
AEs and should therefore not be reported as AEs or SAEs.
x
Hospital admissions for surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs. 
x
Results in persistent disability/incapacity
x
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
x
This definition is not intended to include experience of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (eg, sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
x
Is a congenital anomaly/birth defect
x
Including events leading to fetal distress or fetal death
x
Important medical event:
x
Medical or scientific judgement should be exercised in deciding whether SAE reporting 
is appropriate in other situations. This includes important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardise
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious and reported as SAEs using the important medical event criterion.
x
The following AEs must always be reported as SAEs using the important medical 
event criterion, if no other seriousness criteria are applicable:
x
suspicion of transmission of infectious agents via the trial product.
x
risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x the upper limit of normal (ULN) and total bilirubin 
>2 x ULN, where no alternative aetiology exists (Hy's law).
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These are handled under the SAE reporting system.
Description of AEs requiring additional data collection (via specific event form) 
Medication error:
A medication error concerning trial products is defined as:
x
Administration of wrong drug or use of wrong device.
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error 
unless it results in a confirmed administration of wrong drug.
x
Wrong route of administration, such as intramuscular instead of sc.
x
Accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the trial 
subject were likely to happen as judged by the Investigator, although they did not 
necessarily occur.
AE and SAE recording
x
The Investigator will record all relevant AE information in the eCRF and SAE information 
on paper forms.
x
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
x
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory and diagnostics reports) related to 
the event.
x
For all non-serious AEs the applicable forms should be signed when the event is resolved 
or at the end of the trial at the latest. For sign-off of SAE-related forms, refer to “SAE 
reporting via paper CRF” later in this section.
x
Novo Nordisk products used as concomitant medication: if an AE is considered to have a 
causal relationship with a Novo Nordisk marketed product used as concomitant 
medication in the trial, it is important that the suspected relationship is reported to Novo 
Nordisk, eg, in the alternative etiology section on the safety information form. Novo 
Nordisk may need to report this AE to relevant regulatory authorities.
Assessment of severity
The Investigator will assess intensity for each event reported during the trial and assign it to 
one of the following categories:
x
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.
x
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
x
Severe: An event that prevents normal everyday activities.
Note: Severe is a category used for rating the intensity of an event; and both an AE and 
SAE can be assessed as severe. An event is defined as ‘serious’ when it meets at least 
one of the outcomes described in the definition of an SAE and not when it is rated as 
severe.
Assessment of causality
The Investigator is obligated to assess the relationship between trial product and the 
occurrence of each AE/SAE.
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as:
x
Probable - Good reason and sufficient documentation to assume a causal relationship.
x
Possible - A causal relationship is conceivable and cannot be dismissed.
x
Unlikely - The event is most likely related to aetiology other than the trial product.
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to trial product administration will be 
considered and investigated.
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The Investigator should use the investigator’s brochure for the semaglutide product and the 
summary of product characteristics for the dulaglutide product for the assessment. For each 
AE/SAE, the Investigator must document in the medical records that he/she has reviewed the 
AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report. However, it is important that the Investigator 
always makes an assessment of causality for every event before the initial 
transmission of the SAE data.
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Final outcome
The Investigator will select the most appropriate outcome:
x
Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
x
Recovering/resolving: The condition is improving, and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has 
died from another AE.
x
Recovered/resolved with sequelae: The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
x
Not recovered/not resolved: The condition of the subject has not improved, and the 
symptoms are unchanged, or the outcome is not known.
x
Fatal: This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with 
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be reported 
as an SAE.
x
Unknown: This term is only applicable if the subject is lost to follow-up.
Follow-up of AE and SAE
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Novo Nordisk to 
elucidate the nature and/or causality of the AE or SAE as fully as possible (eg, severe
hypersensitivity reactions). This may include additional laboratory tests (eg, skin prick test) or 
investigations, histopathological examinations, or consultation with other health care 
professionals.
If a subject dies during participation in the trial or during a recognised follow-up period, the 
Investigator should provide Novo Nordisk with a copy of autopsy report including 
histopathology.
New or updated information will be recorded in the case report form (CRF).
SAE reporting via paper CRF
x
Relevant CRF forms (AE safety information and specific event forms) must be forwarded to Novo 
Nordisk.
x
The Investigator needs to complete the AE and safety information form within the designated 
reporting time frames (as illustrated in Figure 2).
x
If the eCRF is unavailable for more than 24 hours, then the site will use the paper AE form.
Contact details for SAE reporting can be found in the Investigator trial master file.
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