Clinical trial NCT02453711
Conditions: Metabolism and Nutrition Disorder Obesity
Sponsor: Novo Nordisk A/S
Start date: 2015-10-01; Completion date: 2017-04-12
Enrollment: 957 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of this trial is to investigate safety and efficacy of once-daily semaglutide in obese subjects without diabetes mellitus.

Detailed description:

Arms: arm 1: Dose 0.05 mg arm 2: Dose 0.05 or 0.1 mg with dose escalation every fourth week arm 3: Dose 0.05, 0.1 or 0.2 mg with dose escalation every fourth week arm 4: Dose 0.05, 0.1, 0.2 or 0.3 mg with dose escalation every fourth week arm 5: Dose 0.05, 0.1, 0.2, 0.3, or 0.4 mg with dose escalation every fourth week arm 6: Dose 0.05, 0.1, 0.2 or 0.3 mg with dose escalation every second week arm 7: Dose 0.05, 0.1, 0.2, 0.3, or 0.4 mg with dose escalation every second week arm 8: Dose 0.6, 1.2, 1.8, 2.4, 3.0 mg with dose escalation every week arm 9: Placebo arm matching active arm Sema 0.05 mg arm 10: Placebo arm matching active arm Sema 0.1 mg arm 11: Placebo arm matching active arm Sema 0.2 mg arm 12: Placebo arm matching active arm Sema 0.3 mg arm 13: Placebo arm matching active arm Sema 0.4 mg arm 14: Placebo arm matching active arm Sema 0.3 mg (fast dose escalation) arm 15: Placebo arm matching active arm Sema 0.4 mg (fast dose escalation) arm 16: Placebo arm matching active arm Lira 3.0 mg
Interventions: intervention 1: semaglutide intervention 2: liraglutide intervention 3: placebo
Intervention descriptions: intervention 1: Once-daily subcutaneous (s.c., under the skin) administration with dose escalation. intervention 2: Once-daily subcutaneous (s.c., under the skin) administration with dose escalation. intervention 3: Once-daily subcutaneous (s.c., under the skin) administration.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02453711 
Sponsor trial ID: 
NN9536-4153 
Official title of study: 
Investigation of safety and efficacy of once-daily semaglutide 
in obese subjects without diabetes mellitus 
Document date: 
24 October 2017 
 


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CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
1 of 100
Protocol
Trial ID: NN9536-4153
Investigation of safety and efficacy of once-daily semaglutide
in obese subjects without diabetes mellitus
A 52-week, randomised, double-blind, placebo-controlled, nine-armed, parallel group, multi-centre, 
multinational trial with liraglutide 3.0 mg as active comparator
Trial phase: 2
Protocol originator
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
2 of 100
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary....................................................................................................................................................9
2
Flow chart ................................................................................................................................................12
3
Background information and rationale for the trial............................................................................15
3.1
Background information..............................................................................................................15
3.1.1
Glucagon-like peptide-1 ............................................................................................15
3.1.2
Semaglutide ...............................................................................................................15
3.1.3
Liraglutide..................................................................................................................16
3.1.4
Nonclinical data.........................................................................................................16
3.1.5
Clinical data...............................................................................................................17
3.2
Rationale for the trial...................................................................................................................19
4
Objectives and endpoints........................................................................................................................20
4.1
Objectives ....................................................................................................................................20
4.2
Endpoints .....................................................................................................................................20
4.2.1
Primary endpoint........................................................................................................20
4.2.2
Secondary endpoints..................................................................................................20
5
Trial design ..............................................................................................................................................23
5.1
Type of trial .................................................................................................................................23
5.2
Rationale for trial design..............................................................................................................24
5.3
Treatment of subjects...................................................................................................................25
5.3.1
Semaglutide treatment ...............................................................................................25
5.3.2
Liraglutide treatment..................................................................................................26
5.3.3
Missed dose................................................................................................................26
5.3.4
Nutritional and physical activity counselling ............................................................26
5.4
Treatment after discontinuation of trial product ..........................................................................26
5.5
Rationale for treatment ................................................................................................................27
6
Trial population.......................................................................................................................................28
6.1
Number of subjects......................................................................................................................28
6.2
Inclusion criteria ..........................................................................................................................28
6.3
Exclusion criteria.........................................................................................................................28
6.4
Discontinuation of trial product criteria and withdrawal of informed consent............................29
6.5
Rationale for trial population.......................................................................................................30
7
Milestones.................................................................................................................................................32
8
Methods and assessments .......................................................................................................................33
8.1
Visit procedures...........................................................................................................................33
8.1.1
Screening, re-screening and screening failures..........................................................33
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
3 of 100
8.1.2
Fasting visits ..............................................................................................................33
8.1.3
Missed visits ..............................................................................................................34
8.1.4
Discontinuation of trial product.................................................................................34
8.1.5
Withdrawn subjects....................................................................................................34
8.1.6
Subject training..........................................................................................................34
8.1.7
Investigator’s assessment...........................................................................................35
8.2
Subject related information..........................................................................................................35
8.2.1
Demography...............................................................................................................35
8.2.2
Concomitant illness and medical history...................................................................36
8.2.2.1
History of concomitant cardiovascular disease...................................36
8.2.2.2
History of gallbladder disease.............................................................36
8.2.2.3
History of psychiatric disorders ..........................................................36
8.2.2.4
History of breast neoplasms ................................................................36
8.2.2.5
History of colon neoplasms.................................................................37
8.2.3
Concomitant medication............................................................................................37
8.2.3.1
Evaluation of antihypertensive and lipid-lowering treatment .............37
8.2.4
Tobacco use ...............................................................................................................37
8.3
Laboratory assessments ...............................................................................................................37
8.4
Assessments for efficacy..............................................................................................................38
8.4.1
Body Measurements ..................................................................................................38
8.4.1.1
Body weight ........................................................................................38
8.4.1.2
Height..................................................................................................39
8.4.1.3
Body mass index .................................................................................39
8.4.1.4
Waist and hip circumference...............................................................39
8.4.2
Systolic and diastolic blood pressure.........................................................................39
8.4.3
Blood samples............................................................................................................40
8.4.4
Patient reported outcome questionnaires ...................................................................40
8.5
Assessments for safety.................................................................................................................41
8.5.1
Physical Examination ................................................................................................41
8.5.2
ECG ...........................................................................................................................41
8.5.3
Pulse...........................................................................................................................41
8.5.4
Breast neoplasms follow-up.......................................................................................42
8.5.5
Colon neoplasms follow-up.......................................................................................42
8.5.6
Mental health questionnaires .....................................................................................42
8.5.6.1
Referral to a mental health professional..............................................42
8.5.7
Adverse Events ..........................................................................................................43
8.5.8
Nausea questionnaire.................................................................................................43
8.5.9
Hypoglycaemic episodes ...........................................................................................43
8.5.10
Adverse events requiring special forms in the eCRF.................................................44
8.5.11
Blood samples............................................................................................................48
8.5.12
Pregnancy test............................................................................................................48
8.5.13
Anti-semaglutide antibodies ......................................................................................49
8.6
Other assessments........................................................................................................................49
8.6.1
Semaglutide plasma concentration ............................................................................49
8.6.2
Dosing diary...............................................................................................................49
8.6.3
Nutritional counselling ..............................................................................................49
8.6.4
Physical activity counselling......................................................................................50
8.7
Specific safety assessments..........................................................................................................50
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
4 of 100
8.7.1
Subjects developing type 2 diabetes mellitus ............................................................50
8.7.2
Thyroidectomy...........................................................................................................51
8.7.3
Suspicion of acute pancreatitis...................................................................................51
8.7.4
Suspicion of severe hypersensitivity..........................................................................52
8.7.5
Suspicion of immune complex disease......................................................................52
8.8
Subject compliance......................................................................................................................52
9
Trial supplies ...........................................................................................................................................53
9.1
Trial products...............................................................................................................................53
9.2
Labelling......................................................................................................................................53
9.3
Storage .........................................................................................................................................53
9.4
Drug accountability and destruction............................................................................................54
9.5
Auxiliary supplies........................................................................................................................54
10 Interactive web response system............................................................................................................55
11 Randomisation procedure and breaking of blinded codes..................................................................56
11.1
Breaking of blinded codes ...........................................................................................................56
12 Adverse events, technical complaints and pregnancies .......................................................................57
12.1
Definitions ...................................................................................................................................57
12.2
Reporting of adverse events.........................................................................................................60
12.3
Follow-up of adverse events........................................................................................................63
12.4
Technical complaints and technical complaint samples ..............................................................64
12.4.1
Reporting of technical complaints .............................................................................64
12.4.2
Collection, storage and shipment of technical complaint samples ............................64
12.5
Pregnancies in female subjects ....................................................................................................65
12.6
Precautions and/or overdose ........................................................................................................66
12.7
Committees related to safety........................................................................................................66
12.7.1
Novo Nordisk safety committee ................................................................................66
12.7.2
Event adjudication committee....................................................................................67
12.7.3
Calcitonin monitoring committee ..............................................................................67
13 Case report forms....................................................................................................................................68
13.1
Corrections to case report forms..................................................................................................68
13.2
Case report form flow..................................................................................................................69
13.3
Electronic collection of questionnaires........................................................................................69
14 Monitoring procedures ...........................................................................................................................70
15 Data management....................................................................................................................................71
16 Computerised systems.............................................................................................................................71
17 Statistical considerations ........................................................................................................................72
17.1
Sample size calculation................................................................................................................72
17.2
Definition of analysis sets............................................................................................................74
17.3
Primary endpoint..........................................................................................................................74
17.4
Secondary endpoints....................................................................................................................78
17.4.1
Efficacy endpoints .....................................................................................................78
17.4.2
Safety endpoints.........................................................................................................80
17.5
Pharmacokinetic and pharmacodynamic modelling ....................................................................82
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
5 of 100
18 Ethics........................................................................................................................................................84
18.1
Benefit-risk assessment of the trial..............................................................................................84
18.2
Informed consent .........................................................................................................................87
18.3
Data handling...............................................................................................................................88
18.4
Information to subject during the trial .........................................................................................88
18.5
Premature termination of the trial and/or trial site.......................................................................88
19 Protocol compliance................................................................................................................................89
20 Audits and inspections ............................................................................................................................89
21 Critical documents ..................................................................................................................................90
22 Responsibilities........................................................................................................................................91
23 Reports and publications........................................................................................................................92
23.1
Communication of results............................................................................................................92
23.1.1
Authorship .................................................................................................................93
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................93
23.2
Investigator access to data and review of results.........................................................................93
24 Retention of clinical trial documentation and human biospecimens..................................................94
24.1
Retention of clinical trial documentation.....................................................................................94
24.2
Retention of human biospecimens...............................................................................................94
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............95
26 Indemnity statement ...............................................................................................................................96
27 References................................................................................................................................................97
Appendix A
Monitoring of calcitonin
Appendix B
IWQoL-Lite for Clinical Trials
Appendix C
Patients’ global impression of change
Appendix D
Nausea questionnaire
Appendix E
MESI and AEs with additional data collection
Attachment I – Global list of key staff and relevant departments and vendors
Attachment II – Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
6 of 100
Table of Figures   
Page
Figure 5–1
Trial design.............................................................................................................................24
Figure 12–1
Initial reporting of AEs...........................................................................................................62
Table of Tables
Page
Table 5–1
Duration of dose escalation period for semaglutide treament arms........................................25
Table 8–1
Equation for estimating BMR.................................................................................................50
Table 9–1
Storage of trial product...........................................................................................................54
Table 12–1
Adverse events with additional data collection ......................................................................60
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
7 of 100
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
Alanine aminotransaminase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
BMR
basal metabolic rate
CPK
creatine phosphokinase
C-SSRS
Columbia Suicidality Severity Rating Scale
CRF
case report form
CTR
clinical trial report
DPP-4
dipeptidyl peptidase 4
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FPFV
first patient first visit
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
HRQoL
health-related quality of life
hsCRP
High-sensitivity C reactive protein
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
8 of 100
IRB
institutional review board
IWRS
interactive web response system
IWQoL-Lite
Impact of Weight on Quality of Life Lite
LDL
low density lipoprotein
LPLV
last patient last visit
MAR
missing at random
MESI
medical event of special interest
MHP
mental health professional
MMRM
mixed model for repeated measurements
NRS
numeric rating scale
PD
pharmacodynamic
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetic
PRO
patient reported outcome
RET
re-arranged during transfection
SAE
serious adverse event
s.c.
subcutaneous(ly)
SF-36
Short Form-36
SMBG
self-measured blood glucose
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEE
total energy expenditure
TMM
Trial Materials Manual
TSH
thyroid-stimulating hormone
UTN
Universal Trial Number
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
9 of 100
1
Summary
Primary objective
To assess and compare the dose-response of five doses of once-daily semaglutide versus placebo in 
inducing and maintaining weight loss after 52 weeks in obese subjects without diabetes mellitus
Primary endpoint
Relative change from baseline in body weight (%) at 52 weeks
Key secondary objectives
To compare the effect of once-daily semaglutide versus once-daily liraglutide 3.0 mg in inducing 
and maintaining weight loss after 52 weeks in obese subjects without diabetes mellitus
To compare the effects of once-daily semaglutide to placebo and once-daily liraglutide 3.0 mg on:
–
Glucose metabolism parameters
Key secondary endpoints
!
Proportion (%) of subjects with weight loss of ≥5% of baseline body weight at 52 weeks
!
Proportion (%) of subjects with weight loss of ≥10% of baseline body weight at 52 weeks
Change from baseline to 52 weeks in:
!
Other parameters of weight loss
–
Body weight (kg)
!
Glucose metabolism parameters:
–
Glycosylated haemoglobin (HbA1c)
–
Fasting plasma glucose (FPG)
Trial design
This is a 52-week, randomised, double-blind, placebo-controlled, nine-armed, parallel group, multi-
centre, multinational trial comparing once-daily subcutaneous administration of semaglutide in five 
different doses (ranging from 0.05 mg/day to 0.4 mg/day) with placebo in obese subjects without 
diabetes mellitus. Liraglutide 3.0 mg/day is included as an active comparator. The trial is double-
blinded between active and placebo treatment. The total trial duration for the individual subject will 
be approximately 60 weeks. 
To ensure a sufficiently large sample of men, an upper limit will be implemented, allowing no more 
than 70% of the trial population to be women and the randomisation will be stratified according to 
sex.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
10 of 100
Subjects will be randomised in a balanced manner (6:1 active:placebo) for each of the 8 active 
treatment arms. The placebo arms are considered as one, giving a total of 9 arms. The treatment 
arms are:
!
semaglutide at randomised target dose 0.05, 0.1, 0.2, 0.3, or 0.4 mg (for dose levels above 
0.05 mg, dose escalation will take place every fourth week)
!
semaglutide at randomised target dose 0.3 or 0.4 mg (starting dose 0.05 mg with dose escalation 
every second week)
!
liraglutide 3.0 mg (starting dose 0.6 mg with dose escalation every week)
!
placebo (matching each of the active treatment arms)
Subjects in all treatment arms including placebo will receive nutritional counselling and a calorie-
reduced diet by a dietician or equivalent qualified delegate as well as physical activity counselling 
by a qualified person on a monthly basis beginning at the randomisation visit.
Trial population:
A total of 935 subjects is planned to be randomised and this will not exceed 963 randomised 
subjects. Based on an assumption of a 30% screening failure rate, 1,336 subjects are planned to be 
screened.
Key inclusion criteria:
!
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
!
Male or female, age ≥ 18 years at the time of signing inform consent
!
Body mass index (BMI) ≥ 30.0 kg/m2 at the screening visit
!
At least one unsuccessful weight loss attempt per investigator judgement
Key exclusion criteria:
!
A HbA1c ≥ 6.5% at screening or diagnosed with type 1 or type 2 diabetes mellitus
!
Treatment with glucose lowering agent(s) within 90 days before screening
!
Screening calcitonin ≥ 50 ng/L (pg/mL)
!
Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia 
syndrome type 2
!
History of pancreatitis (acute or chronic)
!
Obesity induced by endocrine disorders (e.g. Cushing Syndrome)
!
Treatment with any medication within 90 days before screening that based on investigator’s 
judgement may cause significant weight change
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
11 of 100
!
Previous surgical treatment for obesity (liposuction and/or abdominoplasty performed > 1 year 
before screening is allowed)
!
History of major depressive disorder within 2 years before randomisation
!
Any lifetime history of a suicidal attempt
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice)
Assessments:
Efficacy
!
Body measurements (body weight in kg)
!
Glucose metabolism (HbA1c, FPG)
Safety
!
Adverse events
!
Pulse
!
Mental health
!
Biochemistry and haematology
!
Antibodies against semaglutide
Trial products:
The following trial products will be supplied by Novo Nordisk A/S, Denmark:
!
Semaglutide 1.0 mg/ml, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Semaglutide placebo, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Liraglutide 6.0 mg/ml, solution for injection, 3.0 ml pre-filled PDS290 pen-injector
!
Liraglutide placebo, solution for injection, 3.0 ml pre-filled PDS290 pen-injector
CONFIDENTIAL


Protocol
UTN: U1111-1155-4660
Date:
17 April 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN9536-4153
EudraCT no.: 2014-001540-38
Version:
1.0
Page:
12 of 100
2
Flow chart
Screening Randomi-
sation
Dose escalation / Maintenance
Maintenance period
EOT
FU
Trial product 
discontinuation
52-week FU1
Visit Number 
1
2
3
4
5
6
7
8
9
10 11
12
13
14
15
16
17
18
19
20
21
22x
Weeks in relation to visit 2
-1
0
2
4
6
8
10 12 14 16 18
20
24
28
32
36
40
44
48
52
59
52
Visit window, days
+3 to -7
± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2
± 2
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
- 5
± 5
SUBJECTS
Informed consent (18.2)
X
In/exclusion criteria (6.2, 6.3)
X
X
Discontinuation of trial product criteria (6.4, 8.1.4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography (8.2.1)
X
Medical history/concomitant illness (8.2.2)
X
History of concomitant cardiovascular disease 
(8.2.2.1)
X
History of gallbladder disease (8.2.2.2)
X
History of psychiatric disorders (8.2.2.3)
X
History of breast neoplasms2 (8.2.2.4)
X
History of colon neoplasms (8.2.2.5)
X
Concomitant medications (8.2.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Evaluation of antihypertensive and lipid-lowering 
treatment(8.2.3.1)
X
X
X
X
Tobacco use (8.2.4)
X
EFFICACY
Body weight (8.4.1.1)
X
X3
X X3 X
X
X
X
X X3 X
X
X
X3
X
X
X3
X
X
X3
X
X
Height (8.4.1.2)
X
Waist and hip circumference (8.4.1.4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Systolic and diastolic blood pressure, sitting (8.4.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c (8.4.3)
X
X
X
X
X
X
X
Fasting plasma glucose (8.4.3)
X
X
X
X
X
X
hsCRP (8.4.3)
X
X
X
Lipids (8.4.3)
X
X
X
X
X
X


Protocol
UTN: U1111-1155-4660
Date:
17 April 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN9536-4153
EudraCT no.: 2014-001540-38
Version:
1.0
Page:
13 of 100
Screening Randomi-
sation
Dose escalation / Maintenance
Maintenance period
EOT
FU
Trial product 
discontinuation
52-week FU1
Visit Number 
1
2
3
4
5
6
7
8
9
10 11
12
13
14
15
16
17
18
19
20
21
22x
Weeks in relation to visit 2
-1
0
2
4
6
8
10 12 14 16 18
20
24
28
32
36
40
44
48
52
59
52
Visit window, days
+3 to -7
± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2
± 2
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
- 5
± 5
Nutritional compliance (8.6.3)
X
X
X
X
X
X
X
X
X
X
X
X
X
IWQoL-Lite for Clinical Trials4 (8.4.4)
X
X
X
X
SF-36 questionnaire4 (8.4.4)
X
X
X
Patients’ global impression of change4 (8.4.4)
X
X
SAFETY
Physical examination (8.5.1)
X
X
ECG (8.5.2)
X
X
X
Pulse, sitting (8.5.3)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Breast neoplasms follow-up2 (8.5.4)
X
X
Colon neoplasms follow-up (8.5.5)
X
X
Mental health questionnaires (8.5.6)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events5 (8.5.7)
X
X5
X5 X5 X5 X5 X5 X5 X5 X5 X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X5
X
Technical complaints (12.4)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Haematology (8.5.11)
X
X
X
X
X
X
X
Biochemistry (8.5.11)
X
X
X
X
X
X
X
Calcitonin (8.5.11, 12.7.3)
X
X
X
X
X
X
X
Pregnancy test6 (8.5.12)
X
X
X
X7
X7
X
X7
X7
X
X7
X7
X
X7
X7
X
X
Anti-semaglutide antibodies8, 9 (8.5.13)
X
X
X
X
X
X
X
X
OTHER ASSESSEMENTS
Semaglutide plasma concentration9 (8.6.1)
X
X
X
X
X
X
X
X
X
Nutritional and physical activity counselling (8.6.3, 
8.6.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
Dispensing of trial product (9.4)
X
X
X
X
X
Drug Accountability (9.4)
X
X
X
X
X
IWRS session (10)
X
X
X
X
X
X
X
REMINDERS


Protocol
UTN: U1111-1155-4660
Date:
17 April 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN9536-4153
EudraCT no.: 2014-001540-38
Version:
1.0
Page:
14 of 100
Screening Randomi-
sation
Dose escalation / Maintenance
Maintenance period
EOT
FU
Trial product 
discontinuation
52-week FU1
Visit Number 
1
2
3
4
5
6
7
8
9
10 11
12
13
14
15
16
17
18
19
20
21
22x
Weeks in relation to visit 2
-1
0
2
4
6
8
10 12 14 16 18
20
24
28
32
36
40
44
48
52
59
52
Visit window, days
+3 to -7
± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2 ± 2
± 2
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
- 5
± 5
Handout ID card (8.1.1)
X
Training in trial product and pen handling (8.1.6, 
9.1)
X
Dispense dosing diary (8.6.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect dosing diary and record in eCRF (8.6.2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Attend visit fasting (8.1.2)
X
X
X
X
X
X
X10
Abbreviations: ECG = Electrocardiogram, EOT = end-of-treatment, FU = follow-up, HbA1c = glycosylated hemoglobin, hsCRP = high-sensitivity C reactive protein, IWRS = interactive 
web response system, IWQoL-Lite = Impact of Weight on Quality Of Life Lite, SF-36 = Short Form-36
1) Only applicable for subjects who discontinue trial product before visit 20. Subjects discontinued from trial product should be encouraged to come for the EOT visit and FU visit and have 
the Trial product discontinuation 52-week FU visit scheduled 52 weeks (± 5 days) after randomisation
2) History of breast neoplasms and breast neoplasms follow-up should only be performed for female subjects
3) Fasting body weight
4) Will only be done in the US. The questionnaires must be completed by the subject and should preferably be completed after conclusion of all fasting-related activities, but before any 
other visit-related activities
5) If the subject experienced nausea within 24 hours before a visit, use the nausea questionnaire (see section 8.5.8). If a hypoglycaemic episode is reported, please refer to section 8.5.9.
6 For women of childbearing potential: Pregnancy testing will be performed on a monthly basis throughout the trial. Urine pregnancy test should be performed at any time during the trial if 
a mentrual period is missed, or as required by local law
7) At these visits, urine pregnancy testing will be performed
8) Subjects must be instructed to withhold their trial product dose in the morning until blood sampling has been performed at the visit.. This is not applicable for subjects that have 
discontinued trial product. Samples taken at the follow-up visit (visit 21) must be taken fasting (as a minimum by only having consumed water for at least 2 hours).
9) Anti-semaglutide antibodies and semaglutide plasma concentrations must only be drawn for subjects in the semaglutide treatment arms or the matching placebo arms.
10) The subject should be fasting for a minimum of 2 hours (only water consumption allowed) prior to the anti-semaglutide antibody sampling at visit 21


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
15 of 100
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
Obesity is one of the most significant public health challenges globally. It’s impact is considerable 
in the Western world but it is now also an emerging epidemic in developing countries 3. Lately the 
American Medical Association, the National Institutes of Health, The Obesity Society and the 
American Association for Clinical Endocrinology have recognised the seriousness of obesity and 
the related comorbidities by classifying obesity as a disease4. Obesity can lead to serious health 
consequences including hypertension, atherosclerosis, hyperglycaemia, dyslipidaemia, certain types 
of cancer and obstructive sleep apnoea (OSA)5,6.
Although not all people with obesity develop health problems, the risk of obesity-related 
complications and comorbidities increases with increasing BMI, and even a moderate weight loss of 
5–10% has been shown to have significant health benefits in terms of improving glycaemic control, 
reducing progression to type 2 diabetes mellitus (T2DM) and improving other weight-related 
comorbidities, as well as physical symptoms and quality of life7-9.
3.1.1
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the L-cells in the small 
intestine. GLP-1 has a glucose-dependent stimulatory effect on insulin and inhibitory effect on 
glucagon secretion from the pancreatic islets (i.e. when plasma glucose levels are above 
normal)10,11. Furthermore, GLP-1 is a physiological regulator of appetite and food intake and GLP-1 
receptors are present in several areas of the brain involved in appetite regulation. Physiologically,
GLP-1 has a pronounced inhibitory effect on gastric emptying; however this effect seems to 
diminish upon chronic exposure12-14. Endogenous GLP-1 has a very short elimination half-life of 
<1.5 minutes after intravenous administration due to rapid degradation by ubiquitous dipeptidyl 
peptidase (DPP-4)15. Development of a GLP-1 receptor agonist (GLP-1 RA) with longer half-life 
has been necessary to enable effective treatment option for T2DM and obesity.
3.1.2
Semaglutide
Semaglutide is a potent human GLP-1 RA with a half-life of approximately 160 hours, suitable for 
both once daily (subcutaneous (s.c.) and oral) and once weekly s.c. administration. It is structurally 
similar to liraglutide (Victoza® and Saxenda®), a once daily GLP-1 RA developed by Novo Nordisk 
and approved in several countries for the treatment of T2DM and weight management, respectively. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
16 of 100
For the semaglutide molecule the principal mechanism of protraction is albumin binding facilitated 
by a large fatty acid derived chemical moiety attached to the lysine in position 26. In vitro receptor 
studies have shown that semaglutide is a potent and selective GLP-1 RA, and animal studies using 
non-diabetic rats, non-diabetic pigs and diabetic mice have shown lowering of blood glucose and 
inhibition of food intake.
3.1.3
Liraglutide
Liraglutide is a long-acting once daily GLP-1 analogue. Liraglutide 3.0 mg (Saxenda®) has recently 
been submitted to various Health Authorities worldwide and is approved in USA, Canada, and EU
for the indication of weight management16. Liraglutide 1.2 and 1.8 mg (Victoza®) is approved in 
multiple countries for the treatment of T2DM. Compared to human GLP-1, liraglutide has a C16 
fatty (palmitic) acid chain attached at position 26 (lysine) of the peptide, and has lysine at position 
34 replaced by arginine. In vitro receptor studies have shown that liraglutide is a selective, potent 
and full agonist of the cloned human GLP-1 receptor. In animal studies, peripheral administration of 
liraglutide, led to specific activation of the GLP-1 receptors in the hypothalamus, which increased 
key satiety and decreased key hunger signals, thereby leading to lowering of body weight. In 
humans, liraglutide lowers body weight primarily through loss of fat mass with relative reduction in 
visceral fat being greater than subcutaneous fat17.
A total of 52 clinical trials with liraglutide for T2DM and weight management have been completed 
(including doses up to 3.0 mg). The trials were conducted world-wide. Out of more than 11,000 
subjects, more than 7,500 subjects were exposed to liraglutide for up to three years. In the weight 
management programme, subjects treated with liraglutide 3.0 mg experienced a dose-dependent 
weight loss ranging between 5.7% and 9.2% (6.0-8.8 kg) depending on the trial, whereas subjects 
treated with placebo (on diet and exercise alone) had a mean weight loss between 0.2% and 3.1% 
(0.2-3.0 kg). In addition to weight-lowering, for subjects treated with liraglutide 3.0 mg there was a 
decrease in systolic blood pressure and the prevalence of pre-diabetes was significantly reduced
compared to subjects treated with placebo. The safety evaluation was favourable with the main 
tolerability finding being gastrointestinal adverse events. Cases of gallstones (cholelithiasis) and 
inflammation of the gallbladder (cholecystitis) were reported more commonly in adult subjects 
treated with liraglutide 3.0 mg compared to placebo.
3.1.4
Nonclinical data
The nonclinical programme for semaglutide was designed according to the ICH M3 guideline to 
support clinical development. The standard nonclinical data package required to support phase 3 
clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. Semaglutide was generally well-
tolerated in animals (mice, rats and cynomolgus monkeys). Two potential safety issues have been 
identified and these are detailed below.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
17 of 100
Thyroid C-cell tumours in rodents
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin.C-cell changes have not been observed in long-term studies in non-
human primate.The observed pattern of effects in mice and rats (thyroid C-cell hyperplasia
preceded by increase in serum calcitonin) and lack of these effects in the non-human primate and in 
man suggest that the mechanism by which semaglutide acts on the thyroid C-cells in rodents is the 
same as has been demonstrated for other GLP-1RAs, including liraglutide. According to this 
mechanism,C-cell hyperplasia is mediated by the GLP-1receptorand is not associated with RET
(re-arranged during transfection)activation, and rodents appear to be particularlysensitive, whereas 
humansarenot. The relevance for human subjects is currently unknown, but considered to be low.
In the present trial,calcitonin will be measured on a regular basis and guidance toinvestigators of 
further evaluation and action on elevated plasma calcitonin concentrationswill be carried out by an 
independent group of thyroid experts, the calcitonin monitoring committee (see Appendix A). This 
will ensure appropriate and consistent handling of elevated calcitonin levels across trials.
Teratogenicity in rats
Semaglutide caused embryo-foetal malformations in the rat through a GLP-1 receptor mediated 
effect on the inverted yolk sac placenta leading to impaired nutrient supply to the developing 
embryo. Primates do not have an inverted yolk sac placenta which makes this mechanism unlikely 
to be of relevance to humans and cynomolgus monkeys. In the developmental toxicity studies in 
cynomolgus monkey, a marked pharmacology mediated maternal body weight loss coincided with 
increased early foetal loss; however, there was no indication of a teratogenic potential of 
semaglutide in this species. As a precaution female subjects who are pregnant, breast-feeding or 
intend to become pregnant will not be included in the trial. Likewise, females of childbearing 
potential not using an adequate contraceptive method throughout the trial including the 7-week 
follow-up period are not eligible for treatment with trial product. During the trial, pregnancy tests 
will be done at site visits.
3.1.5
Clinical data
Semaglutide is currently being investigated in the T2DM clinical development programme
(NN9535). Currently no dedicated data in obese subjects without T2DM exist. Doses up to 1.6 mg
with weekly dosing have been tested and doses up to 0.4 mg with daily dosing are planned in 
dedicated trials. As of 20 December 2014, 6 clinical pharmacology trials (trials NN9535-1820, 
NN9535-3679, NN9535-3633, NN9535-3616, NN9535-3819, and NN9535-4010) and 1 phase 2 
trial (trial NN9535-1821) have been completed with semaglutide. In the completed trials, 553 
subjects have been exposed to semaglutide. Thereof, 192 were healthy subjects (both single and 
multiple dosing), 313 were subjects with T2DM and 48 were subjects with varying degrees of renal 
impairment (4 with T2DM). In addition, 22 healthy subjects have been exposed to semaglutide 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
18 of 100
(s.c.) in the oral administration semaglutide project (NN9924). A total of 8 therapeutic confirmatory 
trials with nearly 8000 subjects enrolled were ongoing (as of 20 December 2014) including a 
104-week trial comparing the long-term safety (including cardiovascular risk) and efficacy of 
semaglutide versus placebo as add on to standard-of-care treatment. In parallel, 10 clinical 
pharmacology trials are ongoing to investigate the metabolism of semaglutide, the impact of hepatic 
impairment on the PK-profile of semaglutide and the effect of semaglutide on several aspects of 
glycaemic control, appetite regulation, QTc-prolongation and drug-drug interaction with selected 
oral drugs. These investigations are being performed in different populations including healthy 
subjects, subjects with T2DM, obese subjects and subjects with hepatic impairment.
Efficacy
As of 20 December 2014, the efficacy of semaglutide in subjects with T2DM has been investigated 
in one phase 2 dose range finding trial (NN9535-1821). The trial was a 12-week, randomised, 
double-blind, placebo- and active-controlled trial in which 411 adults with T2DM received once 
weekly s.c. injection of 1 of 5 semaglutide dose levels (0.1-1.6 mg), once-daily s.c. injection of 
open-label liraglutide (1.2 mg or 1.8 mg) or once-weekly s.c. injection of placebo. No diet and 
exercise intervention was instituted in trial NN9535-1821. Statistically significant weight loss was 
observed in the semaglutide groups (including doses of 0.8 mg and above) of up to 4.82 kg 
compared to 1.18 kg in the placebo group. Glycosylated haemoglobin (HbA1c) was significantly 
decreased up to -1.19% (placebo adjusted estimated treatment difference). Dose-dependency was 
established both for weight loss and glycaemic parameters.
Safety
Consistent with findings with other GLP-1 RAs, the most frequent adverse events (AEs) were 
gastrointestinal disorders (nausea and vomiting); most of the events were mild in intensity and 
transient in nature. Hypoglycaemia has been observed in subjects receiving semaglutide, and these 
events have mainly been minor. An increase in heart rate has been observed in subjects exposed to 
semaglutide in line with the increase seen with other GLP-1 RAs. The implications of this increase 
are currently unknown. 
As is the case with all protein-based pharmaceuticals, subjects treated with semaglutide may 
develop immunogenic and allergic reactions. Few allergic reactions have been reported in 
connection with semaglutide treatment. These have mainly been mild and transient. More 
generalised reactions, including urticaria, rash, pruritus and a single case of angioedema have also 
been observed. Few injection site reactions have been reported. These have mainly been mild and 
transient in nature.
Please refer to the current versions of the semaglutide s.c. (project NN9535), T2DM, Investigator’s 
Brochure and liraglutide (project NN8022) weight management, Investigator’s Brochure for further 
details.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
19 of 100
For an assessment of benefits and risks of the trial, see section 18.1.
3.2
Rationale for the trial
Semaglutide is a long-acting GLP-1 RA currently under development for treatment of T2DM.
Based on results from studies with semaglutide and liraglutide and supported by scientific literature 
on GLP-1 RAs, semaglutide is expected to lower body weight primarily by reducing energy intake, 
and not by affecting energy expenditure as semaglutide is known to enter specific areas of the brain 
relevant for reduction of energy intake18.
The semaglutide phase 2 dose-finding trial (NN9535-1821) in subjects with T2DM without 
nutritional and physical activity counselling supports the effect of semaglutide in lowering body 
weight, as semaglutide 1.6 mg/week provided an absolute weight loss of 4.8 kg (baseline body 
weight of 84.9 kg). The trial showed a clear dose-dependent response on weight loss over 12 weeks 
of treatment, indicating that higher weight losses could be expected with even higher doses than 
those previously investigated. Based on the mode of action of semaglutide, it is hypothesised that 
semaglutide at doses up to 0.4 mg/day may provide even greater weight loss. 
Clinical trials in the liraglutide weight management development programme (NN8022) have 
shown that liraglutide 3.0 mg provides a clinically meaningful weight loss; the weight loss ranged
between 5.7 and 9.2% (placebo ranged between 0.2 and 3.1%) in the individual trials. However,
based on early clinical data and the different molecular properties of semaglutide compared to 
liraglutide, superior weight loss is expected with semaglutide.
The purpose of the present trial is to investigate the potential of semaglutide at five dose levels to 
induce weight loss in obese subjects without diabetes mellitus compared to placebo and liraglutide 
3.0 mg. Furthermore, a fast escalation regimen will be investigated balancing time to reach target 
dose with tolerability. Safety and tolerability including the formation of anti-semaglutide antibodies 
will be investigated.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT no.: 2014-001540-38
Page:
20 of 100
4
Objectives and endpoints
4.1
Objectives
Primary objective
!
To assess and compare the dose-response of five doses of once-daily semaglutide versus 
placebo in inducing and maintaining weight loss after 52 weeks in obese subjects without 
diabetes mellitus
Secondary objectives
!
To compare the effect of once-daily semaglutide versus once-daily liraglutide 3.0 mg in 
inducing and maintaining weight loss after 52 weeks in obese subjects without diabetes mellitus
!
To compare the effects of once-daily semaglutide to placebo and once-daily liraglutide 3.0 mg 
on:
–
Glucose metabolism
–
Cardiovascular risk factors
–
Change in antihypertensive and lipid-lowering medical treatment
–
Compliance with dietary counselling
–
Patient reported weight-related quality of life and general health status
!
To compare the safety and tolerability of five dose levels of once-daily semaglutide with 
placebo and once-daily liraglutide 3.0 mg in obese subjects without diabetes mellitus
!
To compare efficacy of dose escalation every 2 weeks versus that of dose escalation every 4
weeks for two dose levels of once-daily semaglutide after 52 weeks in obese subjects without 
diabetes mellitus
!
To compare tolerability of dose escalation every 2 weeks versus that of dose escalation every 4 
weeks for two dose levels of once-daily semaglutide in obese subjects without diabetes mellitus
!
To examine criteria for identifying early responders that predict weight loss after 52 weeks
4.2
Endpoints
4.2.1
Primary endpoint
!
Relative change from baseline in body weight (%) at 52 weeks
4.2.2
Secondary endpoints
Supportive secondary efficacy endpoints
!
Proportion (%) of subjects with weight loss of ≥5% of baseline body weight at 52 weeks*
!
Proportion (%) of subjects with weight loss of ≥10% of baseline body weight at 52 weeks*
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!
Change from baseline to 52 weeks in:
Other parameters of weight loss:
–
Body weight (kg)*
–
Waist circumference (cm)
–
Waist to hip circumference ratio (waist(cm)/hip(cm))
–
BMI (kg/m2)
Glucose metabolism:
–
HbA1c*
–
FPG*
–
Shift in glycaemic category (normoglycaemia, pre-diabetes, T2DM)
Cardiovascular risk factors:
–
Systolic and diastolic blood pressure
–
Lipids (total cholesterol [TC], low density lipoprotein cholesterol [LDL cholesterol], high 
density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein cholesterol 
[VLDL cholesterol], triglycerides [TG], free fatty acids [FFA])
–
Cardiovascular biomarker (high sensitivity C reactive protein [hsCRP])
Patient reported weight-related quality of life and general health status:
–
Impact of Weight on Quality of Life-Lite (IWQoL-Lite) for Clinical Trials: Total score and 
scores on the individual sub-domains
–
Short form-36 (SF-36): Physical and mental component summary scores and scores on the 
individual sub-domains: Physical functioning, role functioning, bodily pain, general health, 
vitality, social functioning, role emotional and mental health
Proportion of subjects with change (decrease, no change, increase) in concomitant medications:
–
Antihypertensive medications
–
Lipid-lowering medications
!
Compliance with nutritional counselling
Supportive secondary safety endpoints
!
Number of treatment-emergent AEs during the trial
!
Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic 
episodes during the trial
!
Number of new and ongoing treatment-emergent nausea, vomiting, diarrhoea and constipation 
events by week
!
Nausea:
–
Individual scores of nausea questionnaire
–
Severity by numeric rating scale (NRS) score
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!
Change from baseline to 52 weeks in:
–
ECG
–
Pulse
–
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
–
Biochemistry (creatinine, CPK, urea, albumin, bilirubin [total], alanine aminotransaminase
(ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, 
calcium [total], amylase, lipase, calcitonin, TSH)
–
Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) and 
Patient Health Questionnaire-9 (PHQ-9)
!
Anti-semaglutide antibodies during and after treatment
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov
and EudraCT)
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5
Trial design
5.1
Type of trial
This is a 52-week, randomised, double-blind, placebo-controlled, nine-armed, parallel group, multi-
centre, multinational trial comparing once-daily subcutaneous administration of semaglutide in five 
different doses (ranging from 0.05 mg/day to 0.4 mg/day) with placebo in obese subjects without 
diabetes mellitus. Once-daily administration of two doses of semaglutide (0.3 mg/day and 0.4
mg/day) will be tested in a fast escalation regimen to investigate the effect of a different regimen on 
efficacy, safety and tolerability. Additionally, liraglutide 3.0 mg/day is included as an active 
comparator. The total trial duration for the individual subjects will be approximately 60 weeks. The 
trial includes a 1-week screening period, followed by a 52-week treatment period and a follow-up 
visit after 7 weeks.
A total of 935 subjects is planned to be randomised and this will not exceed 963 randomised 
subjects. Based on an assumption of a 30% screening failure rate, 1,336 subjects are planned to be 
screened. Subjects will be randomised in a balanced manner (6:1 active:placebo) to receive a daily 
target dose of (for details see Figure 5–1):
!
semaglutide 0.05, 0.1, 0.2, 0.3, or 0.4 mg (dose escalation every fourth week)
!
semaglutide 0.3 or 0.4 mg (dose escalation every second week)
!
liraglutide 3.0 mg (dose escalation every week)
!
placebo (matching each of the active treatment arms)
The placebo group will be subdivided into eight arms with different injection volumes 
corresponding to the different dose levels of semaglutide and liraglutide 3.0 mg.
Subjects in all treatment arms including placebo will receive nutritional counselling and a calorie-
reduced diet by a dietician or equivalent qualified delegate as well as physical activity counselling 
by a qualified person on a monthly basis beginning at the randomisation visit.
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* Each active treatment arm is blinded towards placebo with matching injection volumes, but not towards the other 
treatment arms.
Figure 5–1
Trial design
5.2
Rationale for trial design
It is broadly recognised that obesity is a chronic disease related to multiple serious co-morbidities4. 
This mandates chronic treatment and currently few effective and safe treatment options are 
available.
The present trial is a 52-week, randomised, double-blind, placebo-controlled, nine-armed, parallel 
group, multi-centre, multinational trial. To avoid bias in the assessment of the different semaglutide 
doses and the liraglutide dose, the trial will be double-blinded within treatment arm to placebo. The 
treatment arms will not be blinded towards each other because of different dose escalations, 
different pens, and different target doses.
A trial duration of 52 weeks is considered adequate in terms of establishing a clinically meaningful 
weight loss and is in accordance with regulatory guidelines19,20. Furthermore, a 52-week trial period 
is considered to be sufficient to characterise the semaglutide safety and tolerability profile.
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It is known from other trials in weight management4,21 including the majority of the liraglutide 
weight management trials that the trial population mainly consist of women (up to 80%). To ensure 
a sufficiently large sample of men, an upper limit will be implemented, allowing no more than 70% 
of the trial population to be women and the randomisation will be stratified according to sex.
As the high doses of semaglutide require a long time to reach the target dose, a fast escalation 
regimen is investigated in order to decrease the time-to-target dose. 
As gastrointestinal AE rates are anticipated to increase with higher doses and with large excursions 
in the semaglutide plasma concentration, semaglutide is dosed once daily to ensure less variability 
in concentrations. Dose escalation every fourth week is chosen to reach steady state at each dose 
level before increasing the dose. This could potentially reduce gastrointestinal AEs. However, for 
the higher doses, the time before target dose is reached is prolonged and this could mean that the 
maximisation of weight loss early in the treatment period might be missed. Therefore a fast 
escalation regimen (for two doses) is being investigated with dose escalation every second week.
5.3
Treatment of subjects
5.3.1
Semaglutide treatment
The dosing of semaglutide will be once daily with dose escalation to the next dose every fourth
week or every second week until the randomised target dose is reached (see Figure 5–1). For all 
semaglutide arms, the dosing will start at 0.05 mg/day, and then increase to 0.1 mg/day followed by 
increments of 0.1 mg/day until the target dose is reached. Once the target dose is reached, the dose 
level should be maintained. The dose changes will be recorded in the eCRF
Duration of the dose escalation period for the semaglutide treatment arms are listed in Table 5–1.
Table 5–1
Duration of dose escalation period for semaglutide treament arms
Treatment arm
Projected duration of dose escalation to reach target dose
Dose escalation every fourth week
Semaglutide 0.05 mg/day
0 weeks
Semaglutide 0.1 mg/day
4 weeks
Semaglutide 0.2 mg/day
8 weeks
Semaglutide 0.3 mg/day
12 weeks
Semaglutide 0.4 mg/day
16 weeks
Dose escalation every second week
Semaglutide 0.3 mg/day
6 weeks
Semaglutide 0.4 mg/day
8 weeks
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The escalation regimen should be followed. In case of intolerable gastrointestinal adverse events as 
judged by the investigator, dose escalation can be postponed:
!
Dose escalation every fourth week: 
–
can be postponed up to 7 days
–
maximum allowed duration on each dose step is 5 weeks
!
Dose escalation every second week: 
–
can be postponed up to 4 days
–
maximum allowed duration on each dose step is 2 weeks + 4 days
If intolerable gastrointestinal adverse events persist, the subject should be evaluated against 
discontinuation of trial product criteria (see section 6.4).
5.3.2
Liraglutide treatment
In order to reduce the level of gastrointestinal side effects, liraglutide is gradually escalated up to 
the maintenance dose. The dose will gradually be escalated to 3.0 mg starting with 0.6 mg/day and 
with a dose level increment of 0.6 mg every 7 days. If subjects do not tolerate an increase in dose 
during dose escalation, the investigator has the option to individualise the dose escalation with a 
total delay of up to 7 days. All subjects must reach the target dose of 3.0 mg liraglutide no later than 
5 weeks after randomisation (see Figure 5–1). If this is not possible, the subject should be evaluated 
against discontinuation of trial product criteria (see section 6.4). Once the target dose is reached the 
dose level should be maintained.
5.3.3
Missed dose
If a subject forgets to inject a dose, the dose can be administered as soon as the subject remembers. 
However, if it is more than 12 hours since the subject should have administered the dose, they 
should skip the missed dose. Then take the next dose as usual on the following day.
5.3.4
Nutritional and physical activity counselling
All subjects will receive nutritional and physical activity counselling starting at visit 2 
(randomisation) and monthly at the site visits.
The subjects will be counselled to a hypocaloric diet with an energy deficit of approximately 
500 kcal/day and an increase in physical activity (recommended minimum 150 minutes/week).
Please refer to section 8.6.3 and 8.6.4 for description of counselling and procedures.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products the investigator should discuss potential weight management 
options with the subject.
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5.5
Rationale for treatment
Subjects are enrolled for a treatment period of one year in order to be able to evaluate the full effect 
of treatment on the primary and secondary endpoints as well as to be able to make a reasonable 
safety assessment. This is further based on the knowledge from liraglutide 3.0 mg trials where the 
maximum effect on weight loss occurs around 40 weeks (36 weeks on target dose) and the 
regulatory authorities’ guidelines on trials in weight management stating that duration of at least 
1 year is deemed appropriate to evaluate efficacy and safety and tolerability19,20.
The comparators in the trial are placebo and liraglutide 3.0 mg. Placebo is used in order to evaluate 
the absolute safety and efficacy of once-daily semaglutide and to reduce the sample size. All 
subjects including those treated with comparator will receive nutritional and physical activity
counselling. Liraglutide is included to compare to an approved once daily weight management 
treatment.
The semaglutide doses of 0.05 mg/day to 0.4 mg/day have been chosen to carefully investigate the 
optimal semaglutide dose with a satisfactory balance of efficacy and safety for the majority of 
subjects.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 1,336
Number of subjects planned to be randomised: 935 (30% screen failure rate)
Number of subjects expected to complete the trial: 561 (40% trial product discontinuation rate)
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered "yes".
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, age ≥ 18 years at the time of signing informed consent
3. Body Mass Index (BMI) ≥ 30.0 kg/m2 at the screening visit
4. Stable body weight i.e. less than 5 kg self-reported change within 90 days before screening
5. At least one unsuccessful weight loss attempt per investigator judgement
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. A HbA1c ≥ 6.5% at screening or diagnosed with type 1 or type 2 diabetes mellitus
2. Hypothyroidism/hyperthyroidism defined as TSH > 6 mIU/L or < 0.4 mIU/L
3. Treatment with glucose lowering agent(s) within 90 days before screening
4. Screening calcitonin ≥ 50 ng/L (pg/mL)
5. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia 
syndrome type 2
6. History of pancreatitis (acute or chronic)
7. Obesity induced by an endocrinologic disorder (e.g. Cushing Syndrome)
8. Treatment with any medication within 90 days before screening that based on investigator’s 
opinion may cause significant weight change
9. Diet attempts using herbal supplements or over-the-counter medications within 90 days before 
screening
10. Participation in an organised weight reduction program (e.g. WeightWatchers®) within 90 days 
before screening
11. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion, naltrexone, 
GLP-1 RAs alone or in combination prescribed for weight loss or any other medication that 
could promote weight loss in the opinion of the investigator within 90 days before screening
12. Previous surgical treatment for obesity (liposuction and/or abdominoplasty is allowed if 
performed > 1 year before screening)
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13. History of major depressive disorder within 2 years before randomisation
14. History of other severe psychiatric disorders (e.g. schizophrenia, bipolar disorder)
15. A Patient Health Questionaire-9 (PHQ-9) score of ≥15 at screening or randomisation
16. Any lifetime history of a suicidal attempt
17. Any suicidal behaviour within 30 days before randomisation
18. Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) at 
screening or randomisation
19. Surgery scheduled for the trial duration period, except for minor surgical procedures, in the 
opinion of the investigator
20. Systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg at screening
21. History or presence of malignant neoplasms within the last 5 years before screening (except 
basal and squamous cell skin cancer, polyps and in-situ carcinomas)
22. Known or suspected abuse of alcohol or narcotics
23. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures
24. Known or suspected hypersensitivity to trial product(s) or related products
25. Previous participation in this trial. Participation is defined as signed informed consent
26. Subjects from the same household participating in the trial
27. Participation in another clinical trial within 90 days before screening
28. Any condition which, in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol
29. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice)
FOR BELGIUM AND GERMANY: Only highly effective methods of birth control are 
accepted (i.e. one that results in less than 1% per year failure rate when used consistently and 
correctly such as implants, injectables, combined oral contraceptives, some intrauterine device), 
or sexual abstinence or vasectomised partner.
FOR UNITED KINGDOM ONLY: Adequate contraceptive measures are defined as 
established use of oral, injected or implanted hormonal methods of contraception, placement of 
an intrauterine device or intrauterine system, barrier methods of contraception (condom or 
occlusive cap with spermicidal foam/gel/film/cream/suppository), female sterilisation, male 
sterilisation (where partner is sole partner of subject), or true abstinence (when in line with 
preferred and usual lifestyle).
6.4
Discontinuation of trial product criteria and withdrawal of informed consent
If any of the below trial product discontinuation or withdrawal criteria apply, the subject must be 
discontinued from trial product and the procedures in section 8.1.4 (and section 8.1.5, if relevant) 
should be performed.
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Trial product discontinuation criteria
The subject must discontinue from trial product if the following applies:
1. Due to a safety concern at the discretion of the investigator
2. Non-compliance with trial procedures at the discretion of the investigator
3. Included in the trial in violation of the inclusion and/or exclusion criteria
4. Pregnancy
5. Intention of becoming pregnant
6. Participation in another clinical trial throughout the trial
7. In case of code break (see section 11.1)
8. If the target treatment dose of the randomised trial product is not tolerated by the subject
9. Diagnosis of T2DM and treated with other medication(s) than metformin (see section 8.7.1)
10. Diagnosis of acute pancreatitis (as described in section 8.7.3)
11. Diagnosis of medullary thyroid carcinoma
12. Lifestyle changes that contradicts the protocol or advices from site
13. Surgical treatment for obesity
14. Treatment with orlistat, zonisamide, topiramate, lorcaserin, phenteremine, bupropion, 
naltrexone, GLP-1 RAs alone or in combination prescribed for weight loss or any medication 
that could provide weight change in the opinion of the investigator
15. Inadequate psychotherapy and/or pharmacotherapeutic treatment of a subject’s psychiatric 
disorder (see section 8.5.6.1)
16. The subject refuses mental health professional referral and, in investigator’s opinion, it is unsafe 
for the subject to continue (see section 8.5.6.1)
Withdrawal of informed consent
1. The subject may withdraw at will at any time. The subject’s request to discontinue must always 
be respected.
Please see section 8.1.5 for procedures to be performed in case of subject withdrawal.
Subjects who are withdrawn will not be replaced.
6.5
Rationale for trial population
The trial population will consist of obese subjects without diabetes mellitus. Obese subjects 
represent a clinically relevant population to treat for weight loss as they are likely to benefit from 
weight reduction. Subjects with diabetes mellitus have been excluded from the trial, as there may be 
a confounding effect of improvements in glycaemic control on weight loss and as subjects with 
T2DM may have different safety concerns. Control of potential hypo- and hyperglycaemia and 
background medication for treatment of T2DM would be more appropriately handled in a dedicated 
trial investigating subjects with T2DM.
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As first line treatment for obesity should always be lifestyle modification through healthier nutrition 
and increased physical activity22, only subjects who have tried but failed this type of weight loss 
intervention should be included.
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7
Milestones
Planned duration of recruitment period: 20 weeks
End of trial is defined as LPLV.
Recruitment
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects included in the screening period and 
eligible for randomisation can be randomised.
To ensure a sufficiently large sample of men, an upper limit will be implemented, allowing no more 
than 70% of the trial population to be women and the randomisation will be stratified according to 
sex. All investigators should aim to include at least 30% males. All investigators will be notified 
with instructions before the upper limit of women is reached.
Trial registration
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure23, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)24, the Food and Drug Administration Amendment Act (FDAAA)25, 
European Commission Requirements26,27 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 web sites, 
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
Methods and assessments
The following sections describe the assessments and procedures that must be performed during this 
trial. The overview of when they must be performed is included in the flow chart (section 2).
8.1
Visit procedures
8.1.1
Screening, re-screening and screening failures
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial.
Screening failures
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious adverse events from screening 
failures must be transcribed by the investigator into the eCRF. Follow-up of serious adverse events 
(SAEs) must be carried out according to section 12. A screening failure session must be made in the 
IWRS. The case book must be signed.
Re-screening
Re-screening is not allowed.
8.1.2
Fasting visits
At visits 2, 4, 10, 14, 17, and 20 the subjects must attend the visits fasting (see section 2).
Fasting is defined as at least eight hours without food or liquids, except for water. Trial product and 
any medication which should be taken with or after a meal should be withheld on the day of the 
visit until blood sampling and body weight measurements have been performed. If the subject is not 
fasting as required, the subject should be called in for a new visit within the visit window to have 
the fasting procedures done. Fasting procedures include body weight and blood sampling of FPG
and lipids. 
At visit 21, the subject must be fasting for two hours prior to the anti-semaglutide antibody 
sampling (see section 8.5.13).
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8.1.3
Missed visits
If an entire visit is missed and it is not possible to re-schedule the visit within the time window, 
every effort should be made to re-schedule the visit at the earliest possible date before the next visit.
8.1.4
Discontinuation of trial product
If a subject is discontinued from trial product, the investigator must aim to undertake procedures 
similar to those for visit 20 (end of treatment) as soon as possible and the follow-up visit (visit 21) 
should be performed 7 weeks later. All female subjects using an adequate contraceptive method 
should be reminded to continue this for 7 weeks after discontinuation of trial product.
Furthermore, subjects discontinued from trial product must be asked to attend an additional visit 
(visit 22x) taking place 52 weeks (± 5 days) after their randomisation date. The purpose of this visit 
is to record body weight, blood pressure and any AEs since discontinuation of trial product.
If the subject is not willing to attend one or more of the above mentioned visits, it should be 
documented in the subject’s medical record that the subject has refused to attend the visit and why.
For subjects discontinued from trial product, final drug accountability must be performed and a 
treatment discontinuation session must be made in the IWRS. The reason for discontinuation of trial 
product must be recorded in subject’s medical records and the eCRF.
8.1.5
Withdrawn subjects
If a subject is withdrawn from the trial, the investigator must aim to undertake procedures similar to 
those for visit 20 (end of treatment) as soon as possible and the follow-up visit (visit 21) should be 
performed 7 weeks later.
For withdrawn subjects, the end-of-trial form must be completed, and final drug accountability must 
be performed even if the subject is not able to come to the trial site. A treatment discontinuation 
session must be made in the IWRS. The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject’s rights. Where the reasons are obtained, the primary reason for not completing the trial 
must be specified on the end-of-trial form in the eCRF.
8.1.6
Subject training
Dosing diary (see section 8.6.2)
The subject must be provided with diaries at the specified visits (section 2). The investigator should 
instruct the subjects in filling in the diary according to the provided diary instructions (see section 
8.6.2). The diaries dispensed to subjects should be collected at the specified visits (section 2).
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Trial product
Trial product must be dispensed to subjects at the specified visits (2). Trial product will be 
dispensed to the subject by the site, hospital pharmacy or equivalent. At the randomisation visit, the 
subjects will be instructed in the handling of trial product and trained in the use of the pen-injector 
and in the administration of s.c. injection of trial product. The first dose of trial product must be 
injected by the subject at the site.
Nausea and hypoglycaemic episodes recognition
The investigator or delegate will train the subjects in symptom recognition and handling of 
hypoglycaemia and nausea.
Suspected pregnancy
Female subjects must be instructed to contact site if a menstrual period is missed between site visits 
so they can come in for urine pregnancy test.
8.1.7
Investigator’s assessment
It is the responsibility of the investigator or delegated staff to review laboratory reports,
electrocardiograms (ECGs), mental health questionnaires, diaries, patient reported outcome 
questionnaires (PROs), and blood pressure and pulse measurements during the trial.
Review of diaries must be documented either on the documents and/or in the subject’s medical 
record. If clarification of entries or discrepancies in the diary is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject.
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not. All laboratory report printouts must be signed and dated by the 
investigator or delegate. The evaluation of screening results must be dated and signed prior to 
visit 2 (randomisation), for the subsequent visits preferably on the day of evaluation.
Review of ECGs must be documented as described in section 8.5.2.
It is the responsibility of the investigator or delegated staff to review the mental health and PRO 
questionnaires and to report possible AEs immediately following completion. The review must be 
documented.
8.2
Subject related information 
8.2.1
Demography
The following information must be recorded in the subject’s medical record and eCRF:
!
Date of birth (according to local regulation)
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!
Sex
!
Race (according to local regulation)
!
Ethnicity (according to local regulation)
8.2.2
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. visit 1) or found as a 
result of a screening procedure. All concomitant illnesses should be recorded.
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE.
Medical history is a medical event that the subject has experienced in the past (i.e. prior to visit 1). 
Only relevant and significant medical history as judged by the investigator should be recorded. 
Findings of specific medical history described below should only be entered on the specific forms.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
8.2.2.1
History of concomitant cardiovascular disease
Information related to concomitant cardiovascular disease (i.e., myocardial infarction, disorders of 
rhythm or conduction, heart failure incl. New York Heart Association functional classification, 
ischemic heart disease incl. type, percutaneous coronary intervention and coronary artery bypass 
graft surgery, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, 
hypertension, ischemic stroke, transient ischemic attack, haemorrhagic stroke, intracranial artery 
stenosis, carotid artery stenosis, peripheral arterial disease including > 50% stenosis on angiography 
or other imaging) must be recorded.
8.2.2.2
History of gallbladder disease
Information related to gallbladder disease (i.e., pancreatitis, gallstone disease and cholecystitis)
must be recorded.
8.2.2.3
History of psychiatric disorders
Information related to psychiatric disorders (specifically history of depression, substance and 
alcohol abuse, suicidal behaviour, anxiety, mood disorders, insomnia, or sleep disorders) must be 
recorded.
8.2.2.4
History of breast neoplasms
Information related to history of breast neoplasms must be recorded for all female subjects.
Information regarding menopausal status, previous mammograms and outcome, first degree 
relatives with breast cancer and predisposing factors (alcohol intake above recommended local 
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guidelines, hormone replacement therapy, age of menarche, number of births, maternal age at first 
birth, and if the subject ever breastfed) should be recorded.
8.2.2.5
History of colon neoplasms
Information related to history of colon neoplasms, previous endoscopic examination(s) of the colon, 
history of inflammatory bowel disease, and first degree relatives with colon neoplasms must be 
recorded.
8.2.3
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to section 12.2. If the change 
influences the subject's eligibility to continue in the trial, the monitor must be informed.
8.2.3.1
Evaluation of antihypertensive and lipid-lowering treatment
Any antihypertensive and/or lipid-lowering medications must be recorded as concomitant 
medication described above. For any changes from baseline in antihypertensive and/or
lipid-lowering treatment, the investigator must evaluate if the change should be considered as an 
increase, a decrease or no change in treatment at the visits specified (section 2).
8.2.4
Tobacco use
Details of tobacco use must be recorded at the first visit. Tobacco use is defined as smoking at least 
one cigarette, cigar or pipe daily in average. The collected information should include whether or 
not the subject smokes or has smoked.
8.3
Laboratory assessments
The laboratory analyses will be performed by a central laboratory except for analysis of anti-
semaglutide antibodies and semaglutide plasma concentration analysis which will be performed at a 
specialised laboratory. The central laboratory may utilise subcontractors.
Descriptions of laboratory supplies, procedures for obtaining samples, handling, storage and 
shipments of samples, will be given in the trial-specific laboratory manual provided by the central 
laboratory.
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The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to this protocol.
Laboratory samples may be drawn on another day than the day of the actual visit, as long as it is 
within the visit window outlined in the flow chart (see section 2). For some of the samples drawn 
during the trial, it is required that the subject is fasting. If a subject is not fasting at these visits, the
fasting blood sampling (8.1.2) must, as a minimum, be re-scheduled within the visit window.
Laboratory results will be sent by the central laboratory to the investigator on an on-going basis 
except for the anti-semaglutide antibody results and the results of the plasma concentration analysis.
Anti-semaglutide antibody results and the results of the plasma concentration analysis will not be 
provided to the investigator, as these results will not be used for any clinical evaluation during the 
trial and would potentially unblind the treatment.
Samples, including samples for genetic testing and specific safety assessments, will be destroyed on 
an on-going basis or at the latest at the completion of the clinical trial report (CTR). 
Antibody samples may be retained until drug approval by U.S. Food and Drug Administration 
(FDA) and/or European Medicines Agency (EMA). The retained antibody samples may be used for 
further characterisation for antibody responses towards drug if required by health authorities or for 
safety reasons, see section 24.2.
8.4
Assessments for efficacy
8.4.1
Body Measurements
8.4.1.1
Body weight
The body weight should be measured at all visits with an empty bladder, without shoes and only 
wearing light clothing. It should be recorded with one decimal (kg or lb) and preferably using the 
same digital scale throughout the trial. The scale must be calibrated according to the directions for 
use and as a minimum once a year.
Body weight must be measured in fasting state at the fasting visits, and in non-fasting state, at the 
non-fasting visits, see flowchart (section 2). If the subject is not fasting as required, the subject 
should be called in for a new visit within the visit window to have the fasting body weight 
measured.
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8.4.1.2
Height
Height is measured at screening without shoes in centimetres or inches (one decimal).
8.4.1.3
Body mass index
Body mass index will be calculated by the eCRF from visit 1 data and must be in accordance with 
inclusion criterion 3.
8.4.1.4
Waist and hip circumference
The waist circumference will be measured at the specified visits (section 2) and is defined as the 
abdominal circumference located midway between the lower rib margin and the iliac crest.
The hip circumference is defined as the widest circumference around the buttocks.
Three consecutive waist and hip measurements must be performed and are measured in the 
horizontal plane and rounded to the nearest 0.5 cm or 0.2 inches using a non-stretchable measuring 
tape. The same measuring tape should be used throughout the trial.
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing. The subject should be standing, feet together with arms at the side and waist and hip
accessible. The tape should touch the skin but not compress soft tissue and twists in the tape should 
be avoided. The subject should be asked to breathe normally and the measurement should be 
performed in the following order: hip, waist, hip, waist, hip and waist.
8.4.2
Systolic and diastolic blood pressure
For blood pressure at visit 1, three measurements must be performed. The mean value is calculated 
by the eCRF and must be used to evaluate eligibility of the subject in relation to exclusion criterion 
20. For subsequent visits, one measurement of blood pressure must be performed.
The method for measuring systolic and diastolic blood pressure needs to follow the standard clinical 
practice at site, but as a minimum, the following guideline must be adhered to:
!
Avoid caffeine, smoking and exercise at least 30 minutes prior to measuring the blood pressure
!
Blood pressure should be measured in a sitting position, with the legs uncrossed, the back and
arms supported
!
The subject should be sitting for five minutes before the first measurement is taken
!
The same arm and an appropriate cuff size should be used for blood pressure measurements at 
all visits
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8.4.3
Blood samples
Biochemistry
!
HbA1c
!
FPG
!
hsCRP (cardiovascular biomarker)
!
Lipids (total cholesterol [TC], low density lipoprotein cholesterol [LDL cholesterol], high 
density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein cholesterol 
[VLDL cholesterol], triglycerides [TG], free fatty acids [FFA])
8.4.4
Patient reported outcome questionnaires
Patient reported outcome (PRO) questionnaires will only be used for subjects enrolled in the U.S.
speaking English at a sufficient level of fluency, as judged be the investigator (this information will 
be recorded in the eCRF). The trial aims at including approximately 200 subjects filling in the 
questionnaire in English. The PRO questionnaires will be collected at the specified visits 
(section 2).
A modified version of the IWQoL-Lite, the Short Form 36 (SF-36) and a few question regarding 
Patients’ global impression of change assessing subjects’ perceptions of change in their health-
related quality of life (HRQoL) during the trial will be used to investigate the impact of weight loss 
on HRQoL and patient functioning.
All three questionnaires will be available on a tablet computer in a linguistically validated version. 
The questionnaires must be completed by the subject and should preferably be completed after 
conclusion of all fasting-related activities, but before any other visit-related activities. Subjects 
should be given the opportunity to complete the questionnaires by themselves without interruption.
IWQoL-Lite for Clinical Trials
The modified IWQoL-Lite (named IWQoL-Lite for Clinical Trials) is a 23-item instrument 
designed to assess weight-related quality of life. Based on FDA guidance28, there is a need to re-
evaluate and modify this instrument for use as a clinical outcome assessment to support a secondary 
endpoint in clinical trials of obese adults. Please see Appendix B for a clarification of the questions.
To make the re-evaluation of the IWQoL-Lite instrument, SF-36 and patients’ global impression of 
change is used for validation.
SF-36
SF-36 measures the individual’s overall HRQoL on 8 domains: physical functioning, role 
functioning, bodily pain, general health, vitality, social functioning, role emotional and mental 
health29.
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Patients’ global impression of change
A few questions assessing patients’ impression of change during the clinical trial in both their 
overall HRQoL and the specific dimensions of HRQoL addressed in the modified IWQoL-Lite 
must be collected. See Appendix C for clarification of questions.
8.5
Assessments for safety
8.5.1
Physical Examination
Physical examination will be performed at the specified visits (section 2) according to local 
procedure. Physical examination should include general appearance, thyroid gland, respiratory 
system, cardiovascular system, gastrointestinal system including mouth, musculoskeletal system, 
central and peripheral nervous system, skin, lymph node palpation, and head, ears, eyes, nose,
throat and neck, and must be recorded in the subject’s medical record and eCRF. Any abnormal, 
clinically significant findings at screening visit 1 must be recorded as a concomitant illness (see 
section 8.2.2).
8.5.2
ECG
A 12-lead ECG will be performed at the visits specified in the flow chart (2). The investigator or 
delegate must sign, date and interpret the ECG by using the following categories:
!
Normal
!
Abnormal
–
Was the result clinically significant? (Yes/No)
All ECGs will in addition undergo central assessment. Sites will be informed of the central ECG 
evaluation in case this evaluation reveals an abnormal ECG reading. If the abnormality, in the 
opinion of the investigator, represents an unreported AE, such finding must be reported by the 
investigator (see section 12.2).
Additional unscheduled ECG recordings can be performed at the investigator’s discretion at other 
visits than the planned ECG visits. If unscheduled ECGs are recorded and submitted for central 
assessment the reason should be documented and an AE reported (if applicable).
8.5.3
Pulse
Pulse (beat/min) will be recorded in a sitting position after resting for five minutes at the specified
visits (section 2).
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8.5.4
Breast neoplasms follow-up
For all female subjects, information whether any new mammograms have been performed since 
screening must be recorded at the visit as specified in the flow chart (section 2). If yes, reason and 
diagnosis should be recorded to the extent possible.
8.5.5
Colon neoplasms follow-up
Information whether any new endoscopic examination(s) of the colon have been performed since 
screening must be recorded at the visit specified in the flow chart (2). If yes, reason and diagnosis 
should be recorded to the extent possible.
8.5.6
Mental health questionnaires
The mental health of subjects will be assessed by using the C-SSRS30 and PHQ-931 questionnaires 
to meet the regulatory requirements32. The questionnaires will be available on a tablet computer in a 
linguistically validated version and will be filled in at the specified visits (section 2).
The C-SSRS is a detailed questionnaire assessing both suicidal behaviour and suicidal ideation. The 
questionnaire will be administered as an interview by the investigator or a qualified delegate. Prior 
to administering the C-SSRS questionnaire, the investigator or qualified delegate must complete
sufficient training.
Two versions of the scale will be used: a ‘baseline’ version (lifetime assessment, used at screening) 
and a ‘since last visit’ version (used at all subsequent visits).
The PHQ-9 is the 9-item depression module of the patient health questionnaire, which is a self-
administered diagnostic tool used for assessment of mental disorders31. The questionnaire takes 
approximately 10 minutes to complete.
8.5.6.1
Referral to a mental health professional
If a subject has a PHQ-9 score of 10-14 both inclusive the subject should be referred to a mental 
health professional (MHP) if judged relevant by the investigator. If referral is not deemed relevant 
this along with the reason why must be documented in the subject’s medical records.
A subject must be referred to a MHP if:
!
the subject has a PHQ-9 score ≥15 or
!
the subject has any suicidal behaviour or
!
the subject has any suicidal ideation of type 4 or type 5 on any C-SSRS assessment
!
in the opinion of the investigator, it is necessary for the safety of the subject
If one or more of the referral criteria are met, the investigator should explain to the subject why the 
referral and psychiatric evaluation by a MHP is needed. If the subject refuses to be referred to a 
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MHP, the subject’s decision should be documented in subject’s medical record and the investigator 
must assess if it is safe for the subject to continue in the trial or if the subject should be discontinued 
from trial product.
If a subject’s psychiatric disorder can be adequately treated with psychotherapy and/or 
pharmacotherapeutic treatment, then the subject, at the discretion of the investigator (and in 
agreement with the MHP), may continue in the trial. Otherwise, the subject must be discontinued 
from trial product.
8.5.7
Adverse Events
AEs must be recorded at all visits in accordance with the procedures in sections 12.1 and 12.2.
8.5.8
Nausea questionnaire 
All events of nausea must be documented as AEs according to section 12.2. If a subject experiences 
nausea within 24 hours prior to a site visit, the nausea questionnaire in Appendix D must be 
completed. One questionnaire for each event must be reported. The first part of the questionnaire 
will be administered as an interview by the investigator or a qualified delegate, and the second part 
will be completed by the subject.
8.5.9
Hypoglycaemic episodes
All subjects will at randomisation be instructed in symptom recognition and handling of 
hypoglycaemia.
Hypoglycaemic episodes may be identified by:
!
Subject reporting of symptoms of hypoglycaemia or
!
FPG values ≤ 3.9 mmol/L (70 mg/dL) from blood sampling at site visits
Since the laboratory results from blood sampling are not reported on the day of the site visit the 
investigator should follow up with the subject as soon as possible within a week from when the lab 
report is available and collect the following information:
!
Date and time of hypoglycaemic episode
!
The plasma glucose level before treating the episode (if available)
!
Whether the episode was symptomatic
!
Whether the subject was able to treat him/herself
!
Date and time of last trial product administration prior to episode
!
Type and dose of last trial product prior to episode
!
Date and time of last main meal prior to episode (breakfast, lunch or dinner)
!
Whether the episode occurred in relation to physical activity
!
Any sign of fever or other disease
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!
Whether the subject was asleep when the episode occurred
–
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration33.
Oral carbohydrates should not be given if the subject is unconscious.
If the question "Was subject able to treat him/herself?" is answered "No", the following information 
should be recorded:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. family/friend/co-worker or
similar, paramedic, doctor or other, please specify)
!
Where the treatment was administered (i.e. at home/at friends/at work or similar, in an
ambulance, emergency room/hospital or other, please specify)
!
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or
other, please specify)
!
Were symptoms alleviated by the administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet changed, medication
error (i.e. overdose, mix-up between products), other factors not listed, please specify or none)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms?34
–
Autonomic: sweating, trembling, hunger or palpitations
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd
behaviour, impaired balance or incoordination
–
General malaise: headache or malaise
!
Did the subject experience other symptoms? Please specify
!
Description of the episode, if applicable
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety information 
form must also be filled in, see section 12.2.
8.5.10
Adverse events requiring special forms in the eCRF
For some AEs the investigator must fill in a special form in the eCRF in addition to the AE 
reporting described in section 12. The AEs that require special forms in the eCRF are listed in Table 
12–1and in appendix E.
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The below sections will describe which information should be collected for the different events.
Acute coronary syndrome
If an event of acute coronary syndrome is observed during the trial, this must be recorded as an AE 
and on a specific acute coronary syndrome form in the eCRF. The following information must be 
reported if available:
!
Duration of symptoms
!
Changes in ECG
!
Collection of cardiac biomarkers
!
Cardiac imaging
!
Cardiac stress testing
!
Angiography
!
Use of thrombolytic drugs
Coronary revascularisation procedures
If an event of coronary revascularisation is observed during the trial, this must be recorded as an AE 
and on a specific coronary revascularisation form in the eCRF. The following information should be 
obtained:
!
Type of revascularisation performed
!
Indication for the procedure
Cerebrovascular events (stroke or transient ischemic attack)
If a cerebrovascular event is observed during the trial, this must be recorded as an AE and on a 
specific cerebrovascular event form in the eCRF. The following information must be reported if 
available:
!
Type of event (e.g. TIA, stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the condition
!
Treatment given for the condition
Heart failure requiring hospitalisation
If an event of heart failure requiring hospitalisation is observed during the trial, this must be 
recorded as an AE and in addition on a specific heart failure event form in the eCRF. The following 
information must be reported if available:
!
Signs and symptoms of heart failure
!
NYHA Class
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!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
Pancreatitis
If an event of pancreatitis is observed during the trial, this must be recorded as an AE and on a 
specific pancreatitis event form in the eCRF. The following information must be reported if 
available:
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis:
–
Amylase
–
Lipase
–
Alanine aminotransaminase (ALT) and aspartate aminotransferase (AST)
–
Bilirubin
–
Alkaline phosphatase (ALP)
!
Imaging performed and consistency with pancreatic disease
!
Treatment for and complications of the event
!
Relevant risk factors for pancreatic disease including:
–
History of gallstones
–
History of pancreatitis
–
Family history of pancreatitis
–
Trauma
Acute gallbladder disease
If an event of acute gallstone disease or clinical suspicion of this is observed during the trial, this 
must be recorded as an AE and on a specific acute gallstone disease event form in the eCRF. The 
following information should be reported if available:
!
Signs and symptoms of acute gallstone disease
!
Specific laboratory test supporting a diagnosis of gallstone:
–
White blood cell count (WBC)
–
C-reactive protein (CRP)
–
Direct, indirect and total bilirubin
–
ALT and AST
–
Alkaline phosphatase (ALP)
–
Amylase
–
Lipase
!
Imaging performed and consistency with gallstone disease
!
Treatment given for the condition
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!
Relevant risk factors for acute gallstone disease including
–
History of gallstones
–
Family history of gallstones
–
Relevant surgery
Neoplasm (excluding thyroid neoplasms)
All events of neoplasms (excluding thyroid neoplasm) must be recorded as an AE and on a specific 
neoplasm event form in the eCRF. The following information should be obtained if available as part 
of standard of care:
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
!
Risk factors associated to the event
Thyroid disease (including thyroid neoplasms)
If an event of thyroid disease, including any thyroid neoplasms observed during the trial, this must 
be recorded as an AE and on a specific thyroid disease event form in the eCRF. The following 
information must be reported if available:
!
History of thyroid disease
!
Signs and symptoms leading to investigations of thyroid disease
!
Specific laboratory tests describing thyroid function including:
–
TSH
–
Total and free T3 and T4 and Free Thyroid Index
–
Calcitonin
–
Thyroid peroxidase antibodies
–
Thyroglobulin and thyroglobulin antibody
–
Thyroid Stimulating Hormone receptor antibody
!
Diagnostic imaging performed and any prior imaging supporting the disease history 
!
Pathologic examinations
!
Treatment given for the condition
!
Risk factors identified
!
Family history of thyroid disease
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8.5.11
Blood samples
Blood samples for haematology and biochemistry must be collected at the specified visits 
(section 2).
Haematology
!
Haemoglobin
!
Haematocrit
!
Thrombocytes
!
Erythrocytes
!
Leucocytes
!
Differential count
–
Eosinophils
–
Neutrophils
–
Basophils
–
Monocytes
–
Lymphocytes
Biochemistry
!
Creatinine
!
Creatine phospokinase
!
Urea
!
Albumin
!
Bilirubin, total
!
Alanine aminotransaminase (ALT)
!
Aspartate aminotransferase (AST)
!
Alkaline phosphatase
!
Amylase
!
Lipase
!
Sodium
!
Potassium
!
Calcium, total
!
Calcitonin (please refer to Appendix Afor actions to be taken if calcitonin is ≥ 10 ng/L)
!
Tryptase, if hypersensitivity is suspected
!
Thyroid-stimulating hormone (TSH)
8.5.12
Pregnancy test
Females of childbearing potential will have a human chorionic gonadotropin (hCG) serum 
pregnancy test performed at the specified visits in the flow chart (see section 2). 
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Urine pregnancy tests will be performed for females of childbearing potential at the visits specified 
in the flowchart (section 2). This will result in a monthly pregnancy testing. If a female subject 
misses a menstrual period, she should contact site to come in for a urine pregnancy test. Urine 
pregnancy kits will be supplied by the central laboratory. The test will be performed at the site.
Pregnancy testing will not be required for women who have undergone a hysterectomy or bilateral 
tubal ligation, or for women above the age of 50, who have been without menstrual periods for at 
least one year.
8.5.13
Anti-semaglutide antibodies
Blood samples will be drawn during the trial and analysed at a specialised laboratory for 
determination of serum antibodies against semaglutide, including cross reactivity to endogenous 
GLP-1 (see flow chart, section 2). Subjects must be instructed to withhold their trial product dose in 
the morning until blood sampling has been performed at the visit. Samples taken at the follow-up 
visit (visit 21) must be taken fasting (as a minimum by only having consumed water for at least 2 
hours). Samples taken at the follow-up visit which are positive for anti-semaglutide antibodies will 
be further characterised for in vitro neutralising effect towards semaglutide. In addition, samples 
taken at the follow-up visit which are positive for cross-reactivity against endogenous GLP-1 will 
be analysed for in vitro neutralising effect towards endogenous GLP-1.
8.6
Other assessments
8.6.1
Semaglutide plasma concentration
For subjects receiving semaglutide or semaglutide placebo, a single blood sample for measurement 
of plasma semaglutide concentration will be drawn at selected visits (see section 2).
Subjects must be instructed to withhold their trial product dose in the morning until blood sampling 
is performed on the visit.
8.6.2
Dosing diary
All subjects must complete a dosing diary prior to each visit after randomisation until the 
end-of-treatment visit (section 2). The subject must record the date, time, dose and injection site of 
the injection on the day prior to the visit. Furthermore, the subject must fill in if any doses were not 
taken in the previous week. The dosing diaries will be collected at all visits until the end-of-
treatment visit. The information will be transcribed to the eCRF by the investigator or delegate 
together with the exact date and time for blood sampling of plasma concentration, when applicable.
8.6.3
Nutritional counselling
From visit 2 and at all monthly visits (see section 2) subjects will receive nutritional counselling
performed by a dietician or equivalent qualified delegate according to local standard. The 
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nutritional counselling will focus on healthier food choices and subjects will be put on a 
hypocaloric diet with an energy deficit of approximately 500 kcal/day compared to the subject’s 
estimated total energy expenditure (TEE).
Calculation of estimated TEE
The TEE is calculated by multiplying the estimated Basal Metabolic Rate (BMR) (see Table 8–1) 
with a Physical Activity Level (PAL) value of 1.335:
Table 8–1
Equation for estimating BMR
Sex
Age
BMR (kcal/day)
Men
18-30 years
15.057 x actual weight in kg + 692.2
31-60 years
11.472 x actual weight in kg + 873.1
> 60 years
11.711 x actual weight in kg + 587.7
Women
18-30 years
14.818 x actual weight in kg + 486.6
31-60 years
  8.126 x actual weight in kg + 845.6
> 60 years
  9.082 x actual weight in kg + 658.5
Maintenance diet
If a BMI ≤ 22 kg/m2 is reached the recommended energy intake should be recalculated with no kcal 
deficit (maintenance diet) for the remainder of the trial.
Nutritional compliance
Healthy nutrition compliance must be evaluated from visit 4 and at monthly visits (see section 2) by 
the dietician or equivalent qualified delegate (as per local standard), using a numeric rating scale 
(NRS) with a value from 0 to 10, and results must be provided to the investigator. The investigator 
or delegate must record the NRS score into the eCRF.
8.6.4
Physical activity counselling
From visit 2 and at all monthly visits, subjects will receive counselling in physical activity by a 
qualified person. An increase in physical activity (recommended minimum 150 minutes/week) will 
be encouraged.
8.7
Specific safety assessments
8.7.1
Subjects developing type 2 diabetes mellitus
Subjects who develop T2DM during the trial should receive the best standard of care at the 
discretion of the investigator. If the investigator determines that medication(s) other than metformin
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is the best treatment option, the subject must be discontinued from trial product. The medication 
prescribed by the investigator will not be provided nor reimbursed by Novo Nordisk.
8.7.2
Thyroidectomy
Subjects scheduled for thyroidectomy will be asked to inform the investigator prior to the operation.
Thyroidectomy pathology slides
In case a subject undergoes a thyroidectomy (partial or total) for any reason during the trial or after 
the trial secondary to an event reported during the trial, pathology slides of the thyroid tissue will be 
centrally reviewed in addition to the routine examination at the site level. A set of pathology slides,
routinely made after thyroidectomies by the pathology laboratory of the hospital where the 
operation was performed, must be sent for a second reading with evaluation by a pathologist with 
expertise in thyroid and C-cell pathology, who will be blinded to both trial treatment and site 
diagnosis. Once the samples are re-examined they will be sent back to the site laboratory. Both the 
site pathology report and the central pathology report will be reviewed by an external independent 
event adjudication committee (EAC), see section 12.7.2. However, reports for thyroidectomies 
performed after the trial secondary to an event reported during the trial will not be reviewed by the 
EAC nor will the reports be part of the clinical trial database.
Thyroid tissue sample collection in case of thyroidectomy
Subjects to undergo thyroidectomy will in addition be asked to consent to have a small sample of 
the removed thyroid tissue collected for testing of RET Y1062 phosphorylation in the thyroid 
C-cells. This is only applicable if C-cell pathology is confirmed (i.e., hyperplastic or neoplastic 
thyroid C-cells) confirmed by the EAC, and only if allowed by local law. The tissue sample will be 
destroyed after examination.
FOR ISRAEL ONLY: The RET Y1062 phosphorylation and genetic testing will not be performed 
for subjects in Israel.
Genetic testing in case of a confirmed C-cell pathology
Subjects scheduled for thyroidectomy will be asked to consent to be tested (blood sample) to 
identify germline RET gene mutations associated with multiple endocrine neoplasia syndrome type 
2 (MEN2). This RET gene mutation detection will be conducted in subjects with C-cell pathology 
(i.e., hyperplastic or neoplastic thyroid C-cells) confirmed by the EAC. Genetic testing will only be 
performed if allowed by local law and if the subject chooses to consent to it.
8.7.3
Suspicion of acute pancreatitis
In case of acute, severe persistent abdominal pain or other relevant symptoms leading to a suspicion 
of acute pancreatitis, the trial product should promptly be interrupted until pancreatitis is ruled out. 
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Appropriate additional examinations must be performed, including local measurement of amylase 
and lipase activity levels. If acute pancreatitis is ruled out, trial product should be re-initiated at the 
dose level the subject was at when trial product was interrupted. If acute pancreatitis is confirmed 
the subject must be discontinued from trial product (6.4). Appropriate treatment and careful 
monitoring of the subject should be initiated if pancreatitis is confirmed (as a minimum 2 of the 3):
!
severe acute abdominal pain
!
amylase and/or lipase activity levels >3x upper normal range (UNR)
!
characteristic findings on relevant imaging e.g. computerised axial tomography (CT)/magnetic 
resonance imaging (MRI)/ultrasound
8.7.4
Suspicion of severe hypersensitivity
If a severe immediate hypersensitivity reaction to the trial products is suspected, blood sampling for 
assessment of anti-semaglutide/anti-liraglutide IgE antibodies and anti-semaglutide/anti-liraglutide
binding antibodies should be collected after a suitable washout period (minimum 7 weeks for 
semaglutide and 2 weeks for liraglutide). In these cases, it is also recommended to test for tryptase 
(total and/or mature tryptase) within 3 hours of the hypersensitivity reaction. In case a tryptase 
sample was collected within 3 hours of the event of hypersensitivity reaction, a baseline tryptase 
sample should be taken at the same time as the IgE sample is obtained (after washout). Tryptase 
concentrations (if measured) as well as results of anti-semaglutide/anti-liraglutide antibody and 
IgE-isotype anti-semaglutide/anti-liraglutide antibodies will be collected by Novo Nordisk and 
included in the subject narratives.
8.7.5
Suspicion of immune complex disease
If immune complex disease is suspected, a blood sample for central assessment of complement 
levels (C3 and C4) should be drawn.
8.8
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
investigator will remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed. If the subject continues to be non-compliant the investigator 
may discontinue the subject from trial product (see section 6.4).
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM).
Trial products must not be dispensed to any person not included in the trial. Trial product must not 
be used, if it does not appear clear and almost colourless.
9.1
Trial products
The following trial products for subcutaneous injection will be manufactured and supplied by Novo 
Nordisk A/S, Denmark:
!
Semaglutide 1.0 mg/ml, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Semaglutide placebo, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Liraglutide 6.0 mg/ml, solution for injection, 3.0 ml pre-filled PDS290 pen-injector
!
Liraglutide placebo, solution for injection, 3.0 ml pre-filled PDS290 pen-injector
The placebo and active drug are visually identical for both trial products.
All trial products are considered investigational medicinal products (IMPs).
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS.
The investigator must document that direction for use (DFU) is given to the subject orally and in 
writing at the first dispensing visit (visit 2). At the later dispensing visits the investigator or delegate 
should ensure that subjects comply with injection procedures and re-dispense DFU, if needed.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1336, local regulations and trial 
requirements.
9.3
Storage
The investigator must ensure trial product is kept in proper storage conditions, and also record and 
evaluate the storage temperature. The investigator must inform Novo Nordisk immediately if any 
trial product has been stored outside specified conditions (e.g. outside temperature range).
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. The investigator must take 
appropriate action to ensure correct storage.
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Table 9–1
Storage of trial product
Trial product
Storage conditions
(not in-use)
In-use conditions
In-use time1
Semaglutide 1.0 mg/ml
Store in a refrigerator 
(2°C-8°C/36°F-46°F)
Do not freeze
Protect from light
Store below 30°C (86°F)
Do not refrigerate
Do not freeze
Protect from light
Use within 
30 days
Semaglutide placebo
Liraglutide 6.0 mg/ml
Store in a refrigerator 
(2°C-8°C/36°F-46°F)
Do not freeze
Protect from light
Store below 30°C
Do not freeze
Protect from light
US:
Store at room temperature 
(59°F-86°F) or in 
refrigerator (36°F-46°F)
Use within 
1 month
US:
Use within 
30 days
Liraglutide placebo
1 In-use time starts when the pen is taken out of the subject’s refrigerator.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator.
The trial products will be dispensed to each subject as required according to treatment group. The 
IWRS will allocate trial product to the subject at randomisation and each dispensing visit. The 
correct dispensing unit number(s) (DUN(s)) must be dispensed to the subject.
The investigator or delegated person is responsible for ensuring that:
!
Drug accountability is performed using the IWRS drug accountability module
!
Subjects are instructed to return all used, partly used and unused trial product including empty 
packaging material at each dispensing visit and at end-of-treatment visit
Returned trial product (used/partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
9.5
Auxiliary supplies
The following auxiliary supplies will be provided by Novo Nordisk in accordance with the TMM:
!
Needles for pre-filled and NovoPen® 4 pen systems (maximum length to be used is 8 mm)
!
Direction for use for devices
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10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons.
In this trial, the IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site.
Subject logs
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list 
and may be generated from the IWRS.
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11 Randomisation procedure and breaking of blinded codes
A randomisation session will be carried out for all eligible subjects by using the IWRS.
At the randomisation visit (visit 2), eligible subjects will be randomised in a balanced manner 
(6:1 active:placebo) to receive daily dose of: 
!
semaglutide 0.05, 0.1, 0.2, 0.3, or 0.4 mg (dose escalation every fourth week)
!
semaglutide 0.3 or 0.4 mg (dose escalation every second week)
!
liraglutide 3.0 mg (dose escalation every week) or
!
placebo (matching each of the active treatment arms)
Randomisation will be stratified based on the sex of the subject and will be controlled by the IWRS.
An upper limit will be implemented, allowing no more than 70% of the trial population to be 
women. All investigators will be notified with instructions before the upper limit of women is 
reached.
11.1
Breaking of blinded codes
The IWRS will notify Novo Nordisk (monitor and the Global Safety department) immediately after 
the code is broken.
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IWRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department.If IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed inAttachment I.
If the code has been broken the subject must be discontinued from trial product and a treatment 
discontinuation session must be completed in IWRS.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
Adverse event
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to
the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness).
!
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.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see section 8.5.9.
The following three definitions are used when assessing an AE:
!
Severity
–
Mild - no or transient symptoms, no interference with the subject's daily activities.
–
Moderate - marked symptoms, moderate interference with the subject's daily activities.
–
Severe - considerable interference with the subject's daily activities; unacceptable.
!
Causality
Relationship between an AE and the relevant trial product(s):
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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!
Final outcome
–
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.
–
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.
–
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.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
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 fatal outcome must be reported as an 
SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd. 
Suspicion of transmission of infectious agents via the trial product must always be considered 
an SAE. 
a.
The term "life threatening" in the definition of SAE 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 was more 
severe.
b. The term "hospitalisation" is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be regarded as a 
hospitalisation. Hospitalisations for administrative, trial related and social purposes do not constitute AEs and 
should therefore not be reported as AEs or SAEs. Hospital admissions for surgical procedures, planned before trial 
inclusion, are not considered AEs or SAEs.
c.
A substantial disruption of a subject's ability to conduct normal life functions (e.g. following the event or clinical
investigation the subject has significant, persistent or permanent change, impairment, damage or disruption in
his/her body function or structure, physical activity and/or quality of life).
d.
For example intensive treatment in an emergency room or at home of allergic bronchospasm, blood dyscrasiasis or
convulsions that do not result in hospitalisation or development of drug dependency or drug abuse.
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Medical event of special interest
Medication error concerning trial product is considered a medical event of special interest (MESI). 
It is an event which, in the evaluation of safety, has a special focus. This MESI is an AE (SAE or 
non-serious AE) which fulfils one or more of the below defined criteria:
!
Administration of wrong drug or use of wrong device
Note: Use of wrong DUN is not considered a medication error.
!
Wrong route of administration, such as intramuscular instead of subcutaneous
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt)
!
Accidental administration of a lower or higher dose than intended, however 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
Adverse events with additional data collection
Adverse events with additional data collection are AEs defined as critical for the evaluation of 
product safety. Some of these events will furthermore be adjudicated by an external independent 
committee as described in section 12.7.2.
The AEs that require additional data collection can be seen in Table 12–1,including whether they 
will be sent for adjudicationand whether the use of a specific eventform in the eCRFis required. 
For further information regarding definitions andwhich data to collectfor the events that require 
additional data collection, please see section 8.5.10and Appendix E.
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Table 12–1
Adverse events with additional data collection
Event
Event adjudication
Specific event form
Fatal events
Yes
No
Acute coronary syndrome (myocardial infarction or hospitalisation 
for unstable angina)
Yes
Yes
Coronary revascularisation procedure
Yes
Yes
Cerebrovascular event (stroke or transient ischemic attack) 
Yes
Yes
Heart failure requiring hospitalisation
Yes
Yes
Pancreatitis
Yes
Yes
Acute gallbladder disease
No
Yes
Neoplasm (excluding thyroid neoplasms)
Yes
Yes
Thyroid disease (including thyroid neoplasms)
Yes, (only events that 
require thyroidectomy)
Yes
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in labelling text)
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (visit 21). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1.
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
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All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents:
!
Semaglutide T2DM (project NN9535): Investigator’s Brochure37, 10th edition, 2015 or any 
updates hereof
!
Liraglutide weight management (project NN8022): Investigator’s Brochure38, 7th edition, 2015
or any updates hereof
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs.
MESIs, regardless of seriousness, must be reported using both the AE form and the safety 
information form and a medication error form. The medication error form is a form tailored to 
collect specific information related to the individual MESI.
For AEs requiring additional data collection, a specific event form must be completed in addition to 
the AE form.
The AE form for a non-serious AE not fulfilling the MESI criteria should be signed when the event 
is resolved or at the end of the trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar days 
of the investigator's first knowledge of the SAE. Both forms must be signed within 7 calendar 
days from the date the information was entered in the eCRF. For SAEs with additional data 
collection: in addition also the specific event form within 14 calendar days from the 
investigator’s first knowledge of the AE.
!
SAEs fulfilling the MESI criteria: In addition to above, the medication error form within 14 
calendar days of the investigator's first knowledge of the AE.
!
Non-serious AE fulfilling the MESI criteria: The AE form, and safety information form and 
medication error form within 14 calendar days of the investigator’s first knowledge of the 
event.
!
Non-serious AE with additional data collection: The AE form and the additional data collection 
form within 14 calendar days of the investigator’s first knowledge of the event
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!
Events for Adjudication: The Event Adjudication Document Collection Form must be initially
completed within 14 calendar days of the investigator’s first knowledge of the AE.
Medical documentation of the event for adjudication should be provided within 4 weeks of
event identification.
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.
An AE is 
observed and 
reported 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
!
AE form
Fulfilling 
seriousness 
criteria?
Complete ≤ 14 calendar 
days:
!
Medication error form
Complete ≤ 14 calendar 
days: 
!
Medication error form
!
SIF 
Yes
Yes
No
AE: Adverse event
SIF: Safety information form
MESI: Medical event of special interest
Specific event forms are described in section 8.5.10 and Appendix E
*: If the answer to this question is no, no additional forms have to be 
completed 
All timelines are from the investigator’s first knowledge of the event
Requiring 
additional data 
collection?*
Is the MESI criteria 
fulfilled?*
Complete ≤ 14 calendar 
days:
!
Specific event form
Yes
Is the MESI criteria 
fulfilled?*
Requiring 
additional data 
collection?*
Complete ≤ 14 calendar 
days:
!
Specific event form
Yes
Yes
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspectedunexpected 
serious adverse reactions (SUSARs) in accordance with local requirements and GCP.1In 
addition, the investigator will be informed of any trial-related SAEs that may warrant a change 
in any trial procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the IRBs/
IECs of trial product-related SUSARs in accordance with local requirement and GCP1, unless 
locally this is an obligation of the investigator.
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Novo Nordisk products used as concomitant medication:
If a SAE and/or MESI 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, e.g. in the alternative aetiology section on the safety information form. 
Novo Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF.
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs.
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
!
Non-serious AE fulfilling the MESI criteria or non-serious AEs with additional data 
collection: Non-serious AE fulfilling the MESI criteria or non-serious AEs with additional data 
collection must be followed as specified for non-serious AEs. Follow-up information on MESIs
or non-serious AEs with additional data collection should only include new (e.g. corrections or 
additional) information and must be reported within 14 calendar days of the investigator’s first 
knowledge of the information. This is also the case for previously reported non-serious AEs 
which subsequently fulfil the MESI criteria or the criteria for additional data collection.
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow-up with re-
assessment of severity and/or seriousness of the event.
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Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products:
!
Semaglutide 1.0 mg/ml or placebo, 3.0 ml cartridge
!
Liraglutide 6.0 mg/ml or placebo, 3.0 ml PDS290 pen-injector
!
NovoPen® 4
!
Needles for pre-filled pen systems
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, SAEs, and/or 
MESIs.
Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each code or lot number or for each DUN must be completed.
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form must be 
sent with the sample.
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The investigator must ensure that the technical complaint sample contains the code or lot number 
and, if available, the DUN.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see section 9.3).
12.5
Pregnancies in female subjects
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator's first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
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death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs:
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs:
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper safety information form within 5 calendar days of the investigator's first knowledge 
of the SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Semaglutide: Events of nausea, vomiting and headache have been reported in connection with 
accidental administration of semaglutide doses up to 4 mg. No symptoms of hypoglycaemia have 
been reported in connection with overdose of semaglutide. In the event of overdosage, appropriate 
supportive treatment should be initiated according to subject’s clinical signs and symptoms.
Liraglutide: From clinical trials and marketed use of liraglutide overdoses have been reported up to 
24 times the recommended dose (72 mg). Events reported included severe nausea and severe 
vomiting. None of the reports included severe hypoglycaemia. All subjects recovered without 
complications. In the event of overdose, appropriate supportive treatment should be initiated 
according to the subject’s clinical signs and symptoms
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal semaglutide safety committee to perform ongoing safety 
surveillance. The semaglutide safety committee may recommend unblinding of any data for further 
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analysis, and in this case an independent ad hoc group will be established in order to maintain the 
blinding of the trial personnel.
12.7.2
Event adjudication committee
An independent external event adjudication committee is established to perform qualitative or 
quantitative validation of selected AEs according to pre-defined diagnostic criteria. The validation 
is based on review of pre-defined clinical data related to the specific AE. The events are reviewed 
by the event adjudication committee in a blinded manner.
The AEs for adjudication are listed in Table 12–1 and defined in appendix E.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
The EAC is composed of members covering required medical specialities. The EAC members must 
disclose potential conflicts of interest. The EAC will have no authorisation to impact trial conduct, 
trial protocol or protocol amendments.
AEs for adjudication must be reported according to section 12.2. Besides these events, all AEs not 
originally sent for adjudication will be screened as potential adjudication events. The adjudication 
vendor or the EAC can decide to have an AE adjudicated even if not initially sent for adjudication 
by the investigator. In this case, the investigator will be notified and should complete the 
adjudication form within 14 days and provide the data/documents as soon as possible.
The adjudication vendor will ensure that the EAC has access to all medical documents provided by 
the investigator. The EAC will initiate the review and may ask for additional information that the 
investigator needs to provide if available.
The evaluation made by the EAC and by the investigator will be included in the clinical trial report.
A site manual will be provided to each site detailing how the site should provide the relevant 
medical documentation for the adjudication vendor. The anonymisation requirements are also 
described in the site manual.
12.7.3
Calcitonin monitoring committee
The calcitonin monitoring committee will provide recommendations for all calcitonin values 
≥20 ng/L (except for screening failures) to the investigators with regards to further investigation 
and treatment of the individual subject (see Appendix A).
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
!
Technical complaint forms (to be used as backup for electronic reporting or for technical 
complaints where the product has not been allocated to a subject yet)
!
AE forms (only to be used as backup for electronic reporting)
!
Safety information forms (only to be used as backup for electronic reporting)
The paper version of the technical complaint form, AE form, and safety information form must only 
be used to ensure timely reporting when/if the electronic CRF is unavailable.
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks.
If a test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the electronic CRF data may be made by the investigator or the investigator’s 
delegated staff. An audit trail will be maintained in the electronic CRF application containing as a 
minimum: the old and the new data, identification of the person entering the data, date and time of 
the entry and reason for the correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.3
Electronic collection of questionnaires
Novo Nordisk will use a tablet computer at sites for electronic recording of a series of 
questionnaires investigating mental health (see section 8.5.6) and quality of life (see section 8.4.4). 
The tablet computer and related support services will be supplied by an external vendor.
Subjects will be instructed in the use of the tablet computer before entering any data. The tablet
computer will contain built-in edit checks, to ensure that all relevant questions are answered. The 
tablet computer is not intended to support the subsequent review and modification of completed 
entries. In case of need for corrections to the transferred data, a query flow must be initiated by the 
investigator or delegate. An audit trail will be maintained.
All data entered will be transferred automatically from the tablet computer to a database hosted by 
the supplier which is considered source data. Data entered on the devices will upon confirmation of 
successful backup be deleted from the devices.
Data in this database will be viewable to relevant site and Novo Nordisk personnel through a secure 
and password-protected web portal. Data will be transferred to the Novo Nordisk clinical database 
at defined intervals.
Site-specific electronic questionnaire data (in an electronic readable format) will be provided to the 
trial site before access to the supplier database is revoked. This data must be retained at the trial site.
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14 Monitoring procedures
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks for trial sites with active 
subjects (defined as subjects in screening, treatment, or follow-up).
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the CRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
For screening failures, the following data will be source data verified for screening failures:
!
date for obtaining informed consent
!
reason for screening failure
!
serious adverse events (if any)
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original diaries must not be removed from the trial site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
Monitors must review the subject's medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the eCRF. If discrepancies are found, the 
investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. They should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a CRO.
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks.
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock and unblinding of the trial.
Results from the statistical analysis will generally be presented by treatment differences with two-
sided 95% confidence intervals.
The full analysis set (FAS) will be used in the analysis of efficacy endpoints. For safety endpoints 
the safety analysis set will be used.
The 8 different placebo arms will be pooled into one placebo treatment arm in the main analyses. 
This pooling assumes that there is no substantial effect of different placebo volumes or different 
dose escalation on the efficacy and safety endpoints. The validity of this assumption will be 
checked for the primary endpoint by plotting mean data for the 8 placebo arms separately, and by 
evaluating summaries of treatment-emergent adverse events for each placebo arm. Should the 
placebo arms demonstrate substantial differences, appropriate sensitivity analysis will be included. 
The description of planned analysis given here assumes that all 8 placebo arms will be pooled into 
one placebo arm.
In general, the statistical analysis will be made by one statistical model estimation on the full 
dataset including all treatment arms. Statistical inference and data presentations will be separated 
into two parts. Part A concerns identifying the optimal dose and includes inference for the 
liraglutide arm, the semaglutide arms with dose escalation every fourth week, and the pool of the 
placebo arms. Part B concerns identifying the optimal dose escalation regime and includes inference 
for the semaglutide arms with dose escalation every second week, the corresponding semaglutide 
arms (with regards to dose) with dose escalation every fourth week, and the pool of the placebo 
arms.
The baseline value will be defined as the last measured and available value from visit 1 and 2.
In the case of missing data no general imputation will be performed for the analyses, unless 
otherwise specified.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
17.1
Sample size calculation
The sample size calculation is based on the primary endpoint; change from baseline in body weight 
(%) at 52 weeks.
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Part A is a dose-finding trial examining five doses of semaglutide and placebo, and an active 
comparator. The sample size calculation is based on the relative change after 52 weeks treatment in 
the primary endpoint, body weight. In the sample size calculations, it is presumed that the placebo 
groups will be pooled in the analysis, assuming no correlation between body weight change after 52 
weeks and placebo-injected volume. By trial design we expect to have 135 subjects on placebo and 
100 in each active group. In the unfortunate situation that we should not be able to pool all placebo 
arms but only be able to pool the (semaglutide) placebo arms with dose escalation every fourth 
week and (liraglutide) placebo, we will still expect to have at least 100 subjects in the relevant pool 
of placebo subjects. Hence the argumentation below only assumes 100 subjects in the placebo arm 
in a conservative manner and for simplicity. However, at time of analysis we plan to include all 
subjects on placebo as one group in the analysis as described above, if possible.
The following assume 100 subjects randomised in a balanced manner to receive each active 
treatment and being conservative at least 100 evaluable subjects in the placebo arm. In trial 
NN8022-1839, in obese subjects without T2DM a standard deviation of just below 7% was seen for 
observed weight loss (in %) in the liraglutide 3.0 mg arm. A conservative estimate of the dropout 
rate is 40%. A standard deviation of 7% and a sample size of 100 in each treatment arm will allow 
the 95% confidence interval for the estimated difference between two semaglutide doses, with 90% 
probability, to be contained within ±2.5% of the estimate, which is considered to be a sufficient 
precision for determining which doses to use for the continued development of semaglutide in the 
weight management indication.
For the primary endpoint change in body weight after 52 weeks of treatment, a difference 
(semaglutide minus placebo) of 9.5% is expected for completers in the optimal dose group. For the 
withdrawn subjects, who are anticipated to constitute up to 40% of the total trial population, the 
treatment difference (semaglutide minus placebo) is assumed to be 0% giving an overall expected 
treatment difference of 8.2%. The standard deviation will also be increased using the MI approach. 
The standard deviation in the final data is assumed to be up to 8.2%. A standard deviation of 8.2% 
together with an expected difference of 8.2% results in a power of more than 99%.
For part B, in total two times 100 subjects will be randomised to the dose escalation every second
week. Combined with placebo and the two doses corresponding to the ‘every second week’ arms 
(i.e. 0.3 mg/day and 0.4 mg/day) we will have more than five hundred subjects for the inference of 
the dose escalation finding part of the trial. In trial NN8022-1839, nausea, vomiting, and 
constipation were the most common gastrointestinal AEs with incidences between 15% and 40% of 
all subjects on liraglutide 3.0 mg. These AEs are not expected to be less frequent with semaglutide. 
This part of the trial is exploratory in nature and is intended to evaluate the overall safety profile 
with respect to the different types of events and when they occur compared to the escalation steps 
and with a view towards the efficacy response as well. With the given number of subjects, we have 
a reasonable sample size to detect marked clinical relevant difference between the arms.
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17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E939 guidance:
!
The full analysis set (FAS) will include all randomised subjects. Only in exceptional cases may 
subjects be excluded from the FAS. In such cases the reason for exclusion will be justified and 
documented. Subjects in the FAS will contribute to the evaluation ‘as randomised’.
!
The safety analysis set will include all subjects receiving at least one dose of randomised 
treatment. Subjects in the safety analysis set will contribute to the evaluation ‘as treated’.
Any subjects or observations excluded from analysis, and the reason for exclusion will be described 
in the CTR.
17.3
Primary endpoint
The primary endpoint, relative change from baseline in body weight (%) at 52 weeks, will be 
investigated using the following main analysis to compare between the randomised treatment arms
using a multiple imputation (MI) analysis. The main analysis of the primary endpoint will also be 
referred to as the primary analysis as opposed to the sensitivity analysis of the primary endpoint.
Week 52 data from subjects discontinued from trial product that return for visit 22x will be
included. In this pattern mixture model approach withdrawn subjects without visit 22x from all 
treatment arms are assumed to respond as if treated with placebo for the entire trial. Multiple copies 
(100 copies) of the full dataset will be generated by imputing missing values (change from baseline 
in body weight (%) at 52 weeks) based on estimated parameters for the placebo group. This will be 
done as follows:
–
In the first step, 100 copies of the dataset will be generated
–
In the second step, an enriched analysis of covariance model with treatment, region and sex 
as factors and baseline body weight, waist circumference, age and HbA1c as covariates is 
fitted to the change from baseline in body weight (%) at 52 weeks for the completers only
–
In the third step, for each of the 100 copies of the dataset the estimated parameters, and their 
variances, from this model are used to impute missing values at 52 weeks for subjects in all 
treatment arms, based on their region, sex, body weight, waist circumference, age and 
HbA1c at baseline with treatment equal to placebo from the enriched model in step two
–
For each of the 100 complete data sets, the change from baseline in body weight (%) at 
52 weeks is analysed using an analysis of variance model with treatment, region, and sex as 
factors, and baseline body weight as a covariate
–
The estimates and standard deviations for the 100 data sets are pooled into one estimate and 
associated standard deviation using Rubin’s formula:
 m =
1
100 
 m,   


SD =  1
100 
 SD



+ 1 + 1
100
1
100 −1 
(m −m)


, 
 where m and SD are the estimated means and standard deviations 
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Protocol
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Date:
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              for the 100 copies of the dataset, and m,  SD are the pooled estimates.
–
From m and  SD, the 95% confidence interval for the treatment differences and the 
associated p-value are calculated
Pairwise treatment differences between semaglutide doses and placebo, liraglutide and placebo, 
different semaglutide doses, and between semaglutide doses and liraglutide at week 52 will be 
estimated from the model and 95% confidence intervals will be calculated.
In part A, the comparisons of semaglutide doses vs. placebo will have the family wise type I error 
protected in the strong sense. This will be achieved by using Dunnett’s method in which 
simultaneous confidence intervals will be calculated. A significance level of 5% will be applied. 
Further, the focus of this part of the trial is to examine the dose response relationship. In part B, no 
multiplicity adjustment will be performed.
The dose of semaglutide providing a weight loss corresponding to liraglutide 3.0 mg will be 
estimated by fitting a linear approximation to the log dose vs. estimated means for the semaglutide 
doses and compare this to the estimated mean for liraglutide 3.0 mg. This analysis will be based on 
the estimated means and the covariance matrix for the means obtained from the MI analysis. 
Fieller’s method will be used to calculate 95% confidence limits for the estimated dose of 
semaglutide corresponding to liraglutide 3.0 mg. If a linear approximation does not describe the 
log(dose)-response relationship well, a different approximation (e.g. a sigmoidal curve) may be 
investigated.
The MI method does not assume missing at random. It assumes that withdrawn subjects and 
subjects with missing endpoint at week 52 in the placebo arm have a response similar to the 
completers in the placebo arm given similar baseline characteristics. In the active treatment arms,
the assumption is that withdrawn subjects and subjects with missing endpoint at week 52 behave as 
if they have been in the placebo arm during entire trial regardless of the time of discontinuation. In 
this way the assumptions are differential and conservative for estimating the treatment effect. The 
estimate in the primary analysis can be said to be an intention to treat (ITT) estimand or an 
effectiveness estimand in all randomised subjects of the add-on effect of semaglutide to nutritional 
and physical activity counselling.
Based on previous trials in weight management the withdrawal rate from randomised treatment is 
expected to be up to 40%. Semaglutide treatment has in previous (T2DM) trials been effective with 
regard to weight loss, and this should reduce the number of withdrawals due to ineffective therapy. 
Based on previous experience, a higher rate of withdrawal of consent is expected in the placebo 
group compared to active treatment. This difference may be due to lack of efficacy with placebo 
treatment. A higher withdrawal rate due to gastrointestinal adverse events is expected in the high 
dose semaglutide treatment arms and the liraglutide 3.0 mg arm compared to placebo. Apart from 
this, missing data due to adverse events (AEs) is expected to be similar across groups. This 
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emphasises the validity of the primary analysis as a conservative analysis of the treatment effect of 
semaglutide.
The sensitivity of the results with regard to different assumptions for missing data from withdrawn 
subjects will be investigated by plotting weight loss data for withdrawn subjects and compare this
with plots of weight loss data for subjects completing 52 weeks of treatment. Further, for subjects 
that discontinue treatment but provide data at the week 52 visit (22x) plots will compare weight loss 
at last visit on treatment with weight loss at visit 22x. In addition, several sensitivity analyses will 
be performed where different assumptions are made with regard to withdrawn subjects. 
The following sensitivity analyses will be performed:
1. An analysis of covariance (ANCOVA) model comparing the change from baseline in body 
weight (%) at 52 weeks between treatments. Only on-treatment data will be included. Missing 
data at week 52 will be imputed from on-treatment data using the last observation carried 
forward (LOCF) method. The ANCOVA model will include treatment, region, and sex as 
factors, and baseline body weight as a covariate. This analysis corresponds to the primary 
analysis approach used in the liraglutide weight management development programme.
2. An analysis of covariance (ANCOVA) model comparing the change from baseline in body 
weight (%) at 52 weeks between treatments. All available data will be included. Missing data at 
week 52 will be imputed using the subject’s baseline observed weight carried forward (BOCF).
The ANCOVA model will include treatment, region, and sex as factors, and baseline body 
weight as a covariate. This is a conservative analysis which will underestimate the differences 
between semaglutide/liraglutide and placebo.
3. A mixed model for repeated measurements (MMRM) comparing the change from baseline in 
body weight (%) at 52 weeks between treatments. All post randomisation measurements at 
planned visits up to week 52 and obtained before withdrawal from treatment will be included in 
the model as dependent variables. Treatment, region, and sex will be included as fixed factors, 
and the baseline body weight will be included as a covariate. All factors and the covariate will 
be nested under the factor visit. An unstructured covariance matrix will be used to describe the 
variability for the repeated measurements for a subject. Subjects without post randomisation 
measurements of weight will be excluded from the analysis.
4. The primary analysis model (the MI) will be applied to data from subjects attending the 
end-of-treatment visit in fasting state. Any non-fasting measurements will be treated as missing 
measurements.
5. An analysis of covariance (ANCOVA) model comparing the change from baseline in body 
weight (%) at 52 weeks between treatments including only subjects with data for week 52 on 
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treatment (a completer analysis). The ANCOVA model will include treatment, region, and sex 
as factors, and baseline body weight as a covariate.
6. The primary analysis model (MI) will be applied where data from all withdrawn subjects are 
imputed (i.e. data from visit 22x is disregarded).
Further sensitivity analysis may be added at time of reporting as deemed relevant.
The ANCOVA model with LOCF assumes that post treatment discontinuation, the body weight is 
on average stable in both treatment arms. This assumption can be evaluated over the 7 weeks 
follow-up period in withdrawn subjects and in completing subjects. If the assumption holds, the 
treatment effect (effectiveness estimand) in each arm and the treatment difference can be estimated 
from this analysis unbiased. If the withdrawal and the development in both arms are similar, the 
treatment difference can be estimated from this analysis unbiased. If the development in body 
weight after treatment discontinuations differs between active and placebo, this analysis might 
provide an optimistic or over-conservative estimate, depending on the actual circumstances. The 
analysis is included to be able to compare the results with legacy obesity programs, where this 
analysis was the main analysis of the primary endpoints.
The ANCOVA model with BOCF assumes that post treatment discontinuation subjects returns to a 
body weight in the proximity of their baseline body weight regardless of the timing of 
discontinuation. This analysis is expected to provide a conservative estimate (effectiveness 
estimand) of the treatment effect (in each arm). The impact of this assumption on the treatment 
difference depends on withdrawal pattern over time and development of body weight post treatment 
discontinuation and reason for withdrawal. The analysis is typically expected to provide a 
conservative estimate of the treatment difference (effectiveness estimand).
The MMRM model assumes that withdrawn subjects, had they completed the trial, would not have 
behaved differently than completing subjects from the same treatment arm with the same baseline 
characteristic and change in body weight at time of withdrawal. This analysis estimates the 
treatment effect and difference had all subjects stayed on the randomised treatment (efficacy 
estimand).
The MI model on fasting values examines the influence of not being fasting at the end-of-treatment 
visit. This analysis is expected to give similar treatment differences as the main analyses and 
estimate the same estimand.
The ANCOVA analysis in completers is expected to give more positive results than the primary 
analysis. However, this analysis has its own clinical interpretation and will serve as a benchmark
and provide an estimate of the efficacy estimand in the population that tolerate the trial product and 
endure the diet and exercise counselling program.
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The MI model disregarding visit 22x data examine the influence of data from withdrawn subjects 
returning at week 52 on the main analysis. It is difficult to postulate expectation on the results from 
this sensitivity analysis. The analysis estimates the same estimand as the primary analysis.
17.4
Secondary endpoints
For statistical analysis of secondary endpoints, when mentioned below, the analyses methods 
reproduce the main analysis of the primary endpoint by the same MI approach. The endpoint at 
baseline will replace body weight at baseline as covariate. The statistical methodology depends on 
the type of endpoint, but the model factors and covariates are similar to those specified for the 
primary analysis.
17.4.1
Efficacy endpoints
Endpoints addressing weight loss
!
Proportion (%) of subjects with weight loss of ≥ 5% of baseline body weight at 52 weeks
!
Proportion (%) of subjects with weight loss of ≥10% of baseline body weight at 52 weeks
These two dichotomous endpoints will be compared between the treatment arms using a MI 
approach as in the primary analysis based on a logistic regression. The datasets from the primary 
analysis will be reused for this analysis where imputed values for change in body weight will be 
used to generate the dichotome endpoints. Pairwise treatment differences between treatments will 
be estimated from the model and 95% confidence intervals will be calculated.
Change from baseline to 52 weeks in:
!
Body weight (kg)
!
Waist circumference (cm)
!
Waist to hip circumference ratio (waist (cm)/hip (cm))
!
BMI (kg/m2)
These endpoints will be compared between treatments using the MI approach used for the main 
analysis of the primary endpoint (with the corresponding baseline value as covariate).
Endpoints addressing glucose metabolism
Change from baseline to 52 weeks in:
!
HbA1c
!
FPG
!
Shift in glycaemic category (normoglycaemia, pre-diabetes, T2DM)
The endpoints HbA1c and FPG will be compared between treatments using the MI approach used 
for the main analysis of the primary endpoint (with the corresponding baseline value as covariate).
Shift in glycaemic category will be compared between treatments using the proportional odds 
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model (or ordinal logistic regression) and imputing missing measurements in the same fashion as 
used for the main analysis of the primary endpoint.
Glycaemic categories
Normoglycaemia:
!
FPG < 5.6 mmol/L (100 mg/dL) and HbA1c < 5.7%
Pre-diabetes:
!
FPG 5.6-6.9 mmol/L (100-125 mg/dL) (both inclusive) and HbA1c ≤ 6.4%
or
!
FPG ≤ 6.9 mmol/L (125 mg/dL) and HbA1c 5.7-6.4% (both inclusive)
T2DM:
!
FPG ≥ 7.0 mmol/L (126 mg/dL) and/or HbA1c ≥ 6.5%
Endpoints addressing cardiovascular risk factors
Change from baseline to 52 weeks in:
!
Systolic and diastolic blood pressure
!
Lipids (total cholesterol [TC], low density lipoprotein cholesterol [LDL cholesterol], high 
density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein cholesterol 
[VLDL cholesterol], triglycerides [TG], free fatty acids [FFA])
!
Cardiovascular biomarker (high sensitivity C reactive protein [hsCRP])
These endpoints will be compared between treatments using the MI approach used for the main 
analysis of the primary endpoint (with the corresponding baseline value as covariate). For lipids and 
hsCRP a multiplicative model will be used, i.e. the ratio between post randomisation measurements 
and baseline will be calculated instead of differences, and both the dependent variable and covariate 
will be log-transformed. Estimates and CI will be presented as percentage change from baseline.
Endpoints addressing patient reported weight-related quality of life and general health status
Change from baseline to 52 weeks in:
!
Impact of Weight on Quality of Life-Lite (IWQoL-Lite) for Clinical Trials: Total score and 
scores on the individual sub-domains
!
Short form-36 (SF-36): Physical and mental component summary scores and scores on the 
individual sub-domains: Physical functioning, role functioning, bodily pain, general health, 
vitality, social functioning, role emotional and mental health
These endpoints will be compared between treatments using the MI approach used for the main 
analysis of the primary endpoint (with the baseline total score as covariate).
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Endpoints addressing changes in antihypertensive and lipid-lowering medical treatment
Change from baseline to 52 weeks in:
!
Proportion of subjects with change in concomitant medications:
–
Antihypertensive medications
–
Lipid-lowering medications
The endpoint is based on the evaluations made by the investigators and recorded according to the 
description in section 8.2.3.1.The proportion of subjects with any change 
(decrease/no change/increase) in dose and/or drug within the two above classes will be calculated 
and described. These endpoints will be compared between treatments using the proportional odds 
model (or ordinal logistic regression). Only on-treatment data will be considered. Subjects not using 
drugs within the specified categories will count as no-change. The model factors and covariates will 
be identical to the main analysis model.
Endpoint addressing nutritional compliance
Compliance with nutritional counselling will be summarised by week.
Analysis identifying early responders
!
Predictability of weight loss of more than 5% at week 52 by early weight loss response (3%, 
4%, and 5%) after 12, 16, and 20 weeks
The ability of early weight loss of 3%, 4%, and 5% at week 12, 16, 20 to predict long term weight 
loss (5% at week 52) will be described by sensitivity, specificity, positive predictive value, and 
negative predictive value. Receiver operating curve (ROC) will be presented for weight loss at 
week 12, 16 and 20. The analysis will be repeated seperately for each treatment arm.
17.4.2
Safety endpoints
The endpoint “Number of treatment-emergent adverse events during the trial” will be extensively 
described using descriptive statistics and listings.
All adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). An adverse event will be defined as treatment emergent if the onset of the 
adverse event is on or after the first day of trial product administration, and no later than whatever 
comes first of a) last drug date plus seven weeks or b) follow-up visit, or c) last study visit.
Treatment-emergent adverse events will be summarised by system organ class, preferred term, 
seriousness, severity and relation to trial product.
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Endpoint addressing hypoglycaemic episodes:
The endpoint “Number of treatment-emergent severe or blood glucose-confirmed symptomatic 
hypoglycaemic events” will be tabulated according to the definition below. The remainder of the 
low blood glucose events (asymptomatic hypoglycaemic events) will be tabulated as well.
Given that the trial population does not have T2DM at inclusion, the risk of developing 
hypoglycaemia is considered low and hence no blood glucose monitoring will be instituted. 
However, in case of severe hypoglycaemia where third party assistance is needed or in case of a low 
blood glucose value detected by scheduled blood sampling accompanied by relevant symptoms, the
hypoglycaemic episode will qualify for the endpoint analysis.
Classification of hypoglycaemic events
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs on or after the first day of trial product administration, and no later than 
whatever comes first of a) last drug date plus seven weeks or b) follow-up visit, or c) last study 
visit.
The hypoglycaemic episodes will be categorised based on the ADA classification33 of 
hypoglycaemia:
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not 
be available during an event, but neurological recovery following the return of plasma glucose 
to normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
Safety endpoints continued
The endpoint “Number of new and ongoing treatment-emergent nausea, vomiting, diarrhoea and 
constipation events by week” will be summarised by week.
Nausea:
!
Individual scores of nausea questionnaire
!
Severity by numeric rating scale (NRS) score
Nausea questionnaire and NRS score will be summarised by week.
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Changes from baseline to 52 weeks in:
!
EGG
!
Pulse
!
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, differential 
count)
!
Biochemistry (creatinine, CPK, urea, albumin, bilirubin [total], ALT, AST, alkaline 
phosphatase, sodium, potassium, calcium [total], amylase, lipase, calcitonin, TSH)
!
Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) and Patient 
Health Questionnaire-9 (PHQ-9)
will be summarised and described for each treatment arm. Changes in pulse will be compared 
between treatments using an MMRM model as described under sensitivity analysis in section 17.3
(with the baseline pulse value as covariate) based on the safety analysis set. For amylase and lipase 
two statistical analyses will be applied, respectively. The relative change (100*value/baseline) will 
be analysed with an MMRM model as described under sensitivity analysis in section 17.3. The 
relative change and baseline values will be log-transformed prior to the analysis. Subjects having a 
measurement above >3x UNR anytime during treatment (yes/no) will be analysed using a logistic 
regression. For the evaluation of the response, all measurements obtained during treatment will be 
included and these measurements are defined as any scheduled or unscheduled measurements 
obtained from, but not including, baseline and until, and including, end of treatment. Separate 
analyses will be made for amylase and lipase. The results will be presented as odds ratios together 
with the associated 95% confidence intervals.
The endpoint “Anti-semaglutide antibodies during and after treatment” will be described by 
summarising the number and percentage of subjects with antibodies in the different treatment arms.
Similarly, subjects with semaglutide antibodies with neutralising effect and with cross-reactivity
against endogenous GLP-1 will be described by summaries. The primary endpoint will be 
summarised by anti-semaglutide antibody status (positive or negative) at follow-up.
17.5
Pharmacokinetic and pharmacodynamic modelling
Exploratory population PK and PK/PD modelling will be used to evaluate the semaglutide dose-
exposure, the effects of pre-specified covariates on the exposure and the semaglutide exposure-
response on selected efficacy and safety parameters. For the covariate analysis, covariates such as 
sex, body weight and age will be explored.
The population PK modelling will include data from all randomised subjects that were exposed to 
semaglutide, excluding data records with concentration values missing or below LLOQ, and data 
records with incomplete or ambiguous dosing information. Actual time points for dose 
administration and PK sampling will be used. PK/PD modelling will include data from subjects 
included in the population PK modelling, with relevant PD assessments available. 
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Results of the modelling analysis will be presented using criteria which will be pre-specified in a 
modelling analysis plan that is to be finalised before database lock (DBL). The modelling will be 
performed by Quantitative Clinical Pharmacology at Novo Nordisk A/S and will be reported 
separately from the CTR.
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Date:
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18 Ethics
18.1
Benefit-risk assessment of the trial
Risks and precautions for semaglutide
The sections below describe potential risks associated with semaglutide treatment, based on 
findings with other GLP-1 RAs and observations in nonclinical and clinical trials with semaglutide 
administered s.c. once weekly. For each of these risks, mitigating actions have been implemented to 
minimise the risks for subjects enrolled in this trial.
The nonclinical safety programme of semaglutide has revealed no identified safety issues for 
humans based on conventional studies of safety pharmacology, repeat-dose toxicity or genotoxicity.
Thyroid C-cell tumour
The human relevance of the proliferative C-cell changes found in rodents is unknown, but data 
suggest that rodents are more sensitive to the mode of action for induction of C-cell tumours with 
GLP-1 RAs. However, as a precaution subjects with a family or personal history of Multiple 
Endocrine Neoplasia type 2 (MEN 2), familial medullary thyroid carcinoma (MTC), personal 
history of non-familial medullary thyroid carcinoma, and subjects with a screening calcitonin 
≥50 ng/L will be excluded from trial. During the trial calcitonin will be measured on a regular basis
and guidance for investigators of further evaluation and action on elevated plasma calcitonin 
concentrations will be carried out by an independent group of thyroid experts, the Calcitonin 
Monitoring Committee (CMC). This will ensure appropriate and consistent handling of elevated 
levels across trials.
Teratogenicity (nonclinical embryo-foetal toxicity)
Semaglutide has been concluded teratogenic in rats. This effect is regarded to be caused by 
impairment of nutrient supply to the embryo across the inverted yolk sac with placental function. As 
the yolk sac does not play such a role for nutrition of the embryo in humans, this effect is unlikely 
to berelevant for humans. However, as a precaution subjects fulfilling exclusion criterion 29will be 
excludedfrom trial participation. Furthermore, female subjects included in the trial will have 
pregnancy testing performed on a monthly basis.
Gastrointestinal adverse events
Consistent with findings from other GLP-1 RAs, the most frequently reported AEs in the clinical 
trials with semaglutide thus far have been gastrointestinal (GI) disorders (nausea, vomiting, 
diarrhoea, dyspepsia and constipation). However, based on a completed clinical trial 
(NN9535-3819) where slower dose escalation substantially improved the GI tolerability profile, a 4-
week dose escalation regimen has been developed and is used in ongoing clinical phase 3 
programme for semaglutide s.c. administered once weekly as well as for most or the arms in this 
trial.
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Allergic reactions and injection site reactions
As is the case with all protein based pharmaceuticals subjects treated with semaglutide risk 
developing immunogenic and allergic reactions. These may include localised injection site reactions 
or generalised reactions including urticaria, rash or pruritus. Severe allergic reactions such as 
anaphylactic reactions could potentially also pose a risk for subjects treated with semaglutide.
Hypoglycaemia
Based on current knowledge about the GLP-1 RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when a GLP-1 RA is combined with 
sulphonylurea (SU) or insulin in patients with T2DM. The risk for development of hypoglycaemia 
specifically with semaglutide in combination with SU and insulin is unknown due to limited data.
Altered renal function and acute pancreatitis
Based on current knowledge about the GLP-1 RA drug class two potential risks have been found 
relevant:
Firstly, untoward effects of volume depletion, resulting from nausea, vomiting and dehydration, 
such as acute renal failure have been observed in subjects treated with other GLP-1 RAs. As a 
precaution serum creatinine is measured regularly.
Secondly, acute pancreatitis, including reports of severe necrotising and haemorrhagic forms, has 
been associated with other GLP-1 RAs. As a precaution patients with a history of acute or chronic 
pancreatitis will be excluded from the trial. Subjects will be monitored for elevated activity levels of 
amylase and lipase and be informed of the characteristic symptoms of acute pancreatitis.
Risks and precautions for liraglutide
In the liraglutide 3.0 mg weight management programme, the main tolerability finding was 
gastrointestinal AEs. Cases of gallstones (cholelithiasis) and inflammation of the gallbladder 
(cholecystitis) were reported more commonly in adult subjects treated with liraglutide 3.0 mg 
compared to placebo. From literature, it is well-known that obesity carries an increased risk of 
cholelithiasis and that an association between rapid/marked weight loss and the development of 
cholelithiasis is present. In overweight or obese subjects with and without T2DM, treatment with 
liraglutide doses up to 3.0 mg was generally well tolerated. Overweight and obese subjects have an 
increased risk of certain types of cancer. In the weight management programme, the reporting rate 
of neoplasm events confirmed by event adjudication was similar with liraglutide and placebo. A 
numerical imbalance was observed for events of breast neoplasms in females and colorectal 
adenomas in males. Based on the limited number of reports a causal relationship to liraglutide could 
neither be confirmed nor excluded. In conclusion: Liraglutide in doses up to 3.0 mg has a 
well-described and acceptable risk-benefit profile. The maximum liraglutide to be used in the 
current trial (3.0 mg) is therefore considered to be safe.
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Benefits
Subjects will be treated within a regimen anticipated to be better than or equal to the weight 
management they receive at the time of entry into the trial.
Semaglutide has in a phase 2 trial (NN9535-1821) proven to have a clinical meaningful and 
dose-dependent effect on body weight. Doses ≥ 0.8 mg semaglutide provided a greater weight loss 
than liraglutide 1.8 mg. In clinical studies with liraglutide 3.0 mg (Saxenda®) approximately 2/3 of 
the subjects lost more than 5% of their initial body weight and approximately 1/3 lost more than 
10% of their initial body weight. Even a moderate weight loss of 5% has been shown to have 
significant health benefits in terms of improving glycaemic control, reducing progression to T2DM 
and improving the other abovementioned comorbidities (see section 3.1)
Although subjects will have to spend time on site visits and procedures required by trial 
participation, it is expected that all subjects (including those subjects randomised to placebo) will 
benefit from participation through close contact with the trial site, with close follow-up of their 
obesity and a careful medical examination. All of which will most likely result in an intensified 
management of their obesity.
Conclusion
The trial products may be associated with AEs, but relevant precautions have been implemented in 
the design and planned conduct of the trial in order to minimise the risks and inconveniences of 
participation in the trial. These precautions include thorough information regarding the correct 
administration of the trial products and gradual dose adjustment. Furthermore, subjects are informed 
about possible AEs and inconveniences and will be instructed to contact the investigator in case of 
any concerns regarding the trial participation.
When treatment with trial products ends, the subject and investigator will decide on the best 
available treatment.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme in T2DM has not revealed any safety issues that would prohibit administration of once 
weekly doses of 0.5 mg or 1.0 mg semaglutide. As the previously tested doses seem suboptimal for 
the weight management indication, higher doses are investigated in the present trial and based on 
the nature and frequency of the AEs in the T2DM trials it appears to be safe to investigate daily 
doses of up to 0.4 mg. However, as gastrointestinal AEs are expected and are likely to be dose-
dependent, additional safety surveillance will be instituted in all treatment arms during the dose 
escalation period until 4 weeks after last target dose is reached (steady state). It is concluded that the 
risk to the subjects in this trial is low and acceptable in view of the benefits a long-acting GLP-1 
analogue would provide to subjects with obesity.
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18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. This includes the use of an impartial witness where required.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the task may 
be delegated by the investigator to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject's willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
In case a subject undergoes a thyroidectomy a separate informed consent will be obtained for 
collection of thyroid tissue sample and genetic testing (see section 8.7.2).
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue from trial product.
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18.3
Data handling
If the subject is withdrawn from the trial or lost to follow-up, then the subject's data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subject during the trial
During the trial, the subjects may receive information that could include a “welcome to the trial 
letter”, newsletter(s) and a “thank you for your participation letter” after completion of the trial, if 
locally acceptable.
Initiatives for subject retention will be instituted for this trial. These may include retention 
activities, materials and items, if locally acceptable. The retention items will be relevant for the 
subjects’ participation in the trial and/or their obesity and will not exceed local fair market value.
All written information to subjects and retention initiatives must be sent to IRB/IEC for 
approval/favourable opinion and to regulatory authorities for approval or notification according to 
local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database.
Documentation on protocol deviations must be kept in the investigator’s trial master file and 
sponsor trial master file.
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21
Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of Investigator's Brochures37,38
!
Signed and dated Agreement on Protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
For US trial sites:
!
verification under disclosures per Code of Federal Regulations (CFR) of Financial Conflict of 
Interest
!
FDA form 1572 must be completed and signed by the investigator at each site
For sites outside the US:
!
All investigators outside the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together.
By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2.
By signing the protocol, each investigator also agrees to allow Novo Nordisk making investigator’s 
name and information about site name and address publically available if this is required by 
national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator’s trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no unauthorized persons can get access to the 
data.
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. No confidential information shall be disclosed to others without prior written consent 
from Novo Nordisk. Such information shall not be used except in the performance of this trial. The 
information obtained during this trial may be made available to other physicians who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk.
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One (or more) investigator(s) will be appointed by Novo Nordisk to review and sign the clinical 
trial report (signatory investigator(s)) on behalf of all participating investigators. The signatory 
investigator(s) will be appointed based upon the criteria defined by the International Committee of 
Medical Journal Editors for research publications40.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
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, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure23.
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.
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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. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. 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.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors40 (sometimes referred to as the Vancouver 
Criteria).
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database.
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years.
The files from the trial site/institution must be retained for 25 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case, trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
Antibody samples may be stored at the laboratory responsible for analysis for up to 15 years after 
end of trial in case further analysis or characterisation related to antibody response is requested by 
the regulatory authorities. The samples will not be used for other purposes.
None of the data will be identified by name. Antibody samples will be identified only by a subject 
number, a visit number and a trial identification number.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator's 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator’s trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
Australia: 
Complies with Medicines Australia Form of Indemnity for clinical trials version
160104B dated 16 January 2004
Belgium: 
Law concerning experiments on the human person of 07 May 2004 –Article 29:
§1: Even if without fault, the sponsor is liable for the damage which the subject 
and/or his rightful claimants sustain and which shows either a direct or an indirect 
connection with the trial.
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27 References
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14 Kapitza C, Flint A, Hindsberger C, Zdravkovic M. The effect of the once-daily human GLP-1 
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18 Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and 
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351(12):1250-1251.
25 Food and Drug Administration Amendments Act of 2007. 11 Oct 2007.
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26 The European Parliament and the Council of the European Council. Directive 2001/20/EC of 
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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, 
article 11. Official Journal of the European Communities May 2001.
27 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities April 2001.
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for Industry - Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. Dec 2009.
29 Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
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30 Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
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measure. J Gen Intern Med 2001; 16(9):606-613.
32 Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance 
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Clinical Trials (Draft Guidance). 
http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf. Aug 2012. 
33 Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L. et al. Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine 
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34 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med 2001; 18(9):690-705.
35 Human energy requirements. Report of a joint FAO/WHO/UNU expert consultation. FAO: 
food and nutrition technical report series 1. FAO/WHO/UNU. 2004.
36 European Union. The rules governing medicinal products in the European Union, Volume 4, 
Annex 13, manufacture of investigational products - Brussels. 3 Feb 2010.
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37 Investigator's Brochure, Semaglutide (10th Edition) or any updates hereof. Novo Nordisk A/S. 
2015.
38 Novo Nordisk A/S. Investigator's Brochure: Liraglutide in Weight Management (edition 7) or 
any updates hereof. Novo Nordisk A/S, editor.  2015. 
39 Phillips A, Haudiquet V. ICH E9 guideline 'Statistical principles for clinical trials': a case 
study. Stat Med 2003; 22(1):1-11.
40 International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. Dec 2014.
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Protocol - Appendix A
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Appendix A
Monitoring of calcitonin
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
Monitoring of calcitonin
Status:
Final
     
Page:
2 of 5
1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with semaglutide and liraglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L can 
become challenging. 
There are several known confounding factors affecting calcitonin levels, namely renal dysfunction, 
smoking, autoimmune thyroiditis and several drug classes (e.g. proton pump inhibitors, beta-
blockers, H2-blockers and glucocorticoids). Physiology of C-cell activation in various clinical 
conditions and in different patient populations (i.e. with various co-morbidities) is poorly 
understood. There may be various clinical conditions not identified so far which mildly or 
moderately affect calcitonin secretion by C-cells.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
Monitoring of calcitonin
Status:
Final
Page:
3 of 5
2
Calcitonin and C-cell abnormalities - evaluation and follow-up
Subjects with a personal or family history of medullar thyroid cancer (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN 2) or with a screening calcitonin ≥ 50 ng/L will be excluded from 
the trial. 
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. In case a 
subject has an increased calcitonin value ≥ 10 ng/L the algorithm outlined below should be 
followed. The algorithm applies for all calcitonin values including screening values.
All calcitonin values ≥ 20 ng/L (except for screening failures) will be submitted to an independent 
Calcitonin Monitoring Committee (CMC) of thyroid experts, together with relevant supplementary 
data, i.e. subject’s demographics, concomitant medical history, concomitant medications, smoking 
status as well as information about relevant adverse events reported during the trial.
The CMC will provide recommendations to the investigators with regards to further examinations 
and treatment of the individual subject. The CMC will be blinded to trial treatment. 
The summary for the rationale for the use of specific calcitonin values to trigger medical evaluation 
and an overview of the algorithm is provided below:
2.1
CT ≥ 100 ng/L  
The value will be submitted to the CMC and the subject should be discontinued from trial product. 
If the value is a screening value the subject cannot be randomised and the subject must be referred 
to a thyroid specialist. 
These values were found in 0.15% of a population with thyroid nodular disease published by 
Costante et al1 and in one subject (on active comparator) in the liraglutide development program. 
For a calcitonin value of ≥ 100 ng/L, the subject should be assumed to have significant C-cell 
disease and a high likelihood of having medullary carcinoma of the thyroid. Diagnostic evaluation 
should consist of thyroid ultrasound, fine needle aspiration of any nodules >1 cm and potentially 
surgery with neck dissection. Family history of MTC or MEN2 should be evoked and a RET proto-
oncogene analysis should be performed. 
2.2
CT ≥ 50 and < 100 ng/L 
The value will be submitted to the CMC and the investigator will receive guidance from the CMC 
with regards to continuation of trial product. If the value is a screening value the subject can not be 
randomised and the subject should be referred to a thyroid specialist.
These values were found in 0.14% of the population with thyroid nodular disease published by 
Costante et al1. Diagnostic evaluation will likely include ultrasound examination and if available 
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
Monitoring of calcitonin
Status:
Final
Page:
4 of 5
and if there is no contraindication, subjects should undergo a pentagastrin stimulation test. Subjects 
with positive pentagastrin stimulation tests will be considered to undergo surgery. In the US and 
other countries where pentagastrin is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information informing the need for surgery. 
2.3
CT ≥ 20 and < 50 ng/L
The value will be submitted to the CMC. If the subject is a screen failure the subject should be 
referred to a thyroid specialist for further evaluation.
These values are expected to be found in up to 1% of subjects. Based on data from Costante et al1, 
the predictive value of calcitonin levels ≥ 20 and < 50 ng/L for clinically significant C-cell disease 
begins to fall. However, up to 25% of these subjects had a positive pentagastrin stimulation test. 
The likelihood of having a medullary carcinoma >1 cm with calcitonin in this range is extremely 
low. 
2.4
CT ≥ 10 and < 20 ng/L
The value will not be submitted to the CMC. Confounding factors should be evaluated. If drugs 
potentially affecting calcitonin can be discontinued safely, calcitonin can be repeated after a 
washout period. No further actions are needed during the trial if the next calcitonin values remain 
below 20 ng/L.
If the subject is a screening failure or if the value is the last one taken in the trial, the subject should 
preferably be referred to a thyroid specialist for further evaluation.
Costante et al1had 216 (3.7%) patients in this category. One patient out of the 216 had a subsequent 
basal (unstimulated) calcitonin of 33 ng/L, and had C-cell hyperplasia at surgery, a lesion of 
unknown clinical significance. Two other studies used a cutoff of CT > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basalCT >10 and <20 ng/L 
to allow conclusions.2,3
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
Monitoring of calcitonin
Status:
Final
Page:
5 of 5
3
References
1
Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin 
levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with 
thyroid nodules. Journal of Clinical Endocrinology and Metabolism 2007; 92(2):450-455.
2
Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C et al. Sporadic hypercalcitoninemia: 
clinical and therapeutic consequences. Endocrine-Related Cancer 2009; 16(1):243-253.
3
Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and molecular studies in 
patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 
14(2):393-403.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
IWQoL-Lite for Clinical Trials
Status:
Final
     
Page:
1 of 4
Appendix B
Impact of Weight on Quality of Life Lite for Clinical Trials
Questionnaire
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
IWQoL-Lite for Clinical Trials
Status:
Final
     
Page:
2 of 4
For each of the following statements, please select the response that best applies to you currently.
Never
Rarely
Sometimes
Usually
Always
1
I have trouble bending over, for example
to pick things up from the floor or tie my 
shoes.
□
□
□
□
□
2
I get tired or winded walking up one
flight of stairs.
□
□
□
□
□
3
I have difficulty standing for 10 to 15 
minutes.
□
□
□
□
□
4
I feel uncomfortable in small seats in 
public places, such as in airplanes, 
theatres, and sports arenas.
□
□
□
□
□
5
I experience pain, such as pain in my 
knees, hips, or back.
□
□
□
□
□
6
I feel self-conscious eating in restaurants 
or buying groceries.
□
□
□
□
□
7
I feel less confident because of my 
weight.
□
□
□
□
□
8
I feel that others are judging me on the 
basis of my weight.
□
□
□
□
□
9
Others view me as less important or less 
worthy of respect because of my weight.
□
□
□
□
□
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
IWQoL-Lite for Clinical Trials
Status:
Final
     
Page:
3 of 4
Never
Rarely
Sometimes
Usually
Always
10
I get frustrated shopping for clothes.
□
□
□
□
□
11
I get frustrated choosing what to wear.
□
□
□
□
□
12
I feel bad or upset when I see myself in 
pictures.
□
□
□
□
□
13
I feel down or depressed about my 
weight.
□
□
□
□
□
14
I am less interested in sexual activity than 
I would like to be. 
□
□
□
□
□
15
I avoid social gatherings because of my 
weight. 
□
□
□
□
□
16
I am less productive than I would like to
be (at work, home, and/or school) 
because of my weight.
□
□
□
□
□
17
I lack the energy to do the things I would 
like to do.
□
□
□
□
□
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
IWQoL-Lite for Clinical Trials
Status:
Final
     
Page:
4 of 4
Not at 
all true
A little 
true
Moderately 
true
Mostly 
true
Compl
etely 
true
18
I am not as physically active as I would like 
to be. 
□
□
□
□
□
19
I am unable to walk as far or as quickly as I 
would like.
□
□
□
□
□
20
I am worried about my health.
□
□
□
□
□
21
My self-esteem is not what it could be 
because of my weight.
□
□
□
□
□
22
I am self-conscious about my weight. 
□
□
□
□
□
23
I feel frustrated or upset with myself about 
my weight.
□
□
□
□
□
CONFIDENTIAL


Protocol - Appendix C
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
Patient Global Impression of Change
Status:
Final
     
Page:
1 of 2
Appendix C
Patient Global Impression of Change (PGI-C)
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix C
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
Patient Global Impression of Change
Status:
Final
     
Page:
2 of 2
Patient Global Impression of Change (PGI-C) Questions
How would you rate your physical functioning (ability to do physical activities, mobility and 
flexibility, energy, and physical comfort) at your current weight as compared to the beginning 
of the study?
□ Much better
□ Moderately better 
□ A little better
□ No difference 
□ A little worse 
□ Moderately worse 
□ Much worse
How would you rate how you feel (emotions, self-confidence) at your current weight as 
compared to the beginning of the study?
□ Much better
□ Moderately better 
□ A little better 
□ No difference 
□ A little worse 
□ Moderately worse 
□ Much worse
Overall, how would you rate the quality of your life at your current weight as compared to the 
beginning of the study?
□ Much better
□ Moderately better 
□ A little better 
□ No difference 
□ A little worse 
□ Moderately worse 
□ Much worse
CONFIDENTIAL


Protocol - Appendix D
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
Nausea questionnaire
Status:
Final
     
Page:
1 of 4
Appendix D
Nausea questionnaire
This confidential document is the property of Novo Nordisk. No unpublished information contained 
herein may be disclosed without prior written approval from Novo Nordisk. Access to this 
document must be restricted to relevant parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Trial ID:
NN9536-4153
Subj. No:
__ __ __ __ __ __
Visit date: (dd/mmm/yyyy)
__ __І__ __ __І__ __ __ __
Visit:
Nausea questionnaire
_____________________________________________________________________________________________________
The following questions are intended to capture the subject’s experience of any single 
event of nausea over the past 24 hours whilst participating in the NN9536-4153 trial.
If more than one event of nausea were experienced within the previous 24 hours please 
fill out one questionnaire for each event
The questionnaire contains two parts: Six questions for you to ask the subject followed 
by one numeric rating scale (NRS) assessment that must be completed by the subject.
For each of the following questions, please mark an X in the box that best describes 
the subject’s answer. Mark only one box for each question.
1. Has the subject experienced nausea at any time during the last 24 hours?
YES  NO,  if YES please answer questions 2 to 6
2. To the best of the subject’s recollection, at what approximate time did the event of 
nausea occur?      
                     _ _:_ _   (24 hour clock)
3. How long did the subject’s event of nausea last?
Less than 30 
min 
Between 30 
min and 2 
hours 
    Between 2 
and 4 hours 
Between 4 
and 8 hours
More than 8 
hours
     1
     2
     3
     4
     5
CONFIDENTIAL


Trial ID:
NN9536-4153
Subj. No:
__ __ __ __ __ __
Visit date: (dd/mmm/yyyy)
__ __І__ __ __І__ __ __ __
Visit:
4. How much time passed from the latest injection of trial product to the onset of 
nausea?
0 to3 hours 
3 to 6 hours
6 to 12 hours 
12 to 18 hours 
>18 hours
     1
     2
     3
     4
     5
5. How much time passed from the last food intake to the onset of nausea?
0 to1 hours 
1 to 2 hours
2 to 3 hours 
3 to 6 hours 
>6 hours
     1
     2
     3
     4
     5
6. Was the event of nausea accompanied by vomiting?
                                      YES  NO
CONFIDENTIAL


Trial ID:
NN9536-4153
Subj. No:
__ __ __ __ __ __
Visit date: (dd/mmm/yyyy)
__ __І__ __ __І__ __ __ __
Visit:
FOR THE SUBJECT TO FILL IN
A. Please make a single “X” through the number below that best shows how severe 
the nausea became when it was worst
Please do not place your “X” between two boxes
      
Thank You!
Nausea as bad 
as it could be
No nausea
CONFIDENTIAL


Protocol - Appendix E
CONFIDENTIAL
Date:
17 April 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
MESI and AEs with additional
Status:
Final
data collection
Page:
1 of 5
Appendix E
Medical event of special interest (MESI)
and adverse events with additional data collection
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix E
MESI and AEs with additional
Date:
17 April 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN9536-4153
data collection
Version:
1.0
Page:
2 of 5
Medical event of special interest
Event
Definition
Rationale
Event 
adjudication
Medication errors 
concerning trial products
1) Administration of wrong drug or use of wrong device
2) Wrong route of administration, such as intramuscular 
instead of subcutaneous
3) Administration of a high dose with the intention to cause 
harm, e.g. suicide attempt
4) Accidental administration of a lower or higher dose than 
intended, however 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
Standard MESI in all Novo Nordisk clinical trials.
Medication errors are captured to collect information which may be used to 
improve the design, name or packaging of the product and/or information which 
may have an impact on product labelling (for example information about 
substantial overdoses).
No
Adverse events with additional data collection
Event
Definition
Additional data collection
Event 
adjudication
Fatal events
All-cause mortality:
1.
Cardiovascular death,
2.
Non-cardiovascular death,
3.
Undetermined cause of death1
No specific event form for fatal events.
A fatal event must be reported as a SAE as described in the protocol.
Yes
Acute coronary 
syndrome:
!
Myocardial 
Infarction
!
Hospitalisation for 
unstable angina
All types of myocardial infarction (MI) must be reported:
!
Spontaneous MI (including re-infarction and MI 
associated with stent thrombosis)
!
Percutaneous coronary intervention (PCI) related MI
!
Coronary artery bypass graft surgery (CABG) 
related MI
!
Silent MI
All events with symptoms of myocardial ischemia 
requiring hospitalisation must be reported.
If an event of acute coronary syndrome is observed during the trial, this must be 
recorded as an AE and on a specific acute coronary syndrome form in the eCRF. 
The following information must be reported if available:
!
Duration of symptoms
!
Changes in ECG
!
Collection of cardiac biomarkers
!
Cardiac imaging
!
Cardiac stress testing
!
Angiography
!
Use of thrombolytic drugs
Yes


Protocol - Appendix E
MESI and AEs with additional
Date:
17 April 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN9536-4153
data collection
Version:
1.0
Page:
3 of 5
Event
Definition
Additional data collection
Event 
adjudication
Coronary 
Revascularisation 
Procedure
A coronary revascularization procedure is a percutaneous 
coronary intervention (PCI) or an open surgical procedure 
designed to improve myocardial blood flow.
If an event of coronary revascularisation is observed during the trial, this must be 
recorded as an AE and on a specific coronary revascularisation form in the eCRF. 
The following information should be obtained:
!
Type of revascularisation performed
!
Indication for the procedure
Yes
Cerebrovascular event 
(stroke or transient 
ischemic attack)
Transient ischemic attack (TIA) is defined as a transient 
(<24 hours) episode of focal neurological dysfunction 
caused by brain, spinal cord, or retinal ischemia, without 
acute infarction.1
Stroke (Ischemic, haemorrhagic, undetermined) is defined 
as an acute episode of neurological dysfunction caused by 
focal or global brain, spinal cord, or retinal vascular injury 
as a result of haemorrhage or infarction.1
If a cerebrovascular event is observed during the trial, this must be recorded as an 
AE and on a specific cerebrovascular event form in the eCRF. The following 
information must be reported if available:
!
Type of event (e.g. TIA, stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the condition
!
Treatment given for the condition
Yes
Heart failure requiring 
hospitalisation
Clinical manifestations of new episode or worsening of 
existing heart failure requiring hospitalisation.
If an event of heart failure requiring hospitalisation is observed during the trial, this 
must be recorded as an AE and in addition on a specific heart failure event form in 
the eCRF. The following information must be reported if available:
!
Signs and symptoms of heart failure
!
NYHA Class
!
Supportive imaging
!
Supportive laboratory measurements
!
Initiation or intensification of treatment for this condition
Yes
Pancreatitis
Two of following diagnostic criteria fulfilling the 
diagnosis of acute pancreatitis:
1.
severe acute abdominal pain
2.
amylase and/or lipase activity levels >3x upper 
normal range (UNR)
3.
characteristic imaging finding (ultrasound, 
computerised axial tomography (CT), magnetic 
resonance imaging (MRI))
Chronic pancreatitis will be defined by characteristic 
imaging finding (ultrasound, CT, MRI) with abnormal 
pancreatic function tests or characteristic histological 
If an event of pancreatitis is observed during the trial, this must be recorded as an 
AE and on a specific pancreatitis event form in the eCRF. The following 
information must be reported if available:
!
Signs and symptoms of pancreatitis
!
Specific laboratory test supporting a diagnosis of pancreatitis:
o
Amylase
o
Lipase
o
Alanine aminotransaminase (ALT) and aspartate 
aminotransferase (AST)
o
Bilirubin
o
Alkaline phosphatase (ALP)
Yes


Protocol - Appendix E
MESI and AEs with additional
Date:
17 April 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN9536-4153
data collection
Version:
1.0
Page:
4 of 5
Event
Definition
Additional data collection
Event 
adjudication
findings
!
Imaging performed and consistency with pancreatic disease
!
Treatment for and complications of the event
!
Relevant risk factors for pancreatic disease including
o
History of gallstones
o
History of pancreatitis
o
Family history of pancreatitis
o
Trauma
Acute gallbladder 
disease
All types of acute gallbladder or acute biliary disorders
If an event of acute gallstone disease or clinical suspicion of this is observed during 
the trial, this must be recorded as an AE and on a specific acute gallstone disease 
event form in the eCRF. The following information should be reported if available:
!
Signs and symptoms of acute gallstone disease
!
Specific laboratory test supporting a diagnosis of gallstone:
o
White blood cell count (WBC)
o
C-reactive protein (CRP)
o
Direct, indirect and total bilirubin
o
ALT and AST
o
Alkaline phosphatase (ALP)
o
Amylase
o
Lipase
!
Imaging performed and consistency with gallstone disease
!
Treatment given for the condition
!
Relevant risk factors for acute gallstone disease including
o
History of gallstones
o
Family history of gallstones
o
Relevant surgery
No
Neoplasm 
(excluding thyroid 
neoplasms)
All types of neoplasms must be reported including:
!
Malign neoplasm
!
Pre-malignant neoplasm/carcinoma in-situ
!
Benign neoplasm
!
Neoplasm of uncertain or unknown behaviour
For operational reasons, thyroid neoplasms will be 
reported as thyroid disease (see below).
All events of neoplasms (excluding thyroid neoplasms) must be recorded as an AE 
and on a specific neoplasm event form in the eCRF. The following information 
should be obtained if available as part of standard of care:
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment for the event
!
Participation in screening programs
Yes


Protocol - Appendix E
MESI and AEs with additional
Date:
17 April 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN9536-4153
data collection
Version:
1.0
Page:
5 of 5
Event
Definition
Additional data collection
Event 
adjudication
!
Risk factors associated to the event
Thyroid disease 
(including thyroid 
neoplasms
All disorders of thyroid gland must be reported.
For operational reasons, thyroid neoplasms will be 
reported as thyroid disease.
Only events that require thyroidectomy should be sent for 
adjudication
If an event of thyroid disease, including any thyroid neoplasms, observed during 
the trial, this must be recorded as an AE and on a specific thyroid disease event 
form in the eCRF. The following information must be reported if available:
!
History of thyroid disease
!
Signs and symptoms leading to investigations of thyroid disease
!
Specific laboratory tests describing thyroid function including :
o
TSH
o
Total and free T3 and T4 and Free Thyroid Index
o
Calcitonin
o
Thyroid peroxidase antibodies
o
Thyroglobulin and thyroglobulin antibody
o
Thyroid Stimulating Hormone receptor antibody
!
Diagnostic imaging performed and any prior imaging supporting the
disease history
!
Pathologic examinations
!
Treatment given for the condition
!
Risk factors identified
!
Family history of thyroid disease
Yes
(only events 
that require 
thyroi-
dectomy)
1.
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials (DRAFT). Karen A. Hicks, H. M. James Hung, Kenneth W. Mahaffey, Roxana Mehran, Steven E. 
Nissen; Norman L. Strockbridge, Shari L. Targum, Robert Temple; on behalf of the Standardized Data Collection for Cardiovascular Trials Initiative. August 20, 2014. Or any updates hereof


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
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CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
03 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
1 of 4
3URWRFRO$PHQGPHQW
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,QYHVWLJDWLRQRIVDIHW\DQGHIILFDF\RIRQFHGDLO\VHPDJOXWLGH
A 52-week, randomised, double-blind, placebo-controlled, nine-armed, parallel group, multi-centre, 
multinational trial with liraglutide 3.0 mg as active comparator
7ULDOSKDVH
$SSOLFDEOHWR%HOJLXP
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
03 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
2 of 4
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CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
03 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
3 of 4

,QWURGXFWLRQLQFOXGLQJUDWLRQDOHIRUWKHSURWRFRODPHQGPHQW
The rationale for this protocol amendment is to define adequate contraceptive measures for Belgium 
in Exclusion criterion No. 29 as required by the Belgian Health Authorities.
In this protocol amendment: 
x
Any new text is written in italics.
x
Any text deleted from the protocol is written using strike through. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
03 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
4 of 4

&KDQJHV

([FOXVLRQFULWHULD
29. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice) 
)25%(/*,80$1'*(50$1<: Only highly effective methods of birth control are accepted 
(i.e. one that results in less than 1% per year failure rate when used consistently and correctly such 
as implants, injectables, combined oral contraceptives, some intrauterine device), or true sexual 
abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments) or vasectomised partner.
)2581,7('.,1*'2021/<: Adequate contraceptive measures are defined as established 
use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine 
device or intrauterine system, barrier methods of contraception (condom or occlusive cap with 
spermicidal foam/gel/film/cream/suppository), female sterilisation, male sterilisation (where partner 
is sole partner of subject), or true abstinence (when in line with preferred and usual lifestyle).
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
11 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
1 of 6
Protocol Amendment
no 2
to Protocol, final version 1.0
dated 17 April 2015
Trial ID: NN9536-4153
Investigation of safety and efficacy of once-daily semaglutide
in obese subjects without diabetes mellitus
A 52-week, randomised, double-blind, placebo-controlled, nine-armed, parallel group, multi-centre, 
multinational trial with liraglutide 3.0 mg as active comparator
Trial phase: 2
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment 2
CONFIDENTIAL
Date:
11 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
2 of 6
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
11 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
3 of 6
1
Introduction including rationale for the protocol amendment
This global amendment contains one additional assessment for the trial and 4 clarifications:
Change
Rationale for change
Clarification of adequate contraceptive measures 
in Canada for exclusion criterion 29
Health Canada has requested that adequate 
contraceptive measures are defined for Canada
Clarification of data collection of History of 
gallbladder disease
Collection of history information for pancreatitis 
on the specific eCRF form is not relevant
because subjects with a history of pancreatitis 
are excluded from the trial
Addition of standardised assessment of Injection 
site reactions
The FDA has requested that this assessment is 
added to the protocol
Clarification of thyroid disease events that must 
be sent for event adjudication (table 12.1)
Protocol was ambiguous with regards to which 
thyroid disease events should be sent for event 
adjudication
Clarification of figure 12.1
Figure 12.1 did not contain timelines for event 
adjudication
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
11 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
4 of 6
2
Changes
Section 6.3
Exclusion criteria
29. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice)
FOR CANADA ONLY: Only highly effective methods of birth control are accepted (i.e. one that 
results in less than 1% per year failure rate when used consistently and correctly such as implants, 
injectables, combined oral contraceptives, some intrauterine devices), or true sexual abstinence 
(i.e. refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatments) or vasectomised partner.
Section 8.2.2.2 
History of gallbladder disease
Information related to gallbladder disease (i.e., pancreatitis, gallstone gallbladder disease and 
cholecystectomy cholecystitis) must be recorded.
Section 8.5.10 Adverse events requiring special forms in the eCRF
Injection site reaction
If an event of injection site reaction is observed, the following additional information must be 
obtained if available:
!
Type of reaction – local or generalised
!
Symptoms associated with the event
!
Treatment given for the event
!
Association with the trial product(s)
!
Relevant risk factors associated with the event
Section 12.1
Definitions
Table 12.1 is updated as seen below.
Table 12−1
Adverse events with additional data collection
Event
Event adjudication
Specific event form
Fatal events
Yes
No
Acute coronary syndrome (myocardial infarction or hospitalisation 
for unstable angina)
Yes
Yes
Coronary revascularisation procedure
Yes
Yes
Cerebrovascular event (stroke or transient ischemic attack) 
Yes
Yes
Heart failure requiring hospitalisation
Yes
Yes
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
11 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
5 of 6
Pancreatitis
Yes
Yes
Acute gallbladder disease
No
Yes
Neoplasm (excluding thyroid neoplasms)
Yes
Yes
Thyroid disease (including thyroid neoplasms)
Yes, (only events that 
require thyroidectomy 
and/or thyroid 
neoplasms)
Yes
Injection site reaction
No
Yes
Section 12.2
Reporting of adverse events
Figure 12.1 will be replaced by the below figure which contains timelines for event adjudication:
An AE is 
observed and 
reported 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
!
AE form ≤ 14 calendar 
days
Fulfilling 
seriousness 
criteria?
Additional 
data 
collection 
requeried?
Additional 
data 
collection 
required?
Complete ≤ 14 calendar days:
!
Specific event form
!
For medication Error 
(MESI): Medication Error 
form 
No additional forms to 
be completed
Yes
No
Complete ≤ 14 calendar days: 
!
Specific event form
!
For Medication Error 
(MESI):  SIF and 
Medication Error form
Yes
No
No
Yes
Is the AE 
category selected 
for adjudication?
Complete ≤ 14 
calendar days:
!
Adjudication 
form 
Yes
AE: Adverse Event
SIF: safety information form
MESI: Medical event of special interesst
Specific event forms are described in section 8.5.10 
and appendix E
All timelines are from the investigator’s
first knowledge of the event
No
CONFIDENTIAL


Protocol Amendment 2
CONFIDENTIAL
Date:
11 August 2015
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
6 of 6
Appendix E
The following changes are made to the table in Appendix E:
Adverse events with additional data collection
Event
Definition
Additional data collection
Event 
adjudi-
cation
Thyroid disease 
(including 
thyroid 
neoplasms
All disorders of thyroid gland 
must be reported.
For operational reasons, 
thyroid neoplasms will be 
reported as thyroid disease.
Only events that require 
thyroidectomy should be sent 
for adjudication
If an event of thyroid disease, including any thyroid neoplasms, 
observed during the trial, this must be recorded as an AE and 
on a specific thyroid disease event form in the eCRF. The 
following information must be reported if available:
!
History of thyroid disease
!
Signs and symptoms leading to investigations of 
thyroid disease
!
Specific laboratory tests describing thyroid function 
including :
o
TSH
o
Total and free T3 and T4 and Free Thyroid 
Index
o
Calcitonin
o
Thyroid peroxidase antibodies
o
Thyroglobulin and thyroglobulin antibody
o
Thyroid Stimulating Hormone receptor 
antibody
!
Diagnostic imaging performed and any prior imaging 
supporting the disease history 
!
Pathologic examinations
!
Treatment given for the condition
!
Risk factors identified
!
Family history of thyroid disease
Yes
(only events 
that require 
thyroi-
dectomy 
and/or 
thyroid 
neoplasms)
Injection site
reaction
All events of injection site 
reactions must be reported.
All events of injection site reactions must be reported as an AE 
and on a specific injection site reaction event form in the 
eCRF. The following information must be obtained: 
!
Type of reaction – local or generalised
!
Symptoms associated with the event
!
Treatment given for the event
!
Association with the trial product(s)
!
Risk factors associated with the event
No
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
1 of 17
Protocol Amendment
no 3
to Protocol, final version 2.0
dated 13 August 2015
Trial ID:NN9536-4153
Investigation of safety and efficacy of once-daily semaglutide 
in obese subjects without diabetes mellitus
A 52-week, randomised, double-blind, placebo-controlled, nine-armed, parallel group, multi-centre, 
multinational trial with liraglutide 3.0 mg as active comparator
Trial phase: 2
Applicable to all countries 
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
2 of 17
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
1.1
Trial title and trial design...............................................................................................................3
1.2
Statistical considerations................................................................................................................3
1.3
Safety endpoints.............................................................................................................................3
1.4
Definition of hypoglycaemia episodes...........................................................................................4
1.5
Thyroidectomy...............................................................................................................................4
1.6
Retention of clinical trial documentation.......................................................................................4
1.7
Other change..................................................................................................................................4
2
Changes......................................................................................................................................................5
2.1
Section 1 Summary........................................................................................................................5
2.2
Section 2 Flow chart ......................................................................................................................5
2.3
Section 4.2.2 Secondary endpoints................................................................................................5
2.4
Section 5.1 Type of trial ................................................................................................................6
2.5
Section 5.2 Rationale for trial design.............................................................................................6
2.6
Section 8.3 Lab assessments..........................................................................................................6
2.7
Section 8.7.2 Thyroidectomy.........................................................................................................6
2.8
Section 17 Statistical considerations..............................................................................................7
2.8.1
Section 17.1 Sample size calculation...........................................................................8
2.8.2
Section 17.3 Primary endpoint.....................................................................................9
2.8.3
Section 17.4.1 Efficacy endpoints .............................................................................15
2.8.4
Section 17.4.2 Safety endpoints.................................................................................15
2.9
Section 18.2 Informed consent ....................................................................................................17
2.10
Section 24.1 Retention of clinical trial documentation................................................................17
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
3 of 17
1
Introduction including rationale for the protocol amendment
This amendment will serve to address comments raised by the US Food and Drug Administration 
(FDA) during the Investigational New Drug (IND) review and to clarify some trial procedures.
In this protocol amendment:
−
Any new text is written in italics.
−
Any text deleted from the protocol is written using strike through.
The protocol has been amended including the following major changes.
1.1
Trial title and trial design
The trial title and trial design has been changed from a “nine-armed” to a “sixteen-armed” trial 
since operationally there are 16 arms in the trial design.
1.2
Statistical considerations
In addition to the pooling of placebo data, a pairwise comparison between each semaglutide dosing 
regimen and the corresponding placebo dosing regimen will be conducted. The imputation model is 
changed to be consistent with the analysis model across all endpoints. Different numbers of 
imputations will be used to establish stable results. According to recent developments, estimands 
are defined and sensitivity analyses are updated.
The following has been updated:
!
Keep primary statistical analysis including pooled placebo arms and add supportive statistical 
analysis of primary endpoint including eight separate placebo arms
!
Descriptive statistics/plots for both pooled and eight separate placebo arms
In order to evaluate the intention-to-treat (ITT) estimand, the following has been updated:
!
Definition of effectiveness (and efficacy) estimand
!
Keep primary imputation approach, update the imputation model and add a note of the number 
of imputations
!
Replace sensitivity analyses with more appropriate approaches including the suggestions from
FDA (McEvoy 2015)
1.3
Safety endpoints
It has been clarified that safety endpoints including AE and hypoglycaemic episodes will be 
evaluated using the on-treatment observation period and the in-trial observation period. Definitions 
of “in-trial” and “on-treatment” observation periods are added in the statistical section.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
4 of 17
1.4
Definition of hypoglycaemia episodes
It has been clarified that hypoglycaemic episodes will be tabulated according to full ADA 
classifications of hypoglycaemic episodes.
1.5
Thyroidectomy
Thyroid neoplasms are already adjudicated centrally for this trial and the number of thyroid 
neoplasm cases is expected to be very low. Therefore all trial procedures related to collection and 
central reading of thyroid pathology slides are removed.
1.6
Retention of clinical trial documentation
Retention of site files has been changed to 15 years from 25 years to comply with updated Novo 
Nordisk Standard Operating Procedure.
1.7
Other change
Missing table note 8 in the flow chart is added to “Semaglutide plasma concentration”.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
5 of 17
2
Changes
2.1
Section 1 Summary
Trial design
This is a 52-week, randomised, double-blind, placebo-controlled, nine-armed sixteen-armed, 
parallel group, multi-centre, multinational trial comparing once-daily subcutaneous administration 
of semaglutide in five different doses (ranging from 0.05 mg/day to 0.4 mg/day) with placebo in 
obese subjects without diabetes mellitus. Liraglutide 3.0 mg/day is included as an active 
comparator. The trial is double-blinded between active and placebo treatment. The total trial 
duration for the individual subject will be approximately 60 weeks.
Subjects will be randomised in a balanced manner (6:1 active:placebo) for each of the 8 active 
treatment arms. The placebo arms are considered as one, giving a total of 9 arms.
2.2
Section 2 Flow chart
Table note 8 is added.
OTHER ASSESSEMENTS
Semaglutide plasma concentration8,9
(8.6.1)
X X X
X
X
X
X
X
X
8) Subjects must be instructed to withhold their trial product dose in the morning until blood sampling has been performed at the visit.
This is not applicable for subjects that have discontinued trial product. Samples taken at the follow-up visit (visit 21) must be taken 
fasting (as a minimum by only having consumed water for at least 2 hours).
2.3
Section 4.2.2 Secondary endpoints
Supportive secondary safety endpoints
!
Number of treatment-emergent AEs during the trial
!
Number of treatment-emergent severe or blood glucose confirmed symptomatic hypoglycaemic
episodes during the trial
!
Number of new and ongoing treatment-emergent nausea, vomiting, diarrhoea and constipation
events by week
!
Nausea:
−
Individual scores of nausea questionnaire
−
Severity by numeric rating scale (NRS) score
The safety endpoints above will be evaluated using the on-treatment observation period and the 
in-trial observation period based on the safety analysis set (see definition of observation periods in 
section17.4.2)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
6 of 17
2.4
Section 5.1 Type of trial
This is a 52-week, randomised, double-blind, placebo-controlled, nine-armed sixteen-armed, 
parallel group, multi-centre, multinational trial comparing once-daily subcutaneous administration 
of semaglutide in five different doses (ranging from 0.05 mg/day to 0.4 mg/day) with placebo in 
obese subjects without diabetes mellitus. Once-daily administration of two doses of semaglutide 
(0.3 mg/day and 0.4 mg/day) will be tested in a fast escalation regimen to investigate the effect of a 
different regimen on efficacy, safety and tolerability. Additionally, liraglutide 3.0 mg/day is 
included as an active comparator. The total trial duration for the individual subjects will be 
approximately 60 weeks. The trial includes a 1-week screening period, followed by a 52-week 
treatment period and a follow-up visit after 59 weeks.
2.5
Section 5.2 Rationale for trial design
The present trial is a 52-week, randomised, double-blind, placebo-controlled, nine-armed
sixteen-armed, parallel group, multi-centre, multinational trial. To avoid bias in the assessment of 
the different semaglutide doses and the liraglutide dose, the trial will be double-blinded within 
treatment arm to placebo. The treatment arms will not be blinded towards each other because of 
different dose escalations, different pens, and different target doses.
2.6
Section 8.3 Lab assessments
Samples, including samples for genetic testing and specific safety assessments, will be destroyed 
after further analysis on an on-going basis or at the latest at the completion of the clinical trial report 
(CTR). 
2.7
Section 8.7.2 Thyroidectomy
Subjects scheduled for thyroidectomy will be asked to inform the investigator prior to the operation.
Thyroidectomy pathology slides
In case a subject undergoes a thyroidectomy (partial or total) for any reason during the trial or after 
the trial secondary to an event reported during the trial, pathology slides of the thyroid tissue will be 
centrally reviewed in addition to the routine examination at the site level. A set of pathology slides, 
routinely made after thyroidectomies by the pathology laboratory of the hospital where the 
operation was performed, must be sent for a second reading with evaluation by a pathologist with 
expertise in thyroid and C-cell pathology, who will be blinded to both trial treatment and site 
diagnosis. Once the samples are re-examined they will be sent back to the site laboratory. Both the 
site pathology report and the central pathology report will be reviewed by an external independent 
event adjudication committee (EAC), see section 12.7.2. However, reports for thyroidectomies 
performed after the trial secondary to an event reported during the trial will not be reviewed by the 
EAC nor will the reports be part of the clinical trial database.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
7 of 17
Thyroid tissue sample collection in case of thyroidectomy
Subjects to undergo thyroidectomy will in addition be asked to consent to have a small sample of 
the removed thyroid tissue collected for testing of RET Y1062 phosphorylation in the thyroid 
C-cells. This is only applicable if C-cell pathology is confirmed (i.e., hyperplastic or neoplastic 
thyroid C-cells) confirmed by the EAC, and only if allowed by local law. The tissue sample will be 
destroyed after examination.
FOR ISRAEL ONLY: The RET Y1062 phosphorylation and genetic testing will not be performed 
for subjects in Israel.
Genetic testing in case of a confirmed C-cell pathology
Subjects scheduled for thyroidectomy will be asked to consent to be tested (blood sample) to 
identify germline RET gene mutations associated with multiple endocrine neoplasia syndrome type 
2 (MEN2). This RET gene mutation detection will be conducted in subjects with C-cell pathology 
(i.e., hyperplastic or neoplastic thyroid C-cells) confirmed by the EAC. Genetic testing will only be 
performed if allowed by local law and if the subject chooses to consent to it.
2.8
Section 17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock and unblinding of the trial.
Definition of Estimands
Effectiveness estimand
The primary estimand is an effectiveness estimand (de facto) quantifying the average treatment 
effect of once-daily semaglutide relative to placebo and liraglutide 3.0 mg after 52 weeks, as add-
on to nutritional and physical activity counselling, in all randomised subjects regardless of 
adherence to treatment.
Efficacy estimand
In addition, an efficacy estimand (de jure) is quantifying the average treatment effect of once-daily 
semaglutide relative to placebo and liraglutide 3.0 mg after 52 weeks, as add-on to nutritional and 
physical activity counselling, if all randomised subjects had adhered to the assigned treatment 
regimen for the entire planned duration of the trial.
Results from the statistical analysis will generally be presented by treatment differences with two-
sided 95% confidence intervals.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
23 August 2016
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
8 of 17
The full analysis set (FAS) will be used in the analysis of efficacy endpoints. For safety endpoints 
the safety analysis set will be used.
The 8 different placebo arms will be pooled into one placebo treatment arm in the main analyses. 
This pooling assumes that there is no substantial effect of different placebo volumes or different 
dose escalation on the efficacy and safety endpoints. The validity of this assumption will be 
checked for the primary endpoint by plotting mean data for the 8 placebo arms separately, and by 
evaluating summaries of treatment-emergent adverse events for each placebo arm. Should the
placebo arms demonstrate substantial differences, appropriate sensitivity analysis will be included.
The description of planned analysis given here assumes that all 8 placebo arms will be pooled into
one placebo arm.
For the statistical analysis of the primary endpoint, comparisons between each semaglutide 
dose/escalation arm, the liraglutide arm and their corresponding placebo arms will be performed 
in addition to comparisons with the pooled placebo arm. In general, the statistical analysis will be 
made by one statistical model estimation on the full dataset including all treatment arms. Statistical
inference and data presentations will be separated into two parts. Part A concerns identifying the 
optimal dose and includes inference for the liraglutide arm, the semaglutide arms with dose 
escalation every fourth week, the corresponding placebo arms and the pool of the placebo arms. 
Part B concerns identifying the optimal dose escalation regime and includes inference for the 
semaglutide arms with dose escalation every second week, the corresponding semaglutide arms 
(with regards to dose) with dose escalation every fourth week, the corresponding placebo arms and 
the pool of the placebo arms.
Descriptive statistics for all efficacy and safety endpoints are always presented for each of the 
randomised treatment arms and the pool of the placebo arms. Unless otherwise specified, the 
following sections describe the planned analyses using one pooled placebo arm.
The baseline value will be defined as the last measured and available value from visit 1 and 2.
In the case of missing data no general imputation will be performed for the analyses, unless 
otherwise specified.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
2.8.1
Section 17.1 Sample size calculation
For the primary endpoint change in body weight after 52 weeks of treatment, a difference 
(semaglutide minus placebo) of 9.5% is expected for completers (12% in the optimal dose group for
semaglutide vs. 2.5% in placebo). For the withdrawn subjects, who are anticipated to constitute up 
to 40% of the total trial population, the treatment difference (semaglutide minus placebo) is 
assumed to be 0% giving an overall expected treatment difference of 5.78.2% (8.2% in semaglutide 
vs. 2.5% in placebo). The standard deviation will also be increased using the MI approach. The 
standard deviation in the final data is assumed to be up to 8.42% (8.4% in semaglutide vs. 7.0% in 
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placebo). A standard deviation of up to 8.42% together with an expected difference of 5.78.2% 
results in a power of more than 99%, which is not corrected for multiple comparisons between 
different semaglutide arms and placebo.
2.8.2
Section 17.3 Primary endpoint
The primary endpoint, relative change from baseline in body weight (%) at 52 weeks, will be 
investigated using the following main analysis to compare between the randomised treatment arms 
using a multiple imputation (MI) analysis. The main analysis of the primary endpoint will also be 
referred to as the primary analysis as opposed to the sensitivity analysis of the primary endpoint. 
Week 52 data from subjects discontinued from trial product that return for visit 22x will be 
included. In this pattern mixture model approach withdrawn subjects without visit 22x from all 
treatment arms are assumed to respond as if treated with placebo for the entire trial. Multiple copies 
(100 copies) of the full dataset will be generated by imputing missing values (change from baseline 
in body weight (%) body weight (kg) at 52 weeks) based on estimated parameters for the placebo 
group. This will be done as follows:
−
In the first step, 100 copies of the dataset will be generated
−
In the second step, an enriched analysis of covariance (ANCOVA) model with treatment
region and sex as factors and baseline body weight, waist circumference, age and HbA1c as 
covariates is fitted to body weight (kg) the change from baseline in body weight (%) at 52 
weeks using only placebo subjects with non-missing body weight measurements at baseline 
and week 52 for the completers only
−
In the third step, for each of the 100 copies of the dataset the estimated parameters, and their 
variances, from this model are used to impute missing values at 52 weeks for subjects in all 
treatment arms, based on their region, sex, and body weight, waist circumference, age and 
HbA1c at baseline with treatment equal to placebo from the enriched model in step two
−
For each of the 100 complete data sets, the change from baseline in body weight (%) at 52 
weeks is analysed using an ANCOVA analysis of variance model with treatment (nine 
classes including one for pooled placebo), region, and sex as factors, and baseline body 
weight as a covariate
−
The estimates and standard deviations for the 100 data sets are pooled into one estimate and 
associated standard deviation using Rubin’s formula:
 =

		 ∑

		

,   =  
		 ∑


		

+ 1 +

		 

		 ∑
( −)
		

,
where mi and SDi are the estimated means and standard deviations for each of the 100 copies of the 
dataset, and mMI, SDMI are the pooled MI estimates.
−
From mMI and SDMI, the 95% confidence interval for the treatment differences and the 
associated p-value are calculated
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If 100 copies are not sufficient to establish stable results, a higher number will be used. The 
multiple imputations will be generated using Novo Nordisk trial number 95364153 as seed number.
Pairwise treatment differences between semaglutide doses and placebo, liraglutide and placebo, 
different semaglutide doses, and between semaglutide doses and liraglutide at week 52 will be 
estimated from the model and 95% confidence intervals will be calculated.
In part A, the comparisons of semaglutide doses vs. placebo will have the family wise type I error 
protected in the strong sense. This will be achieved by using Dunnett’s method in which 
simultaneous confidence intervals will be calculated. A significance level of 5% will be applied. 
Further, the focus of this part of the trial is to examine the dose response relationship. In part B, no 
multiplicity adjustment will be performed.
The dose of semaglutide providing a weight loss corresponding to liraglutide 3.0 mg will be 
estimated by fitting a linear approximation to the log dose vs. estimated means for the semaglutide 
doses and compare this to the estimated mean for liraglutide 3.0 mg. This analysis will be based on 
the estimated means and the covariance matrix for the means obtained from the MI analysis. 
Fieller’s method will be used to calculate 95% confidence limits for the estimated dose of 
semaglutide corresponding to liraglutide 3.0 mg. If a linear approximation does not describe the 
log(dose)-response relationship well, a different approximation (e.g. a sigmoidal curve) may be 
investigated.
The MI method does not assume missing at random. It assumes that withdrawn subjects and 
subjects with missing endpoint at week 52 in the placebo arm have a response similar to the 
completers in the placebo arm given similar baseline characteristics. In the active treatment arms, 
the assumption is that withdrawn subjects and subjects with missing endpoint at week 52 behave as 
if they have been in the placebo arm during entire trial regardless of the time of discontinuation. In 
this way the assumptions are differential and conservative for estimating the treatment effect. The 
estimate in the primary analysis can be said to be an intention to treat (ITT) estimand or an 
effectiveness estimand in all randomised subjects of the add-on effect of semaglutide to nutritional 
and physical activity counselling.
Based on previous trials in weight management the withdrawal rate from randomised treatment is 
expected to be up to 40%. Semaglutide treatment has in previous (T2DM) trials been effective with 
regard to weight loss, and this should reduce the number of withdrawals due to ineffective therapy. 
Based on previous experience, a higher rate of withdrawal of consent is expected in the placebo 
group compared to active treatment. This difference may be due to lack of efficacy with placebo 
treatment. A higher withdrawal rate due to gastrointestinal adverse events is expected in the high 
dose semaglutide treatment arms and the liraglutide 3.0 mg arm compared to placebo. Apart from 
this, missing data due to adverse events (AEs) is expected to be similar across groups. This 
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emphasises the validity of the primary analysis as a conservative analysis of the treatment effect of 
semaglutide.
The main analysis of the primary endpoint using the pool of the placebo arms will be repeated 
using the 8 different placebo arms. This supportive analysis includes comparisons between each 
semaglutide dose/escalation arm, the liraglutide arm and their corresponding placebo arms. As in 
the primary analysis, week 52 data from subjects discontinued from trial product that return for 
visit 22x will be included, and withdrawn subjects without visit 22x from all treatment arms are 
assumed to respond as if treated with placebo. In contrast to the primary analysis, a single 
imputation (SI) approach instead of MI will be used to handle missing body weight measurements 
at week 52, where subjects in each active treatment arm are imputed with the average of the 
corresponding placebo arm.
Pairwise treatment differences between each semaglutide dose/escalation arm, the liraglutide arm 
and their corresponding placebo arms at week 52 will be estimated from the model and the 95% 
confidence interval and associated p-value will be calculated.
For the supportive analysis, a dose-response analysis similar as for the primary analysis will be 
performed.
The sensitivity of the results with regard to different assumptions for missing data from withdrawn 
subjects will be investigated by plotting weight loss data for withdrawn subjects and compare this 
with plots of weight loss data for subjects completing 52 weeks of treatment. Further, for subjects 
that discontinue treatment but provide data at the week 52 visit (22x) plots will compare weight loss 
at last visit on treatment with weight loss at visit 22x. In addition, several sensitivity analyses will 
be performed where different assumptions are made with regard to withdrawn subjects.
The following sensitivity analyses will be performed to address the effectiveness estimand:
!
An ANCOVA model based on a multiple imputation approach as described by McEvoy40,
where missing body weight measurements at week 52 for discontinuing subjects are imputed
by sampling from values obtained from retrieved subjects in each randomisation arm and
according to the timing (monthly) of last available observation on randomised treatment
(LAO-OT). Missing body weight measurements at week 52 for subjects on treatment are
imputed by sampling from subjects completing treatment in the relevant randomisation arm.
Thus, the imputation model for each randomised treatment arm and timing of LAO-OT is a
linear regression of body weight (kg) at week 52 on the factors and covariates used in the
primary MI approach with no interactions and including LAO-OT of body weight as
covariate. If timing by month is too restricted, quarters, half-years, or excluding timing will
be used.
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The first sensitivity analysis assumes that withdrawn subjects, who return for visit 22x, are 
representative for subjects, who withdrew from the same randomised treatment but are not 
retrieved at week 52. Similarly, it is assumed that subjects, who complete the randomised treatment, 
are representative for subjects, who were randomised to the same treatment arm and have a 
missing week 52 body weight measurement due to other reasons than withdrawal from randomised 
treatment. 
!
A weighted ANCOVA model where returning treatment discontinuing subjects are up-
weighted relative to their proportion of all withdrawn subjects to account for the subjects
not returning for assessments at week 5240. Similar subjects with measurements at week 52
on treatment are up-weighted relative to their proportion of all subjects who completed
treatment with trial product. The up-weighing is done by randomisation arm and the timing
of LAO-OT. Subjects who are missing the body weight measurement at week52 are
assigned a weight of 0.
The second sensitivity analysis is based on the same assumptions as the first sensitivity analysis. In 
contrast, this weighted analysis can be carried out in situations where it is not possible to realise 
multiple imputation according to McEvoy40due to e.g. toofew available body weight 
measurements from retrieved subjects or the small size of the eight separateplacebo arms.
!
An ANCOVA modelisbased on a single imputation approach as done by Sacks41. Missing
body weight measurements at week 52 for withdrawn subjects are imputed using a weight
regain rate of 0.3kg/month after last available observation (LAO). Change from baseline is
truncated whenever the extrapolation would lead to a positive weight gain relative to
baseline. When a subject's body weight at discontinuation represented a gain in weight
relative to baseline, no additional gain will be imputed, but the unfavourable gain is carried
forward to week 52. Missing body weight measurements at week 52 for subjects on
treatment will be imputed using LAO. The weight regain imputation will be done for all
randomised arms. Additionally, a version where only the active arms use the regain rate
while the placebo arms use LAO (corresponding to a weight regain rate of0 kg/month) will
be performed.
The third sensitivity analysis assumes that subjects, who withdraw from randomised active or 
placebo treatment, lose any treatment effect linearly after discontinuation. In the additional version 
subjects discontinuing placebo treatment are assumed to experience no change in treatment effect 
since LAO.
!
An ANCOVA model is based on a tipping point approach. In a similar manner as above for
a range of weight regain rates (starting from 0.1 kg/month and in intervals of 0.1 kg/month)
for subjects in the active treatment arms, who discontinued treatment with trial product but
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Protocol Amendment
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Trial ID: NN9536-4153
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were not retrieved at week 52, will be used to define a tipping point in which superiority of 
semaglutide disappears. In this analysis, subjects on placebo will be imputed by LAO.
The fourth sensitivity analysis assumes that subjects, who withdraw from randomised active 
treatment, lose any treatment effect linearly after discontinuation and that subjects, who withdraw 
from randomised placebo treatment, experience no change in treatment effect since LAO.
Dose-response analysis will be repeated based on estimates derived from the first three sensitivity 
analyses.
1. An analysis of covariance (ANCOVA) model comparing the change from baseline in body
weight (%) at 52 weeks between treatments. Only on-treatment data will be included. Missing 
data at week 52 will be imputed from on-treatment data using the last observation carried 
forward (LOCF) method. The ANCOVA model will include treatment, region, and sex as 
factors, and baseline body weight as a covariate. This analysis corresponds to the primary 
analysis approach used in the liraglutide weight management development programme. 
2. An analysis of covariance (ANCOVA) model comparing the change from baseline in body
weight (%) at 52 weeks between treatments. All available data will be included. Missing data at 
week 52 will be imputed using the subject’s baseline observed weight carried forward (BOCF). 
The ANCOVA model will include treatment, region, and sex as factors, and baseline body 
weight as a covariate. This is a conservative analysis which will underestimate the differences 
between semaglutide/liraglutide and placebo.
The following model will be performed to address the efficacy estimand:
3. A mixed model for repeated measurements (MMRM) comparing the change from baseline in
body weight (%) at 52 weeks between treatments. All post randomisation measurements at
planned visits up to week 52 and obtained before withdrawal from treatment will be included in
the model as dependent variables. Treatment, region, and sex will be included as fixed factors,
and the baseline body weight will be included as a covariate. All factors and the covariate will
be nested under the factor visit. An unstructured covariance matrix will be used to describe the
variability for the repeated measurements for a subject. Subjects without post randomisation
measurements of weight will be excluded from the analysis.
The MMRM model assumes that withdrawn subjects, had they completed the trial, would not have 
behaved differently than completing subjects from the same treatment arm with the same baseline 
characteristic and change in body weight at time of withdrawal.
4. The primary analysis model (the MI) will be applied to data from subjects attending the end-of-
treatment visit in fasting state. Any non-fasting measurements will be treated as missing 
measurements.
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5. An analysis of covariance (ANCOVA) model comparing the change from baseline in body
weight (%) at 52 weeks between treatments including only subjects with data for week 52 on 
treatment (a completer analysis). The ANCOVA model will include treatment, region, and sex 
as factors, and baseline body weight as a covariate.
6. The primary analysis model (MI) will be applied where data from all withdrawn subjects are
imputed (i.e. data from visit 22x is disregarded).
Further sensitivity analysis may be added at time of reporting as deemed relevant.
The ANCOVA model with LOCF assumes that post treatment discontinuation, the body weight is 
on average stable in both treatment arms. This assumption can be evaluated over the 7 weeks 
follow-up period in withdrawn subjects and in completing subjects. If the assumption holds, the 
treatment effect (effectiveness estimand) in each arm and the treatment difference can be estimated 
from this analysis unbiased. If the withdrawal and the development in both arms are similar, the 
treatment difference can be estimated from this analysis unbiased. If the development in body 
weight after treatment discontinuations differs between active and placebo, this analysis might 
provide an optimistic or over-conservative estimate, depending on the actual circumstances. The 
analysis is included to be able to compare the results with legacy obesity programs, where this 
analysis was the main analysis of the primary endpoints.
The ANCOVA model with BOCF assumes that post treatment discontinuation subjects returns to a 
body weight in the proximity of their baseline body weight regardless of the timing of 
discontinuation. This analysis is expected to provide a conservative estimate (effectiveness 
estimand) of the treatment effect (in each arm). The impact of this assumption on the treatment 
difference depends on withdrawal pattern over time and development of body weight post treatment 
discontinuation and reason for withdrawal. The analysis is typically expected to provide a 
conservative estimate of the treatment difference (effectiveness estimand).
The MMRM model assumes that withdrawn subjects, had they completed the trial, would not have 
behaved differently than completing subjects from the same treatment arm with the same baseline 
characteristic and change in body weight at time of withdrawal. This analysis estimates the 
treatment effect and difference had all subjects stayed on the randomised treatment (efficacy 
estimand).
The MI model on fasting values examines the influence of not being fasting at the end-of-treatment 
visit. This analysis is expected to give similar treatment differences as the main analyses and 
estimate the same estimand.
The ANCOVA analysis in completers is expected to give more positive results than the primary 
analysis. However, this analysis has its own clinical interpretation and will serve as a benchmark 
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Date:
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Trial ID: NN9536-4153
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and provide an estimate of the efficacy estimand in the population that tolerate the trial product and 
endure the diet and exercise counselling program. 
The MI model disregarding visit 22x data examine the influence of data from withdrawn subjects 
returning at week 52 on the main analysis. It is difficult to postulate expectation on the results from 
this sensitivity analysis. The analysis estimates the same estimand as the primary analysis.
2.8.3
Section 17.4.1 Efficacy endpoints
Endpoints addressing glucose metabolism
Change from baseline to 52 weeks in:
!
HbA1c
!
FBG
!
Shift in gGlycaemic category (normoglycaemia, pre-diabetes, T2DM)
2.8.4
Section 17.4.2 Safety endpoints
All adverse events, hypoglycaemic episodes as well as nausea, vomiting, diarrhoea and 
constipation events will be classified and analysed as ‘in-trial’ and ‘on-treatment’.
In-trial is defined as the observation period from randomisation to last contact with trial site. On-
treatment is defined as the observation period from first trial product administration to last trial 
product administration with a 7 weeks ascertainment window.
The endpoint “Number of treatment-emergent adverse events during the trial” will be extensively 
described using descriptive statistics and listings.
All adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). An adverse event will be defined as treatment emergent if the onset of the 
adverse event is on or after the first day of trial product administration, and no later than whatever 
comes first of a) last drug date plus seven weeks or b) follow-up visit, or c) last study visit.
Treatment-emergent aAdverse events will be summarised by system organ class, preferred term, 
seriousness, severity and relation to trial product.
Endpoint addressing hypoglycaemic episodes:
The endpoint “Number of treatment-emergent severe or blood glucose-confirmed symptomatic 
hypoglycaemic episodes events” will be tabulated according to the ADA definition below. The 
remainder of the low blood glucose events (asymptomatic hypoglycaemic events) will be tabulated 
as well.
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Given that the trial population does not have T2DM at inclusion, the risk of developing 
hypoglycaemia is considered low and hence no blood glucose monitoring will be instituted. 
However, in case of severe hypoglycaemia where third party assistance is needed or in case of a low 
blood glucose value detected by scheduled blood sampling accompanied by relevant symptoms, the 
hypoglycaemic episode will qualify for the endpoint analysis.
ADA Classification of hypoglycaemic episodes events
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period on or after the first day of trial 
product administration, and no later than whatever comes first of a) last drug date plus seven weeks 
or b) follow-up visit, or c) last studyvisit.
The hypoglycaemic episodes will be categorised based on the ADA classification33of 
hypoglycaemia:
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not
be available during an event, but neurological recovery following the return of plasma glucose
to normal is considered sufficient evidence that the event was induced by a low plasma glucose
concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L (70
mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9
mmol/L (70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia
are not accompanied by a plasma glucose determination but that was presumably caused by a
plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Given that the trial population does not have T2DM at inclusion, the risk of developing 
hypoglycaemia is considered low and hence no blood glucose monitoring will be instituted. 
However, in case of severe hypoglycaemia where third party assistance is needed or in case of a 
low blood glucose value detected by scheduled blood sampling accompanied by relevant symptoms, 
the hypoglycaemic episode will qualify for the endpoint analysis.
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period. on or after the first day of trial 
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Trial ID: NN9536-4153
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product administration, and no later than whatever comes first of a) last drug date plus seven weeks 
or b) follow-up visit, or c) last study visit
Safety endpoints continued
The endpoint “Number of new and ongoing treatment-emergent nausea, vomiting, diarrhoea and
constipation events by week” will be summarised by week.
2.9
Section 18.2 Informed consent
In case a subject undergoes a thyroidectomy a separate informed consent will be obtained for 
collection of thyroid tissue sample and genetic testing (see section 8.7.2).
2.10
Section 24.1 Retention of clinical trial documentation
The files from the trial site/institution must be retained for 15 25 years after the completion of the 
trial, or longer if required by local regulations or Novo Nordisk. In any case, trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02453711 
Sponsor trial ID: 
NN9536-4153 
Official title of study: 
Investigation of safety and efficacy of once-daily semaglutide 
in obese subjects without diabetes mellitus 
Document date: 
24 October 2017 
 


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CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
1 of 21
Statistical Analysis Plan
Trial ID: NN9536-4153
Investigation of safety and efficacy of once-daily semaglutide
in obese subjects without diabetes mellitus
A 52-week, randomised, double-blind, placebo-controlled, sixteen-armed, parallel group,
multi-centre, multinational trial with liraglutide 3.0 mg as active comparator
Author:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
2 of 21
Table of contents   Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.2
Scope of the statistical analysis plan..........................................................................................5
2
Statistical considerations .....................................................................................................................5
2.1
Sample size calculation............................................................................................................6
2.2
Definition of analysis sets........................................................................................................8
2.3
Primary endpoint ....................................................................................................................8
2.4
Secondary endpoints .............................................................................................................12
2.4.1
Efficacy endpoints................................................................................................13
2.4.2
Safety endpoints...................................................................................................15
2.5
Pharmacokinetic and pharmacodynamic modelling............................................................17
3
Changes to the statistical analyses planned in the protocol..............................................................18
3.1
Deviation from analyses as described in the protocol:..............................................................18
3.2
Additional analyses not described in the protocol: ...................................................................20
4
References ..........................................................................................................................................21
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
3 of 21
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
Alanine aminotransaminase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
BMR
basal metabolic rate
CPK
creatine phosphokinase
C-SSRS
Columbia Suicidality Severity Rating Scale
CRF
case report form
CTR
clinical trial report
DPP-4
dipeptidyl peptidase 4
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FPFV
first patient first visit
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
HRQoL
health-related quality of life
hsCRP
High-sensitivity C reactive protein
ICMJE
International Committee of Medical Journal Editors
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
4 of 21
IEC
independent ethics committee
IRB
institutional review board
IWRS
interactive web response system
IWQoL-Lite
Impact of Weight on Quality of Life Lite
LDL
low density lipoprotein
LPLV
last patient last visit
MAR
missing at random
MESI
medical event of special interest
MHP
mental health professional
MMRM
mixed model for repeated measurements
NRS
numeric rating scale
PD
pharmacodynamic
PHQ-9
Patient Health Questionnaire-9
PK
pharmacokinetic
PRO
patient reported outcome
RET
re-arranged during transfection
SAE
serious adverse event
s.c.
subcutaneous(ly)
SF-36
Short Form-36
SMBG
self-measured blood glucose
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TEE
total energy expenditure
TMM
Trial Materials Manual
TSH
thyroid-stimulating hormone
UTN
Universal Trial Number
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
5 of 21
1
Introduction
1.1
Trial information
The trial  is a 52-week, randomised, double-blind, placebo-controlled, sixteen-armed, parallel 
group, multi-centre, multinational trial comparing once-daily subcutaneous administration of 
semaglutide in five different doses (ranging from 0.05 mg/day to 0.4 mg/day) with placebo in obese 
subjects without diabetes mellitus. Once-daily administration of two doses of semaglutide (0.3 
mg/day and 0.4 mg/day) will be tested in a fast escalation regimen to investigate the effect of a 
different regimen on efficacy, safety and tolerability. Additionally, liraglutide 3.0 mg/day is 
included as an active comparator. The total trial duration for the individual subjects will be 
approximately 60 weeks. The trial includes a 1-week screening period, followed by a 52-week 
treatment period and a follow-up visit after 59 weeks.
1.2
Scope of the statistical analysis plan
This SAP is based on the protocol “Investigation of safety and efficacy of once-daily semaglutide in 
obese subjects without diabetes mellitus”, version 3.0, and amendment 3.
The SAP contains the statistical section 17 from the protocol with some clarifications as a few non-
substantial changes where needed. Technical and detailed elaborations of the statistical analyses are
specified in the protocol and the SPS.
2
Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before
database lock and unblinding of the trial.
Definition of Estimands
Effectiveness estimand
The primary estimand is an effectiveness estimand (de facto) quantifying the average treatment 
effect of once-daily semaglutide relative to placebo and liraglutide 3.0 mg after 52 weeks, as add-on 
to nutritional and physical activity counselling, in all randomised subjects regardless of adherence 
to treatment.
Efficacy estimand
In addition, an efficacy estimand (de jure) is quantifying the average treatment effect of once-daily 
semaglutide relative to placebo and liraglutide 3.0 mg after 52 weeks, as add-on to nutritional and 
physical activity counselling, if all randomised subjects had adhered to the assigned treatment 
regimen for the entire planned duration of the trial.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
6 of 21
Results from the statistical analysis will generally be presented by treatment differences with two-
sided 95% confidence intervals.
The full analysis set (FAS) will be used in the analysis of efficacy endpoints. For safety endpoints 
the safety analysis set will be used.
The 8 different placebo arms will be pooled into one placebo treatment arm in the main analyses. 
This pooling assumes that there is no substantial effect of different placebo volumes or different 
dose escalation on the efficacy and safety endpoints. The validity of this assumption will be 
checked for the primary endpoint by plotting mean data for the 8 placebo arms separately, and by 
evaluating summaries of adverse events for each placebo arm. 
For the statistical analysis of the primary endpoint, comparisons between each semaglutide 
dose/escalation arm, the liraglutide arm and their corresponding placebo arms will be performed in 
addition to comparisons with the pooled placebo arm. Statistical inference and data presentations 
will be separated into two parts. Part A concerns identifying the optimal dose and includes inference 
for the liraglutide arm, the semaglutide arms with dose escalation every fourth week, the 
corresponding placebo arms and the pool of the placebo arms. Part B concerns identifying the 
optimal dose escalation regime and includes inference for the semaglutide arms with dose 
escalation every second week, the corresponding semaglutide arms (with regards to dose) with dose 
escalation every fourth week, the corresponding placebo arms and the pool of the placebo arms.
Descriptive statistics for all efficacy and safety endpoints are always presented for each of the 
randomised treatment arms and the pool of the placebo arms. Unless otherwise specified, the 
following sections describe the planned analyses using one pooled placebo arm.
The baseline value will be defined as the last measured and available value from visit 1 and 2.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
2.1
Sample size calculation
The sample size calculation is based on the primary endpoint; change from baseline in body weight 
(%) at 52 weeks.
Part A is a dose-finding trial examining five doses of semaglutide and placebo, and an active 
comparator. The sample size calculation is based on the relative change after 52 weeks treatment in 
the primary endpoint, body weight. In the sample size calculations, it is presumed that the placebo 
groups will be pooled in the analysis, assuming no correlation between body weight change after 52 
weeks and placebo-injected volume. By trial design we expect to have 135 subjects on placebo and 
100 in each active group. In the unfortunate situation that we should not be able to pool all placebo 
arms but only be able to pool the (semaglutide) placebo arms with dose escalation every fourth 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
7 of 21
week and (liraglutide) placebo, we will still expect to have at least 100 subjects in the relevant pool 
of placebo subjects. Hence the argumentation below only assumes 100 subjects in the placebo arm 
in a conservative manner and for simplicity. However, at time of analysis we plan to include all 
subjects on placebo as one group in the analysis as described above, if possible.
The following assume 100 subjects randomised in a balanced manner to receive each active 
treatment and being conservative at least 100 evaluable subjects in the placebo arm. In trial 
NN8022-1839, in obese subjects without T2DM a standard deviation of just below 7% was seen for 
observed weight loss (in %) in the liraglutide 3.0 mg arm. A conservative estimate of the dropout 
rate is 40%. A standard deviation of 7% and a sample size of 100 in each treatment arm will allow 
the 95% confidence interval for the estimated difference between two semaglutide doses, with 90% 
probability, to be contained within ±2.5% of the estimate, which is considered to be a sufficient 
precision for determining which doses to use for the continued development of semaglutide in the 
weight management indication.
For the primary endpoint change in body weight after 52 weeks of treatment, a difference 
(semaglutide minus placebo) of 9.5% is expected for completers (12% in the optimal dose group for 
semaglutide vs. 2.5% in placebo). For the withdrawn subjects, who are anticipated to constitute up 
to 40% of the total trial population, the treatment difference (semaglutide minus placebo) is 
assumed to be 0% giving an overall expected treatment difference of 5.7% (8.2% in semaglutide vs. 
2.5% in placebo). The standard deviation will also be increased using the MI approach. The 
standard deviation in the final data is assumed to be up to 8.4% (8.4% in semaglutide vs. 7.0% in 
placebo. A standard deviation of up to 8.4% together with an expected difference of 5.7% results in 
a power of more than 99%, which is not corrected for multiple comparisons between different 
semaglutide arms and placebo.
For part B, in total two times 100 subjects will be randomised to the dose escalation every second 
week. Combined with placebo and the two doses corresponding to the ‘every second week’ arms 
(i.e. 0.3 mg/day and 0.4 mg/day) we will have more than five hundred subjects for the inference of 
the dose escalation finding part of the trial. In trial NN8022-1839, nausea, vomiting, and 
constipation were the most common gastrointestinal AEs with incidences between 15% and 40% of 
all subjects on liraglutide 3.0 mg. These AEs are not expected to be less frequent with semaglutide. 
This part of the trial is exploratory in nature and is intended to evaluate the overall safety profile 
with respect to the different types of events and when they occur compared to the escalation steps 
and with a view towards the efficacy response as well. With the given number of subjects, we have 
a reasonable sample size to detect marked clinical relevant difference between the arms.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
8 of 21
2.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E91guidance:
!
The full analysis set (FAS) will include all randomised subjects. Only in exceptional cases may
subjects be excluded from the FAS. In such cases the reason for exclusion will be justified and
documented. Subjects in the FAS will contribute to the evaluation ‘as randomised’.
!
The safety analysis set will include all subjects receiving at least one dose of randomised
treatment. Subjects in the safety analysis set will contribute to the evaluation ‘as treated’.
Any subjects or observations excluded from analysis, and the reason for exclusion will be described 
in the CTR.
2.3
Primary endpoint
The primary endpoint, relative change from baseline in body weight (%) at 52 weeks, will be 
investigated using the following main analysis to compare between the randomised treatment arms 
using a multiple imputation (MI) analysis. The main analysis of the primary endpoint will also be 
referred to as the primary analysis as opposed to the sensitivity analysis of the primary endpoint. 
Week 52 data from subjects discontinued from trial product that return for visit 22x will be 
included. In this pattern mixture model approach withdrawn subjects without visit 22x from all 
treatment arms are assumed to respond as if treated with placebo for the entire trial. Multiple copies 
(100 copies) of the full dataset will be generated by imputing missing values (body weight (kg) at 
52 weeks) based on estimated parameters for the placebo group. This will be done as follows:
!
In the first step, 100 copies of the dataset will be generated
!
In the second step, an analysis of covariance (ANCOVA) model with region and sex as factors
and baseline body weight as covariates is fitted to body weight (kg) at 52 weeks using only
placebo subjects with non-missing body weight measurements at baseline and week 52
!
In the third step, for each of the 100 copies of the dataset the estimated parameters, and their
variances, from this model are used to impute missing values at 52 weeks for subjects in all
treatment arms, based on their region, sex and body weight at baseline from the model in step
two
!
For each of the 100 complete data sets, the change from baseline in body weight (%) at
52 weeks is analysed using an ANCOVA model with treatment (nine classes including one for
pooled placebo), region, and sex as factors, and baseline body weight as a covariate
!
The estimates and standard deviations for the 100 data sets are pooled into one estimate and
associated standard deviation using Rubin’s formula:
m = 1
100 
m,


SD =  1
100 
SD



+ 1 + 1
100
1
100 −1
(m −m)


,
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
9 of 21
where m and SD are the estimated means and standard deviations 
              for the 100 copies of the dataset, and m,
SD are the pooled estimates.
!
From m and SD, the 95% confidence interval for the treatment differences and the 
associated p-value are calculated
If 100 copies are not sufficient to establish stable results, a higher number will be used. The 
multiple imputations will be generated using Novo Nordisk trial number 95364153 as seed number.
Pairwise treatment differences between semaglutide doses and placebo, liraglutide and placebo, 
different semaglutide doses, and between semaglutide doses and liraglutide at week 52 will be 
estimated from the model and 95% confidence intervals will be calculated.
In part A, the comparisons of semaglutide doses vs. placebo will have the family wise type I error 
protected in the strong sense. This will be achieved by using Dunnett’s method in which 
simultaneous confidence intervals will be calculated. A significance level of 5% will be applied. 
Further, the focus of this part of the trial is to examine the dose response relationship. In part B, no 
multiplicity adjustment will be performed.
The dose of semaglutide providing a weight loss corresponding to liraglutide 3.0 mg will be 
estimated by fitting a linear approximation to the log dose vs. estimated means for the semaglutide 
doses and compare this to the estimated mean for liraglutide 3.0 mg. This analysis will be based on 
the estimated means and the covariance matrix for the means obtained from the MI analysis. 
The delta method will be used to calculate 95% confidence limits for the estimated dose of 
semaglutide corresponding to liraglutide 3.0 mg. If a linear approximation does not describe the 
log(dose)-response relationship well, a different approximation (e.g. a sigmoidal curve) may be 
investigated.
The MI method does not assume missing at random. It assumes that withdrawn subjects and 
subjects with missing endpoint at week 52 in the placebo arm have a response similar to the 
completers in the placebo arm given similar baseline characteristics. In the active treatment arms, 
the assumption is that withdrawn subjects and subjects with missing endpoint at week 52 behave as 
if they have been in the placebo arm during entire trial regardless of the time of discontinuation. In 
this way the assumptions are differential and conservative for estimating the treatment effect. 
Based on previous trials in weight management the withdrawal rate from randomised treatment is 
expected to be up to 40%. Semaglutide treatment has in previous (T2DM) trials been effective with 
regard to weight loss, and this should reduce the number of withdrawals due to ineffective therapy. 
Based on previous experience, a higher rate of withdrawal of consent is expected in the placebo 
group compared to active treatment. This difference may be due to lack of efficacy with placebo 
treatment. A higher withdrawal rate due to gastrointestinal adverse events is expected in the high 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
10 of 21
dose semaglutide treatment arms and the liraglutide 3.0 mg arm compared to placebo. Apart from 
this, missing data due to adverse events (AEs) is expected to be similar across groups. This 
emphasises the validity of the primary analysis as a conservative analysis of the treatment effect of 
semaglutide.
The main analysis of the primary endpoint using the pool of the placebo arms will be repeated using 
the 8 different placebo arms. This supportive analysis includes comparisons between each 
semaglutide dose/escalation arm, the liraglutide arm and their corresponding placebo arms. As in 
the primary analysis, week 52 data from subjects discontinued from trial product that return for visit 
22x will be included, and withdrawn subjects without visit 22x from all treatment arms are assumed 
to respond as if treated with placebo. In contrast to the primary analysis, a single imputation (SI) 
approach instead of MI will be used to handle missing body weight measurements at week 52, 
where subjects in each active treatment arm are imputed with the average of the corresponding 
placebo arm.
Pairwise treatment differences between each semaglutide dose/escalation arm, the liraglutide arm 
and their corresponding placebo arms at week 52 will be estimated from the model and the 95% 
confidence interval and associated p-value will be calculated.
For the supportive analysis, a dose-response analysis similar as for the primary analysis will be 
performed.
The sensitivity of the results with regard to different assumptions for missing data from withdrawn 
subjects will be investigated by plotting weight loss data for withdrawn subjects and compare this 
with plots of weight loss data for subjects completing 52 weeks of treatment. Further, for subjects 
that discontinue treatment but provide data at the week 52 visit (22x) plots will compare weight loss 
at last visit on treatment with weight loss at visit 22x. In addition, several sensitivity analyses will 
be performed where different assumptions are made with regard to withdrawn subjects. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
11 of 21
The following sensitivity analyses will be performed to address the effectiveness estimand:
An ANCOVA model based on a multiple imputation approach as described by McEvoy2, where
missing body weight measurements at week 52 for discontinuing subjects are imputed by sampling 
from values obtained from retrieved subjects in each randomisation arm and according to the timing 
(monthly) of last available observation on randomised treatment (LAO-OT). Missing body weight 
measurements at week 52 for subjects on treatment are imputed by sampling from subjects 
completing treatment in the relevant randomisation arm. Thus, the imputation model for each 
randomised treatment arm and timing of LAO-OT is a linear regression of body weight (kg) at week 
52 on the factors and covariates mentioned above (except treatment) with no interactions and 
including LAO-OT of body weight as covariate. If timing by month is too restricted, quarters, half-
years, or excluding timing will be used.
The first sensitivity analysis assumes that withdrawn subjects, who return for visit 22x, are 
representative for subjects, who withdrew from the same randomised treatment but are not retrieved 
at week 52. Similarly, it is assumed that subjects, who complete the randomised treatment, are 
representative for subjects, who were randomised to the same treatment arm and have a missing 
week 52 body weight measurement due to other reasons than withdrawal from randomised 
treatment.
A weighted ANCOVA model where returning treatment discontinuing subjects are up-weighted 
relative to their proportion of all withdrawn subjects to account for the subjects not returning for 
assessments at week 522. Similar subjects with measurements at week52 on treatment are up-
weighted relative to their proportion of all subjects who completed treatment with trial product. The 
up-weighing is done by randomisation arm and the timing of LAO-OT. Subjects who are missing 
the body weight measurement at week 52are assigned a weight of 0.
The second sensitivity analysis is based on the same assumptions as the first sensitivity analysis. In 
contrast, this weighted analysis can be carried out in situations where it is not possible to realise 
multiple imputation according to McEvoy2due to e.g. too few available body weight measurements 
from retrieved subjects or the small size of the eight separate placebo arms.
An ANCOVA model is based on a single imputation approach as done by Sacks3. Missing body 
weight measurements at week 52 for withdrawn subjects are imputed using a weight regain rate of 
0.3 kg/month after last available observation (LAO). Change from baseline is truncated whenever 
the extrapolation would lead to a positive weight gain relative to baseline. When a subject's body 
weight at discontinuation represented a gain in weight relative to baseline, no additional gain will be 
imputed, but the unfavourable gain is carried forward to week 52. Missing body weight 
measurements at week 52 for subjects on treatment will be imputed using LAO. The weight regain 
imputation will be done for all randomised arms. Additionally, a version where only the active arms 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
12 of 21
use the regain rate while the placebo arms use LAO (corresponding to a weight regain rate of 0 
kg/month) will be performed.
The third sensitivity analysis assumes that subjects, who withdraw from randomised active or 
placebo treatment, lose any treatment effect linearly after discontinuation. In the additional version 
subjects discontinuing placebo treatment are assumed to experience no change in treatment effect 
since LAO.
An ANCOVA model is based on a tipping point approach. In a similar manner as above for a range 
of weight regain rates (starting from 0.1 kg/month and in intervals of 0.1 kg/month) for subjects in 
the active treatment arms, who discontinued treatment with trial product but were not retrieved at 
week 52, will be used to define a tipping point in which superiority of semaglutide disappears. In 
this analysis, subjects on placebo will be imputed by LAO.
The fourth sensitivity analysis assumes that subjects, who withdraw from randomised active 
treatment, lose any treatment effect linearly after discontinuation and that subjects, who withdraw 
from randomised placebo treatment, experience no change in treatment effect since LAO.
Dose-response analysis will be repeated based on estimates derived from the first three sensitivity 
analyses. 
The following model will be performed to address the efficacy estimand:
!
A mixed model for repeated measurements (MMRM) comparing the change from baseline in
body weight (%) at 52 weeks between treatments. All post randomisation measurements at
planned visits up to week 52 and obtained before withdrawal from treatment will be included in
the model as dependent variables. Treatment, region, and sex will be included as fixed factors,
and the baseline body weight will be included as a covariate. All factors and the covariate will
be nested under the factor visit. An unstructured covariance matrix will be used to describe the
variability for the repeated measurements for a subject. Subjects without post randomisation
measurements of weight will be excluded from the analysis.
The MMRM model assumes that withdrawn subjects, had they completed the trial, would not have 
behaved differently than completing subjects from the same treatment arm with the same baseline 
characteristic and change in body weight at time of withdrawal.
2.4
Secondary endpoints
For statistical analysis of secondary endpoints, when mentioned below, the analyses methods 
reproduce the main analysis of the primary endpoint by the same MI approach. The endpoint at 
baseline will replace body weight at baseline as covariate. The statistical methodology depends on 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
13 of 21
the type of endpoint, but the model factors and covariates are similar to those specified for the 
primary analysis.
2.4.1
Efficacy endpoints
Descriptive statistics for efficacy endpoint will be tabulated using on-treatment period defined as 
the period from first trial product administration to last trial product administration. 
Endpoints addressing weight loss
!
Proportion (%) of subjects with weight loss of ≥ 5% of baseline body weight at 52 weeks
!
Proportion (%) of subjects with weight loss of ≥ 10% of baseline body weight at 52 weeks
These two dichotomous endpoints will be compared between the treatment arms using a MI 
approach as in the primary analysis based on a logistic regression. The datasets from the primary 
analysis will be reused for this analysis where imputed values for change in body weight will be 
used to generate the dichotomous endpoints. Pairwise treatment differences between treatments will 
be estimated from the model and 95% confidence intervals will be calculated.
Change from baseline to 52 weeks in:
!
Body weight (kg)
!
Waist circumference (cm)
!
Waist to hip circumference ratio (waist (cm)/hip (cm))
!
BMI (kg/m2)
These endpoints will be compared between treatments using the MI approach used for the main 
analysis of the primary endpoint (with the corresponding baseline value as covariate).
Endpoints addressing glucose metabolism
Change from baseline to 52 weeks in:
!
HbA1c
!
FPG
!
Glycaemic category (normoglycaemia, pre-diabetes, T2DM)
The endpoints HbA1c and FPG will be compared between treatments using the MI approach used 
for the main analysis of the primary endpoint (with the corresponding baseline value as covariate). 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
14 of 21
Endpoints addressing cardiovascular risk factors
Change from baseline to 52 weeks in:
!
Systolic and diastolic blood pressure
!
Lipids (total cholesterol [TC], low density lipoprotein cholesterol [LDL cholesterol], high
density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein cholesterol
[VLDL cholesterol], triglycerides [TG], free fatty acids [FFA])
!
Cardiovascular biomarker (high sensitivity C reactive protein [hsCRP])
These endpoints will be compared between treatments using the MI approach used for the main 
analysis of the primary endpoint (with the corresponding baseline value as covariate). For lipids and 
hsCRP a multiplicative model will be used, i.e. the ratio between post randomisation measurements 
and baseline will be calculated instead of differences, and both the dependent variable and covariate 
will be log-transformed. Estimates and CI will be presented as percentage change from baseline.
Endpoints addressing patient reported weight-related quality of life and general health status
Change from baseline to 52 weeks in:
!
Impact of Weight on Quality of Life-Lite (IWQoL-Lite) for Clinical Trials: individual items
!
Short form-36 (SF-36): Physical and mental component summary scores and scores on the
individual sub-domains: Physical functioning, role functioning, bodily pain, general health,
vitality, social functioning, role emotional and mental health
These endpoints will be compared between treatments using the MI approach used for the main 
analysis of the primary endpoint (with the baseline total score as covariate).
Endpoints addressing changes in antihypertensive and lipid-lowering medical treatment
Change from baseline to 52 weeks in:
Proportion of subjects with change in concomitant medications:
!
Antihypertensive medications
!
Lipid-lowering medications
The endpoint is based on the evaluations made by the investigators and recorded according to the 
description in the protocol.The proportion of subjects with any change (decrease / no change /
increase) in dose and/or drug within the two above classes will be calculated and described. 
Endpoint addressing nutritional compliance
Compliance with nutritional counselling will be summarised by week.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
15 of 21
Analysis identifying early responders
!
Predictability of weight loss of more than 5% at week 52 by early weight loss response (3%,
4%, and 5%) after 12, 16, and 20 weeks
The ability of early weight loss of 3%, 4%, and 5% at week 12, 16, 20 to predict long term weight 
loss (5% at week 52) will be described by sensitivity, specificity, positive predictive value, and 
negative predictive value. Receiver operating curve (ROC) will be presented for weight loss at 
week 12, 16 and 20. The analysis will be repeated seperately for each treatment arm.
2.4.2
Safety endpoints
All adverse events, hypoglycaemic episodes as well as nausea, vomiting, diarrhoea and constipation 
events will be classified and analysed as ‘in-trial’ and ‘on-treatment’. 
In-trial is defined as the observation period from randomisation to last contact with trial site. On-
treatment is defined as the observation period from first trial product administration to last trial 
product administration with a 7 weeks ascertainment window. 
The endpoint “Number of adverse events during the trial” will be extensively described using 
descriptive statistics and listings.
All adverse events will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
Adverse events will be summarised by system organ class, preferred term, seriousness, severity and 
relation to trial product.
Endpoint addressing hypoglycaemic episodes:
The endpoint “Number of hypoglycaemic episodes” will be tabulated according to the ADA 
definition below. 
ADA Classification of hypoglycaemic episodes
The hypoglycaemic episodes will be categorised based on the ADA classification4
of hypoglycaemia:
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not
be available during an event, but neurological recovery following the return of plasma glucose
to normal is considered sufficient evidence that the event was induced by a low plasma glucose
concentration.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
16 of 21
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L (70
mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9
mmol/L (70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia
are not accompanied by a plasma glucose determination but that was presumably caused by a
plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Given that the trial population does not have T2DM at inclusion, the risk of developing 
hypoglycaemia is considered low and hence no blood glucose monitoring will be instituted. 
However, in case of severe hypoglycaemia where third party assistance is needed or in case of a low 
blood glucose value detected by scheduled blood sampling accompanied by relevant symptoms, the 
hypoglycaemic episode will qualify for the endpoint analysis.
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period. 
Safety endpoints continued
The endpoint “Number of new and ongoing nausea, vomiting, diarrhoea and constipation events by 
week” will be summarised by week.
Nausea:
!
Individual scores of nausea questionnaire
!
Severity by numeric rating scale (NRS) score
Nausea questionnaire and NRS score will be summarised by week.
Changes from baseline to 52 weeks in:
!
EGG
!
Pulse
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
17 of 21
!
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, differential
count)
!
Biochemistry (creatinine, CPK, urea, albumin, bilirubin [total], ALT, AST, alkaline
phosphatase, sodium, potassium, calcium [total], amylase, lipase, calcitonin, TSH)
!
Mental health assessed by Columbia Suicidality Severity Rating Scale (C-SSRS) and Patient
Health Questionnaire-9 (PHQ-9)
will be summarised and described for each treatment arm. Changes in pulse will be compared 
between treatments using an MMRM model as described under sensitivity analysis (with the 
baseline pulse value as covariate) based on the safety analysis set. For amylase and lipase two 
statistical analyses will be applied, respectively. The relative change (100*value/baseline) will be 
analysed with an MMRM model as described under sensitivity analysis. The relative change and 
baseline values will be log-transformed prior to the analysis. 
The endpoint “Anti-semaglutide antibodies during and after treatment” will be described by 
summarising the number and percentage of subjects with antibodies in the different treatment arms. 
Similarly, subjects with semaglutide antibodies with neutralising effect and with cross-reactivity 
against endogenous GLP-1 will be described by summaries. The primary endpoint will be 
summarised by anti-semaglutide antibody status (positive or negative) at follow-up.
2.5
Pharmacokinetic and pharmacodynamic modelling
Exploratory population PK and PK/PD modelling will be used to evaluate the semaglutide dose-
exposure, the effects of pre-specified covariates on the exposure and the semaglutide exposure-
response on selected efficacy and safety parameters. For the covariate analysis, covariates such as 
sex, body weight and age will be explored.
The population PK modelling will include data from all randomised subjects that were exposed to 
semaglutide, excluding data records with concentration values missing or below LLOQ, and data 
records with incomplete or ambiguous dosing information. Actual time points for dose 
administration and PK sampling will be used. PK/PD modelling will include data from subjects 
included in the population PK modelling, with relevant PD assessments available. 
Results of the modelling analysis will be presented using criteria which will be pre-specified in a 
modelling analysis plan that is to be finalised before database lock (DBL). The modelling will be 
performed by Quantitative Clinical Pharmacology at Novo Nordisk A/S and will be reported 
separately from the CTR.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
18 of 21
3
Changes to the statistical analyses planned in the protocol
3.1
Deviation from analyses as described in the protocol:
!
No summary/analysis of IWQoL scores since questionnaire is not validated yet (will be
validated after DBL)
The following text:
“Impact of Weight on Quality of Life-Lite (IWQoL-Lite) for Clinical Trials: Total score and scores 
on the individual sub-domains”
has been replaced by:
“Impact of Weight on Quality of Life-Lite (IWQoL-Lite) for Clinical Trials: Individual items”
!
No logistic regression for amylase/lipase outliers since there are either no or too few
observations in category >3x UNR
The following text has been deleted:
“Subjects having a measurement above >3x UNR anytime during treatment (yes/no) will be 
analysed using a logistic regression. For the evaluation of the response, all measurements obtained 
during treatment will be included and these measurements are defined as any scheduled or 
unscheduled measurements obtained from, but not including, baseline and until, and including, end 
of treatment. Separate analyses will be made for amylase and lipase. The results will be presented 
as odds ratios together with the associated 95% confidence intervals.”
!
No ordinal logistic regression for change in antihypertensive or lipid-lowering medications   due
to too few subjects changing this type of medication  during the trial
The following text has been deleted:
”These endpoints will be compared between treatments using the proportional odds model (or 
ordinal logistic regression). Only on-treatment data will be considered. Subjects not using drugs 
within the specified categories will count as no-change. The model factors and covariates will be 
identical to the main analysis model.”
!
Glycaemic categorisation will not be reported, since the categorisation is not aligned with the
usual diagnosis criteria which require repeated testing to confirm the diagnosis and allows for
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
19 of 21
the diagnosis to be made based on random glucose assessments and/or 2-hour glucose 
assessments during an oral glucose tolerance test.
The following text:
“Change from baseline to 52 weeks in:
!
HbA1c
!
FPG
!
Glycaemic category (normoglycaemia, pre-diabetes, T2DM)”
has been replaced by
“Change from baseline to 52 weeks in:
!
HbA1c
!
FPG”
Furthermore the following text has been deleted:
“Glycaemic categories
Normoglycaemia:
!
FPG < 5.6 mmol/L (100 mg/dL) and HbA1c < 5.7%
Pre-diabetes:
!
FPG 5.6-6.9 mmol/L (100-125 mg/dL) (both inclusive) and HbA1c ≤ 6.4%
or
!
FPG ≤ 6.9 mmol/L (125 mg/dL) and HbA1c 5.7-6.4% (both inclusive)
T2DM:
!
FPG ≥ 7.0 mmol/L (126 mg/dL) and/or HbA1c ≥ 6.5%”
and the following text has been deleted:
“Shift in glycaemic category will be compared between treatments using the proportional odds 
model (or ordinal logistic regression) and imputing missing measurements in the same fashion as 
used for the main analysis of the primary endpoint.”
!
Delta method instead of Fieller’s method to calculate confidence intervals in dose-response
modelling due to problem with the implementation of Fieller’s method
The following text:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
20 of 21
“Fieller’s method will be used to calculate 95% confidence limits for the estimated dose of 
semaglutide corresponding to liraglutide 3.0 mg.”
has been replaced by:
“The delta method will be used to calculate 95% confidence limits for the estimated dose of 
semaglutide corresponding to liraglutide 3.0 mg.”
!
Clarification that the on-treatment observation period for safety endpoints includes an
ascertainment window, whereas the on-treatment observation for efficacy endpoints does not.
The following text has been added:
“Descriptive statistics for efficacy endpoint will be tabulated using on-treatment period defined as 
the period from first trial product administration to last trial product administration.”
3.2
Additional analyses not described in the protocol:
!
Dose-response modelling for GI AEs and body weight responder to support risk-benefit
discussion
Analyses of the dose-response for the proportion of subjects meeting three different response 
criteria:
!
Discontinued due to a gastro-intestinal adverse event (on-treatment).
!
Having a gastro-intestinal adverse event (on-treatment)
!
Meeting the weight loss threshold of 5% at week 52 (in-trial)
Data from the fast escalation regimens will not be used in these analyses. Pooled data from the 
placebo arms (corresponding to a dose of zero mg) will be included if deemed appropriate. 
The model will be developed ad hoc after un-blinding of the data and aim for an appropriate fit of 
the dose-response relation versus dose or log(dose) with a logistic dose-response relation as the 
default option. If placebo is included in the analyses and log(dose) provides the best fit the dose of 
placebo will arbitrarily be set to a small value (e.g. 0.001 mg). 
For the on-treatment analyses, the dose-response analysis will be modelled via a logistic regression 
of the response status (Y/N) per patient with dose level as covariate. The response status of each 
patient will be based on what is observed while the patient is on treatment, i.e. on whether a patient 
discontinues treatment due to a gastro-intestinal AE or experiences such an AE while on treatment. 
Hence, no imputation will be conducted and intercept and regression coefficient will be estimated 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 May 2017
1RYR1RUGLVN
Trial ID: NN9536-4153
Version:
1.0
UTN: U1111-1155-4660
Status:
Final
EudraCT No.: 2014-001540-38
Page:
21 of 21
from a single analysis of the observed data. The resulting coefficients of interest comprise the 
intercept and the regression coefficient on dose from the logistic regression model.
The in-trial dose-response analysis of weight loss exceeding 5% will be based on estimated 
treatment log-odds obtained via logistic regression on datasets generated for the primary analysis
using multiple imputations for change in body weight. The coefficients for the logistic dose-
response model will be obtained from a linear regression using dose as an independent variable and 
estimated log-odds as the dependent variable.
If the logistic regression for 5% body weight responders cannot be fitted (e.g. due to too many 
subjects fulfilling this criteria) the 5% threshold will be replaced by a threshold of 10%.
4
References
1.
Phillips A, Haudiquet V. ICH E9 guideline 'Statistical principles for clinical trials': a case
study. Stat Med. 2003;22(1):1-11; discussion 3-7.
2.
McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat.
2016;26(1):30-6.
3.
Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of
weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J
Med. 2009;360(9):859-73.
4.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia
and diabetes: a report of a workgroup of the American Diabetes Association and the
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
1 of 10
Statistical documentation – sample size calculation
Assumptions and results
The sample size calculation is based on the primary endpoint; change from baseline in 
body weight (%) at 52 weeks.
Part A is a dose-finding trial examining five doses of semaglutide and placebo, and an 
active comparator. The sample size calculation is based on the relative change after 52 
weeks treatment in the primary endpoint, body weight. In the sample size calculations, it 
is presumed that the placebo groups will be pooled in the analysis, assuming no 
correlation between body weight change after 52 weeks and placebo-injected volume. By 
trial design we expect to have 135 subjects on placebo and 100 in each active group. In 
the unfortunate situation that we should not be able to pool all placebo arms but only be 
able to pool the (semaglutide) placebo arms with dose escalation every fourth week and 
(liraglutide) placebo, we will still expect to have at least 100 subjects in the relevant pool
of placebo subjects. Hence the argumentation below only assumes 100 subjects in the 
placebo arm in a conservative manner and for simplicity. However, at time of analysis we 
plan to include all subjects on placebo as one group in the analysis as described above, if 
possible.
The following assume 100 subjects randomised in a balanced manner to receive each 
active treatment and being conservative at least 100 evaluable subjects in the placebo 
arm. In trial NN8022-1839, in obese subjects without T2DM a standard deviation of just 
below 7% was seen for observed weight loss (in %) in the liraglutide 3.0 mg arm. A 
conservative estimate of the dropout rate is 40%. A standard deviation of 7% and a 
sample size of 100 in each treatment arm will allow the 95% confidence interval for the 
estimated difference between two semaglutide doses, with 90% probability, to be 
contained within ±2.5% of the estimate, which is considered to be a sufficient precision 
for determining which doses to use for the continued development of semaglutide in the
weight management indication.
For the primary endpoint change in body weight after 52 weeks of treatment, a 
difference (semaglutide minus placebo) of 9.5% is expected for completers (12% in the 
optimal dose group for semaglutide vs. 2.5% in placebo). For the withdrawn subjects, 
who are anticipated to constitute up to 40% of the total trial population, the treatment 
difference (semaglutide minus placebo) is assumed to be 0% giving an overall expected 
treatment difference of 5.7% (8.2% in semaglutide vs. 2.5% in placebo). The standard 
deviation will also be increased using the MI approach. The standard deviation in the final 
data is assumed to be up to 8.4% (8.4% in semaglutide vs. 7% in placebo). A standard 
deviation of up to 8.4% together with an expected difference of 5.7% results in a power 
of more than 99%, which is not corrected for multiple comparisons between different 
semaglutide arms and placebo.
For part B, in total two times 100 subjects will be randomised to the dose escalation 
every second week. Combined with placebo and the two doses corresponding to the 
‘every second week’ arms (i.e. 0.3 mg/day and 0.4 mg/day) we will have more than five 
hundred subjects for the inference of the dose escalation finding part of the trial. In trial 
NN8022-1839, 
nausea, 
vomiting, 
and
constipation 
were 
the 
most 
common 
gastrointestinal AEs with incidences between 15% and 40% of all subjects on liraglutide 
3.0 mg. These AEs are not expected to be less frequent with semaglutide. This part of 
the trial is exploratory in nature and is intended to evaluate the overall safety profile with 
respect to the different types of events and when they occur compared to the escalation 
steps and with a view towards the efficacy response as well. With the given number of 
subjects, we have a reasonable sample size to detect marked clinical relevant difference 
between the arms.
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
2 of 10
SAS program code
Path to program:
P:\nn9536\nn9536-4153\current\stats\document\0100_protocol\0110_sample_size
/*********************************************************************************************
Project    :  Semaglutide obesity
Study      :  NN9536-4153
Name       :  powerph2_NN9536-4153.sas
Description:  Sample size calculation for the NN9536-4153 trial phase II  
               trial for semaglutide obesity                
----------------------------------------------------------------------------------------------
               Init
Programmer  : HHg Apr2014
Text        :
UPdate log  : LKOO 2014-12-08   
*********************************************************************************************/
/*
dm log 'clear' wpgm;
dm output 'clear' wpgm;
options symbolgen;
ods output file = "";
*/
/***********************************************************************
* Power for phase 2 trial dose selection of semaglutide for obesity   
***********************************************************************/
/*********************************************************************************************
** Standard assumptions:
** A standard deviation of 7% (in completers/placebo) 
** a sample size of 100 in each treatment arm  
** 40% WD, 
** an expected effect of 10% (best Sema) using LOCF [MMLA want us to keep 10, even TPP says 
12]
** (8% on lira using LOCF),
** 2.5 in placebo  (using 3.0 for placebo completers, does not make a noticable difference)
** Missing data: MI using copy placebo/reference
** 
*********************************************************************************************/
%let sd_pbo=7;
%let meanP=2.5;
%let WD=0.4;
%let meanS_locf=10;
%let meanL_locf=8;
/*
first calculations of emplied completer effects and recalculate derived means with MI and SD 
with MI 
(usually we assume that LOCF give ½ETD in WD subjects)
This gives the following mean effects in completers
sema_All = (1-WD)*Sema_comp + WD * (placebo + ½*(sema_comp-placebo) = 10
The implied effect in Sema_completers is:
Sema_comp = (10-½*WD*placebo)/(1-½*WD)
*/
%let meanSC=%sysevalf( (&meanS_locf-0.5*&WD*&meanP)/(1-0.5*&WD)  );
%let meanLC=%sysevalf( (&meanL_locf-0.5*&WD*&meanP)/(1-0.5*&WD)  );
%put Sema completer: &meanSC;
%put Lira completer: &meanLC;
/*********************************************************************************************
** Thus we are assuming (approximately) a 
** 12% WL in Sema completers on optimal dose
** 9.5% WL in Lira completers (similar to 1839 data)
*********************************************************************************************/
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
3 of 10
%let meanSC=12;
%let meanLC=9.5;
/* 
With MI the ALL WL with 40 WD rate will then be:
*/
%let meanS=%sysevalf( (1-&WD)*&meanSC + &WD*&meanP   );
%let meanL=%sysevalf( (1-&WD)*&meanLC + &WD*&meanP   );
%put Placebo: &meanP. ;
%put Sema: &meanS;
%put Lira: &meanL;
/*********************************************************************************************
****************************************
** Thus we expect LSmean weight loss (40% WD)
** 8.2% WL in Sema all on optimal dose
** 6.7% WL in Lira all 
**********************************************************************************************
****************************************/
* regarding SD to use: *;
%let ETDc=%sysevalf(&meanSC-&meanP);
data b;
  sd_s= sqrt(&sd_pbo*&sd_pbo + &WD*(1-&WD)*&ETDc*&ETDc);
call symput ('sd_s', sd_s);
  sd_l= sqrt(&sd_pbo*&sd_pbo + &WD*(1-&WD)*(&meanLC-&meanP)*(&meanLC-&meanP));
call symput ('sd_l', sd_l);
run;
title 'SD in Sema and Lira for full population WD=40pct';
proc print data=b;
run;
/*********************************************************************************************
** Thus we expect sd in Sema arms (40% WD) is
** When the missing data procedure is MI (jump to reference/copy placebo) the SD in the active 
group become sqrt ( sd^2 +p(1-p)*ETD^2 )
** sd_s=8.4
** sd_s=7.8
*********************************************************************************************/
************************* CALCULATIONS ******************************************************;
/*********************************************************************************************
* with the above assumptions
* will allow the 95% confidence interval 
*  for the estimated difference between two arms, with 90% probability, to be contained within 
±2.5%;
*********************************************************************************************/
proc power; 
title 'Estimating the probability for the width of the confidence interval for the estimated 
difference';
  twosamplemeans CI = diff 
  alpha = 0.05
  stddev =&sd_s  
  groupweights = 1 | 1
  halfwidth = 2.5
  probwidth = .
  ntotal = 200;  
run;
/***********************************************************************
  Marginal power for primary endpoint: relative change in body weight
  4W/QD arms WD rate 40%
  We have high power: >99.9%
***********************************************************************/
%let diff=%sysevalf(&meanS - &meanP ) ;
proc power;
title "Power for semaglutide vs. placebo - relative change in body weight";
            twosamplemeans
            alpha=0.05
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
4 of 10
            dist=normal
            test=diff_satt
            gmeans =&meanP | &meanS
            nulldiff=0
            sides=1
            GROUPSTDDEVS = (&sd_pbo  &sd_s)
            power=.
            ntotal = 200;
run;
/***********************************************************************
  Marginal power for primary endpoint: relative change in body weight
  2W/QD arms WD rate 50%
  We still have high power: 99.6%
***********************************************************************/
%let WD2=0.5;
data c;
  sd_s2= sqrt(&sd_pbo*&sd_pbo + &WD2*(1-&WD2)*&ETDc*&ETDc);
  call symput ('sd_s2', sd_s2);
  meanS2=%sysevalf( (1-&WD2)*&meanSC + &WD2*&meanP   );
  call symput ('meanS2', meanS2);
run;
proc print data = c;
run;
proc power;
title "Power for semaglutide vs. placebo - relative change in body weight (WD=50%)";
            twosamplemeans
            alpha=0.05
            dist=normal
            test=diff_satt
            gmeans =&meanP | &meanS2
            nulldiff=0
            sides=1
            GROUPSTDDEVS = &sd_pbo | &sd_s2 
            power=.
            ntotal = 200;
run;
/***********************************************************************
  Marginal powers for secondary endpoints: proportion of subjects loosing 
  5% respectively 10% of initial body weight at end of treatment
***********************************************************************/
/* relative weight loss are expected to follow a normal distribution, for semaglutide
   we expect a mean of 12% in completers and a standard deviation of 7% (in completers).
   This leads to an expected proportion in completers of subjects loosing 10% about 60% 
   The expected proportion loosing 5% or more is about 80%; both calculated below 
   For Placebo the numbers are set to 35% and 10% (1839)
   With MI and WD=40%, gives proportion of 5% responder: 64%, and proportion of 10% responder: 
40%
   For Lira the corresponding numberes are: proportion of 5% responder: 58%, and proportion of 
10% responder: 32%
*/
data prob;
  prob_placebo05 = 0.35 /*1 - cdf('NORMAL', 5, 2.5, 7) */ ;
  prob_sema05_c  = 1 - cdf('NORMAL', 5, &meanSC, &sd_pbo) ;
  prob_sema05    = (1-&WD)*(prob_sema05_c) + &WD*(prob_placebo05);
  prob_placebo10 = 0.1 /* 1 - cdf('NORMAL', 10, 2.5, 7) */ ;
  prob_sema10_c  = 1 - cdf('NORMAL', 10, &meanSC, &sd_pbo);
  prob_sema10    = (1-&WD)*(prob_sema10_c) + &WD*(prob_placebo10);
  prob_lira05_c  = 1 - cdf('NORMAL', 5, &meanLC, &sd_pbo);
  prob_lira05    = (1-&WD)*(prob_lira05_c) + &WD*(prob_placebo05);
  prob_lira10_c  = 1 - cdf('NORMAL', 10, &meanLC, &sd_pbo);
  prob_lira10    = (1-&WD)*(prob_lira10_c) + &WD*(prob_placebo10);
  call symput('placebo_5pct', prob_placebo05);
  call symput ('sema_5pct', prob_sema05);
  call symput('placebo_10pct', prob_placebo10);
  call symput ('sema_10pct', prob_sema10);
run;
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
5 of 10
title 'Estimating the proportion of subjects loosing 5%/10% or more based on the assumption of 
normal distribution with mean 12 (sema, completer) respectively 2.5 (placebo) and SD of 7% and 
WD=40pct';
proc print data=prob;
run;
%macro chi(sema= , placebo= , pct= , title= );
* chi square test;
title &title.;
proc power; 
  twosamplefreq test=pchi 
  groupproportions = (&sema. &placebo.) 
  nullproportiondiff = 0
  power = .
  npergroup = 100;
  ods output output=Power;
run;
data power&pct.;
  set power;
  sema_prob=Proportion1;
  placebo_prob=Proportion2;
  drop error info Proportion1 Proportion2 index;
run;
proc print data = power&pct.;
run;
%mend chi;
%chi(sema=&sema_5pct., placebo=&placebo_5pct., pct=5, title="Power for semaglutide vs. placebo 
- 5pct Responders");
%chi(sema=&sema_10pct., placebo=&placebo_10pct., pct=10, title="Power for semaglutide vs. 
placebo - 10pct Respondres");
* Power for 5% responder: 99%
* Power for 10% responder: >99.9%
*;
/***************************************************************************
  power calculation for comparison between liraglutide 3.0 and semaglutide
****************************************************************************/
proc power;
title "Power for semaglutide vs. Lira 3.0 - relative change in body weight";
            twosamplemeans
            alpha=0.05
            dist=normal
            test=diff_SATT
            gmeans =&meanL | &meanS
            nulldiff=0
            sides=1
            GROUPSTDDEVS = &sd_l | &sd_s
            power=.
            ntotal = 200;
run;
proc power;
title "Sample Size for semaglutide vs. Lira 3.0 - relative change in body weight";
            twosamplemeans
            alpha=0.05
            dist=normal
            test=diff_SATT
            gmeans =&meanL | &meanS
            nulldiff=0
            sides=1
            GROUPSTDDEVS = &sd_l | &sd_s
            power=.90
            ntotal =.;
run;
* Power for Sema vs Lira 3.0:  36.7%
* samplesize for Sema vs Lira 3.0: 500 ptt pr arm
*;
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
6 of 10
/******************************************************************************
  power calculation for comparison GI side effect between two semaglutide arms
  (50% chosen as a worst case number)
*******************************************************************************/
title 'Power for GI side effects between arms. Conservative one arm have 50pct event rate';
proc power; 
  twosamplefreq test=pchi 
  groupproportions = (.5 .305) 
  nullproportiondiff = 0
  power = .
  npergroup = 100;
  ods output output=Power;
run;
* so 80% power to show a difference from 50% to 30% *;
proc power; 
  twosamplefreq test=pchi 
  groupproportions = (.5 .28) 
  nullproportiondiff = 0
  power = .
  npergroup = 100;
  ods output output=Power;
run;
* so 90% power to show a difference from 50% to 28% *;
/*********************************************************************************************
**
  power calculation for comparison dropu out due to GI side effect between two semaglutide 
arms
  (15% chosen as a relistic conservative number)
**********************************************************************************************
**/
title 'Power for GI side effects between arms. Conservative one arm have 15pct event rate';
proc power; 
  twosamplefreq test=pchi 
  groupproportions = (.15 .035) 
  nullproportiondiff = 0
  power = .
  npergroup = 100;
  ods output output=Power;
run;
* so 80% power to show a difference from 15% to 3.5% *;
* Conclussion: WRT nausea we will need to look at the overall picture and do biomodeling and 
common sense
*;
/*******************************************************************************
** update of TPP numbers assuming 12% with LOCF
********************************************************************************/
* caluculation of MI sema WL =X if LOCF WL=12%
*;
%let meanS_locf2=12;
%let meanSC2=%sysevalf( (&meanS_locf2-0.5*&WD*&meanP)/(1-0.5*&WD)  );
%put Sema completer: &meanSC2;
%let meanSC=14.4;
%let meanS2=%sysevalf( (1-&WD)*&meanSC2 + &WD*&meanP   );
%put Sema: &meanS2;
* thus 12% with LOCF correspond to 9.6 with MI and 40% WD
* and to 14.4% in completers
*;
data prob2;
  prob_placebo05 = 0.35 /*1 - cdf('NORMAL', 5, 2.5, 7) */ ;
  prob_placebo10 = 0.1 /* 1 - cdf('NORMAL', 10, 2.5, 7) */ ;
  prob_sema05_c  = 1 - cdf('NORMAL', 5, &meanSC2, &sd_pbo) ;
  prob_sema05    = (1-&WD)*(prob_sema05_c) + &WD*(prob_placebo05);
  prob_sema10_c  = 1 - cdf('NORMAL', 10, &meanSC2, &sd_pbo);
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
7 of 10
  prob_sema10    = (1-&WD)*(prob_sema10_c) + &WD*(prob_placebo10);
run;
title 'Estimating the proportion of subjects loosing 5%/10% or more based on the assumption of 
normal distribution with mean 14.4 (sema, completer) respectively 2.5 (placebo) and SD of 7% 
and WD=40pct';
proc print data=prob2;
run;
* thus 12% with LOCF correspond to the following with MI and 40% WD
* 5% responders: 68%
* 10% responders: 48%
*;
SAS program output
SD in Sema and Lira for full population WD=40pct
Obs
sd_s
sd_l
18.405957.79487
Estimating the probability for the width of the confidence interval for the estimated difference
The POWER Procedure
Confidence Interval for Mean Difference
Fixed Scenario Elements
Distribution
Normal
Method
Exact
Alpha
0.05
CI Half-Width
2.5
Standard Deviation
8.40595
Group 1 Weight
1
Group 2 Weight
1
Total Sample Size
200
Number of Sides
2
Prob Type
Conditional
Computed Prob(Width)
Prob(Width)
0.908
Power for semaglutide vs. placebo - relative change in body weight
The POWER Procedure
Two-Sample t Test for Mean Difference with Unequal Variances
Fixed Scenario Elements
Distribution
Normal
Method
Exact
Number of Sides
1
Null Difference
0
Nominal Alpha
0.05
Group 1 Mean
2.5
Group 2 Mean
8.2
Group 1 Standard Deviation
7
Group 2 Standard Deviation8.40595
Total Sample Size
200
Group 1 Weight
1
Group 2 Weight
1
Computed Power
Actual AlphaPower
0.05 >.999
Power for semaglutide vs. placebo - relative change in body weight
Obs sd_s2meanS2
18.45946
7.25
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
8 of 10
Power for semaglutide vs. placebo - relative change in body weight (WD=50%)
The POWER Procedure
Two-Sample t Test for Mean Difference with Unequal Variances
Fixed Scenario Elements
Distribution
Normal
Method
Exact
Number of Sides
1
Null Difference
0
Nominal Alpha
0.05
Group 1 Mean
2.5
Group 2 Mean
7.25
Group 1 Standard Deviation
7
Group 2 Standard Deviation8.459462
Total Sample Size
200
Group 1 Weight
1
Group 2 Weight
1
Computed Power
Actual AlphaPower
0.05
0.996
Estimating the proportion of subjects loosing 5%/10% or more based on the assumption of normal distribution with
mean 12 (sema, completer) respectively 2.5 (placebo) and SD of 7% and WD=40pct
Ob
s
prob_placeb
o05
prob_sema0
5_c
prob_sem
a05
prob_placeb
o10
prob_sema1
0_c
prob_sem
a10
prob_lira0
5_c
prob_lir
a05
prob_lira1
0_c
prob_lir
a10
1
0.35
0.84134
0.64481
0.1
0.61245
0.40747
0.73984
0.58390
0.47153
0.32292
Power for semaglutide vs. placebo - 5pct Responders
The POWER Procedure
Pearson Chi-square Test for Two Proportions
Fixed Scenario Elements
Distribution
Asymptotic normal
Method
Normal approximation
Null Proportion Difference
0
Group 1 Proportion
0.644807
Group 2 Proportion
0.35
Sample Size per Group
100
Number of Sides
2
Alpha
0.05
Computed Power
Power
0.990
Power for semaglutide vs. placebo - 5pct Responders
ObsAnalysis
NullProportionDiffNPerGroupSidesAlphaPowersema_probplacebo_prob
1TwoSampleFreq
0
1002
0.05
0.990
0.64481
0.35
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
9 of 10
Power for semaglutide vs. placebo - 10pct Respondres
The POWER Procedure
Pearson Chi-square Test for Two Proportions
Fixed Scenario Elements
Distribution
Asymptotic normal
Method
Normal approximation
Null Proportion Difference
0
Group 1 Proportion
0.407471
Group 2 Proportion
0.1
Sample Size per Group
100
Number of Sides
2
Alpha
0.05
Computed Power
Power
>.999
Power for semaglutide vs. placebo - 10pct Respondres
ObsAnalysis
NullProportionDiffNPerGroupSidesAlphaPowersema_probplacebo_prob
1TwoSampleFreq
0
1002
0.05
0.999
0.40747
0.1
Power for semaglutide vs. Lira 3.0 - relative change in body weight
The POWER Procedure
Two-Sample t Test for Mean Difference with Unequal Variances
Fixed Scenario Elements
Distribution
Normal
Method
Exact
Number of Sides
1
Null Difference
0
Nominal Alpha
0.05
Group 1 Mean
6.7
Group 2 Mean
8.2
Group 1 Standard Deviation7.79487
Group 2 Standard Deviation8.40595
Total Sample Size
200
Group 1 Weight
1
Group 2 Weight
1
Computed Power
Actual AlphaPower
0.05
0.367
Sample Size for semaglutide vs. Lira 3.0 - relative change in body weight
The POWER Procedure
Two-Sample t Test for Mean Difference with Unequal Variances
Fixed Scenario Elements
Distribution
Normal
Method
Exact
Number of Sides
1
Null Difference
0
Nominal Alpha
0.05
Group 1 Mean
6.7
Group 2 Mean
8.2
Group 1 Standard Deviation7.79487
Group 2 Standard Deviation8.40595
Nominal Power
0.9
Group 1 Weight
1
Group 2 Weight
1
Computed N Total
Actual AlphaActual PowerN Total
0.05
0.900
1002
CONFIDENTIAL


NN9536-4153
Statistical documentation – sample size calculation
06-SEP-2016
10 of 10
Power for GI side effects between arms. Conservative one arm have 50pct event rate
The POWER Procedure
Pearson Chi-square Test for Two Proportions
Fixed Scenario Elements
Distribution
Asymptotic normal
Method
Normal approximation
Null Proportion Difference
0
Group 1 Proportion
0.5
Group 2 Proportion
0.305
Sample Size per Group
100
Number of Sides
2
Alpha
0.05
Computed Power
Power
0.808
Power for GI side effects between arms. Conservative one arm have 50pct event rate
The POWER Procedure
Pearson Chi-square Test for Two Proportions
Fixed Scenario Elements
Distribution
Asymptotic normal
Method
Normal approximation
Null Proportion Difference
0
Group 1 Proportion
0.5
Group 2 Proportion
0.28
Sample Size per Group
100
Number of Sides
2
Alpha
0.05
Computed Power
Power
0.897
Power for GI side effects between arms. Conservative one arm have 15pct event rate
The POWER Procedure
Pearson Chi-square Test for Two Proportions
Fixed Scenario Elements
Distribution
Asymptotic normal
Method
Normal approximation
Null Proportion Difference
0
Group 1 Proportion
0.15
Group 2 Proportion
0.035
Sample Size per Group
100
Number of Sides
2
Alpha
0.05
Computed Power
Power
0.806
Estimating the proportion of subjects loosing 5%/10% or more based on the assumption of normal distribution with
mean 14.4 (sema, completer) respectively 2.5 (placebo) and SD of 7% and WD=40pct
Obsprob_placebo05prob_placebo10prob_sema05_cprob_sema05prob_sema10_cprob_sema10
1
0.35
0.1
0.90976
0.68586
0.73401
0.48041
CONFIDENTIAL


MedDRA searches in NN9536-4153
Author:
Nina Engberg Jungdal, 
Safety Surveillance GLP-1 & Obesity


NN9536
Clinical Trial Report
Date:
26 September 2017
Status:
Final
1RYR1RUGLVN
NN9536-4153
MedDRA searches
Version:
1.0
Page:
1 of 4
Terms used for predefined MedDRA search for adverse events of acute renal failure, allergic reactions, cardiac arrhythmia, gallbladder 
disorders, gastrointestinal adverse events, hepatic adverse events, injection site reactions, medication errors, neoplasms, rare events, 
transmission of an infectious agent via trial product and thyroid disorders
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Adverse event search                
Search criteria                                                  
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Acute renal failure
SMQ 'Acute renal failure' (narrow scope)
Allergic reactions
NNMQ 'Allergic reactions' including:
SMQ Anaphylactic reaction (narrow scope)
SMQ Angioedema (narrow scope)
SMQ Severe cutaneous adverse reactions (narrow scope)
SMQ Anaphylactic/anaphylactoid shock conditions (narrow scope)
SMQ Hypersensitivity (narrow scope)
Cardiac arrhythmia
SMQ ‘Cardiac arrhythmias’ including:
SMQ Arrhythmia related investigations, signs and symptoms
SMQ Cardiac arrhythmia terms (incl bradyarrhythmias and tachyarrhythmias)
SMQ Congenital and neonatal arrhythmias
Gallbladder disorders
NNMQ ‘Gallbladder related disorders’ including:
SMQ Biliary tract disorders
SMQ Biliary system related investigations, signs and symptoms
SMQ Gallbladder related disorders
SMQ Gallstone related disorders
SMQ Infectious biliary disorders
Gastrointestinal adverse events
SOC 'Gastrointestinal disorders'
—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
SMQ: standard MedDRA query, NNMQ: Novo Nordisk MedDRA query, SOC: system organ class


NN9536
Clinical Trial Report
Date:
26 September 2017
Status:
Final
1RYR1RUGLVN
NN9536-4153
MedDRA searches
Version:
1.0
Page:
2 of 4
Terms used for predefined MedDRA search for adverse events of acute renal failure, allergic reactions, cardiac arrhythmia, 
gallbladder disorders, gastrointestinal adverse events, hepatic adverse events, injection site reactions, medication errors, 
neoplasms, rare events, transmission of an infectious agent via trial product and thyroid disorders
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Adverse event search                  Search criteria                                                  
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Hepatic adverse events
SMQ ‘Drug related hepatic disorders – comprehensive search’ including:
SMQ Cholestasis and jaundice of hepatic origin
SMQ Drug related hepatic disorders – severe events only
SMQ Liver related investigations, signs and symptoms
SMQ Liver-related coagulation and bleeding disturbances
Injection site reactions
NNMQ 'Injection site reactions' including:
HLT Administration site reactions
HLT Application and instillation site reactions
HLT Infusion site reactions
HLT Injection site reactions
Medication error
NNMQ 'Medication error' including:
HLGT Medication errors
HLGT Device issues
HLGT Product Quality Issue
HLT Complications associated with device NEC
HLT Overdoses NEC
HLT Underdoses NEC
PT Contraindicated drug administered
PT Drug administered to patient of inappropriate age
Neoplasms                        
NNMQ 'Neoplasm’ including: 
SOC Neoplasms benign, malignant and unspecified (including cysts and polyps)
(primary and secondary terms)
SMQ Biliary neoplasms
SMQ Breast neoplasms, malignant and unspecified
—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
SMQ: standard MedDRA query, NNMQ: Novo Nordisk MedDRA query, HLT: high level term, HLGT: high level group term, NEC: not 
elsewhere classified, PT: preferred term, SOC: system organ class


NN9536
Clinical Trial Report
Date:
26 September 2017
Status:
Final
1RYR1RUGLVN
NN9536-4153
MedDRA searches
Version:
1.0
Page:
3 of 4
Terms used for predefined MedDRA search for adverse events of acute renal failure, allergic reactions, cardiac arrhythmia, 
gallbladder disorders, gastrointestinal adverse events, hepatic adverse events, injection site reactions, medication errors, 
neoplasms, rare events, transmission of an infectious agent via trial product and thyroid disorders
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Adverse event search                  Search criteria                                                  
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
SMQ Liver neoplasms, benign (incl cysts and polyps) 
SMQ Liver neoplasms, malignant and unspecified
SMQ Malignancies
SMQ Malignant lymphomas
SMQ Oropharyngeal neoplasms
SMQ Ovarian neoplasms, malignant and unspecified
SMQ Premalignant disorders
SMQ Prostate neoplasms, malignant and unspecified
SMQ Skin neoplasms, malignant and unspecified
SMQ Uterine and fallopian tube neoplasms, malignant and unspecified                        
Rare events
NNMQ ‘Rare’ excluding all search strings included in any of the other medical areas
NNMQ ‘Rare’ includes:
SMQ Acute renal failure (narrow scope)
SMQ Agranulocytosis (narrow scope)
SMQ Anaphylactic reaction (narrow scope)
SMQ Cardiac arrhythmias 
SMQ Cholestasis and jaundice of hepatic origin 
SMQ Guillain-Barre syndrome (narrow scope)
SMQ Haematopoietic cytopenias affecting more than one type of blood cell 
SMQ Haematopoietic leukopenia 
SMQ Haematopoietic thrombocytopenia (narrow scope)
SMQ Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions (narrow scope)
SMQ Hepatitis, non-infectious
SMQ Severe cutaneous adverse reactions (narrow scope)
SMQ Interstitial lung disease (narrow scope)
—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
SMQ: standard MedDRA query, NNMQ: Novo Nordisk MedDRA query


NN9536
Clinical Trial Report
Date:
26 September 2017
Status:
Final
1RYR1RUGLVN
NN9536-4153
MedDRA searches
Version:
1.0
Page:
4 of 4
Terms used for predefined MedDRA search for adverse events of acute renal failure, allergic reactions, cardiac arrhythmia, 
gallbladder disorders, gastrointestinal adverse events, hepatic adverse events, injection site reactions, medication errors, 
neoplasms, rare events, transmission of infectious agent via trial product and thyroid disorders
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Adverse event search                  Search criteria                                                  
-————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
SMQ Neuroleptic malignant syndrome (narrow scope)
SMQ Pseudomembranous colitis (narrow scope)
SMQ Retroperitoneal fibrosis (narrow scope)
SMQ Acute Pancreatitis (narrow scope)
SOC Congenital, familial and genetic disorders (primary and secondary routed 
PTs)
HLT Acute and chronic pancreatitis (primary and secondary routed PTs)
HLT Angioedemas (primary and secondary routed PTs)
HLT Glomerulonephritis and nephrotic syndrome (primary and secondary routed 
PTs)
HLT Nephritis NEC (primary and secondary routed PTs)
PT Disseminated intravascular coagulation
PT Multi-organ failure
Suspected transmission of an
infectious agent
NNMQ 'Suspected transmission of an infectious agent' including:
HLT Infectious disorders carrier (only primary terms)   
HLT Infectious transmissions (only primary terms)
Thyroid disorders
NNMQ 'Thyroid disorders' including:
SMQ Hyperthyroidism
SMQ Hypothyroidism 
HLGT Thyroid gland disorders (incl both primary and secondary linked PTs) 
PT Thyroglossal cyst
PT Blood calcitonin abnormal
PT Blood calcitonin increased
PT Ectopic calcitonin production
PT Hypercalcitoninaemia
PT Blood calcitonin
PT Calcitonin secretion disorder
—————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
SMQ: standard MedDRA query, HLT: high level term, NEC: not elsewhere classified, PT: preferred term, NNMQ: Novo Nordisk 
MedDRA query, HLGT: high level group term,