Effect and Safety of Liraglutide 3.0 mg as an Adjunct to Intensive Behaviour Therapy for Obesity in a Non-specialist Setting
Phase: PHASE3
Conditions: Metabolism and Nutrition Disorder, Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02963935 
Sponsor trial ID: 
NN8022-4274 
Official title of study: 
Effect and safety of liraglutide 3.0 mg as an adjunct to 
intensive behaviour therapy for obesity in a non-specialist 
setting (SCALETM IBT) 
Document date: 
19 December 2018 
 

Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Appendix A - Monitoring of Calcitonin ...........................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 - Global ........................................................................................................
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Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4274
Clinical Trial Report
Appendix 16.1.1
19 December 2018 
1.0
Final
16.1.1 Protocol and protocol amendments
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Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 

Protocol
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Trial ID: NN8022-4274
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Protocol
Trial ID: NN8022-4274
SCALE™ IBT
Effect and safety of liraglutide 3.0 mg as an adjunct to intensive 
behaviour therapy for obesity in a non-specialist setting
Trial phase: 3b
Protocol originator
1797- TrialOps 2, Obesity.
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 No unpublished information contained herein may be 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 No unpublished information contained herein may be 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:
14 September 2016
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Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
Final
EudraCT no.: 2015-005592-24
Page:
2 of 109
Table of Contents
Page
Protocol .............................................................................................................................................................1
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................13
3
Background information and rationale for the trial............................................................................18
3.1
Background information..............................................................................................................18
3.2
Rationale for the trial...................................................................................................................19
4
Objectives and endpoints........................................................................................................................20
4.1
Objectives ....................................................................................................................................20
4.2
Endpoints .....................................................................................................................................20
4.2.1
Primary endpoints......................................................................................................20
4.2.2
Secondary endpoints..................................................................................................20
4.2.2.1
Confirmatory secondary endpoints .....................................................20
4.2.2.2
Supportive secondary endpoints..........................................................21
5
Trial design ..............................................................................................................................................22
5.1
Type of trial .................................................................................................................................22
5.2
Rationale for trial design..............................................................................................................22
5.3
Treatment of subjects...................................................................................................................23
5.3.1
Investigational medicinal product..............................................................................23
5.3.2
Counselling (intensive behaviour therapy) ................................................................24
5.4
Treatment after discontinuation of trial product ..........................................................................25
5.5
Rationale for treatment ................................................................................................................25
6
Trial population.......................................................................................................................................27
6.1
Number of subjects......................................................................................................................27
6.2
Inclusion criteria ..........................................................................................................................27
6.3
Exclusion criteria.........................................................................................................................27
6.4
Randomisation criterion...............................................................................................................28
6.5
Criteria for premature discontinuation of trial product................................................................28
6.6
Withdrawal from trial ..................................................................................................................29
6.7
Subject replacement.....................................................................................................................29
6.8
Rationale for trial population.......................................................................................................29
7
Milestones.................................................................................................................................................30
8
Methods and assessments .......................................................................................................................31
8.1
Visit procedures...........................................................................................................................31
8.2
Subject-related information/assessments.....................................................................................33
8.2.1
Demography...............................................................................................................33
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8.2.2
Concomitant illness and medical history...................................................................33
8.2.3
Concomitant medication............................................................................................34
8.2.4
Childbearing potential................................................................................................35
8.2.5
Tobacco use ...............................................................................................................35
8.2.6
Amount of alcohol consumed....................................................................................35
8.2.7
Weight history, including weight-related comorbidities............................................36
8.2.8
Barriers and motivation interview .............................................................................36
8.2.9
7-day food diary in screening period .........................................................................36
8.3
Efficacy assessments....................................................................................................................36
8.3.1
Body weight...............................................................................................................36
8.3.2
Height ........................................................................................................................36
8.3.3
Waist circumference ..................................................................................................36
8.3.4
HbA1C.........................................................................................................................37
8.3.5
Fasting plasma glucose..............................................................................................37
8.3.6
Vital signs (blood pressure) .......................................................................................37
8.3.7
Clinical outcome assessments....................................................................................37
8.3.8
Six-minute walking distance test ...............................................................................39
8.4
Safety assessments.......................................................................................................................39
8.4.1
Physical examination.................................................................................................40
8.4.2
Adverse events...........................................................................................................40
8.4.2.1
Medication error..................................................................................40
8.4.2.2
Adverse events requiring additional data collection ...........................40
8.4.3
Vital signs (pulse)......................................................................................................42
8.4.4
Electrocardiogram......................................................................................................42
8.4.5
Hypoglycaemic episodes ...........................................................................................43
8.4.6
Patient Health Questionnaire-9..................................................................................43
8.4.7
Columbia Suicidal Severity Rating Scale..................................................................44
8.4.8
Breast and colon neoplasms follow up ......................................................................44
8.5
Laboratory assessments ...............................................................................................................44
8.5.1
Laboratory assessments for efficacy..........................................................................45
8.5.2
Laboratory assessments for safety .............................................................................45
8.6
Other assessments........................................................................................................................46
8.6.1
Trial product usage ....................................................................................................46
8.6.2
Food diary and tracking of physical activity..............................................................47
8.6.3
Training in the PDS290 pen-injector.........................................................................47
8.6.4
Inquire about mood....................................................................................................47
8.7
Subject compliance......................................................................................................................47
8.7.1
Adherence to dietary and physical activity................................................................48
8.8
Additional safety assessments......................................................................................................48
8.8.1
Suspicion of acute pancreatitis...................................................................................48
8.8.2
Suspicion of acute gallstone disease..........................................................................49
8.8.3
Neoplasm ...................................................................................................................49
8.8.4
Hepatic event (suspicion of drug-induced liver injury) .............................................50
8.8.5
Depression, suicidal ideation/behaviour....................................................................50
9
Trial supplies ...........................................................................................................................................52
9.1
Trial products...............................................................................................................................52
9.2
Labelling and directions for use...................................................................................................52
9.3
Storage .........................................................................................................................................53
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Protocol
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9.4
Drug accountability and destruction............................................................................................53
9.5
Auxiliary supplies........................................................................................................................54
10 Interactive voice/web response system ..................................................................................................55
11 Randomisation procedure and breaking of blinded codes..................................................................56
11.1
Breaking of blinded codes ...........................................................................................................56
12 Adverse events, and technical complaints and pregnancies................................................................57
12.1
Definitions ...................................................................................................................................57
12.1.1
Adverse event ............................................................................................................57
12.1.2
Serious adverse event.................................................................................................58
12.1.3
Non-serious adverse event.........................................................................................59
12.1.4
Medication errors.......................................................................................................59
12.1.5
Adverse events requiring additional data collection..................................................60
12.1.6
Technical complaints.................................................................................................60
12.2
Reporting of adverse events.........................................................................................................61
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..................................................................................................................................65
12.5.1
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
13 Case report forms....................................................................................................................................68
13.1
Corrections to case report forms..................................................................................................68
13.2
Case report form flow..................................................................................................................69
14 Monitoring procedures ...........................................................................................................................70
15 Data management....................................................................................................................................71
16 Computerised systems.............................................................................................................................72
17 Statistical considerations ........................................................................................................................73
17.1
Sample size calculation................................................................................................................75
17.2
Definition of analysis sets............................................................................................................77
17.3
Primary endpoints........................................................................................................................78
17.3.1
Analytical methods addressing the effectiveness estimand for the primary 
endpoints....................................................................................................................78
17.3.1.1
Statistical model for the primary endpoint % weight change..............78
17.3.1.2
Statistical model for the primary endpoint 5% responders .................79
17.3.2
Handling of missing values for the effectiveness estimand.......................................79
17.3.2.1
Handling of missing values at baseline...............................................79
17.3.2.2
Handling of missing values at week 56...............................................79
17.3.3
Analysis method addressing the efficacy estimand for the primary endpoints..........81
17.3.4
Subgroup analyses for primary endpoints..................................................................82
17.4
Secondary endpoints....................................................................................................................84
17.4.1
Confirmatory secondary endpoints............................................................................84
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN8022-4274
Version:
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UTN: U1111-1177-5059 
Status:
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17.4.2
Description of the hierarchical testing procedure to address the effectiveness 
estimand for primary and confirmatory secondary endpoints ...................................85
17.4.3
Supportive secondary endpoints ................................................................................87
17.4.3.1
Efficacy endpoints...............................................................................87
17.4.3.2
Safety endpoints..................................................................................88
18 Ethics........................................................................................................................................................92
18.1
Benefit-risk assessment of the trial..............................................................................................92
18.2
Informed consent .........................................................................................................................94
18.3
Data handling...............................................................................................................................95
18.4
Information to subjects during trial..............................................................................................96
18.5
Premature termination of the trial and/or trial site.......................................................................96
19 Protocol compliance................................................................................................................................97
19.1
Protocol deviations ......................................................................................................................97
19.2
Prevention of missing data...........................................................................................................97
20 Audits and inspections ............................................................................................................................98
21 Critical documents ..................................................................................................................................99
22 Responsibilities......................................................................................................................................100
23 Reports and publications......................................................................................................................100
23.1
Communication of results..........................................................................................................101
23.1.1
Authorship ...............................................................................................................102
23.1.2
Site-specific publication(s) by investigator(s) .........................................................102
23.2
Investigator access to data and review of results.......................................................................102
24 Retention of clinical trial documentation............................................................................................103
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............104
26 Indemnity statement .............................................................................................................................105
27 References..............................................................................................................................................106
Appendix A Monitoring of Calcitonin
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
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Protocol
CONFIDENTIAL
Date:
14 September 2016
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Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
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EudraCT no.: 2015-005592-24
Page:
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Table of Figures
Page
Figure 5–1
Trial Design ...........................................................................................................................22
Figure 8–1
Hallway marking for the six minute walking distance test.....................................................39
Figure 12–1
Reporting of AEs....................................................................................................................62
Figure 17–1
Illustration of imputation approaches for the effectiveness estimand ....................................83
Table of Tables
Page
Table 5–1
Dose Escalation and treatment period ....................................................................................23
Table 9–1
Trial products..........................................................................................................................52
Table 9–2
Storage conditions ..................................................................................................................53
Table 17–1
Taxonomy of week 56 assessments being available or missing.............................................75
Table 17–2
General specifications for sample size and power calculation ...............................................75
Table 17–3
Assumptions, marginal power and effective power for each confirmatory endpoint in 
the hierarchical testing procedure given an anticipated number of 282 randomised 
subjects ...................................................................................................................................77
Table 17–4
Factors and covariates for the analysis of the primary endpoints..........................................78
Table 17–5
Overview of handling of missing values ................................................................................84
Table 17–6
Hierarchical order and type of statistical method to address the effectiveness estimands 
for primary and confirmatory secondary endpoints................................................................86
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Date:
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Trial ID: NN8022-4274
Version:
4.0
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Status:
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List of abbreviations
AD
available drop-out
ADA
American Diabetes Association
AE
adverse event
ALP
alkaline phosphatase 
ALT
alanine aminotransaminase 
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AT
available on treatment
BMI
body mass index
CCDS
Company Core Data Sheet 
CLAE
clinical laboratory adverse event
CMS
Centers for Medicare & Medicaid Services 
COA
clinical outcome assessments
CRF
case report form
C-SSRS
Columbia suicide severity rating scale
CTR
clinical trial report
DILI
drug-induced liver injury
DUN
dispensing unit number
ECG
Electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FFA
free fatty acids 
FSFV
first subject first visit
FPG
fasting plasma glucose
GCP
Good clinical practise
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
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Protocol
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Date:
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Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
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HDL
high-density lipoprotein
hs-CRP
High sensitivity C-reactive protein
IBT
Intensive behaviour therapy
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
INR
international normalised ratio
IRB
institutional review board
ITT
intention- to-treat
IWQoL-Lite for CT
Impact of Weight on Quality of Life-Lite for Clinical Trials
IWRS
interactive voice/web response system
LAO
last available observation
LAO-OT
last available observation (of body weight) on randomised treatment 
LDL
low-density lipoprotein
LLOQ
lower limit of quantification
LSFV
last subject first visit
LSLV
last subject last visit
MCS
mental component summary
MCID
Minimal Clinically Important Difference  
MD
missing drop-out
MedDRA
Medical Dictionary for Drug Regulatory Activities
MEN2
multiple endocrine neoplasia type 2
MHP
mental health professional 
MI
Multiple Imputation
MT
missing on treatment
MTC
medullary thyroid carcinoma 
NIH
National Institutes of Health 
NYHA
New York Heart Association
OR
odds ratio 
PCS
physical component summary
PGI-C
Patients’ global impression of change
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PGI-S
Patients’ global impression of status
PHQ-9
Patient Health Questionnaire-9
PG
plasma glucose
PRO
patient reported outcome
PYE
patient years of exposure
PYO
patient years of observation
sBP
systolic blood pressure
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
SD
standard deviations
SDV
source data verification
SIF
safety information form
SF-36
short form-36 version 2.0 acute
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
T3
Triiodothyronine
T4
Thyroxine
TBL
total bilirubin
TC
total cholesterol
TG
Triglycerides
TMM
trial materials manual
TSH
thyroid stimulating hormone
UNL
upper normal limit
UNR
upper normal range
UTN
Universal Trial Number
VLDL
very low density lipoprotein
wANCOVA
weighted analysis of covariance  
WC
waist circumference
WRSS
Weight related sign and symptom measure
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Date:
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Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
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Page:
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1
Summary
Objectives and endpoints:
Primary objective
To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to CMS-IBT*, on weight loss 
effectiveness in subjects with obesity
*Intensive Behaviour Therapy for obesity in a primary care setting according to Centers for 
Medicare & Medicaid Services (CMS) visit schedule
Primary endpoints
Primary endpoints addressing the primary objective:

Change in body weight (%) from baseline to week 56

Proportion of subjects losing at least 5% of baseline body weight at week 56
Secondary objectives

To establish the effects of liraglutide 3.0 mg vs. placebo, as an adjunct to CMS-IBT, on 
cardiometabolic and relevant efficacy endpoints in subjects with obesity

To establish the safety and tolerability of liraglutide 3.0 mg vs. placebo, as an adjunct to 
CMS-IBT, in subjects with obesity
Key secondary endpoints

Proportion of subjects losing more than 10% of baseline body weight at week 56

Proportion of subjects losing more than 15% of baseline body weight at week 56

Proportion of subjects losing ≥4% of baseline body weight at week 16
Change from baseline to week 56 in:

Waist circumference (cm)

Systolic blood pressure (mmHg)

Six minutes walking distance (m)

Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT), 
physical functioning score

IWQoL-Lite for CT, mental/emotional functioning score
Trial design:
This is a 56-week, randomised, double-blind, placebo-controlled, two-armed multi-centre trial in 
subjects with obesity, who have not been diagnosed with type 1 or 2 diabetes mellitus.
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A total of 282 subjects will be randomised in a 1:1 manner to receive either liraglutide 3.0 mg or 
placebo, as an adjunct to CMS-IBT.
Throughout the 56-week treatment period, subjects will attend site visits to monitor response to 
treatment and 23 brief (approximately 15-minute) CMS-IBT counselling visits.
A 30-day follow-up period is included after the 56-week treatment period in accordance with FDA 
guidance.
Trial population:
The planned number of subjects to be randomised on trial product is 282.
Key inclusion criteria
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. BMI ≥ 30 kg/m2
3. Male or female, age ≥18 years at the time of signing informed consent
Key exclusion criteria
1. HbA1c ≥6.5% (at screening visit), or diagnosis of type 1 or type 2 diabetes mellitus
2. Recent history of cardiovascular disease (myocardial infarction or stroke within the past 6 
months), severe congestive heart failure (NYHA class III, IV), or second degree or greater 
heart block
3. Personal or family history of Medullary Thyroid Carcinoma (MTC), or Multiple Endocrine 
Neoplasia type 2 (MEN2)
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice)
5. Use in past 90 days of medications known to induce significant weight loss (e.g.,
prescription weight loss medications) or weight gain (e.g., chronic use of oral steroids, 
second generation antipsychotics)
6. History of pancreatitis (acute or chronic)
7. History of major depressive disorder within the past 2 years
8. Any lifetime history of a suicide attempt
9. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic 
≥180 mmHg or diastolic ≥110 mmHg)
10. History of malignancy (except for non-melanoma skin cancer) within the past 5 years
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
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EudraCT no.: 2015-005592-24
Page:
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Assessments:
Efficacy

Body measurement (weight and waist circumference)

Blood pressure

Six minutes walking distance (m)

Clinical outcome assessments (IWQoL-Lite for CT, Short Form 36 v2.0 acute)
Safety

Adverse events

Resting pulse

ECG

Biochemistry and haematology
Trial products:
The following products will be delivered by Novo Nordisk A/S Denmark:

Liraglutide 6 mg/mL, solution for injection, 3.0 ml PDS290 pen-injector

Liraglutide placebo, solution for injection, 3.0 ml PDS290 pen-injector
CONFIDENTIAL

Protocol
UTN: U1111-1177-5059 
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4274
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Version:
4.0
Page:
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2
Flow chart
Screening
Randomisation
Dose escalation
Maintenance period
Follow-up9
End-of-
treatment
On site visit no.
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
Weeks in relation to visit 2
-1
0
1
2
3
4
6
8
1
0
1
2
1
4
1
6
1
8
2
0
2
2
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
Visit window, days
-7
±
2
±
2
±
2
±
2
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
5
±
5
±
5
±
5
±
5
±
5
±
5
±
5
+
5
SUBJECTS
Informed Consent 18.2
x
Barriers and motivation interview 8.2.8
x
Weight history, including weight-related 
comorbidities 8.2.7
x
In/exclusion criteria 6.2 and 6.3
x
x
Randomisation criterion  6.4
x
Criteria for premature discontinuation of 
trial product 6.5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography 8.2.1
x
Childbearing potential 8.2.4
x
Concomitant illness/medical history 8.2.2
x
History of gallstone disease 8.2.2
x
History of breast neoplasms 8.2.2
x
History of colon neoplasms 8.2.2
x

Protocol
UTN: U1111-1177-5059 
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4274
EudraCT no.: 2015-005592-24
Version:
4.0
Page:
14 of 109
Screening
Randomisation
Dose escalation
Maintenance period
Follow-up9
End-of-
treatment
On site visit no.
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
Weeks in relation to visit 2
-1
0
1
2
3
4
6
8
1
0
1
2
1
4
1
6
1
8
2
0
2
2
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
Visit window, days
-7
±
2
±
2
±
2
±
2
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
5
±
5
±
5
±
5
±
5
±
5
±
5
±
5
+
5
History of psychiatric disorders 8.2.2
x
Concomitant medication 8.2.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tobacco use 8.2.5
x
Amount of alcohol consumed 8.2.6
x
Counselling1 5.3.2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adherence to trial product, dietary and 
physical activity 8.7.1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
EFFICACY
Height 8.3.2
x
Body weight 8.3.1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Waist circumference 8.3.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Six minute walking distance test 8.3.8
x
x
x
HbA1c 8.3.4
x
x
x
Fasting plasma glucose 8.3.5
x
x
Vital signs (blood pressure) 8.3.6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Lipids 8.5.1
x
x
Impact of Weight on Quality of Life-Lite for 
x
x
x
x
x
x
x
x

Protocol
UTN: U1111-1177-5059 
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4274
EudraCT no.: 2015-005592-24
Version:
4.0
Page:
15 of 109
Screening
Randomisation
Dose escalation
Maintenance period
Follow-up9
End-of-
treatment
On site visit no.
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
Weeks in relation to visit 2
-1
0
1
2
3
4
6
8
1
0
1
2
1
4
1
6
1
8
2
0
2
2
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
Visit window, days
-7
±
2
±
2
±
2
±
2
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
5
±
5
±
5
±
5
±
5
±
5
±
5
±
5
+
5
Clinical Trials Version 8.3.7
SF36 v2.0 Acute 8.3.7
x
x
x
x
x
x
x
x
Patients’ global impression of change2 8.3.7
x
x
x
x
x
x
x
Patients’ global impression status28.3.7
x
x
x
x
x
x
x
x
x
Weight related sign and symptom measure 
8.3.7
x
x
x
x
x
x
x
x
x
SAFETY
Physical examination 8.4.1
x
x
Pregnancy test3 8.5.2
x
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
x5
ECG 8.4.4
x
x
Adverse Events 8.4.2 and 12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Breast neoplasm follow-up4 8.4.8
x
x
Colon neoplasms follow-up 8.4.8
x
x
Haematology 8.5.2
x
x
x
x
Biochemistry6 8.5.2
x
x
x
x
Calcitonin 8.5.2
x
x
x
Vital signs (pulse) 8.4.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

Protocol
UTN: U1111-1177-5059 
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4274
EudraCT no.: 2015-005592-24
Version:
4.0
Page:
16 of 109
Screening
Randomisation
Dose escalation
Maintenance period
Follow-up9
End-of-
treatment
On site visit no.
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
Weeks in relation to visit 2
-1
0
1
2
3
4
6
8
1
0
1
2
1
4
1
6
1
8
2
0
2
2
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
Visit window, days
-7
±
2
±
2
±
2
±
2
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
5
±
5
±
5
±
5
±
5
±
5
±
5
±
5
+
5
PHQ-9 8.4.6
x
x
C-SSRS 8.4.7
x
x
TRIAL MATERIAL
IWRS session 10
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispensing visit 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
TRIAL REMINDERS
Trial product usage 8.6.1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense food diary7 8.6.2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense physical activity tracker 8.6.2
x
Dispense direction for use and instruct in 
pen handling 9.2 and 8.6.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Inquire about mood 8.6.4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense subject ID card 8.1
x
Attend visit fasting8
x
x
Review diary and transcribe to eCRF 8.7.1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Collect questionnaires
x
x
x
x
x
x
x
x
x

Protocol
UTN: U1111-1177-5059 
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4274
EudraCT no.: 2015-005592-24
Version:
4.0
Page:
17 of 109
1Counselling is the intensive behaviour therapy (CMS-IBT)
2 PGI-S and PGI-C questions are different for the WRSS and 6MWT
3For women of childbearing potential: A negative pregnancy test (s-HCG) is required for inclusion
4Breast neoplasm follow up form is to be filled up only for female subjects
5A urine pregnancy test must be performed at any time during the trial if there is a suspicion of pregnancy or if a menstrual period is missed, or as 
required by local law
6Estimated Glomerular Filtration Rate (eGFR) is calculated at each visit with biochemistry. hs-CRP is only measured at Visit 2 and Visit 24.
7At screening a paper food diary is dispensed, which the subject should fill in for minimum 5 days before randomisation visit in order to meet the 
randomisation criterion. At all other visits paper diaries will be provided to the subject, if this is his/her preferred method for recording daily dietary 
intake 
8Subject is not allowed to eat or drink at least eight hours overnight before attending a fasting visit (water consumption is allowed)
9The follow up visit should be performed 30 days after the end of treatment as a minimum

Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
Final
EudraCT no.: 2015-005592-24
Page:
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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 common, serious and costly. In the U.S. alone, more than one-third of adults and 17% of 
youth have obesity 3. Obesity is a multifactorial, chronic disease that is associated with major 
comorbidities, including hypertension, hyperglycemia, T2DM, dyslipidemia, certain types of 
cancer, obstructive sleep apnea and atherosclerosis4, 5 6 7 in combination leading to reduced life 
expectancy8, 9. Patients with obesity also suffer from physical symptoms (e.g., joint pain, urinary 
incontinence), functional limitations (e.g., impaired mobility), and psycho-social problems (e.g.,
body image disorders and depression)10-14. In 2010, overweight and obesity were estimated to cause 
3.4 million deaths, 4% of years of life lost, and 4% of disability-adjusted life years worldwide15.
Intensive behaviour therapy for obesity has produced mean weight losses of 8-10% of initial weight 
across clinical trials16 and significant reductions in the risk for developing T2DM and 
cardiovascular disease17, 18. Importantly, shorter-term and perhaps more patient-centric benefits of 
weight loss, such as alleviation of symptoms of obesity (joint pain, urinary incontinence), functional 
limitations (such as decreased mobility), depression, and improved quality of life has also been
observed19.
Weight losses of this magnitude can be induced by a high intensity program of lifestyle 
modification consisting of hypo-caloric diet, increased physical activity, and frequent behaviour 
therapy provided in counselling sessions in 6 months. This is the frequency of group or individual 
counselling recommended by a recent NIH expert panel20. It is also the frequency of brief 
(approximately 15-minutes) individual counselling prescribed and reimbursed in primary care for 
patients with obesity (body mass index (BMI) ≥30 kg/m2) by the Centers for Medicare and 
Medicaid Services (CMS)21.
After 6 months, most subjects will equilibrate (caloric intake balancing energy expenditure) and 
will require adjustment of energy balance if they are to lose additional weight. Continued 
intervention contact after initial weight loss treatment is associated with better maintenance of lost 
weight, with more frequent visits associated with greater weight loss20. The CMS schedule specifies 
monthly visits after 6 months21. Remarkably, the efficacy of the specific CMS model of counselling 
(CMS-IBT) has not been evaluated.
CONFIDENTIAL

Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
Final
EudraCT no.: 2015-005592-24
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Adding weight loss medication to high intensity lifestyle modification typically results in a mean 
weight loss equal to the sum of the two separate interventions22-24.
Larger weight losses of 10-15% are associated with greater improvements in risk factors and other 
patient-relevant outcomes25-27.
For an assessment of benefits and risks of the trial, see Section 18.1
3.2
Rationale for the trial
To evaluate the combined effect of CMS-IBT and liraglutide 3.0 mg, this 56-week trial will 
compare the CMS-recommended schedule of lifestyle counselling (CMS-IBT: 15 sessions in 6 
months, 8 sessions in months 7 to 13) to CMS-IBT used in combination with liraglutide 3.0 mg in a 
primary care (i.e., non-specialist) setting.
It will employ the principal components of an effective high-intensity, on-site comprehensive 
lifestyle intervention20 by:
1. prescription of a moderately reduced-calorie diet
2. a program of increased physical activity
3. the use of behavioural strategies to facilitate adherence to diet and activity recommendations, as 
defined by the “5A framework” (Ask, Assess, Advise, Agree, Assist)28-31.
For an assessment of benefits and risks of the trial, see Section 18.1
CONFIDENTIAL

Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
Final
EudraCT no.: 2015-005592-24
Page:
20 of 109
4
Objectives and endpoints
4.1
Objectives
Primary objective
To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to CMS-IBT*, on weight loss 
effectiveness in subjects with obesity
*Intensive Behaviour Therapy for obesity in a primary care setting according to Centers for 
Medicare & Medicaid Services (CMS) visit schedule
Secondary objectives

To establish the effects of liraglutide 3.0 mg vs. placebo, as an adjunct to CMS-IBT, on 
cardiometabolic and relevant efficacy endpoints in subjects with obesity

To establish the degree of adherence to randomised trial product, caloric diet and physical 
activity, and to explore the effect thereof on weight loss in subjects with obesity

To establish the safety and tolerability of liraglutide 3.0 mg vs. placebo, as an adjunct to 
CMS-IBT, in subjects with obesity
4.2
Endpoints
4.2.1
Primary endpoints

Change in body weight (%) from baseline to week 56

Proportion of subjects losing at least 5% of baseline body weight at week 56
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints addressing the first and second of secondary objectives:

Proportion of subjects losing more than 10% of baseline body weight at week 56

Proportion of subjects losing more than 15% of baseline body weight at week 56

Proportion of subjects losing ≥4% of baseline body weight at week 16
Change from baseline to week 56 in:

Waist circumference (cm)

Systolic blood pressure (mmHg)

Six minutes walking distance (m)

Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT), 
physical functioning score

IWQoL-Lite for CT, mental/emotional functioning score
CONFIDENTIAL

Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
Final
EudraCT no.: 2015-005592-24
Page:
21 of 109
Only primary and confirmatory secondary endpoints have been selected for disclosure (e.g. 
clinicaltrials.gov and EudraCT).
4.2.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
Change from baseline to week 56 in:

HbA1c (%)

Fasting plasma glucose (mg/dL)

Diastolic blood pressure (mmHg) 

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])

Short Form-36 v2.0 acute (SF-36) (physical component summary (PCS), mental component
summary (MCS) and subdomains)

Weight related sign and symptom (WRSS) measure, total score
Proportion of subjects with the following at week 56: 

≥ 2 T-score points increase from baseline in SF-36 PCS

≥ 3 T-score points increase from baseline in SF-36 MCS
Number of weeks (completed calendar weeks) from randomisation to week 56 adherent to:

Trial product

Caloric diet

Physical activity

Caloric diet and physical activity

Trial product, caloric diet and physical activity
Supportive secondary safety endpoints

Adverse events from randomisation until and including the follow-up visit (see Section 
17.4.3.2)
Change from baseline to week 56 in:

Physical examination

Resting pulse

ECG

Laboratory measurements
CONFIDENTIAL

Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
Final
EudraCT no.: 2015-005592-24
Page:
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5
Trial design
5.1
Type of trial
This is a 56-week, randomised, double-blind, placebo-controlled, two-armed multi-centre trial in 
subjects with obesity, who have not been diagnosed with type 1 or type 2 diabetes mellitus.
A total of 282 subjects will be randomised in a 1:1 manner to receive either liraglutide 3.0 mg or 
placebo, as an adjunct to CMS-IBT.
Throughout the 56-week treatment period, subjects will attend site visits to monitor response to 
treatment and 23 brief (approximately 15-minute) behavioural counselling visits (see Section 2).
A 30-day follow-up period is included after the 56-week treatment period in accordance with FDA 
guidance32.
Figure 5–1
Trial Design
5.2
Rationale for trial design
A randomised controlled and double-blinded trial design is used to minimise bias in the assessment 
of the effect and safety of liraglutide 3.0 mg vs placebo, both as an adjunct to CMS-IBT18, 23. 
To minimise missing data and in line with current clinical recommendations33, subjects 
discontinuing randomised treatment prematurely are encouraged to stay in the trial and continue 
CMS-IBT and the scheduled site visits. This is to mimic the ‘real-world’ situation of an approved 
weight loss drug. CMS-IBT consists of a frequent structured counselling, reduced calorie diet and 
increased physical activity is an integrated part of the trial 
CONFIDENTIAL

Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
Final
EudraCT no.: 2015-005592-24
Page:
23 of 109
Weekly dose escalation of the trial drug (see Table 5–1) is included in accordance with the 
Saxenda® US prescribing information34.
Based on the weight loss time course established in phase 3a trials, trial duration of 56 weeks is 
considered sufficient to measure the full effect of liraglutide 3.0 mg on the weight loss curve.
5.3
Treatment of subjects
5.3.1
Investigational medicinal product
The investigational medicinal product (IMP) is injected subcutaneously (s.c.) once daily for 56 
weeks. Dose escalation of trial product will take place during the first 4 weeks after randomisation 
(see Table 5–1).
Table 5–1
Dose Escalation and treatment period
IMP
Dose
Duration
Liraglutide/placebo
0.6 mg
1 week
Liraglutide/placebo
1.2 mg
1 week
Liraglutide/placebo
1.8 mg
1 week
Liraglutide/placebo
2.4 mg
1 week
Liraglutide/placebo
3.0 mg
52 weeks
Follow up period
0 mg
4 weeks
If the subject does not tolerate an increased dose during the dose escalation window, the 
investigator can delay the dose escalation by maintaining the subject at the current dosage step for 
one additional week. Such a delay is allowed only once during dose escalation (i.e. maximum 
allowed time for complete dose escalation to 3.0 mg is 5 weeks). After reaching the maintenance 
dose (3.0 mg), the dose and dosing frequency should not be changed. 
If a single dose is missed, once-daily regimen should be resumed as prescribed at the next 
scheduled dose. If more than 3 consecutive days have elapsed since the last dose, subject should re-
initiate dose escalation, (i.e., restart the dosing at 0.6 mg and follow the dose escalation schedule 
again). This is done to reduce the occurrence of gastrointestinal symptoms associated with re-
initiation of treatment.
NB: Additional or increased dose should not be taken to make up for missed doses. 
Trial product can be taken at any time of day, irrespective of timing of meals. Trial product can be 
injected subcutaneously in the abdomen, thigh, or upper arm. The injection site and timing can be 
changed without dose adjustment. 
NB: Trial product must not be administered intravenously or intramuscularly.
CONFIDENTIAL

Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
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EudraCT no.: 2015-005592-24
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If a subject cannot tolerate the 3.0 mg dose, or if any of the other treatment discontinuation criteria 
are met, then treatment with trial product must be discontinued. For treatment discontinuation 
reasons, please refer to Section 6.5. In case this happens, it is acceptable to restart trial product (at 
the discretion of investigator and according to the local clinical practice); the dose must be escalated 
according to the algorithm above, and date of restart and rationale must be documented in the CRF. 
5.3.2
Counselling (intensive behaviour therapy)
The CMS intensive behaviour therapy (CMS-IBT) will consist of counselling on diet, physical 
activity and other lifestyle modifications. Subjects will attend a total of 23 individual approximate 
15-minutes sessions during the 56 weeks.
The CMS-IBT will be delivered by a primary care physician, a nurse practitioner, a clinical nurse 
specialist, or physician assistant. Registered dieticians are also eligible to provide lifestyle 
counselling under CMS rules, when supervised by a nurse practitioner or physician35. The 
individual performing the CMS-IBT is called interventionist in this protocol. Interventionists will 
be trained in obesity and its behavioural management prior to beginning the trial and provided on-
going assistance and share better practice in how to perform CMS-IBT during the trial. The content 
of the CMS-IBT is based on an abbreviated version of the Diabetes Prevention Program (DPP) 
employing the 5A counselling framework (Ask, Assess, Advise, Agree, Assist)36,37. 
The structure and content of each CMS-IBT session is specified in an IBT guide, consisting of an 
interventionist part and a subject hand out. Generally each CMS-IBT session will begin with the 
subject being weighed and informed of the weight change. Then the subject and interventionist will 
review the subject’s completion of food and physical activity records (see Section 8.7.1) and the 
interventionist assists with solving individual problems.
In addition to the above, each CMS-IBT session will cover a specific topic, for example, advice on 
diet or physical activity as well as lifestyle modification (e.g., challenging negative thoughts, 
obtaining social support). Most of the topics will be accompanied by a homework assignment from 
the IBT guide to be completed before the next session with the interventionist.
CMS-IBT sessions that cannot be completed on-site (because of illness, travel, etc.), may be 
completed on telephone in few cases.
Calorie targets 
Caloric deficit and diet composition are aligned with clinical evidence-based guidelines for 
management of overweight and obesity in adults20.
CONFIDENTIAL

Protocol
CONFIDENTIAL
Date:
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Trial ID: NN8022-4274
Version:
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Daily caloric target throughout the trial for subjects will be based on body weight at randomisation:

Subjects weighing less than 200 lbs will be prescribed a diet of 1200 kcal/day

Subjects weighing between 200 lbs and 300 lbs will be prescribed a diet calculated as:
 	
	  (	) = 
 ℎ () ∗6 (	/)

Subjects weighing more than 300 lbs will be prescribed 1800 kcal/day
The initial caloric target will be kept throughout the trial. If a subject achieves a BMI ≤ 22 kg/m2, 
the recommended energy intake will be re-calculated with no caloric deficit for the remainder of the 
trial.
The diet will consist of conventional foods with approximately 15-20% kcal from protein, 20-35% 
from fat, and the remainder from carbohydrate. Carbohydrate intake should be monitored by the 
interventionist. Carbohydrate intake from vegetables, fruits, whole grains, legumes and dairy 
products should be advised38. Meal plans may be provided.
Subjects will be instructed to record their food and calorie intake daily (see Section 8.7.1).
Physical activity targets
All subjects will initially be prescribed 100 minutes physical activity per week (e.g., walking or 
similar aerobic activity). Subjects should be physically active in bouts of >10 minutes in duration 
with moderate intensity (such as brisk walking), and the physical activity should be spread equally 
across 4-5 days each week. Physical activity should progress gradually by 25 minutes every 4 
weeks until 250 minutes/week, consistent with targets required for maintenance of lost weight39.
Subjects will be instructed to record their physical activity daily using a physical activity tracker 
provided by NN (see Section 8.7.1)17, 37.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, the subject should be switched to a suitable marketed product at 
the discretion of the investigator.
After premature discontinuation of trial product (temporary/permanent), the subject should still 
remain in the trial and follow the IBT sessions and site visits if possible, see Section 8.1. The 
investigator must note down in the medical record and eCRF if the subject has re-started the trial 
product, see Section 5.3.1.
5.5
Rationale for treatment
Subjects are treated for a period of 56 weeks in order to be able to evaluate the full effect of 
treatment with liraglutide 3.0 mg on the primary and secondary endpoints. This is based on the 
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knowledge from previous liraglutide 3.0 mg trials. Also, the regulatory authorities’ guidelines for 
trials in weight management state that the duration of at least 1 year is deemed appropriate to 
evaluate efficacy, safety and tolerability.
The comparator in the trial is placebo in order to evaluate the absolute safety and efficacy of 
liraglutide 3.0 mg.
Combining frequent behavioural counselling, highly structured hypo-caloric diets and increased 
physical activity is an effective tool for achieving and maintaining weight loss. It has been shown to 
be more effective than less intensive lifestyle modification programs for inducing weight loss18, and 
combining IBT and pharmacologic treatment leads to more weight loss than pharmacologic 
treatment alone23. Subjects in the trial will receive CMS-IBT irrespective of the treatment arm they 
belong to. 
The CMS-IBT mandates 22 sessions within a span of one year (52 weeks). Since the treatment
duration is 56 weeks, an extra CMS-IBT session has been added at week 56. 
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be randomised: 282
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. BMI ≥ 30 kg/m2
3. Maximum 5 kg self-reported weight change within the past 90 days since screening
4. Age ≥18 years at the time of signing informed consent
5. Increased physical activity is considered to be safe as judged by the investigator
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”.
1. HbA1c ≥6.5% (at screening visit), or diagnosis of type 1 or type 2 diabetes mellitus
2. Recent history of cardiovascular disease (myocardial infarction or stroke within the past 6 
months), severe congestive heart failure (NYHA class III, IV), or second degree or greater heart 
block
3. Hypersensitivity to liraglutide or any product components
4. Personal or family history of Medullary Thyroid Carcinoma (MTC), or Multiple Endocrine 
Neoplasia type 2 (MEN2)
5. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure as 
required by local regulation or practice)
6. Uncontrolled thyroid disease, defined as TSH > 6 mIU/L or < 0.4 mIU/L (at screening visit)
7. Use in past 90 days since screening of medications known to induce significant weight loss 
(e.g., prescription weight loss medications) or weight gain (e.g., chronic use of oral steroids, 
second generation antipsychotics)
8. History of (or plans for) weight loss surgery (e.g. bariatric, intra-gastric balloons, maestro 
system) or implant of weight loss device (e.g., Reshape, vBloc). However, liposuction and/or 
abdominoplasty performed > 1 year before screening is allowed
9. History of pancreatitis (acute or chronic)
10. History of major depressive disorder within the past 2 years since screening 
11. Diagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder)
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12. A Patient Health Questionaire-9 (PHQ-9) score of ≥15 at screening or randomisation
13. Any lifetime history of a suicide attempt
14. Any suicidal behaviour within the past 30 days since screening 
15. Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) 
within the past 30 days at screening or randomisation
16. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic ≥180 
mmHg or diastolic ≥110 mmHg)  
17. History of malignancy (except for non-melanoma skin cancer) within the past 5 years
18. Any disorder, not covered by any of the other exclusion criteria, which in the investigator’s 
opinion, might jeopardise the subject’s safety or compliance with the protocol
19. Known or suspected abuse of alcohol or narcotics
20. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures
21. Subjects from the same household participating in the trial
22. Participation in any clinical trial with or without an investigational medicinal product within the 
past 90 days before screening
23. Previous participation in this trial. Participation is defined as signed informed consent
6.4
Randomisation criterion
1. Have kept a food diary for at least 5 days (minimum one entry per day) in the period between 
screening and randomisation
To be randomised, the above randomisation criterion must be answered “yes”.
6.5
Criteria for premature discontinuation of trial product 
Efforts must be made so that subjects attend and complete all scheduled visit procedures. Subjects
should stay in the trial regardless of adherence to randomised treatment, visit schedule or missing 
assessments. Only subjects who decline any further contact with the site in relation to the trial or 
withdraw consent are considered as withdrawn from the trial (see Section 6.6).
The subject may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The subject must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of any of the inclusion and/or exclusion criteria and/or 
randomisation criteria
2. Safety concern (not covered by any of below criteria) or unacceptable intolerability to trial 
product, as judged by the investigator
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3. Hypersensitivity to trial product(s). If a hypersensitivity reaction occurs, discontinue trial 
product and other suspect medications and promptly seek medical advice
4. Pregnancy
5. Intention of becoming pregnant
6. Suspicion of pancreatitis (see Section 8.4.2.2 and 8.8.1)
7. Suspicion of acute gallstone disease (see Section 8.4.2.2 and 8.8.2)
8. Suspicion of drug-induced liver injury (DILI) (see Section 8.4.2.2 and 8.8.4)
9. Calcitonin ≥100 ng/L
10. Psychiatric disorder(s) that cannot be adequately treated with psycho- and/or pharmacotherapy
(see Section 8.4.2.2, 8.8.5 and 8.6.4).
11. Initiation of anti-obesity medication and/or (plans for) weight loss surgery
12. Initiation of treatment with glucagon-like peptide-1 receptor agonist (GLP-1 RA)
13. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product
See Section 8.1 for procedures to be performed for subjects discontinuing trial product prematurely.
It is allowed for subjects meeting the premature discontinuation criteria or who have wished to 
discontinue prematurely to be restarted on the trial product should the suspicion not be confirmed or 
if the condition has been resolved at the investigator’s discretion. Trial product may be restarted for 
subjects meeting discontinuation criteria 7 should the gallbladder be removed.
6.6
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. See Section 8.1 for procedures to be performed for subjects 
withdrawing consent. The trial drug cannot be re-initiated if the consent has been withdrawn. 
6.7
Subject replacement
Subjects who discontinue trial product prematurely will not be replaced.
6.8
Rationale for trial population 
The trial will be conducted in subjects with obesity without T2DM. Subjects with obesity represent 
a clinically relevant population to treat for weight loss as they are likely to benefit from weight 
reduction. Subjects with T2DM 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. 
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7
Milestones
Planned duration of recruitment period: 10 weeks.
End of trial is defined as last subject last visit (LSLV). End of treatment is defined as visit 24 for 
each subject.
Recruitment:
The screening and randomisation rate will be followed closely via the interactive voice/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 screened during the 
recruitment period and found eligible for randomisation can be randomised within the timelines 
specified in the flow chart (see Section 2).
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 Disclosure40, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)41, the Food and Drug Administration Amendment Act42, European 
Commission Requirements43, 44 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
8.1
Visit procedures
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see Section 2).
Informed consent must be obtained before any trial-related activity; see Section 18.2.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
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.
Fasting requirements
The subjects should be fasting when attending some visits, please see flow chart (Section 2). 
Fasting is defined as at least 8 hours without food and drink intake, except water and other 
prescribed medication. Trial product and other glucose lowering agents should be withheld on the 
day of the visit until blood sampling have been performed. If the subject attends a fasting visit in a 
non-fasting state, the blood sampling should be re-scheduled within the visit window.
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 (SAEs) from 
screening failures must be transcribed by the investigator into the eCRF. Follow-up on 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 is NOT allowed if the subject has failed one of the inclusion, exclusion, or 
randomisation criteria, this includes re-sampling if the subject has failed one of the inclusion or 
exclusion criterion related to laboratory parameters.  
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Premature discontinuation of trial product
The subject may discontinue trial product for several different reasons and after different treatment 
durations.
If a subject meets a discontinuation criterion, the trial product must be immediately discontinued 
and the date should be noted in the medical records and eCRF. Discontinuation can be either 
temporary or permanent. The last paragraph of Section 6.5 outlines which discontinuation can be 
considered temporary. The investigator must note down the date in the medical record and the 
eCRF once there is resolution and the subject has re-started the trial product.
The subject may also wish to discontinue trial product temporarily or permanently, irrespective 
meeting any criteria. Discontinuation of treatment with trial product, whether temporary or 
permanent, must not prompt the investigator to withdraw the subject from the trial. Instead, the 
subject should maintain adherence to trial visits (including CMS-IBT) and procedures to the extent 
possible.
In cases where the subject is not willing to attend all scheduled visits after discontinuation of trial 
product, efforts must be made to collect as much of the scheduled data as possible. Especially 
important is collection of the data points (primarily body weight) at visit 24 (week 56). Statistical 
considerations emphasizing the importance can be found in Section 17.
Premature trial product discontinuation should be registered in the eCRF and in IWRS. The trial 
product can be interrupted by performing a ‘treatment status’ session in IWRS, to indicate subject 
should no longer receive trial product. The primary reason for discontinuation of trial product must 
be specified when recording the treatment discontinuation in the eCRF. If the discontinuation of 
trial product is judged permanent or of a longer period, drug accountability until discontinuation 
must be performed in IWRS. 
If the subject has previously discontinued trial product, it is possible, at the discretion of the 
investigator and at the wish of the subject, to re-initiate treatment with trial product. This will only 
apply, if it can be confirmed that the subject has not withdrawn consent, and does not fulfil any of 
the criteria leading to permanent discontinuation or if a criterion leading to temporary 
discontinuation has been resolved. A ‘treatment status’ session is performed in the IWRS, to 
indicate that the subject should again receive trial product. See Section 10 for registration in IWRS.
This should be further noted in the medical records and eCRF.
Withdrawal from trial
A subject who wishes to withdraw their consent must be withdrawn from the trial. If a subject wants 
to withdraw consent, the investigator must aim to undertake procedures similar to those for end-of-
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treatment visit, as soon as possible. If the subject agrees, the follow-up visit must be performed at 
least 30 days after discontinuation of trial product.
The end-of-trial form in the eCRF must be completed, and final drug accountability must be 
performed even if the subject is not able to come to the trial site. The investigator must perform a 
‘treatment status’ session in IWRS and discontinue trial product for this subject. The case book
must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, 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 withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
Lost to follow-up
If a subject loses contact with the study staff or does not come for visit 24 or visit 25, attempts must 
be made to locate the subject and obtain relevant safety information. A subject cannot be deemed 
lost to follow-up until at least substantial contacts with family/relatives/family physician have been 
attempted. Subject information may be retrieved from other health care professionals, medical 
records or publicly available records. A subject will only be considered lost to follow-up in case 
vital status cannot be determined at the time of visit 25 for that subject.
8.2
Subject-related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:

Date of birth (according to local regulation)

Sex

Ethnicity (according to local regulation)

Race (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., at the screening visit) 
or found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product. 
Medical history is a medical event that the subject has experienced in the past. Only relevant and 
significant medical history as judged by the investigator should be recorded. Findings of specific 
medical history described below should be entered on the specific forms.
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The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. Any clinically significant 
worsening of a concomitant illness must be reported as an AE.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigator’s own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party (e.g., primary 
physician). The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
Findings of specific medical history described below should also be entered on the specific forms in 
the eCRF: 
History of gallstone disease
Information related to gallstone disease (i.e., gallstone disease and cholecystectomy) must be 
recorded.
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 
guidelines, hormone replacement therapy, age of menarche, number of births, maternal age at first 
birth, and if the subject ever breastfed) should be recorded.
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.
History of psychiatric disorders
Information related to psychiatric disorders (specifically history of depression, substance and 
alcohol abuse, suicidal ideation/behaviour, anxiety, mood disorders, insomnia, or sleep disorders) 
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.
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Details of any concomitant medication must be recorded at visit 1. Changes in concomitant 
medication must be recorded at each visit as they occur. The investigator must assess the 
concomitant medication at every visit for any changes.
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation. 
If a change in concomitant medication is due to an AE, then this must be reported according to 
Section 12. If the change influences the subject’s eligibility to continue in the trial, the monitor must 
be informed.
8.2.4
Childbearing potential  
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.2. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 1 week after end of treatment.
Female of non-childbearing potential is defined as:
–
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation 
–
Postmenopausal defined as no menses for 12 months without an alternative medical cause
–
Other medical reasons preventing childbearing potential
8.2.5
Tobacco use 
Details of tobacco use must be recorded at visit 1. Smoking is defined as smoking at least one 
cigarette or equivalent daily. 
Smoking status:

Never smoked

Previous smoker

Current smoker
8.2.6
Amount of alcohol consumed
Details of alcohol use must be recorded at visit 1. Alcohol consumption should be collected. 
Alcohol use is defined as consumption of minimum one unit of alcohol per week on average.
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8.2.7
Weight history, including weight-related comorbidities
Information regarding maximum lifetime weight, progression of weight pattern, family history of 
weight and previous weight loss attempts (e.g., maximum weight loss) must be recorded for all 
subjects.
8.2.8
Barriers and motivation interview
The barriers and motivation interview identifies barriers to lifestyle change and compliance with the 
protocol. The interview guide will ensure that these are addressed during CMS-IBT sessions. The 
interview guide will be available in local language.
8.2.9
7-day food diary in screening period
A food diary will be dispensed to the subjects at the screening visit to ensure that randomised 
subjects are able to comply with the protocol requirements for daily recording of food intake.
8.3
Efficacy assessments
All assessments and samples collected at randomisation will be considered as baseline for efficacy, 
unless otherwise specified.
8.3.1
Body weight
The body weight should be measured at all visits without shoes, on an empty bladder and only 
wearing light clothing. It should be measured on a digital scale to the nearest 0.1 kg or lb using the 
same scale throughout the trial. The scale must be calibrated yearly as a minimum.
BMI will be calculated by the eCRF from visit 1 data and must be in accordance with inclusion 
criterion 2. BMI will be calculated as follows:
BMI = weight (kg)/height2 (m2) or 
BMI = (weight (lb)/height2 (inch2))*703
8.3.2
Height
Height is measured at screening without shoes to the nearest cm or inch with one decimal.
8.3.3
Waist circumference
The waist circumference will be measured at the specified visits (see Section 2) and is defined as 
the abdominal circumference located midway between the lower rib margin and the iliac crest.
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Waist circumference is measured in the horizontal plane and rounded to the nearest cm or inch
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 and wearing light clothing. The subject 
should be standing, feet together with arms at the side and waist 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.
8.3.4
HbA1C
Blood samples will be drawn at the specified visits (see Section 2) for measurement of HbA1c. 
8.3.5
Fasting plasma glucose
FPG is measured in order to evaluate metabolic control. The subject must attend these visits fasting. 
For definition of fasting, see Section 8.1.
A FPG result ≤3.9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as a 
clinical laboratory adverse event (CLAE) at the discretion of the investigator (see Section 12.1.1).
8.3.6
Vital signs (blood pressure)
For blood pressure, measurement with a precision of minimum 2 mmHg must be performed. The 
value must be used to evaluate eligibility of the subject in relation to exclusion criterion. 
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 measurement is taken. The same 
arm and an appropriate cuff size should be used for blood pressure measurements at all visits.
8.3.7
Clinical outcome assessments
Clinical outcome assessments (COA) are used to collect clinical data for all subjects enrolled in the 
trial at the visits specified in Section 2. The questionnaires are linguistically validated to fluent 
language of all subjects participating.
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.
Each of the questionnaires takes approximately 10 minutes to complete.
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The questionnaires are:
Impact of Weight on Quality of Life-Lite for Clinical Trials Version
The IWQoL-Lite for CT questionnaire is a 22-item modified version of an instrument designed to 
assess weight-related quality of life45.  
Alongside this trial in another project, Novo Nordisk is adapting the IWQoL-Lite for CT by 
conducting additional concept elicitation with patients, cognitive interviewing, consultation with 
expert clinicians, translatability assessment, and psychometric validation. Development and 
validation process is aligned with the FDA PRO guidance (2009)46.
Short Form 36 v2.0 acute
Short Form 36 v2.0 acute (SF-36)47 is a 36-item, patient-reported survey of patient health. SF-36 
measures the subject’s overall HRQoL (Health related quality of life) on 8 domains: physical 
functioning, role functioning, bodily pain, general health, vitality, social functioning, role emotional 
and mental health.
In addition SF-36 is included to validate the outcome of IWQoL-Lite for CT and WRSS 
questionnaires.
Patients’ global impression of change
The PGI-C assesses subjects’ impressions of change during the clinical trial. It is used to establish 
the Minimal Clinically Important Difference (MCID) as part of the psychometric properties of the 
Weight related sign and symptom measure (WRSS) questionnaire and support the 6 minute walk 
test.
Patients’ global impression of status
The PGI-S assesses subjects’ impressions of status at the time in the clinical trial. It is used to 
establish the MCID as part of the psychometric properties of the WRSS questionnaire and support 
the 6 minute walk test.
Weight related sign and symptom measure
The WRSS measures the presence and bothersome associated with weight-related symptoms. It is a 
tool to assess the multifaceted aspects of obesity on symptom experience in subjects with obesity.
In this trial, Novo Nordisk is validating the WRSS. Development and validation process is aligned 
with the FDA PRO guidance (2009)46.
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8.3.8
Six-minute walking distance test
The six-minute walking distance test (6MWT) is a common test of functional exercise capacity that 
assesses the distance a subject can walk in 6 minutes. A direct and timed measure of walking 
ability, the 6MWT is technically simple, reproducible, and when administrators are well trained, 
readily standardised. The goal is for the subject to walk as far as possible in six minutes without 
running. The subject is allowed to self-pace and rest as needed as they traverse back and forth along 
a marked walkway of 66 feet (20 m) (see Figure 8–1). The primary outcome is the distance covered 
in feet over 6 minutes48, 49. 
To ensure adequate 6MWT standardisation across clinical sites and test administrators, training 
materials will be developed and provided to all clinical sites prior to subject recruitment.  
Specifically, all principal investigators and 6MWT clinical site administrators will receive an 
instruction manual, providing detailed instructions for administration of the 6MWT.  In addition to 
the instruction manual, each 6MWT administrator will have a checklist that must be completed 
prior to initiating each test administration to confirm and document that specific test administration 
criteria are met (e.g., the test is assessed along a flat, straight, enclosed corridor that is at least 6 feet 
wide; proper footwear as judged by the investigator is worn by the subject or otherwise noted)50.  
The clinical outcome assessments (PGI-S and PGI-C) will support the test and help establish the 
MCID of the test.
Figure 8–1
Hallway marking for the six minute walking distance test
8.4
Safety assessments
All assessments and samples collected at randomisation will be considered as baseline for safety, 
unless otherwise specified.
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8.4.1
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, abdomen, musculoskeletal 
system, central and peripheral nervous system, skin, lymphoid 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).
Physical examination performed at screening will be considered as baseline.
8.4.2
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12. 
8.4.2.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form for medication error must be completed in the eCRF in addition to the AE form: 

Trial product(s) involved 

Classification of medication error

Whether the subject experienced any adverse event(s) as a result of the medication error 

Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4.
8.4.2.2
Adverse events requiring additional data collection
For the following AEs, additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:

Acute gallstone disease

Neoplasm 

Pancreatitis

Depression, suicidal ideation/behaviour

Hepatic event (Suspicion of DILI)
In case any of these events fulfil the criteria for a SAE, please report accordingly, see Section 12. 
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Acute gallstone disease
If an event of acute gallstone disease or clinical suspicion of this is observed during the trial, the 
following additional information should be reported if available on the acute gallstone disease form: 

Signs and symptoms of acute gallstone disease

Specific laboratory test supporting a diagnosis of gallstone disease (see Section 8.8.2)

Imaging performed and consistency with gallstone disease

Treatment given for the event

Relevant risk factors associated with the event
Neoplasm
All events of benign, pre-malignant/carcinoma in-situ and malignant neoplasms must be reported 
during the trial and the following additional information should be obtained if available as part of 
standard of care on the neoplasm form:

Type of neoplasm

Signs and symptoms leading to identification of event

Diagnostic imaging

Pathological examination results

Treatment given for the event

Participation in screening programs

Relevant risk factors associated with the event
Pancreatitis
If an event of pancreatitis, acute or chronic is observed during the trial, the following information 
must be reported, if available on the pancreatitis form: 

Signs and symptoms of pancreatitis

Specific laboratory test supporting a diagnosis of pancreatitis (see Section 8.8.1)

Imaging performed and consistency with pancreatic disease

Treatment given for the event

Relevant risk factors associated with the event
Depression, suicidal ideation/behaviour
If an event of depression, suicidal ideation or behaviour or clinical suspicion of this is observed 
during the trial the following additional information should be reported if available on the 
Depression, suicidal ideation/behaviour form: 

Signs and symptoms of depression, suicidal ideation or behaviour

Relevant risk factors associated with the event

Treatment given for the event
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Hepatic event (suspicion of drug induced liver injury)
In case of suspicion of DILI, following additional information should be reported if available on the 
drug induced liver injury form:

Signs and symptoms of drug induced liver injury

Specific laboratory test supporting a diagnosis of drug induced liver injury (see Section 
8.8.3)

Treatment given for the event

Relevant risk factors associated with the event
Prompt testing (at central laboratory) including alanine aminotransaminase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), international normalised ratio (INR) and total 
bilirubin (TBL) should be done and trial product should be discontinued until the abnormalities 
return to normal or baseline state.
Additional clinical information such as related symptoms, risk factors and contributing conditions 
(e.g., viral hepatitis, autoimmune hepatitis, alcoholic hepatitis, hepatobiliary or pancreatic disorders) 
should be gathered to seek a possible cause of the observed laboratory test abnormalities.
The event should be reported as an AE requiring additional data collection (see Section 12.1.5).
8.4.3
Vital signs (pulse)
Pulse (beats/minutes) will be recorded in a sitting position after resting for five minutes at the 
specified visits (Section 2).
8.4.4
Electrocardiogram
An electrocardiogram (ECG) will be performed at the visits specified in the flow chart (Section 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)
Clinically significant is 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.
If the result is clinically significant, the investigator must report such an abnormal finding as an AE 
or SAE (see Section 12.2).
ECG performed at screening will be considered as baseline.
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8.4.5
Hypoglycaemic episodes
Liraglutide increases insulin secretion and reduces glucagon secretion in a glucose dependent 
manner. Thus, the stimulation of insulin release and inhibition of glucagon release subsides as the 
blood glucose decreases and approach euglycemia. Therefore, the risk of hypoglycaemia in subjects 
without T2DM is considered to be low. 
A hypoglycaemic episode during the trial should be recorded as an AE according to standard AE 
reporting (see Section 12). 
Subjects should be instructed in potential symptoms of hypoglycaemia: sweating, trembling, hunger 
or palpitations (rapid or irregular heart beat), confusion, drowsiness, speech difficulty, visual 
disturbances, odd behaviour, impaired balance or incoordination (reduced ability to coordinate 
movement). 
According to ADA classification, a severe episode of hypoglycaemia is defined as 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 low plasma glucose concentration51. Such a severe episode 
of hypoglycaemia must be reported as a SAE (see Section 12.2).
Blood glucose meters will not be handed out to subjects in this trial.
8.4.6
Patient Health Questionnaire-9 
The patient health questionnaire-9 (PHQ-9) is a 9-item depression module of the patient health 
questionnaire, which is a self-administered diagnostic tool used for assessment of mental 
disorders52. The questionnaire will be available in a linguistically validated version in subject’s 
fluent language. Subjects should be given the opportunity to complete the questionnaires by 
themselves without interruption. It takes approximately 10 minutes to complete.
A PHQ-9 ≥ 15 excludes the subject from participation in the trial.
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8.4.7
Columbia Suicidal Severity Rating Scale 
The Columbia suicidal severity rating scale (C-SSRS)53 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. The questionnaire will be available in a linguistically 
validated version in the subject’s fluent language. It takes approximately 10 minutes to complete.
Prior to administering the C-SSRS questionnaire, the investigator or qualified delegate must 
complete sufficient training. Any suicidal ideation of type 4 or 5 within the past 30 days at 
screening or randomisation excludes the subject from participation in the trial.
8.4.8
Breast and colon neoplasms follow up
These forms must be completed at the end-of-treatment and follow-up visit, even if a subject 
prematurely discontinues treatment with trial product. The breast neoplasm follow up form should 
be filled in only for female subjects.
If a subject withdraws consent, the subject must be encouraged to provide this information. 
8.5
Laboratory assessments
The laboratory analyses will be performed by a central laboratory. The central laboratory may 
utilise subcontractors.
Descriptions of assay methods, laboratory supplies and procedures for obtaining samples, handling, 
transportation and storage of samples and information regarding who will perform the assessments, 
will be described in a trial specific laboratory manual, provided by the central laboratory (for central 
laboratory details, see Attachment 1). 
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 Section 8.2.2 and Section 12).
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 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. 
Samples will be destroyed no later than at finalisation of the clinical trial report (CTR). 
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The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed (e.g., to follow up on AEs) this must be done at a local 
laboratory.
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not. If clinically significant, the investigator must report these as 
clinical laboratory adverse events (CLAE) according to Section 12.1.1. 
All laboratory report printouts must be reviewed, 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.
8.5.1
Laboratory assessments for efficacy
Blood samples must be collected at the specified visits (Section 2).

HbA1c

Fasting plasma glucose (FPG)

Lipids (TC, LDL cholesterol, HDL cholesterol, VLDL cholesterol, TG, FFA)
A FPG result ≤3.9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as a 
CLAE at the discretion of the investigator (see Section 12.1.1).
8.5.2
Laboratory assessments for safety
Pregnancy test
Females of childbearing potential will have a human chorionic gonadotropin (hCG) serum 
pregnancy test performed at the visits specified in the flow chart (see Section 2). 
Urine pregnancy tests will be performed for females of childbearing potential if there is suspicion of 
pregnancy or if she misses a menstrual period, at the visits specified in the flow chart (Section 2). 
She should contact the site to come in for a urine pregnancy test. Urine pregnancy kits will be 
supplied by the central laboratory.
Pregnancy testing will not be required for women not of childbearing potential (see Section 8.2.4)
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Biochemistry
Blood samples for biochemistry must be collected at the specified visits (Section 2).

Creatinine

Urea (blood urea nitrogen)

Uric acid

Alanine aminotransaminase (ALT)

Aspartate aminotransferase (AST)

Alkaline phosphatase (ALP)

Albumin

Amylase

Lipase

Sodium

Potassium

Calcium, total

Calcitonin (please refer to Appendix A for actions to be taken if calcitonin is ≥ 10 ng/L)

TSH*

Bilirubin, total (TBL)

hs-CRP**

GFR, estimated 
*If TSH levels are out of normal range , the investigator must perform additional testing:

Total and free T3 and T4 and Free Thyroid Index

Thyroid peroxidase antibodies
** hs-CRP is only measured at Visit 2 and Visit 24.
Haematology
Blood samples for haematology must be collected at the specified visits (Section 2).

Haemoglobin

Haematocrit

Thrombocytes

Erythrocytes

Leucocytes
8.6
Other assessments
8.6.1
Trial product usage
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Information on premature discontinuation, and permanent discontinuation of trial product will be 
collected and recorded in the eCRF. If the trial product is re-started, the investigator must note this 
in the medical record.
8.6.2
Food diary and tracking of physical activity
The subjects will be requested to fill in a food diary daily, where all meals and their caloric content 
are recorded. The interventionist can provide a paper food diary or the subject can use another 
tracker, tool or app to register food intake, as preferred by the subject.
Daily minutes of physical activity will be captured using a device provided by Novo Nordisk. The 
subject’s adherence with diet and physical activity must be reviewed at all CMS-IBT visits by the 
interventionist (see Section 8.7.1). The adherence will be further recorded in the eCRF.
8.6.3
Training in the PDS290 pen-injector
The subjects must be trained in how to handle the PDS290 pen-injector when handed out the first 
time. Training must be repeated during the trial at each visit if needed, in order to ensure correct use 
of the device. The following should be emphasised:

Always use a new needle for each injection as this will prevent contamination and blocked 
needles

When using the first time, priming the pen to ensure product flow 

The needle should be kept in the skin while counting slowly to 6 (or as described in the 
direction for use) after the dose counter has returned to zero after injection. If the needle is 
removed too early then the full dose may not have been delivered.
8.6.4
Inquire about mood
The subject should be asked about the mood as per flow chart (see Section 2), for example – ‘How 
has your mood been since the last contact?’ 
In case the subject reports any adverse events, these should be collected and reported as an AE.
Depression and suicidal ideation/behaviour should be reported as AEs requiring additional data 
collection (see Section 8.4.2.2 and Section 12). 
8.7
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.
Compliance with trial product: At each visit, the investigator should ask the subject whether the 
subject has continuously been using the trial product since last visit. If the subject has stopped using 
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trial product, the investigator should fill in the date for the last dose in the eCRF. If the subject has 
had a pause using trial product longer than one week since last visit, but has started using trial 
product again, the investigator should fill in the dates corresponding to the last day on trial product 
and the first day on trial product in the eCRF.
8.7.1
Adherence to dietary and physical activity  
Adherence to the dietary and physical activity will be assessed by the interventionist performing the 
CMS-IBT at all visits. At each CMS-IBT session, the interventionist must, for each calendar week 
since the last visit, assess and record the number of days per calendar week, where the subject has 
entered information in the food diary (see Section 5.3.2). In addition, how physically active the 
subject has been per week for each calendar week since the last visit will be recorded. The result 
must be noted in the subjects’ record in eCRF.  
If a subject is found to be non-adherent, the interventionist should remind the subject of the 
importance of following the advice given. The interventionist will help the subjects solve issues 
with non-adherence as part of the counselling (see Section 5.3.2).
8.8
Additional safety assessments
8.8.1
Suspicion of acute pancreatitis
If pancreatitis is suspected, trial product should promptly be discontinued (no ‘treatment status’ 
session should be made in IWRS before diagnosis of acute pancreatitis is confirmed) and 
appropriate management should be initiated. Appropriate additional examinations must be 
performed, including local measurement of amylase and lipase.
The event should be reported as an AE requiring additional data collection (see Section 8.4.2.2 and 
Section 12).
The diagnosis of acute pancreatitis requires two of the following three features: 

Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back)

Serum lipase activity (and/or amylase activity) at least three times greater than the upper 
limit of normal

Characteristic findings of acute pancreatitis on imaging (CT/MRI).
Abdominal pain
Most patients with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 minutes; it is frequently unbearable and characteristically persists for more than 
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24 hours without relief. The pain is often associated with nausea and vomiting. Physical 
examination usually reveals severe upper abdominal tenderness at times associated with guarding. 
Lipase and amylase
In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum 
lipase may remain elevated slightly longer than amylase. The level of the serum amylase and/or 
lipase does not correlate with the severity of acute pancreatitis. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis. 
If acute pancreatitis is confirmed, the subject must be permanently discontinued from trial product 
and appropriate treatment and careful monitoring of the subject should be initiated. Furthermore, 
the subject should still remain in the trial (see Section 8.1). 
If acute pancreatitis is ruled out, trial product should be re-initiated at the investigator’s discretion.
8.8.2
Suspicion of acute gallstone disease
In case of suspicion of acute gallstone disease or cholelithiasis, the trial product should promptly be 
discontinued (no ‘treatment status’ session should be made in IWRS before a diagnosis of acute 
gallstone disease is confirmed). Appropriate treatment and careful monitoring should be initiated.  
Furthermore, the subject should remain in the trial (see Section 8.1)
The event should be reported as an AE requiring additional data collection (see Section 8.4.2.2 and 
Section 12).
If acute gallstone disease is confirmed, the trial product must be permanently discontinued. 
Appropriate treatment and careful monitoring of the subject should be initiated. Furthermore, the 
subject should remain in the trial (see Section 8.1). 
Trial product can be restarted at the investigator´s discretion if cholelithiasis is ruled out or the 
gallbladder has been removed.
8.8.3
Neoplasm
In case of neoplasm, please consider if the trial drug should be discontinued (no ‘treatment status’ 
session should be made in IWRS before a diagnosis is confirmed). The event must be reported as an 
AE requiring additional data collection (see Section 8.4.2.2 and Section 12). 
Appropriate treatment and careful monitoring of the subject should be initiated as per local clinical 
practice. Furthermore, the subject should be encouraged to remain in the trial (see Section 8.1). 
Trial product can be re-initiated at the investigator´s discretion if diagnosis is not supported.
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8.8.4
Hepatic event (suspicion of drug-induced liver injury)
Please consider discontinuing trial product if :
1) ALT or AST >5xUNL, or 
2) ALT or AST > 3x UNL and (total bilirubin >2xUNL or INR >1.5), or 
3) ALT or AST >3xUNL with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
For the above events, prompt repeat testing at central laboratory, of ALT, AST, ALP, INR and total 
bilirubin should be done. Thereafter, repeat testing (at central laboratory) of ALT, AST, ALP, INR 
and total bilirubin should be done regularly until the abnormalities return to normal or baseline 
state. Additional clinical information such as related symptoms, risk factors and contributing 
conditions (e.g. viral hepatitis, autoimmune hepatitis, alcoholic hepatitis, hepatobiliary or pancreatic 
disorders) should be gathered to seek a possible cause of the observed laboratory test abnormalities. 
Although the trial product is discontinued, no ‘treatment status’ session should be made in IWRS 
and the subject should remain in the trial.
The event should be reported as an AE requiring additional data collection (see Section 8.4.2.2 and 
Section 12). 
If DILI is confirmed, the subject should permanently discontinue the trial product. Appropriate 
treatment and careful monitoring of the subject should be initiated. However, the subject should 
remain in the trial (see Section 8.1). 
Trial product can be re-initiated at the investigator´s discretion, if diagnosis of DILI is not 
supported.
8.8.5
Depression, suicidal ideation/behaviour
In case of depression or suicidal ideation/behaviour (see Section 8.6.4), please consider if the trial 
drug should be discontinued (no ‘treatment status’ session should be made in IWRS before a 
diagnosis is confirmed). The event must be reported as an AE requiring additional data collection 
(see Section 8.4.2.2 and Section 12). 
Appropriate treatment and careful monitoring of the subject should be initiated. A subject should be 
referred to a MHP if he/she has:

symptoms of moderate or more severe depression, 

or any suicidal behaviour, 

or any suicidal thoughts with some intent to act, irrespective of whether accompanied by a 
specific plan.
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In case the subject refuses to consult the MHP, the investigator must state in the medical records 
whether it is considered safe for the subject to stay in the trial. Trial product can be re-initiated at 
the investigator´s discretion, if a diagnosis is not supported.
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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 comprises investigational medicinal products (IMP); both active and placebo. 
Trial product must not be used, if it does not appear clear and colourless or almost colourless.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
Liraglutide 6 mg/mL
(IMP)
6 mg/mL 
Solution for 
injection
Subcutaneous 
injection (s.c.)
3 mL PDS290 
pen-injector
Placebo
(IMP)
NA
Liraglutide and placebo are visually identical, to ensure double-blinding in the trial.
9.2
Labelling and directions for use
The trial products will be labelled in accordance with Annex 1354, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation. 
The investigator must document that direction for use is given to the subject orally and in writing at 
the first dispensing visit (visit 2). At the following visits, the investigator will confirm with the 
subject that the direction for use is still available and that the subject is using the trial product 
correctly.
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9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage 
conditions
(not-in-use)
In-use conditions
In-use timea
Liraglutide 6 mg/mL
Store in a 
refrigerator 
(36°F-46°F)
Do not freeze
Protect from 
light
Store at room 
temperature
(59°F-86°F),
or in refrigerator 
(36°F-46°F)
Do not freeze
Protect from light
Use within 30 
days
Placebo
a In-use time starts when the product is taken out of the subject’s refrigerator.
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g., outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
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.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site 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 and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
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Dispensed trial product must be accounted for at pen level; either recorded as used/partly used, 
unused or lost. Distributed and returned pens are subject to be sent for destruction, thus may not be 
re-allocated to new subjects.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.5
Auxiliary supplies
Auxiliary supplies comprise supplies other than trial products. The following auxiliary supplies will 
be provided by Novo Nordisk in accordance with the TMM:

Needles for pre-filled pen (maximum length to be used is 8 mm)

Directions for use for pre-filled pen
Only needles provided by Novo Nordisk must be used for administration of trial product.  
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10
Interactive voice/web response system
A trial-specific interactive web response system (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. 
IWRS is used for: 

Screening

Screening failure

Randomisation

Medication arrival

Dispensing

Treatment status 

Code break

Drug accountability

Data change
IWRS user manuals will be provided to each trial site.
Premature treatment discontinuation and re-initiation
If the investigator or the subject has decided to discontinue treatment, but the subject has not 
withdrawn consent, it is possible to re-initiate treatment, if no discontinuation criteria are met (see 
Section 8.1). The subject will remain in the same treatment arm, and a new dose escalation period 
will be started, if the subject resumes treatment. The investigator must make a note and record dates 
of any discontinuation and re-initiation in the medical records and eCRF.
To register discontinuation of trial product (temporary or permanent), a ’treatment status’ session is 
performed in the IWRS, to indicate subject should no longer receive trial product. Similarly, if the 
treatment should later be re-initiated, a ’treatment status’ session is performed in the IWRS, to 
indicate subject should again receive trial product. 
Withdrawal
In the case subject has withdrawn consent, a ‘treatment status’ session must be performed in IWRS, 
to indicate that subject should no longer receive trial product. If possible after confirmation by the 
monitor, the subject will be registered as ‘withdrawal’, to ensure that subject is not allowed to re-
initiate trial product.
If the subject is temporarily lost to follow up during the trial, the IWRS session should not be 
completed until the scheduled Visit 24 at week 56 to confirm the final status.
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11 Randomisation procedure and breaking of blinded codes
A randomisation session will be carried out for eligible subjects using the IWRS. The eligible 
subjects will be randomised centrally 1:1 to either liraglutide 3.0 mg or placebo.
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 discontinue treatment with trial product and a treatment session must be 
completed in IWRS.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
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 or other trial 
procedures performed before exposure to trial product (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.
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 a SAE 
criterion, the AE must be reported as a 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 a 
SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
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 a 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. 
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
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 
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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 dyscrasia or convulsions that does not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as a SAE using the important medical event 
criterion if no other seriousness criteria are applicable:

suspicion of transmission of infectious agents via the trial product 

risk of liver injury defined as alanine aminotransaminase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of a SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:

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 s.c.

Administration of an overdose with the intention to cause harm, misuse or abuse of trial 
product

Accidental administration of a lower or higher dose than intended. That is a dose lower or 
higher than 0.6, 1.2, 1.8, 2.4 and 3.0 mg respectively (within 24 hours). 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
If the subject discontinues trial product prematurely, this should not be reported as a medication 
error (see Section 8.4.2.1).
Medication errors must be reported on an AE form and a specific event form for medication error.
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12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety.
The below lists AEs that require completion of specific event forms in the eCRFs (see Section 
8.4.2.2)

Acute gallstone disease

Neoplasm 

Pancreatitis

Hepatic event (suspicion of DILI)

Depression, suicidal ideation/behaviour
For details of these events, see Section 8.8.
12.1.6
Technical complaints
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)

All packaging material including labelling

Problems related to devices (e.g., to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)  
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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 (30 days). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below (see 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?”
In addition, the subject should be asked about the mood for example – ‘How has your mood been 
since the last contact?’ 
All AEs, observed by the investigator or subject, must be reported by the investigator and evaluated. 
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. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
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 requiring reporting on a specific event form: In addition to the above, the 
specific event form must be signed within 14 calendar days from the investigator’s first 
knowledge of the AE.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form 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 form into the 
eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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AE identified
Does the AE require 
a specific event 
form?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs: 
< 14 calendar days
Is the Adverse Event 
serious or non-
serious?
AE form
Non-serious
Serious
No
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness.
AEs requiring specific event forms are descibed in Section 12.1.4 and 12.1.5.
No additional action
AE: Adverse Event   SIF: Safety Information form
Figure 12–1
Reporting of AEs 
Novo Nordisk assessment of AE expectedness
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Company Core Data Sheet (CCDS), current version and any updates thereto.
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 ICH GCP1. 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 ICH GCP1, 
unless locally this is an obligation of the investigator.
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Novo Nordisk products used as concomitant medication 
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
concomitant medication in the trial, it is important that the suspected relationship is reported to 
Novo Nordisk (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.
The investigator must ensure that the recording of 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.
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.
SAEs after end of trial: If the investigator becomes aware of a SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
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ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial. 
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 

Liraglutide 6 mg/ml, 3 ml PDS290 pen-injector

Placebo PDS290 pen-injector

Novo Nordisk needles for pen-injector
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 and/or SAEs.
Technical complaints must be reported on a separate technical complaint form: 

One technical complaint form must be completed for each affected DUN 

If DUN is not available, a technical complaint form for each code or lot number 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 complaints within 5 calendar days

Technical complaint assessed as related to a SAE within 24 hours
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 copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
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The investigator must ensure that the technical complaint sample contains the code or lot number, 
and, if available, the DUN. All parts of the DUN should be returned.
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.  
12.5
Pregnancies
12.5.1
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 new born infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
new born 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 new born 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 
new born 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 a SAE.
Forms and timelines for reporting AEs
Non-serious AEs:

AE forma within 14 calendar days of the investigator’s first knowledge of the initial or 
follow-up information to the non-serious AE.
Serious AEs: 

AE forma within 24 hours of the investigator’s first knowledge of the SAE.

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.
a 
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or new born infant. If the AE occurred in the foetus or new born infant, the 
AE can only be reported on paper AE and safety information form.
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
From clinical trials and marketed use of liraglutide overdoses have been reported up to 24 times the 
recommended dose (72 mg). One case of a 6-fold overdose (18 mg daily) given for 7 months has 
been reported. Generally, the patients reported severe nausea, vomiting and diarrhoea, but recovered
without complications. None of the reports included severe hypoglycaemia.
In the event of overdose, appropriate supportive treatment should be initiated according to the 
patient’s clinical signs and symptoms. Please refer to the current approved US Saxenda® US 
prescribing information, for details concerning overdose.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal liraglutide safety committee to perform ongoing safety 
surveillance. The liraglutide 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.
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13 Case report forms 
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
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:

AE forms 

Safety information forms 

Technical complaint forms (also to be used to report complaints that are not subject related. 
e.g., discovered at trial site before allocation)
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 eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF 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 have 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. These 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 FSFV 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 eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks until LSLV at the trial site.
The monitor must be given direct access to all source documents (original documents, data and 
records). The monitor will ensure that the eCRFs are completed. 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 eCRF. 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.
The following data will be source data verified for screening failures:

date for obtaining informed consent

reason for screening failure

SAEs (if any)
Source data generated by the trial site can be corrected by person other 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 of the completed diaries or assessment tools must not 
be removed from the trial site. The COAs are completed electronically, thus entries at the site-pads 
are source data and a copy of the entries should be provided to site. The monitor will ensure that the 
eCRFs are completed and that paper CRFs are collected. Monitors will review the subject’s medical 
records and other source data 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. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk. 
Appropriate measures, including encryption of data files containing personally 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 are 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.
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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
Results from the statistical analysis will generally be accompanied by two-sided 95% confidence 
intervals and two-sided p-values.
Superiority will be claimed if the two-sided p-value is less than 5% and the estimated treatment 
difference/ratio favours liraglutide 3.0 mg.
Primary endpoints
The two primary endpoints (see Section 4.2.1) are defined as:

Change in body weight (%) from baseline to week 56

Proportion of subjects losing at least 5% of baseline body weight at week 56
The primary objective is met if superiority of liraglutide 3.0 mg vs. placebo is demonstrated for 
each of the primary endpoints. 
Definition of primary endpoint: % weight change
Change in body weight (%) from baseline to week 56, denoted % weight change, is calculated as 
body weight at week 56 minus body weight at baseline divided by body weight at baseline and 
multiplied by 100; therefore
% weight change= (body weight at week 56-body weight at baseline)
body weight at baseline
×100.
A negative value of % weight change indicates a body weight loss from baseline to week 56.
Definition of primary endpoint: 5% responders
The proportion of subjects having lost at least 5% of baseline body weight at week 56, denoted 5% 
responders, is defined as the proportion having
% weight change ≤ −5%.
A 5% responder is defined as a subject fulfilling this, therefore
5% responder = (
 1 if  % weight change ≤ −5%
 
 0 if  % weight change > −5%
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Definition of estimands
Effectiveness estimand
The primary estimand is an effectiveness estimand (de facto) quantifying the average treatment 
effect of liraglutide 3.0 mg relative to placebo 56 weeks after randomisation, as adjunct to reduced 
caloric diet, increased physical activity and CMS-IBT, in all randomised subjects regardless of 
adherence to treatment.
Efficacy estimand
A secondary efficacy estimand (de jure) is quantifying the average treatment effect of liraglutide 
3.0 mg relative to placebo 56 weeks after randomisation, as adjunct to reduced caloric diet, 
increased physical activity and CMS-IBT, if all randomised subjects had adhered to assigned
treatment regimen for the entire duration of the trial.
Effectiveness estimand at week 16
In addition, an effectiveness estimand (de facto) is quantifying the average treatment effect of 
liraglutide 3.0 mg relative to placebo 16 weeks after randomisation, as adjunct to reduced caloric 
diet, increased physical activity and CMS-IBT, in all randomised subjects regardless of adherence 
to treatment.
Taxonomy of week 56 assessments being available or missing
A given assessment at week 56 may be available or missing and Table 17–1 defines the taxonomy 
for this. Note this is done per assessment not per subject, as subjects may belong to different types 
for different assessments (a subject may have “available on treatment (AT)” for weight but “missing 
on treatment (MT)” for waist circumference).
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Table 17–1
Taxonomy of week 56 assessments being available or missing
Assessment
at week 56
On drug at 
week 56
Type description
Type
Abbreviation
Available
Yes
Available on randomised treatment:
Subjects who did not discontinue randomised treatment 
prematurely. Include those that stop and restart trial 
product.
AT
No
Available drop-outs:
Subjects who discontinued randomised treatment 
prematurely but returned to have an assessment at week 
56; so-called retrieved drop-outs.
AD
Missing
Yes
Missing on randomised treatment:
Subjects who did not discontinue randomised treatment 
prematurely. Include those that stop and restart trial 
product.
MT
No
Missing drop-outs:
Subjects who discontinued randomised treatment 
prematurely and did not return to have an assessment at 
week 56; so-called non-retrieved drop-outs.
MD
17.1
Sample size calculation
The sample size calculation is based on the analysis approach addressing the primary estimand for 
the primary endpoints change in body weight (%) from baseline to week 56 (% weight change) and 
proportion of subjects losing ≥ 5% of baseline body weight at week 56 (5% responders). 
The two primary endpoints will be tested in a hierarchical order. 
The study design is a 1:1 randomisation with 282 subjects in total (141 subjects in each arm). Please 
see Table 17–2 for general specifications on sample size and power calculation.
Table 17–2
General specifications for sample size and power calculation
Endpoint
Statistical test
Minimum required power (%)
% weight change
Two-group Satterthwaite unpooled t test 
on the mean difference with α=0.05 
assuming unequal variances
90.0 (marginal)
5% responders
Pearson chi-square test for two 
independent proportions with α=0.05
90.0 (marginal)
α: two-sided significance level
In the following paragraphs treatment differences and standard deviations (SD) are given without 
units.
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Body weight measurements from returning discontinuing subjects will be used in the primary 
analysis. But for the sample size calculations, it is assumed that all subjects who discontinue will 
not return at week 56 and that they have a % weight change like placebo subjects who completed 
the trial. It is expected that % weight change for liraglutide 3.0 mg subjects who discontinue might 
be somewhere in between completing placebo subjects and completing liraglutide 3.0 mg subjects. 
The assumption is thus expected to lead to a conservative effect estimate. In trial NN8022-1839 in 
non-diabetic subjects and with obesity, around 31% treatment discontinuations were observed in the 
placebo group, around 25% in the liraglutide 3.0 mg group. The calculated sample size ensures 
adequate power if the proportion of discontinuing subjects should be as high as 30%.
Based on findings from NN8022-1839, a difference in % weight change between liraglutide 3.0 mg 
and placebo of -5 (-9% vs. -4%, SD=7) is assumed among completing subjects. For sample size 
calculation, a common SD of 7 was assumed for completers of liraglutide 3.0 mg or placebo. In 
NN8022-1839, a SD of 6.65 was seen for % weight change among subjects completing liraglutide 
3.0 mg at week 56; 5.88 was observed among subjects completing placebo. Adjusting for 30% 
discontinuation and using a mixture distribution, a difference of -3.5 is expected in the primary 
analysis. A sample size of 282 subjects (141 in each arm), gives a marginal power of 98.3%.
For the primary endpoint 5% responders, the expected proportions were calculated based on the 
same assumptions as above. Adjusting for 30% discontinuation gives an expected 5% responders 
proportion of 63% in the liraglutide 3.0 mg arm and 44% in the placebo arm. With 282 subjects,
this results in a marginal power of 90%.
Given these assumptions, the sample size of 282 subjects (141 in each arm), results in a combined 
power of 88.5%. 
The tests of superiority of liraglutide 3.0 mg to placebo for each of the confirmatory endpoints are 
performed hierarchically in the order in which the endpoints are presented (see Sections 4.2.1 and 
4.2.2.1). The two primary endpoints are included in the statistical testing hierarchy, and the primary 
objective will be met if superiority of liraglutide 3.0 mg vs. placebo is demonstrated for each of the
primary endpoints. The test hierarchy is given in Table 17–3 with underlying assumptions, marginal 
power and effective power. The effective was calculated using a naïve and conservative approach, 
which assumes no correlation of endpoints by multiplying the respective marginal powers.
Assumptions made to calculate the power for the two primary endpoints and all confirmatory 
secondary endpoints are also presented in Table 17–3.
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Table 17–3
Assumptions, marginal power and effective power for each confirmatory 
endpoint in the hierarchical testing procedure given an anticipated number of 
282 randomised subjects
Assumed mean (±SD) / 
proportion for completers 
liraglutide 3.0 mg placebo
Expected mean 
(±SD) / proportion 
for liraglutide 
3.0 mg #
Expected 
difference #
Marginal 
power (%)
Effective 
power (%)
% weight 
change
-9.0 (±7.0)
-4.0 (±7.0)
-7.5 (±7.4)
-3.5
98.3
98.3
5% responders
72%
44%
63%
19%
90.0
88.5
10% responders
44%
20%
37%
17%
90.3
79.9
15% responders
20%
6%
15%
9%
75.0
59.9
4% responders 
at week 16
70%
45%
63%
18%
84.2
50.4
WC change
-9.0 (±7.0)
-5.0 (±7.0)
-7.8 (±7.2)
-2.8
90.8
45.8
sBP change
-5.0 (±13.0)
-3.0 (±13.0)
-4.4 (±13.0)
-1.4
14.7
6.7
6MWT change
8.2 (±12.0)
5.8 (±12.0)
7.5 (±12.1)
1.7
21.5
1.4
IWQoL-Lite for 
CT physical 
change
16.0 (±18.0)
11.0 (±18.0)
14.5 (±18.1)
3.5
36.7
0.5
IWQoL-Lite for 
CT mental/ 
emotional 
change
14.0 (±20.0)
11.0 (±20.0)
13.1 (±20.0)
2.1
14.2
0.1
SD   standard deviation, sBP   systolic blood pressure, WC   waist circumference, 6MWT   six minutes walking test, 
IWQoL-Lite for CT   Impact of Weight on Quality of Life-Lite for Clinical Trial Version;
# Adjusted for 30% discontinuation;
Assumptions are based on findings from NN8022-1839.
17.2
Definition of analysis sets
Two analysis sets are defined:

The full analysis set (FAS) includes all randomised subjects according to the intention-to-
treat (ITT) principle. Subjects in the FAS will be analysed as randomised.

The safety analysis set includes all randomised subjects exposed to at least one dose of trial 
drug. Subjects will be analysed as treated.
Any observation excluded from the analysis database will be documented before database lock with 
the reason for exclusion provided.
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17.3
Primary endpoints
The two primary endpoints are as mentioned previously (see start of Section 17):

% weight change

5% responders
17.3.1
Analytical methods addressing the effectiveness estimand for the primary
endpoints
These analyses will use the FAS. The analyses of the primary endpoints use baseline body weight 
and body weight at week 56, and assessments at week 56 may be missing (“missing on treatment 
[MT]” and “missing drop-outs [MD]”). First, a description of the statistical models for the primary
endpoints is given under the assumption of no missing values (i.e. all subjects have body weight 
measurements at baseline and week 56). Subsequently, handling of missing data is described.
17.3.1.1
Statistical model for the primary endpoint % weight change
The primary endpoint % weight change will be analysed using analysis of covariance (ANCOVA)
including the factors and covariates listed in Table 17–4.
Table 17–4
Factors and covariates for the analysis of the primary endpoints
Factors and covariates at 
baseline
Type
Categories
Randomised treatment
Factor
Liraglutide 3.0 mg, placebo
Gender 
Factor
Male, female
BMI (kg/m2)
Factor
[30,35[, [35,40[, ≥40
Body weight (kg)
Covariate
Not applicable
The factors and covariates will be included in the model as main effects in an additive structure. 
The estimated treatment difference between liraglutide 3.0 mg and placebo will be reported together 
with the associated two-sided 95% CI and corresponding p-value. 
The superiority test of liraglutide 3.0 mg vs. placebo will be carried out as follows:
Let μliraglutide and μplacebo denote the true mean of % weight change for liraglutide 3.0 mg and placebo 
group, respectively. The hypothesis and the alternative are:
H: μliraglutide ≥ μplacebo against the alternative HA: μliraglutide < μplacebo.
The hypothesis will be rejected and superiority claimed, if the upper limit of the estimated two-
sided 95% CI of the treatment difference is below 0.
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17.3.1.2
Statistical model for the primary endpoint 5% responders 
This binary endpoint will be analysed using a logistic regression model. Factors and covariates will 
be those listed in Table 17–4. The estimated odds ratio (OR) between liraglutide 3.0 mg and 
placebo will be reported together with the associated two-sided 95% CI and corresponding p-value.
Let ORliraglutide/placebo denote the true odds ratio between liraglutide 3.0 mg and placebo. The 
hypothesis and the alternative are:
H: ORliraglutide/placebo ≤ 1 against the alternative HA: ORliraglutide/placebo > 1
The hypothesis will be rejected and superiority claimed, if the lower limit of the estimated two-
sided 95% CI is above 1.
17.3.2
Handling of missing values for the effectiveness estimand
17.3.2.1
Handling of missing values at baseline
If an assessment has been made both at screening and randomisation, the value from the 
randomisation visit will be used as the baseline value. If the value measured at the randomisation 
visit is missing and the assessment has been made at screening, then the screening value will be 
used as the baseline value.
17.3.2.2
Handling of missing values at week 56 
Missing values at week 56 will be imputed and the relevant endpoints will be derived from the 
imputed values. Several approaches for imputation of missing values at week 56 will be applied. 
First, a description of the primary imputation approach used to address the effectiveness estimand 
for the primary endpoints is given. This is followed by a description of a number of sensitivity 
analyses.
Primary approach for handling of missing values
The primary approach for multiple imputations of missing values of body weight at week 56 (type 
MT+MD) for both the liraglutide 3.0 mg and placebo group is by sampling among all available 
assessments at week 56 in the placebo group (type AT+AD). This approach is also known as jump 
to reference and makes the assumption that subjects instantly after discontinuation lose any effect of 
randomised treatment beyond what can be expected from placebo treatment as adjunct to diet and 
exercise55. Body weight measurements at visits between baseline and week 56 are not used for this 
imputation approach. The multiple imputation approach is done in three steps.

Imputation: Step 1 defines an imputation model based on placebo subjects, which is used to 
impute missing body weight values at week 56 in both arms. This will be done 100 times 
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and results in 100 complete data sets. A more detailed explanation of this step is given 
below.

Analysis: Step 2 analyses each of the 100 complete data sets, using the statistical model 
defined in Section 17.3.1.1 and 17.3.1.2, and saves the 100 estimation results.

Pooling: Step 3 integrates the 100 estimation results into a final result using Rubin’s 
formula.
The imputation model in step 1, uses placebo subjects from FAS with non-missing body weight 
measurements at baseline and week 56. The imputation model is a linear regression of body weight 
(kg) at week 56 on the factors and covariates listed in Table 17–4 (except randomised treatment) 
with no interactions. The estimated posterior distribution for the parameters (regression coefficients 
and variances) in the imputation model is then used to impute missing week 56 body weight values 
for both randomised treatment arms.
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 80224274 as seed number.
Sensitivity analyses of the primary endpoints for the effectiveness estimand
The sensitivity analyses will address the robustness of the primary approach for handling of missing 
values. In particular the sensitivity analyses address how assumptions on how body weight 
progresses after discontinuation of randomised treatment impact the estimated treatment difference 
between liraglutide 3.0 mg and placebo. The sensitivity analyses include the following.

A multiple imputation approach as described by McEvoy56 where missing body weight 
measurement at week 56 for non-retrieved drop-outs (type MD) are imputed by sampling 
from values obtained from retrieved drop-outs (type AD) in each randomised treatment arm 
and according to the timing (monthly) of last available observation (of body weight) on 
randomised treatment (LAO-OT). Missing body weight measurements at week 56 for 
subjects on drug treatment (type MT) are imputed by sampling from type AT in the relevant 
randomised treatment 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 56 on the factors 
and covariates listed in Table 17–4 (except randomised treatment arm) with no interactions 
and LAO-OT of body weight. If timing by month is too restrictive, quarters, half-years, or 
excluding timing will be used.

A weighted ANCOVA (wANCOVA) where returning drug discontinuing subjects (AD) are 
up-weighted relative to their proportion of all drug discontinuing subjects (AD+MD) to 
account for the subjects not returning for assessments at week 5656. Similarly, AT subjects 
are up-weighted relative to their proportion of all drug continuing subjects (AT+MT). The 
up-weighing is done by randomised treatment arm and the timing of LAO-OT. Subjects who 
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are missing the weight measurement at week 56 (MD+MT) are assigned a weight of 0 
(zero).

A single imputation approach as done by Sacks57. Missing weight measurement at week 56 
for subjects who drop-out (type MD) are imputed using a weight regain rate of 0.3 kg/month 
after last available observation (LAO) of body weight. Change from baseline is truncated 
whenever the extrapolation would lead to a positive weight gain relative to baseline. LAO 
does not need to be the same as LAO-OT as subjects are allowed to come to scheduled visits 
after discontinuing randomised treatment. When a subject's LAO represents a gain in weight 
relative to baseline, no additional gain will be imputed, and the unfavourable gain is carried 
forward to week 56. Missing weight measurement at week 56 for subjects on treatment (type 
MT) will be imputed using the LAO. The weight regain imputation will be done for both 
randomised treatment arms. Additionally, a version where only the liraglutide 3.0 mg arm 
uses the regain rate while the placebo arm uses LAO (corresponding to a weight regain rate 
of 0 kg/month) will be performed.

Tipping point analysis. 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 MD in liraglutide 3.0 mg 
arm will be used to define a tipping point in which superiority of liraglutide 3.0 mg 
disappears. In this analysis, the placebo arm will be imputed by LAO.
Figure 17–1 and Table 17–5 give an overview of the handling of missing values at week 56 
assessments.
Additional sensitivity analyses
Additional analyses will investigate how sensitive the primary statistical models (for primary 
endpoints) are to the choice of factors and covariates in the model as follows: A model resembling 
the primary analysis models using the same imputation method (jump to reference) adjusting only 
for baseline body weight and randomised treatment arm. The imputation model (step 1) will be 
same as for the primary approach.
For the binary primary endpoint, the risk difference (unadjusted for any factors and covariates) and 
corresponding 95% CI will also be calculated.
17.3.3
Analysis method addressing the efficacy estimand for the primary endpoints
The efficacy estimand for % weight change will be assessed using a mixed model for repeated 
measurements (MMRM). The MMRM will use assessments only from subjects who are taking the 
randomised treatment until end of trial or at first discontinuing of trial drug (either temporarily or 
permanently). A pause of less than three consecutive days is not regarded as discontinuation for this 
analysis. This means that assessments at week 56 for retrieved drop-outs (type AD) will be 
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discarded. The MMRM will be fitted using % weight change and the same factors and covariates 
(Table 17–4) as for the primary analyses all nested within visit. An unstructured covariance matrix 
for measurements within the same subject will be employed, assuming that measurements for 
different subjects are independent. 
The efficacy estimand for 5% responders will be assessed using the same MMRM. From the 
MMRM individually predicted values for % weight change at week 56 will be used to classify each 
subject as 5% responder or not. This classification will then be analysed using a logistic regression 
model with treatment as the only factor.
17.3.4
Subgroup analyses for primary endpoints
For the primary estimand, subgroup analyses will be done for the factors listed and categorised as in 
Table 17–4. For baseline weight, categories based on quartiles will be used. The subgroup analyses 
will be done separately for each of these by including interaction term(s) with randomised treatment
arm in the respective models (ANCOVA or logistic regression).
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Figure 17–1
Illustration of imputation approaches for the effectiveness estimand
An arrow indicates from which group an imputation is done
AT = Available on randomised treatment
MT = Missing on randomised treatment
AD = Available drop-out
MD = Missing drop-out
Jump to reference (multiple imputation)
Liraglutide
Placebo
AT+AD
MT+MD
MT+MD
AT+AD
Sacks (single imputation)
Liraglutide
Placebo
AT
AD
MT
MD
AT
AD
MT
MD
LAO + 0.3 kg/month
LAO
LAO
LAO
LAO: Last available observation irrespective of whether on randomised treatment or not
McEvoy (multiple imputation)
Liraglutide
Placebo
AT
AD
MT
MD
AT
AD
MT
MD
McEvoy is done by timing (e.g. monthly) of randomised treatment discontinuation
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Table 17–5
Overview of handling of missing values
Approach
Description
Assumptions
Jump to reference
(multiple imputation)
Liraglutide and placebo MT+MD imputed 
from placebo AT+AD (i.e., all available 
placebo assessments at week 56)
- Liraglutide MD lose any treatment effect 
instantly after drop-out
- Placebo AT and placebo AD are assumed 
to have the same weight loss
McEvoy
(multiple imputation)
Separately for the two randomised treatment
arms:
MD imputed from AD by matching on time 
(month) of drop-out
MT imputed from AT
- AD is representative of the MD for each 
randomised treatment arm
- AT is representative of the MT for each 
randomised treatment arm
Weighted ANCOVA
(wANCOVA)
No imputation.
Separately for the two randomised treatment
arms:
AD subjects are up-weighted relative to their 
proportion of AD+MD and timing of drop-
out
AT subjects are up-weighted relative to their 
proportion of AT+MT
- AD is representative of the MD for each 
randomised treatment arm
- AT is representative of the MT for each 
randomised treatment arm
Sacks
(single imputation)
Liraglutide MD imputed by minimum of 
LAO+0.3 kg and baseline value for each 
month from drop-out to week 56
and either 
a) Placebo MD imputed by minimum of 
LAO+0.3 kg and baseline value for each 
month from drop-out to week 56
or
b) MT (both randomised treatment arms) and 
placebo MD are imputed by LAO
a) Liraglutide and placebo MD lose any 
treatment effect linearly after drop-out.
b) Only liraglutide MD lose any treatment 
effect linearly after drop-out. No change in 
treatment effect since LAO for others.
Tipping point
(single imputation)
Liraglutide MD imputed by minimum of 
LAO+X kg (X in steps of 0.1) and baseline 
value for each month from drop-out to week 
56.
MT (both randomised treatment arms) and 
placebo MD are imputed by LAO
Only liraglutide MD lose any treatment 
effect linearly after drop-out. No change in 
treatment effect since LAO for others
AT   available on randomised treatment, MT   missing on randomised treatment, AD   available drop-out, MD   missing drop-
out, LAO   last available observation, LAO-OT  last available observation on randomised treatment.
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints are listed in Section 4.2.2.1.
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All confirmatory secondary endpoints, except proportion of subjects losing at least 4% of baseline 
body weight at week 16, are planned to be assessed at week 56 and will be analysed using the same 
primary MI approach as used for the primary endpoints and to address the effectiveness estimand. 
The statistical model for continuous confirmatory secondary endpoints will be ANCOVA with 
covariates listed in Table 17–4 with baseline body weight replaced by baseline measurement of 
endpoint to be analysed. Binary confirmatory secondary endpoints will be analysed using logistic 
regression in the same way as for 5% responders.
The effectiveness estimand at week 16 will be assessed using the confirmatory secondary endpoint 
of proportion of subjects losing at least 4% of baseline body weight at week 16. Subjects with 
missing values for weight at week 16 will be considered non-responders.
Sensitivity analyses will be carried out for all confirmatory secondary endpoints, except for 
proportion of subjects losing at least 4% of baseline body weight at week 16. See Table 17–6 for 
details on planned analysis methods, multiple imputation approach and sensitivity analyses.
The efficacy estimand will also be assessed for confirmatory secondary endpoints, except for 
proportion of subjects losing at least 4% of baseline body weight at week 16, using MMRM as 
described for the primary endpoints.
17.4.2
Description of the hierarchical testing procedure to address the effectiveness 
estimand for primary and confirmatory secondary endpoints
The tests of superiority of liraglutide 3.0 mg to placebo for each of the endpoints are tested in a 
hierarchical manner in the order in which the endpoints are presented. The two primary endpoints 
are included in the statistical testing hierarchy below, even though the primary objective will only 
be met if superiority of liraglutide 3.0 mg vs. placebo is demonstrated for each of the primary 
endpoints. The test hierarchy is given in Table 17–6. The first endpoints to be tested are all 
assessing aspects of weight loss (e.g., relative change in body weight, achieving a certain magnitude 
of weight loss, and change in waist circumference); these endpoints are followed by endpoints 
assessing change in weight-related comorbidities and/or consequences of excess body weight and
‘feeling and function’ indicators.
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Table 17–6
Hierarchical order and type of statistical method to address the effectiveness 
estimands for primary and confirmatory secondary endpoints
Test 
order
Endpoint
Endpoint
Type
Statistical 
model
MI approach
Sensitivity analyses #
            Primary endpoints
1
Change in body weight (%) from baseline 
to week 56
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Sacks
Tipping pointUnadjusted 
ANCOVA
2
Proportion of subjects losing at least 5% of 
baseline body weight at week 56
Binary
Logistic 
Regression
Jump to 
reference
McEvoy
Sacks
Tipping point
Risk difference
            Confirmatory secondary endpoints
3
Proportion of subjects losing more than 
10% of baseline body weight at week 56
Binary
Logistic 
Regression
Jump to 
reference
McEvoy
Tipping point
4
Proportion of subjects losing more than 
15% of baseline body weight at week 56
Binary
Logistic 
Regression
Jump to 
reference
McEvoy
Tipping point
5
Proportion of subjects losing at least 4% of 
baseline body weight at week 16 (addresses 
the effectiveness estimand for week 16)
Binary
Logistic 
Regression
Not needed, as subjects with missing body 
weight values at week 16 will be considered 
non-responders.
6
Change from baseline to week 56 in waist 
circumference (cm) 
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
7
Change from baseline to week 56 in 
systolic blood pressure (sBP) (mmHg)
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
8
Change in six-minute walking distance (m) 
from baseline to week 56
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
9
Change in total quality of life score from 
baseline to week 56 as assessed by IWQoL-
Lite
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
10
Change in physical function score from 
baseline to week 56 as assessed by IWQoL-
Lite
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
MI  Multiple Imputation;
#   See Table 17–5.
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17.4.3
Supportive secondary endpoints
17.4.3.1
Efficacy endpoints
Supportive secondary efficacy endpoints addressing the secondary efficacy objectives are listed in 
Section 4.2.2.2.
Secondary endpoints addressing the first of the secondary efficacy objectives
Supportive secondary endpoints will be evaluated to address the effectiveness estimand. These 
endpoints will be analysed using the same MI approach as used for the primary and confirmatory 
endpoints and to address the effectiveness estimand.
The statistical model for continuous endpoints will be ANCOVA with covariates listed in
Table 17–4 with baseline body weight replaced by baseline measurement of endpoint to be 
analysed. The statistical model for proportions will be analysed using logistic regression.
Secondary endpoints addressing the second of the secondary efficacy objectives
Adherence, used both as an endpoint and as a factor for weight loss will be investigated in an 
exploratory manner. In addition to the adherence definitions, analyses and displays presented 
below, alternative definitions, analyses and displays may be made if deemed relevant. These will be 
described as post-hoc analyses when reporting the trial.

Adherence to trial product is defined as at least one administration of trial product per week

Adherence to caloric diet is defined as at least one food diary entry for five days per week

Adherence to physical activity is defined as at least 50% of the target minutes per week

Adherence to caloric diet and physical activity is defined as being adherent to both caloric 
diet and physical activity

Adherence to trial product, caloric diet and physical activity is defined as being adherent to 
all three randomised trial product, caloric diet and physical activity
Number of weeks adherent to treatment will be analysed by fitting a regression model for count data 
(e.g. negative binomial) with factors and covariates listed in Table 17–4.
Further, the association of adherence to trial product, caloric diet and/or physical activity with 
relative change of body weight will be explored across the total planned treatment duration. For that 
purpose, the following variables will be derived: First, the total treatment period (from 
randomisation to end-of-treatment visit) will be divided into four periods (each e.g. 12 (visit 2 to 
10), 12 (visit 10 to 16), 16 (visit 16 to 20) and 16 (visit 20 to 24) weeks). Second, number of weeks 
adherent to trial product, caloric diet or physical activity during each of the four periods will be 
divided by total number of weeks of the respective period. Then, MMRM will be performed 
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including randomised treatment, BMI, gender, baseline body weight, period, normalised adherence 
to trial product, caloric diet and physical activity as factors and covariates as well as the interaction 
terms between randomised treatment, period and normalised adherence to trial product, caloric diet 
and physical activity.
In addition, relative change of body weight will be summarized descriptively stratified by visits and 
different adherence categories, which will be defined based on the distribution of observed data.
Exploratory analysis of week 16 responders
In this exploratory analysis, subjects who lost ≥4% of their baseline body weight at week 16 after 
randomisation are considered as ‘week 16 responders’. Subjects who lost <4% of their baseline 
body weight at week 16 after randomisation are considered as ‘week 16 non-responders’. Hence, 
four ‘week 16 response’ groups can be defined:
1. ≥4% weight loss at 16 weeks (liraglutide 3.0 mg)
2. <4% weight loss at 16 weeks (liraglutide 3.0 mg )
3. ≥4% weight loss at 16 weeks (placebo)
4. <4% weight loss at 16 weeks (placebo) 
The change in body weight (%) from baseline to week 56 will be explored among the four ‘week 16 
response’ groups based on descriptive statistics only. Since the comparisons of the four ‘week 16 
response’ groups are influenced by post-randomisation factors, no formal testing will be done.
17.4.3.2
Safety endpoints
Descriptive statistics for all safety endpoints will be provided with the aim to compare liraglutide 
3.0 mg and placebo. All analyses and tabulations will be done using the safety analysis set. Unless 
otherwise stated, no formal statistical analyses are planned for the safety endpoints. 
Adverse events
AEs will be coded using the current version of Medical Dictionary for Regulatory Activities 
(MedDRA). All AEs will be presented based on system organ class, high level group term and 
preferred terms.
Adverse events will be classified and analysed as ‘in trial’ and ‘on drug’ defined in terms of patient 
years of observation (PYO) and patient years of exposure (PYE), respectively. For each subject, 
PYO is defined as number of days from date of randomisation until and including date of follow-up 
visit or date of last contact. For each subject PYE is defined as time intervals of exposure to trial 
drug including an ascertainment window of 14 days for each exposure interval.
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AEs, which occurred while the subject was in trial or on drug will be summarised descriptively, 
whereas AEs, which occurred before first exposure to trial drug or after the follow-up visit will only 
be presented in listings. AEs will be displayed in terms of the number of subjects with at least one
event (N), the percentage of subjects with at least one event (%), the number of events (E) and the 
event rate per 100 years (R). Furthermore, AEs will be summarised by seriousness, severity, 
relation to trial drug, premature treatment discontinuation due to AE and outcome.
Summary tables by system organ class, high level group term and preferred term will be made for 
all AEs, SAEs, AEs possibly or probably related to trial drug, severe AEs, AEs occurring in at least 
5% of the subjects in any arm, and AEs occurring in at least 1% of the subjects in any treatment 
arm.
AEs requiring completion of specific event forms will be presented in tables and listings. In 
addition, time to occurrence of these AEs will be presented in cumulative incidence plots. 
Physical examination
Outcome of the physical examination at screening and change in the physical examination category 
at week 56 will be summarised in tables.
Pulse
Pulse (beats/min) at baseline and change of pulse at week 56, will be summarised in tables by week 
and treatment. Additionally, categories based on the maximum change from baseline until week 56 
(>0, >5, >10, >20 beats/min) and categories based on the maximum value until week 56 (>80, >90, 
>100 beats/min) will be included in summary tables. Additionally, change in pulse from baseline to 
week 56 will be evaluated in the trial observation period similar to the primary analysis for the 
primary estimand but using the safety analysis set.
ECG
Shifts in the ECG category from screening to week 56 will be summarised in tables.
Laboratory measurements
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
Laboratory safety parameters are measured throughout the trial and comprise haematology and 
biochemistry as defined in the flow chart.
The distribution of each continuous laboratory parameter will be presented using box plots by 
treatment and week. Continuous laboratory parameters will be compared to the relevant reference 
ranges and results will be presented.
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Amylase and lipase
Shifts from baseline to highest value in trial period to UNL, 2xUNL and 3xUNL will be 
summarised in tables.
Mean plots, geometric mean plots and box plots by gender, visit and treatment will be prepared. 
Change from week 0 to week 56 will also be presented by empirical distribution plots.
Number and percentage of subjects with amylase and lipase levels ≥UNL, ≥2xUNL or ≥3xUNL 
will be tabulated by week and treatment. Subjects with values ≥2xUNL will additionally be 
presented with spaghetti plots.
Additionally, change in amylase and lipase from baseline to week 56 will be evaluated in the in trial 
observation period similar to the primary analysis for the primary estimand but using the safety 
analysis set.
Calcitonin
Number, percentage and incidence of subjects with persistent (all post-baseline measurements) and 
incidental (at least one post-baseline measurement) increases in calcitonin for the criteria below will 
be tabulated for all subjects, males and females.

From baseline <UNL to ≥UNL

From baseline <UNL to ≥20 ng/L

From baseline <UNL to ≥50 ng/L

From baseline <20 ng/L to ≥20 ng/L

From baseline <50 ng/L to ≥50 ng/L
Number and percentage of subjects with calcitonin levels ≥UNL, ≥1.5xUNL or ≥20 ng/L and ≥50 
ng/L will be tabulated by visit and treatment.
A summary table showing number and percentage of observations < and ≥ LLOQ, minimum, Q25, 
median, Q75, maximum and geometric mean will be prepared by gender, visit and treatment. 
The distribution of the calcitonin values across treatment group and time will be shown in plots by 
gender and total actual levels. Geometric means will be plotted by visit and treatment in order to 
assess the pattern of the longitudinal changes. 
In addition, a scatter plot of baseline vs. maximum post-baseline calcitonin value will be prepared.
Longitudinal changes with calcitonin ≥20ng/L will be evaluated with spaghetti plots.
Subjects with at least one post-baseline calcitonin value above 20 ng/L will be listed. 
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The listings will include treatment, age, gender, smoking habits at baseline, risk factor information 
(use of relevant concomitant medication at time of assessment [proton pump inhibitors and H2 
blockers] and medical history of thyroid disorder) and calcitonin values.
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18 Ethics
18.1 
Benefit-risk assessment of the trial
The trial will be conducted in compliance with ICH GCP 1, applicable regulatory requirements and 
in accordance with the Declaration of Helsinki 2.
Risks and precautions
The sections below describe identified and potential risks associated with liraglutide treatment. The 
identified/potential risks are based on findings in non-clinical and clinical trials with liraglutide as 
well as other GLP-1 RAs. For each of these risks, mitigating actions have been implemented to 
minimise the risks for subjects enrolled in this trial.
Neoplasms
Subjects with overweight and obesity have an increased risk of certain types of cancer. In the 
clinical development programme for liraglutide 3.0 mg, the reporting rate of neoplasm events 
confirmed by external independent event adjudication committee was similar with liraglutide and 
placebo. Thus, the overall risk of neoplasms and cancer in the weight management trials was low 
and balanced between treatment groups.
Thyroid C-cell tumours
Liraglutide causes thyroid C-cell tumours (MTC) at clinically relevant exposures in both genders of 
rats and mice. Studies in mice demonstrated that liraglutide-induced C-cell proliferation was 
dependent on the GLP-1 receptor and that liraglutide did not cause activation of the rearranged 
during transfection (RET) protooncogene in thyroid C-cells. Human relevance of thyroid C-cell 
tumours in mice and rats is unknown and has not been determined by clinical or nonclinical studies. 
Data from the intensive monitoring of calcitonin (a marker for MTC) in plasma in the liraglutide 
clinical development programme, do not support an effect of liraglutide on calcitonin levels in 
humans. As a precaution subjects with personal or family history of MTC, or MEN2 will not be 
enrolled in the trial. Calcitonin will be monitored as per flow chart, see Section 2. Subjects with 
elevated calcitonin (≥ 100 ng/L) will be discontinued on liraglutide 3.0 mg and appropriate clinical 
follow-up will be initiated, see Appendix A.
Breast and colon tumours
Based on a limited number of reports in the clinical development programme for liraglutide 3.0 mg, 
a numerical imbalance was observed for events of breast neoplasms in females and colorectal 
adenomas in males. There were too few cases to determine whether these cases were related to 
liraglutide. In addition, there are insufficient data to determine whether liraglutide has an effect on 
pre-existing breast neoplasia. Two positively adjudicated cases of malignant colorectal carcinoma 
were reported in liraglutide-treated subjects and none in placebo-treated subjects. 
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Heart rate increase
In the clinical development programme, mean increase in resting heart rate (by 2-3 beats per 
minute) as well as a slight decrease in systolic blood pressure has been observed. The long-term 
clinical effects of the increase in resting heart rate have not been established. There is no indication 
that the effect on resting heart rate is dose dependent and the increase in heart rate disappears upon 
treatment discontinuation. When initiating treatment with liraglutide 3.0 mg, heart rate should be 
monitored at regular intervals consistent with usual clinical practice.
Allergic reactions
As in the case with all protein-based pharmaceuticals, treatment with liraglutide may evoke allergic 
reactions. These may include urticaria, rash, pruritus as well as anaphylactic reactions. As a 
precaution, subjects with known or suspected hypersensitivity to trial product(s) or related products 
will not be enrolled in the trial. In addition, subjects will be instructed to contact the site staff as 
soon as possible for further guidance if suspicion of a hypersensitivity reaction occurs
Pancreatitis
An association between the use of GLP-1RAs and pancreatitis has been suggested based on case 
reports received in clinical trials and during the post-marketing experience with liraglutide (in 
T2DM) and other GLP-1RAs. Few events of pancreatitis have been reported in clinical trials with 
liraglutide in weight management. After initiation of liraglutide 3.0 mg, subjects must be observed 
carefully for signs and symptoms of pancreatitis (see Section 8.8.1). If pancreatitis is suspected, 
liraglutide 3.0 mg should promptly be discontinued and appropriate management should be 
initiated. If pancreatitis is confirmed, liraglutide 3.0 mg should not be restarted. Subjects with a 
history of pancreatitis are excluded from participation in the trial.
Acute gallstone disease
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 in 
the clinical development programme for liraglutide 3.0 mg. From literature, it is well-known that 
obesity carries an increased risk of cholelithiasis and that an association between rapid and/or 
marked weight loss and the development of cholelithiasis is present58.  If cholelithiasis is suspected, 
treatment should be discontinued and gallbladder examination and appropriate clinical follow-up 
should be initiated.
Gastrointestinal adverse events
The most frequently reported adverse events in subjects treated with liraglutide 3.0 mg were 
gastrointestinal (nausea and diarrhoea), with onset during the first weeks; these were mostly mild to 
moderate, and transient. Other gastrointestinal adverse events (GI AEs) included: dyspepsia, 
vomiting, constipation, and abdominal pain. Clinical trials have indicated that a low starting dose 
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with gradual dose escalation diminishes GI AEs compared with more aggressive dosing regimens. 
If subjects do not tolerate an increased dose during dose escalation, dose escalation may be delayed 
for approximately one additional week.
Renal impairment
GLP-1 RAs may cause nausea, vomiting or diarrhoea leading to loss of fluids (dehydration). 
Dehydration may cause renal impairment and acute renal failure. Subjects treated with liraglutide 
3.0 mg should be advised of the potential risk of dehydration in relation to gastrointestinal side 
effects and take precautions to avoid fluid depletion. 
Benefits
In the present trial, subjects will be treated withca a regimen anticipated to be better than or equal to 
the weight management they receive at the time of entry into the trial. In the clinical development 
programme, 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 modest weight loss 
decreases the risk of type 2 diabetes mellitus (T2DM), hypertension and premature cardio-vascular 
death in patients with obesity (see Section 3.1). Furthermore, improvements in patient reported 
health-related quality of life and physical function have been observed with weight loss. 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 the 
behavioural counselling and increased physical activity, with close follow-up of their obesity and a 
careful medical examination. All of which will result in an intensified management of their obesity.
Conclusion
Necessary 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. It is important to note that the target population for liraglutide 3.0 mg is already at 
serious risk from obesity and its associated major co-morbidities. The overall efficacy and safety 
results from the weight management programme demonstrated that the benefit-risk balance is in 
favour of liraglutide 3.0 mg, as an adjunct to a reduced-calorie diet and increased physical activity, 
within the investigated population of subjects with overweight and obesity.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP 1 and the requirements in the Declaration of 
Helsinki2.
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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 according to local 
requirements.
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. A voluntary, signed 
and personally dated informed consent must be obtained from the subject before any trial-related 
activity.  
The investigator must ensure the subject has ample time to come to a decision whether or not to 
participate in the trial. The responsibility for seeking informed consent must remain with the 
investigator, but the investigator may delegate the task 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.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task 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.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow-up, then the subject’s data will be handled 
as follows:

Data already collected and any data collected at the end-of-trial visit including follow-up 
visits will be retained by Novo Nordisk, entered into the database and used for the CTR. 

Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data are used, it will always be in accordance with local regulations and IRBs/IECs.
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18.4
Information to subjects during 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 the 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 benefit-risk 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
19.1
Protocol deviations
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. Documentation on protocol deviations must be kept in the investigator trial 
master file and sponsor trial master file.
19.2
Prevention of missing data
Considerable effort must be made by the investigator to avoid missing data, including minimising 
the number of subjects withdrawing from the trial.
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. The subjects will be carefully informed about the trial 
procedures before signing informed consent, so that they are fully aware of the implications of 
participating in the trial. 
Measures will be implemented during trial conduct to encourage subjects to complete the trials; 
these will be described in detail in trial specific retention mitigation plans and may include subject 
newsletters, appreciation items and various local initiatives.
For subjects discontinuing treatment, the investigator should encourage continued attendance to the 
CMS-IBT visits until the primary outcome measure at 56 weeks. Furthermore, re-initiation of 
treatment is allowed at the discretion of investigator, as described (Section 8.1).
Surveillance of subject retention will be performed throughout the trial by Novo Nordisk with focus 
on reasons for premature discontinuation of trial product or withdrawal of consent to initiate 
mitigations as needed in collaboration with the trial sites.
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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, written notification from Novo Nordisk 
must be received and 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 brochure, SmPC or similar labelling as appropriate

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

For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP 1
applicable regulatory requirements and the Declaration of Helsinki2
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
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 and must ensure adequate 
supervision of the conduct of the trial at the trial 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 and documented 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 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 trial master file. The documents including the subject identification 
code list must 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).
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. 
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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 CTR for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators. The signatory investigator will be 
appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications59.
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 Disclosure40.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example, when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. 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. 
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23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors59 (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. 
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24 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 at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, 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.  
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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 CTR 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 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 CTR 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.
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27 References
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Trial ID: NN8022-4274
Version:
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UTN: U1111-1177-5059 
Status:
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Protocol
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Trial ID: NN8022-4274
Version:
4.0
UTN: U1111-1177-5059 
Status:
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Version:
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CONFIDENTIAL

Liraglutide
CONFIDENTIAL
Date:
14 September 2016
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Trial ID: NN8022-4274
Version:
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Protocol - Appendix A
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Appendix A
NN8022-4274
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.

Liraglutide
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-05592-24
Page:
2 of 6
Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Calcitonin monitoring...............................................................................................................................4
1.1
Calcitonin ≥ 100 ng/L....................................................................................................................4
1.2
Calcitonin ≥ 50 and < 100 ng/L.....................................................................................................4
1.3
Calcitonin ≥ 10 and <50 ng/L........................................................................................................5
2
References..................................................................................................................................................6
CONFIDENTIAL

Liraglutide
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-05592-24
Page:
3 of 6
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 liraglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) is 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 is 
less clear with regards to indication of the neoplasia. 
There are several known confounding factors affecting calcitonin levels, e.g.:

renal dysfunction

smoking

autoimmune thyroiditis

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

Liraglutide
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-05592-24
Page:
4 of 6
1
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. 
In case a subject has a calcitonin value ≥ 10 ng/L, the algorithm outlined below should be followed. 
The algorithm applies for all calcitonin values including screening values.
Please report clinically significant abnormal values as an adverse event (see Section 12 in the 
protocol).
1.1
Calcitonin ≥ 100 ng/L  
Action: The subject (even if a screen failure) must immediately be referred to a thyroid specialist 
for further evaluation and the trial product must be discontinued (see protocol section 6.5 premature 
discontinuation of trial product). The subject can remain in the trial; however, all suspected 
medications must be discontinued until diagnosis has been established. 
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease.1 All of these patients were diagnosed with MTC resulting in a positive predictive 
value of 100 %.
Diagnostic evaluation should include: 

thyroid ultrasound

fine needle aspiration of any nodules >1 cm 

potentially surgery with neck dissection
In case a subject is diagnosed with MTC, it is common clinical practice to explore the family 
history of MTC or MEN2 and perform a genetic test for RET proto-oncogene mutation.
1.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject (even if a screen failure) must be referred to a thyroid specialist for further 
evaluation. The subject can remain in the trial and continue on trial product. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease1 Two of these subjects were diagnosed with MTC and two were diagnosed with C-
cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly of 50%.
Diagnostic evaluation should include: 

thyroid ultrasound examination 

if available and there are no contraindication, a pentagastrin stimulation test. Subjects with 
positive pentagastrin stimulation tests should be considered to undergo surgery 
CONFIDENTIAL

Liraglutide
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-05592-24
Page:
5 of 6

if pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy may add 
important clinical information about the need for surgery.
1.3
Calcitonin ≥ 10 and <50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol. 
If the subject is a screen failure, or if the value is from the last sample taken in the trial, the subject 
should be referred to a thyroid specialist for further evaluation.
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease.1 . The predictive value of a C-cell 
anomaly for this calcitonin level was 8.3%. However, the likelihood of having a medullary 
carcinoma >1 cm with calcitonin in this range is extremely low. 
For calcitonin values 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient out of 
the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell hyperplasia at 
surgery. Two other studies used a cut-off 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 
conclusions2, 3
CONFIDENTIAL

Liraglutide
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4274
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-05592-24
Page:
6 of 6
2
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. J Clin Endocrinol Metab. 2007;92(2):450-5.
2.
Scheuba C, Kaserer K, Moritz A, Drosten R, Vierhapper H, Bieglmayer C, et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat Cancer. 2009;16(1):243-
53.
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

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
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4274
Clinical Trial Report
Appendix 16.1.1
17 December 2018
1.0
Final
CONFIDENTIAL

Protocol Amendment no 1
CONFIDENTIAL
Date:
08 March 2018
Novo Nordisk
Trial ID: NN8022-4274
Version:
1.0
UTN: U1111-1177-5059
Status:
Final
EudraCT no: 2015-005592-24
Page:
1 of 8
Protocol Amendment
no 1
to Protocol, version 4.0
dated 14 September 2016
Trial ID:NN8022-4274
SCALE™ IBT
Effect and safety of liraglutide 3.0 mg as an adjunct to intensive behaviour therapy for obesity 
in a non-specialist setting
Trial phase: 3b
Applicable to all countries 
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 no 1
CONFIDENTIAL
Date:
08 March 2018
Novo Nordisk
Trial ID: NN8022-4274
Version:
1.0
UTN: U1111-1177-5059
Status:
Final
EudraCT no: 2015-005592-24
Page:
2 of 8
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Section 1 Key secondary endpoints ...........................................................................................3
2.2
Section 2 Flow chart..................................................................................................................4
2.3
Section 4.2.2.1 Confirmatory secondary endpoints ....................................................................5
2.4
Section 4.2.2.2 Supportive secondary endpoints ........................................................................5
2.5
Section 8.5.2 Laboratory assessments for safety ........................................................................6
2.6
Section 17.1 Sample size calculation .........................................................................................7
2.7
Section 17.4.2 Description of the hierarchical testing procedure to address the effectiveness 
estimand for primary and confirmatory secondary endpoints .....................................................8
CONFIDENTIAL

Protocol Amendment no 1
CONFIDENTIAL
Date:
08 March 2018
Novo Nordisk
Trial ID: NN8022-4274
Version:
1.0
UTN: U1111-1177-5059
Status:
Final
EudraCT no: 2015-005592-24
Page:
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1
Introduction including rationale for the protocol amendment
      Rationale for the changes:

To reflect the outcome of the Impact of Weight on Quality of Life-Lite for Clinical Trials 
(IWQoL-Lite for CT) questionnaire validation and the recommendations from regulatory 
authorities to include the Short-form 36 (SF-36) questionnaire as a confirmatory secondary 
endpoint; the endpoint section and statistical hierarchy have been updated. 

Due to the low power to demonstrate a difference between active treatment and placebo, 
systolic blood pressure has been added as a supportive secondary endpoint and removed as a 
confirmatory secondary endpoint. 

To reflect the degree of uncertainty, the six minute walking distance test (6MWT) has been
moved to the bottom of the statistical hierarchy. 

Minor edits to Flow chart for clarity and accuracy.
In this protocol amendment:

Any new text is written in italics.

Any text deleted from the protocol is written using strike through.

Any new text in the Flow chart is written in italics and highlighted with yellow 
2
Changes
2.1
Section 1 Key secondary endpoints 
Change from baseline to week 56 in:

Waist circumference (cm)

Systolic blood pressure (mmHg)

Six minutes walking distance (m)

Short Form-36 (SF-36) v2.0 acute, physical functioning score

Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT), 
physical functioning domain (5-items) score

IWQoL-Lite for CT, mental/emotional functioning score

Six minute walking distance test (m)
CONFIDENTIAL

Protocol Amendment no 1
UTN: U1111-1177-5059
Date:
08 March 2018
Status:
Final
Novo Nordisk
Trial ID: NN8022-4274
EudraCT no: 2015-005592-24
Version:
1.0
Page:
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2.2
Section 2 Flow chart 
Screening
Randomisation
Dose Escalation
Maintenance period
End-of-treatment
(EOT)
Follow-up11
On site visit number
1
2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
2
2
2
3
2
4
2
5
Weeks in relation to visit 2
-1
0
1
2
3
4
6
8
1
0
1
2
1
4
1
6
1
8
2
0
2
2
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
56
60
EOT+30 days
Visit window, days
-7
±
2
±
2
±
2
±
2
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
5
±
5
±
5
±
5
±
5
±
5
±
5
±5
+5
SAFETY
Adverse Events 8.4.2 and 12
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

Protocol Amendment no 1
CONFIDENTIAL
Date:
08 March 2018
Novo Nordisk
Trial ID: NN8022-4274
Version:
1.0
UTN: U1111-1177-5059
Status:
Final
EudraCT no: 2015-005592-24
Page:
5 of 8
2.3
Section 4.2.2.1 Confirmatory secondary endpoints
Confirmatory secondary endpoints addressing the first and second of secondary objectives:

Proportion of subjects losing more than 10% of baseline body weight at week 56

Proportion of subjects losing more than 15% of baseline body weight at week 56

Proportion of subjects losing ≥4% of baseline body weight at week 16
Change from baseline to week 56 in:

Waist circumference (cm)

Systolic blood pressure (mmHg)

Six minutes walking distance (m)

Short Form-36 (SF-36) v2.0 acute, physical functioning score

Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for 
CT), physical functioning domain (5-items) score

IWQoL-Lite for CT, mental/emotional functioning score

Six minute walking distance test (m)
2.4
Section 4.2.2.2 Supportive secondary endpoints 
Change from baseline to week 56 in:

HbA1c (%)

Fasting plasma glucose (mg/dL)

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg) 

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]) 

Short Form-36 v2.0 acute (SF-36) (physical component summary (PCS), mental component

summary (MCS) and subdomains)

SF-36 v2.0 acute:
o
role-physical score
o
bodily pain score
o
general health score
o
vitality score
o
social functioning score
o
role-emotional score
o
mental health score
o
physical component summary (PCS)
o
mental component summary (MCS)
CONFIDENTIAL

Protocol Amendment no 1
CONFIDENTIAL
Date:
08 March 2018
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Trial ID: NN8022-4274
Version:
1.0
UTN: U1111-1177-5059
Status:
Final
EudraCT no: 2015-005592-24
Page:
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
IWQoL-Lite for CT
o
pain/discomfort domain score
o
psychosocial domain score
o
total score

Weight related sign and symptom (WRSS) measure, total score
Proportion of subjects with the following at week 56: 
Subjects who after 56 weeks achieve (yes/no):

≥ 4.3 T-score points increase from baseline in SF-36 physical functioning score
≥ 2 3.8 T-score points increase from baseline in SF-36 PCS

≥ 3 4.6 T-score points increase from baseline in SF-36 MCS

Responder definition value for IWQoL-Lite for CT physical function domain (5-items) score
2.5
Section 8.5.2 Laboratory assessments for safety 
Biochemistry
*If TSH levels are out of normal range, the investigator must perform additional testing: 

Total and free T3 and T4 and Free Thyroid Thyroxine Index

Thyroid peroxidase antibodies 
CONFIDENTIAL

Protocol Amendment no 1
CONFIDENTIAL
Date:
08 March 2018
Novo Nordisk
Trial ID: NN8022-4274
Version:
1.0
UTN: U1111-1177-5059
Status:
Final
EudraCT no: 2015-005592-24
Page:
7 of 8
2.6
Section 17.1 Sample size calculation
Table 17.3
Assumptions, marginal power and effective power for each confirmatory 
endpoint in the hierarchical testing procedure given an anticipated number of 
282 randomised subjects
Assumed mean (±SD) / 
proportion for completers 
liraglutide 3.0 mg   placebo
Expected mean (±SD) 
/ proportion for 
liraglutide 3.0 mg #
Expected 
difference #
Marginal 
power 
(%)
Effective 
power 
(%)
% weight 
change
-9.0 (±7.0)
-4.0 (±7.0)
-7.5 (±7.4)
-3.5
98.3
98.3
5% responders
72%
44%
63%
19%
90.0
88.5
10% responders
44%
20%
37%
17%
90.3
79.9
15% responders
20%
6%
15%
9%
75.0
59.9
4% responders 
at week 16
70%
45%
63%
18%
84.2
50.4
WC change
-9.0 (±7.0)
-5.0 (±7.0)
-7.8 (±7.2)
-2.8
90.8
45.8
sBP change
-5.0 (±13.0)
-3.0 (±13.0)
-4.4 (±13.0)
-1.4
14.7
6.7
6MWT change
8.2 (±12.0)
5.8 (±12.0)
7.5 (±12.1)
1.7
21.5
1.4
SF-36 PF
3.7 (±8.0)
2.4 (±8.0)
3.3 (±8.0)
0.9
15.8
7.2
IWQoL-Lite for 
CT physical 
change
IWQoL-Lite for 
CT PF 
16.0 (±18.0)
11.0 (±18.0)
14.5 (±18.1)
3.5
36.7
0.5 2.7
IWQoL-Lite for 
CT mental/ 
emotional 
change
14.0 (±20.0)
11.0 (±20.0)
13.1 (±20.0)
2.1
14.2
0.1
6MWT change
8.2 (±12.0)
5.8 (±12.0)
7.5 (±12.1)
1.7
21.5
0.6
SD   standard deviation, sBP   systolic blood pressure, WC waist circumference, 6MWT   six minutes walking test, SF-
36 PF   Short Form-36 v2.0 acute physical functioning score, IWQoL-Lite for CT PF   Impact of Weight on Quality of 
Life-Lite for Clinical Trial Version Physical function domain (5- items) score, IWQoL-Lite for CT   Impact of Weight 
on Quality of Life-Lite for Clinical Trial Version, 6MWT   six minute walking distance test;
# Adjusted for 30% discontinuation; 
Assumptions are based on findings from NN8022-1839
CONFIDENTIAL

Protocol Amendment no 1
CONFIDENTIAL
Date:
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Trial ID: NN8022-4274
Version:
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EudraCT no: 2015-005592-24
Page:
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2.7
Section 17.4.2 Description of the hierarchical testing procedure to address the 
effectiveness estimand for primary and confirmatory secondary endpoints
Table 17.6
Hierarchical order and type of statistical method to address the effectiveness 
estimands for primary and confirmatory secondary endpoints
Test 
order
Endpoint
Endpoint
Type
Statistical 
model
MI 
approach
Sensitivity 
analyses #
            Confirmatory secondary endpoints
7
Change from baseline to week 56 in systolic blood 
pressure (sBP) (mmHg)
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
87
Change in six-minute walking distance (m) from 
baseline to week 56
Change from baseline to week 56 in Short Form-
36 (SF-36) v2.0 acute physical functioning score
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
98
Change in total quality of life score from baseline 
to week 56 as assessed by IWQoL-Lite
Change from baseline to week 56 in impact of 
Weight on Quality of Life-Lite (IWQoL-Lite for 
CT), physical function domain (5-items) score
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
109
Change in physical function score from baseline to 
week 56 as assessed by IWQoL-Lite
Change in six minute walking distance test (m) 
from baseline to week 56
Continuous ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
CONFIDENTIAL