Clinical trial NCT02963922
Conditions: Metabolism and Nutrition Disorder Obesity
Sponsor: Novo Nordisk A/S
Start date: 2017-02-06; Completion date: 2018-09-25
Enrollment: 396 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of this trial is to investigate effect and safety of liraglutide 3.0 mg in subjects with overweight or obesity and type 2 diabetes mellitus treated with basal insulin.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Liraglutide 3.0 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Injected subcutaneously (s.c., under the skin) once daily intervention 2: Injected subcutaneously (s.c., under the skin) once daily

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02963922  
Sponsor trial ID: 
NN8022-4272 
Official title of study: 
Effect and safety of liraglutide 3.0 mg in subjects with 
overweight or obesity and type 2 diabetes mellitus treated with 
basal insulin 
Document date: 
18 February 2019 
 


Link
Link
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List of contents
Protocol ...............................................................................................................................................
Appendix A - Monitoring of calcitonin.............................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 - Global ........................................................................................................
Protocol amendment 2 - Global ........................................................................................................
Protocol amendment 3 - Global ........................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4272
Clinical Trial Report
Appendix 16.1.1
)HEUXDU\

)LQDO
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
1 of 123
Protocol
Trial ID: NN8022-4272
SCALE™ Insulin
Effect and safety of liraglutide 3.0 mg in subjects with overweight or 
obesity and type 2 diabetes mellitus treated with basal insulin
Trial phase: 3b
Protocol originator
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
2 of 123
Table of Contents
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................11
2
Flow chart ................................................................................................................................................15
3
Background information and rationale for the trial............................................................................21
3.1
Background information..............................................................................................................21
3.2
Rationale for the trial...................................................................................................................21
4
Objectives and endpoints........................................................................................................................22
4.1
Objectives ....................................................................................................................................22
4.2
Endpoints .....................................................................................................................................22
4.2.1
Primary endpoints......................................................................................................22
4.2.2
Secondary endpoints..................................................................................................22
4.2.2.1
Confirmatory secondary endpoints .....................................................22
4.2.2.2
Supportive secondary endpoints..........................................................23
5
Trial design ..............................................................................................................................................25
5.1
Type of trial .................................................................................................................................25
5.2
Rationale for trial design..............................................................................................................26
5.3
Treatment of subjects...................................................................................................................27
5.3.1
Investigational medicinal product..............................................................................27
5.3.2
Non-investigational medicinal products ....................................................................28
5.3.2.1
Oral antidiabetic medication ...............................................................28
5.3.2.2
Treatment with insulin throughout the trial.........................................28
5.3.3
Counselling (intensive behaviour therapy) ................................................................31
5.4
Treatment after discontinuation of trial product ..........................................................................32
5.5
Rationale for treatment ................................................................................................................32
6
Trial population.......................................................................................................................................34
6.1
Number of subjects......................................................................................................................34
6.2
Inclusion criteria ..........................................................................................................................34
6.3
Exclusion criteria.........................................................................................................................34
6.4
Randomisation criterion...............................................................................................................36
6.5
Criteria for premature discontinuation of trial product................................................................36
6.6
Withdrawal from trial ..................................................................................................................37
6.7
Subject replacement.....................................................................................................................37
6.8
Rationale for trial population.......................................................................................................37
7
Milestones.................................................................................................................................................39
8
Methods and assessments .......................................................................................................................40
8.1
Visit procedures...........................................................................................................................40
8.2
Subject-related information/assessments.....................................................................................42
8.2.1
Demography...............................................................................................................42
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
3 of 123
8.2.2
Diabetes history and diabetes complications .............................................................42
8.2.3
Hypoglycaemia unawareness.....................................................................................43
8.2.4
Concomitant illness and medical history...................................................................43
8.2.5
Concomitant medication............................................................................................44
8.2.6
Childbearing potential................................................................................................44
8.2.7
Tobacco use ...............................................................................................................45
8.2.8
Amount of alcohol consumed....................................................................................45
8.2.9
Weight history, including weight-related comorbidities............................................45
8.2.10
Barriers and motivation interview .............................................................................45
8.2.11
7-day food diary in screening period .........................................................................45
8.3
Efficacy assessments....................................................................................................................45
8.3.1
Body weight...............................................................................................................46
8.3.2
Height ........................................................................................................................46
8.3.3
Waist circumference ..................................................................................................46
8.3.4
HbA1c .........................................................................................................................46
8.3.5
Fasting plasma glucose..............................................................................................46
8.3.6
Vital signs (blood pressure) .......................................................................................47
8.3.7
Self-measured plasma glucose...................................................................................47
8.3.8
7-point SMPG profile ................................................................................................47
8.3.9
Insulin dose................................................................................................................48
8.3.10
Clinical outcome assessments....................................................................................48
8.4
Safety assessments.......................................................................................................................50
8.4.1
Physical examination.................................................................................................50
8.4.2
Eye examination ........................................................................................................50
8.4.3
Adverse events...........................................................................................................50
8.4.3.1
Medication error..................................................................................51
8.4.3.2
Adverse events requiring additional data collection ...........................51
8.4.4
Hypoglycaemic episodes ...........................................................................................53
8.4.5
Vital signs (pulse)......................................................................................................55
8.4.6
Electrocardiogram......................................................................................................55
8.4.7
Patient health questionnaire-9....................................................................................56
8.4.8
Columbia suicidal severity rating scale .....................................................................56
8.4.9
Breast and colon neoplasm follow up........................................................................56
8.5
Laboratory assessments ...............................................................................................................56
8.5.1
Laboratory assessments for efficacy..........................................................................57
8.5.2
Laboratory assessments for safety .............................................................................57
8.6
Other assessments........................................................................................................................59
8.6.1
Trial product usage ....................................................................................................59
8.6.2
Food record and tracking of physical activity............................................................59
8.6.3
Diabetes diary ............................................................................................................59
8.6.4
Training in the PDS290 pen-injector.........................................................................60
8.6.5
Inquire about mood....................................................................................................60
8.7
Subject compliance......................................................................................................................61
8.8
Additional safety assessments......................................................................................................61
8.8.1
Suspicion of acute pancreatitis...................................................................................61
8.8.2
Suspicion of acute gallstone disease..........................................................................62
8.8.3
Neoplasm ...................................................................................................................62
8.8.4
Hepatic event (suspicion of drug-induced liver injury) .............................................62
8.8.5
Depression, suicidal ideation/behaviour....................................................................63
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
4 of 123
9
Trial supplies ...........................................................................................................................................65
9.1
Trial products...............................................................................................................................65
9.2
Labelling and directions for use...................................................................................................65
9.3
Storage .........................................................................................................................................66
9.4
Drug accountability and destruction............................................................................................66
9.5
Auxiliary supplies........................................................................................................................67
10 Interactive web response system............................................................................................................68
11 Randomisation procedure and breaking of blinded codes..................................................................69
11.1
Breaking of blinded codes ...........................................................................................................69
12 Adverse events, and technical complaints and pregnancies................................................................70
12.1
Definitions ...................................................................................................................................70
12.1.1
Adverse event ............................................................................................................70
12.1.2
Serious adverse event.................................................................................................71
12.1.3
Non-serious adverse event.........................................................................................72
12.1.4
Medication errors.......................................................................................................72
12.1.5
Adverse events requiring additional data collection..................................................73
12.1.6
Technical complaints.................................................................................................73
12.2
Reporting of adverse events.........................................................................................................73
12.3
Follow-up of adverse events........................................................................................................76
12.4
Technical complaints and technical complaint samples ..............................................................77
12.4.1
Reporting of technical complaints .............................................................................77
12.4.2
Collection, storage and shipment of technical complaint samples ............................77
12.5
Pregnancies..................................................................................................................................78
12.5.1
Pregnancies in female subjects ..................................................................................78
12.6
Precautions and/or overdose ........................................................................................................79
12.7
Committees related to safety........................................................................................................80
12.7.1
Novo Nordisk safety committee ................................................................................80
13 Case report forms....................................................................................................................................81
13.1
Corrections to case report forms..................................................................................................81
13.2
Case report form flow..................................................................................................................82
14 Monitoring procedures ...........................................................................................................................83
15 Data management....................................................................................................................................84
16 Computerised systems.............................................................................................................................85
17 Statistical considerations ........................................................................................................................86
17.1
Sample size calculation................................................................................................................88
17.2
Definition of analysis sets............................................................................................................89
17.3
Primary endpoints .....................................................................................................................90
17.3.1
Analytical methods addressing the effectiveness estimand for the primary 
endpoints...................................................................................................................90
17.3.1.1
Statistical model for the primary endpoint % weight change..............90
17.3.1.2
Statistical model for the primary endpoint 5% responders .................91
17.3.2
Handling of missing values for the effectiveness estimand.......................................91
17.3.2.1
Handling of missing values at baseline...............................................91
17.3.2.2
Handling of missing values at week 56...............................................91
17.3.3
Analysis method addressing the efficacy estimand for the primary endpoints..........93
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
5 of 123
17.3.4
Subgroup analyses for primary endpoints..................................................................94
17.4
Secondary endpoints....................................................................................................................96
17.4.1
Confirmatory secondary endpoints............................................................................96
17.4.1.1
Description of the testing procedure to address the effectiveness 
estimand for primary and confirmatory secondary endpoints.............97
17.4.2
Supportive secondary endpoints ................................................................................99
17.4.2.1
Efficacy endpoints...............................................................................99
17.4.2.2
Safety endpoints..................................................................................99
18 Ethics......................................................................................................................................................105
18.1
Benefit-risk assessment of the trial............................................................................................105
18.2
Informed consent .......................................................................................................................108
18.3
Data handling.............................................................................................................................109
18.4
Information to subjects during trial............................................................................................109
18.5
Premature termination of the trial and/or trial site.....................................................................109
19 Protocol compliance..............................................................................................................................110
19.1
Protocol deviations ....................................................................................................................110
19.2
Prevention of missing data.........................................................................................................110
19.3
Protocol compliance for Mexico................................................................................................110
20 Audits and inspections ..........................................................................................................................112
21 Critical documents ................................................................................................................................113
22 Responsibilities......................................................................................................................................114
23 Reports and publications......................................................................................................................115
23.1
Communication of results..........................................................................................................115
23.1.1
Authorship ...............................................................................................................116
23.1.2
Site-specific publication(s) by investigator(s) .........................................................116
23.2
Investigator access to data and review of results.......................................................................116
24 Retention of clinical trial documentation............................................................................................117
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............118
26 Indemnity statement .............................................................................................................................119
27 References..............................................................................................................................................120
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
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
6 of 123
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................25
Figure 12–1
Reporting of AEs....................................................................................................................75
Figure 17–1
Illustration of imputation approaches.....................................................................................95
Figure 17–2
Novo Nordisk classification of hypoglycaemia....................................................................101
Figure 17–3
ADA classification of hypoglycaemia..................................................................................102
Table of Tables
Page
Table 5–1
Dose escalation and treatment period.....................................................................................27
Table 5–2
Increase of basal insulin dose .................................................................................................29
Table 5–3
Decrease of basal insulin dose................................................................................................29
Table 5–4
Bolus insulin adjustment.........................................................................................................30
Table 8–1
Time points for 7-point SMPG profile ...................................................................................48
Table 9–1
Trial products..........................................................................................................................65
Table 9–2
Storage conditions ..................................................................................................................66
Table 17–1
Taxonomy of week 56 assessments being available or missing.........................................87
Table 17–2
General specifications for sample size and power calculation..........................................88
Table 17–3
Assumptions, marginal power and effective power for each confirmatory endpoint 
in the hierarchical testing procedure given an anticipated number of 400 
randomised subjects .............................................................................................................89
Table 17–4
Factors and covariates for the analysis of the primary endpoints ...................................90
Table 17–5
Overview of handling of missing values ................................................................................96
Table 17–6
Hierarchical order and type of statistical model to address the effectiveness 
estimand for primary and confirmatory secondary endpoints.........................................98
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
7 of 123
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
COA
clinical outcome assessment
CRF
case report form
C-SSRS
Columbia suicide severity rating scale
CTR
clinical trial report
DILI
drug-induced liver injury
DPP-IV-i
dipeptidyl peptidase-4 inhibitor
DUN
dispensing unit number
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
Estimated Glomerular Filtration Rate
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 practice
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
8 of 123
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotrophin
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 Version
IWRS
interactive 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
MMRM
mixed model for repeated measurements
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
9 of 123
MT
missing on treatment
MTC
medullary thyroid carcinoma
NPH
Neutral Protamine Hagedorn
NIMP
non-investigational medicinal products
NYHA
New York Heart Association
OAD
oral anti-diabetic (medication)
OR
odds ratio 
PCS
physical component summary
PGI-C
Patients’ global impression of change
PGI-S
Patients’ global impression of status
PHQ-9
Patient Health Questionnaire-9
PYE
patient years of exposure
PYO
patient years of observation
SAE
serious adverse event
SAP
statistical analysis plan
sBP
systolic blood pressure
s.c.
subcutaneous(ly)
SD
standard deviations
SDV
source data verification
SGLT2i
sodium-glucose cotransporter-2 inhibitors
SIF
safety information form
SF-36
short form-36 version 2.0 acute
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
T3
triiodothyronine
T4
thyroxine
TBL
total bilirubin
TC
total cholesterol
TG
triglycerides
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
10 of 123
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
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
11 of 123
1
Summary
Objectives and endpoints
Primary objective
To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on weight loss effectiveness in subjects with overweight or obesity and 
type 2 diabetes mellitus (T2DM) treated with a basal insulin and up to 2 oral antidiabetic (OAD) 
medications (metformin, glitazone, SGLT-2 inhibitor or sulphonylurea).
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
Secondary objectives
To establish the effects of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on relevant efficacy endpoints in subjects with overweight or obesity 
and T2DM treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor or 
sulphonylurea)
To establish the safety and tolerability of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-
calorie diet and increased physical activity, in subjects with overweight or obesity and T2DM 
treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor or 
sulphonylurea)
Key secondary endpoints
!
Proportion of subjects losing more than 10% of baseline body weight at week 56
Change from baseline to week 56 in:
!
Waist circumference
!
Systolic blood pressure
!
HbA1c
!
Fasting plasma glucose
!
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: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
12 of 123
Trial design
This is a 56-week randomised, double-blind, multi-national, multi-centre, placebo-controlled and 
two-armed trial in subjects with overweight or obesity and T2DM treated with basal insulin and up 
to two OADs (metformin, glitazone, SGLT-2 inhibitor or sulphonylurea).
Subjects will be randomised in a 1:1 manner to receive either liraglutide 3.0 mg or placebo, as an 
adjunct to reduced-calorie diet and increased physical activity delivered as part of a comprehensive 
lifestyle intervention program (in this document referred to as Intensive Behaviour Therapy [IBT]).
Subjects treated with sulphonylurea will be stratified between the two arms.
It is recommended that the dose of basal insulin is reduced by 15-20 % for all subjects with HbA1c
≤ 8 % (at the investigator’s discretion) at randomisation, followed by weekly adjustment of insulin 
dose with the aim to achieve same pre-breakfast meal target plasma glucose as well as similar 
glycaemic control in the two treatment arms. Insulin dose should not be reduced for subjects with 
HbA1c > 8% to avoid unacceptable deterioration in glycaemic control.
Trial population
The planned number of subjects to be randomised is 400.
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. Diagnosed with type 2 diabetes mellitus
3. Treatment with up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor or sulphonylurea),
4. Stable treatment with basal insulin according to its label (no requirement of minimum or 
maximum dose) for at least 90 days prior to screening, as judged by the investigator
5. HbA1c 6.0-10.0% (both inclusive)
6. BMI ≥ 27 kg/m2
7. Age ≥ 18 years at the time of signing informed consent
Key exclusion criteria
1. Diagnosis of type 1 diabetes
2. Known hypoglycaemic unawareness as indicated by the investigator according to Clarke’s 
questionnaire question 8 (see Section 8.2.3)
3. Recurrent severe hypoglycaemic episodes within the last year as judged by the investigator
4. Unable or unwilling to perform self-monitoring of plasma glucose according to the protocol 
and to keep a diabetes diary
5. Treatment with any hypoglycaemic medications other than OADs and basal insulin within 
the past 90 days prior to screening
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
13 of 123
6. Treatment with a DPP-IV inhibitor within the past 90 days prior to screening
7. 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
8. Personal or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine 
Neoplasia type 2 (MEN2)
9. 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)
For Germany: Only highly effective methods of birth control are accepted (i.e. one that 
results in less than 1% per year failure rate when used consistently and correctly such as 
implants, injectables, combined oral contraceptives, some intrauterine device), or sexual
abstinence or vasectomised partner
10. 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)
11. History of pancreatitis (acute or chronic)
12. History of major depressive disorder within the past 2 years
13. Any lifetime history of a suicide attempt
14. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic 
≥180 mmHg or diastolic ≥110 mmHg).
15. History of malignancy (except for non-melanoma skin cancer) within the past 5 years
Assessments
Efficacy
!
Weight 
!
Waist circumference
!
Clinical outcome assessments (IWQoL-Lite for CT, Short Form 36 v2.0 acute)
!
Glycaemic parameters (HbA1c, fasting plasma glucose and self-measured plasma glucose)
!
Blood pressure
Safety
!
Adverse events
!
Hypoglycaemic episodes
!
Pulse
!
ECG
!
Biochemistry and haematology
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
14 of 123
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: U1111-1177-4903
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4272
EudraCT no.: 2015-005619-33
Version:
4.0
Page:
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2
Flow chart
Screening
Randomisation
Dose 
Escalation
Maintenance period
End-of-treatment
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
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 8.2.10
x
Weight history, incl. weight-related comorbidities 
8.2.9
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 8.2.6
x
Concomitant illness/medical history 8.2.4
x
Diagnosis of diabetes and diabetes complications 
8.2.2
x
History of gallstone disease 8.2.4
x
History of breast neoplasms 8.2.4
x
History of colon neoplasms 8.2.4
x


Protocol
UTN: U1111-1177-4903
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4272
EudraCT no.: 2015-005619-33
Version:
4.0
Page:
16 of 123
Screening
Randomisation
Dose 
Escalation
Maintenance period
End-of-treatment
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
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 8.2.4
x
Concomitant medication 8.2.5
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 8.2.7
x
Amount of alcohol consumed 8.2.8
x
Counselling1 5.3.3
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
HbA1c 8.3.4
x
x
x
x
x
x
x
Fasting plasma glucose 8.3.5
x
x
x
x
x
x
Self-measured plasma glucose (once-daily)2 8.3.7
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
7-point SMPG profile 8.3.8
x
x
x
x
x
x
Vital signs (blood pressure) 8.3.4
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 Clinical 
Trials Version 8.3.10
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1177-4903
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4272
EudraCT no.: 2015-005619-33
Version:
4.0
Page:
17 of 123
Screening
Randomisation
Dose 
Escalation
Maintenance period
End-of-treatment
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
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
SF-36 v2.0 Acute 8.3.10
x
x
x
x
x
x
x
x
Patient global impression of status8.3.10
x
x
x
x
x
x
x
x
x
Patient global impression of change 8.3.10
x
x
x
x
x
x
x
Weight related sign and symptom measure8.3.10
x
x
x
x
x
x
x
x
x
SAFETY
Physical examination 8.4.1
x
x
Eye examination3 8.4.2
x
Pregnancy test4 8.5.2
x
x5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x
5
x5
ECG 8.4.6
x
x
Adverse Events 8.4.3 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
Hypoglycaemic episodes 8.4.4
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 neoplasms follow up6 8.4.9
x
x
Colon neoplasms follow up 8.4.9
x
x
Haematology 8.5.2
x
x
x
x
Biochemistry7 8.5.2
x
x
x
x
Calcitonin 8.5.2
x
x
x


Protocol
UTN: U1111-1177-4903
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4272
EudraCT no.: 2015-005619-33
Version:
4.0
Page:
18 of 123
Screening
Randomisation
Dose 
Escalation
Maintenance period
End-of-treatment
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
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
Vital signs (pulse) 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
PHQ-9 8.4.7
x
x
C-SSRS 8.4.8
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 and physical activity diary8 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 pedometer  8.6.2
x
Dispense and instruct in diabetes diary 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
x
x
Hand out direction for use and instruct in pen 
handling 8.6.4 and 9.2
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 8.6.5
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 fasting9
x
x
x
x
x
x


Protocol
UTN: U1111-1177-4903
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4272
EudraCT no.: 2015-005619-33
Version:
4.0
Page:
19 of 123
Screening
Randomisation
Dose 
Escalation
Maintenance period
End-of-treatment
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
5
6
6
0
Visit window, days
-7
±
2
±
2
±
2
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2
±
3
±
3
±
3
±
3
±
3
±
3
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3
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3
±
3
±
3
±
5
±
5
±
5
±
5
±
5
±
5
±
5
±
5
+
5
Dispense and instruct in blood glucose (BG) meter 
use 
x
Dispense BG meter auxiliaries
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Insulin dose adjustment10 5.3.2.2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Collect, review and transcribe subject diary into 
eCRF8.6.2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
x
x
Collect questionnaires
x
x
x
x
x
x
x
x
x
1Counselling is the intensive behaviour therapy (IBT)
2 Based on self-measured plasma glucose (SMPG) records. In the first 5 weeks, the basal insulin dose should not exceed entry dose, and bolus insulin 
should not be initiated
3Only if not available within last 90 days before screening
4For women of childbearing potential: A negative pregnancy test (s-HCG) is required for inclusion
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
6Breast neoplasm follow up form is to be filled in by only female subjects
7Estimated Glomerular Filtration Rate (eGFR) is calculated at each visit with biochemistry. hs-CRP is only measured at Visit 2 and Visit 24.
8At screening a 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 


Protocol
UTN: U1111-1177-4903
Date:
14 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN8022-4272
EudraCT no.: 2015-005619-33
Version:
4.0
Page:
20 of 123
9Subject is not allowed to eat or drink at least eight hours overnight before attending a fasting visit (water consumption is allowed)
10Insulin dose should be decreased by 15- 20% at randomisation if HbA1c ≤8%. For insulin adjustments after trial product is terminated, please refer to 
Section 5.4
11The 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: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
21 of 123
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
Many patients with type 2 diabetes mellitus (T2DM) treated with oral antidiabetic medications
(OADs) eventually require insulin to manage the progressive deterioration in glycaemic control3. 
However, weight gain commonly occurs with escalating insulin therapy, reducing patient 
satisfaction and treatment adherence4. 
The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide is approved for the treatment of 
T2DM (1.2 mg and 1.8 mg) Victoza® and weight management (3.0 mg) Saxenda®. Through 
activation of the GLP-1 receptor, it stimulates insulin secretion in a glucose-dependent manner and 
reduces appetite and energy intake. Results from the SCALE™ Diabetes trial demonstrated that 
liraglutide 3.0 mg, as an adjunct to a reduced-calorie diet and increased physical activity, is 
effective for weight loss in subjects with overweight or obesity and T2DM treated with 0-3 OADs 
(metformin, glitazone, sulphonylurea), and associated with improved glycaemic control, reduction 
in the use of hypoglycaemic medications, and risk of hypoglycaemia comparable to what is seen
with lower doses of liraglutide5.
3.2
Rationale for the trial
Previous results suggest that liraglutide 3.0 mg, as an adjunct to a reduced-calorie diet and increased 
physical activity might also be beneficial for patients with overweight or obesity and T2DM treated 
with basal insulin. Through its mechanisms of action, it is presumed to facilitate adherence to 
behaviour change, and by reducing body weight, improve physical functioning, such that increased 
physical activity is easier in those who cannot exercise initially6. Moreover, the anticipated lower 
insulin requirement with liraglutide vs. placebo is expected to further amplify weight loss and 
reduce exercise-related hypoglycaemia, both of which are barriers to effective and sustainable 
weight management.
There is currently no data to support use of liraglutide 3.0 mg, as an adjunct to a reduced-calorie 
diet and increased physical activity, for weight management in patients with T2DM treated with
insulin7-9. However, the combination of basal insulin and liraglutide 1.8 mg is approved for  
maintaining glycaemic control in patients with T2DM10, 11.
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: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
22 of 123
4
Objectives and endpoints
4.1
Objectives
Primary objective
To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on weight loss effectiveness in subjects with overweight or obesity and 
type 2 diabetes mellitus (T2DM) treated with a basal insulin and up to 2 oral antidiabetic (OAD) 
medications (metformin, glitazone, SGLT-2 inhibitor or sulphonylurea).
Secondary objectives
!
To establish the effects of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie 
diet and increased physical activity, on relevant efficacy endpoints in subjects with 
overweight or obesity and T2DM treated with basal insulin and up to 2 OADs (metformin, 
glitazone, SGLT-2 inhibitor or sulphonylurea)
!
To establish the safety and tolerability of liraglutide 3.0 mg vs. placebo, as an adjunct to a 
reduced-calorie diet and increased physical activity, in subjects with overweight or obesity 
and T2DM treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 
inhibitor or sulphonylurea)
4.2
Endpoints
4.2.1
Primary endpoints
Co-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
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints addressing the secondary efficacy objective:
!
Proportion of subjects losing more than 10% of baseline body weight at week 56
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
23 of 123
Change from baseline to week 56 in:
!
Waist circumference
!
Systolic blood pressure
!
HbA1c
!
Fasting plasma glucose
!
IWQoL-Lite for CT, physical functioning score
!
IWQoL-Lite for CT, mental/emotional function score
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:
!
Total daily basal insulin dose (% of pre-trial dose in U)
!
Total daily basal insulin dose (U/kg)
!
Total daily insulin dose (U)
!
Total daily insulin dose (U/kg)
!
7-point self-measure plasma glucose (SMPG) profile, mean daytime glucose value
!
Diastolic blood pressure
!
Lipids (total cholesterol [TC], low density lipoprotein cholesterol [LDL cholesterol], high
density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein cholesterol
[VLDL cholesterol], triglycerides [TG], free fatty acids [FFA])
!
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: 
!
HbA1c <7% and weight loss ≥5%
!
HbA1c <7%, weight loss ≥5% and no documented symptomatic hypoglycaemia
!
≥ 2 T-score points increase from baseline in SF-36 PCS
!
≥ 3 T-score points increase from baseline in SF-36 MCS
Supportive secondary safety endpoints
!
Adverse events from randomisation until and including the follow-up visit
!
Hypoglycaemic episodes until and including the follow-up visit
Change from baseline to week 56 in:
!
Physical examination
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
24 of 123
!
Resting pulse
!
ECG
!
Laboratory measurements
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
25 of 123
5
Trial design
5.1
Type of trial
This is a 56-week randomised, double-blind, multi-national, multi-centre, placebo-controlled and
two-armed trial in subjects with overweight or obesity and T2DM treated with basal insulin and up
to 2 OADs (metformin, glitazone, SGLT-2 inhibitor or sulphonylurea).
Subjects will be randomised in a 1:1 manner to receive either liraglutide 3.0 mg or placebo, as an 
adjunct to reduced-calorie diet and increased physical activity delivered as part of a comprehensive 
lifestyle intervention program (in this document referred to as IBT) (see Figure 5–1 and Section 
5.3.3). Subjects treated with sulphonylurea will be stratified between the two arms.
It is recommended that the dose of basal insulin is reduced for all subjects by 15-20 % for subjects 
with HbA1c ≤ 8 % (at the investigator’s discretion) at randomisation, followed by weekly 
adjustment of insulin dose with the aim to achieve same pre-breakfast meal target plasma glucose as 
described in Section 5.3.2.2, as well as similar glycaemic control in the two treatment arms. Insulin 
dose should not be reduced for subjects with HbA1c > 8% at randomisation to avoid unacceptable 
deterioration in glycaemic control.
Figure 5–1
Trial design
Adjustment of insulin dose may be initiated one week after randomisation; however, in the first five 
weeks after randomisation, the basal insulin dose should not exceed the pre-trial dose and bolus 
insulin should not be initiated, unless deemed necessary by investigator to control unacceptable 
hyperglycaemia (see Section 5.3.2.2).
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5.2
Rationale for trial design
A randomised controlled and double-blinded trial design is chosen to minimise bias in the 
assessment of the effect and safety of liraglutide 3.0 mg vs placebo, both as an adjunct to IBT.
Subjects discontinuing randomised treatment prematurely are encouraged to stay in the trial and 
continue IBT, in alignment with current clinical recommendations12 and to minimise missing data. 
However, if a discontinued subject do not wish to attend the IBT visits, the investigator should still
encourage the subject to come back for V24.
Weekly dose escalation of the trial drug (see Section 5.3.1) is included in accordance with the 
Saxenda® prescribing information7-9. Based on the weight loss time course in SCALE Diabetes™ 
(subjects on 0-3 OADs), a trial duration of 56 weeks is considered sufficient to measure the 
majority of the weight loss curve13.
A 30 day follow-up period for safety is included after the 56 weeks treatment period, in accordance 
with FDA guidance14.
In accordance with clinical guidelines12, 15 16, 17 IBT consisting of frequent structured counselling, 
reduced-calorie diet and increased physical activity is an integrated part of the trial design. 
Reduction of insulin dose at randomisation is recommended to avoid unnecessary hypoglycaemia 
associated with the trial’s interventions: 1. the lifestyle intervention which, through weight loss, will 
improve insulin sensitivity and consequently insulin requirements and/or 2. initiation of liraglutide 
3.0 mg (Saxenda®), which has direct glucose-lowering effects. Conversely, insulin dose will be 
adjusted weekly starting one week after randomisation to avoid unnecessary hyperglycaemia 
associated with the initial reduction of insulin dose. This will primarily affect subjects in the 
placebo group, where lifestyle changes and weight loss are the main sources of improved glycaemic 
control. The dose of sulphonylurea may be reduced by 50% at investigator’s discretion in patients 
using this OAD since hypoglycaemic events are more frequent when combining liraglutide with 
sulphonylurea than with other OADs. Furthermore, subjects treated with sulphonylurea will be 
stratified between the two arms.
Weekly adjustment will also increase the likelihood of achieving similar glycaemic control in the 
two treatment arms. This is important since improvement/deterioration of glycaemic control directly 
impact insulin requirements and indirectly, through changes in insulin dose, body weight changes. 
For information on dose adjustment algorithm, see Section 5.3.2.2.
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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, the 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, (e.g. 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 s.c. 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.
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.
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5.3.2
Non-investigational medicinal products
Non-investigational medicinal products (NIMP) comprise the following: OADs and insulin.
5.3.2.1
Oral antidiabetic medication
Any approved and marketed metformin, glitazone, SGLT-2 inhibitor or sulphonylurea product or
combination products are allowed. Subjects treated with dipeptidyl peptidase-IV (DPP-IV)
inhibitors are excluded from participating in the trial since DPP-IV inhibitors and GLP-1 receptor
agonists should not be combined.
To mitigate sulphonylurea induced hypoglycaemia, subjects treated with sulphonylurea may be at
randomisation be asked to reduce the sulphonylurea dose by 50% at investigator’s discretion. The 
type and dose of other OADs must be kept constant throughout the trial, unless unacceptable 
hypoglycaemia occurs and cannot be managed by reduction of the basal insulin dose.
In case the type of OAD becomes unavailable during the course of the trial, it is allowed per the 
discretion of the investigator to shift to an alternative treatment within the same class. 
5.3.2.2
Treatment with insulin throughout the trial
Any approved and marketed basal insulin (NPH insulin or insulin analogue) is allowed, at any dose, 
if used according to its prescribing information at screening. Once-daily or twice-daily dosing is 
allowed, according to dosing schedule at baseline.
To reduce the risk of hypoglycaemia associated with liraglutide 3.0 mg and lifestyle intervention, it 
is recommended that the dose of basal insulin is reduced by 15-20 % for subjects with HbA1c ≤8 %
(at investigator’s discretion) at randomisation. Furthermore, the basal dose should not exceed the 
pre-trial insulin dose in the first five weeks of liraglutide escalation, unless deemed necessary by 
investigator to treat unacceptable hyperglycaemia.
During the trial, subjects will be required to perform self-measured plasma glucose (SMPG) on 3 
consecutive days, each week prior to basal insulin adjustment and enter the values into the subject 
diabetes diary. In the weeks where no site visits are planned, subjects will adjust their insulin dose 
themselves, according to the algorithm described below (Table 5–2, Table 5–3, and Table 5–4). 
These algorithms are provided to the subject in the diary and is part of the diabetes diary training. In 
the weeks where phone- or face-to-face contact is conducted, investigator will review previous self-
adjustments, and perform adjustment for the current week.
The insulin dose adjustments recorded in the diabetes diary, must be entered in the electronic case 
report form (eCRF).
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Insulin dose adjustments
The aim of this trial is to demonstrate safety and effect of liraglutide 3.0 mg in subjects with T2DM
treated with basal insulin. To this end, reaching similar levels of glycaemic control is important, 
regardless of background medication. Therefore, trial subjects are encouraged, as appropriate, to 
adjust insulin doses according to the below algorithm – with dose increase based on the mean of the 
three pre-breakfast SMPGs measured, and dose decrease based on at least one of the three pre-
breakfast plasma glucose values equal to or below 3.9 mmol/L (70 mg/dL).
Subject using once daily basal insulin will measure SMPG before breakfast and adjust their dose 
based on the 3 SMPGs measured on three consecutive days prior to dose adjustment. It is 
recommended to adjust the basal insulin dose once weekly at the investigator’s discretion. 
Subject using twice daily basal insulin will measure pre-breakfast and pre-dinner SMPG and adjust 
their evening dose based on the three pre-breakfast SMPGs, and their morning dose based on the 
three pre-dinner SMPGs measured on three consecutive days prior to dose adjustment.
Table 5–2
Increase of basal insulin dose
Mean of three pre-breakfast or pre-dinner SMPG
Increase of basal insulin dose
mmol/L
mg/dL
U
4.0 ∀5.0
71 ∀90
No adjustment
5.1 ∀7.0
91 ∀126
+ 2
7.1 ∀8.0
127 ∀144
+ 4
8.1 ∀9.0
145 ∀162
+ 6
> 9.0
> 162
+ 8
Table 5–3
Decrease of basal insulin dose
Lowest of three pre-breakfast or pre-dinner SMPG
Reduction of basal insulin dose
mmol/L
mg/dL
U
< 3.1
< 56
- 4 (or 10 % if the dose > 45 U)
3.1 ∀3.9
56 ∀70
- 2 (or 5 % if the dose >45 U)
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Intensification with bolus insulin
Initiation of bolus insulin can be considered after the 5-week escalation period, and only after 
optimisation of basal insulin dose. These are the steps to take in situations where maximum fasting 
glycaemic control has been achieved and overall glycaemic control is still sub-optimal, and the 
investigator judges that bolus insulin is a necessary safety precaution.
Once bolus insulin is initiated, subjects will start measuring 4 SMPGs – pre-breakfast, pre-lunch, 
pre-dinner and at bedtime, on three consecutive days a week, prior to dose adjustment. It is 
recommended to adjust the bolus insulin dose once weekly at the investigator’s discretion. Bolus 
dose adjustments may be performed according to the below algorithm (Table 5–4), using the 
frequency of pre-prandial and bedtime plasma glucose values as follows:
!
Pre-breakfast bolus insulin should be adjusted according to the 3 consecutive pre-lunch 
SMPGs in the preceding 3 days
!
Pre-lunch bolus insulin should be adjusted according to the 3 consecutive pre-dinner SMPGs 
in the preceding 3 days
!
Pre-dinner bolus insulin should be adjusted according to the 3 consecutive bedtime SMPGs 
in the preceding 3 days
Table 5–4
Bolus insulin adjustment
SMPG values
Adjustment
Frequency rule
mmol/L
mg/dL
U
≤3.9
≤70
- 1
≥1 SMPG below target
4.0-6.0
71-108
0
0-1 SMPGs above target
No SMPG below target
> 6.0
> 108
+ 1
≥2 SMPGs above target
No SMPG below target
Additional face-to-face visits may be scheduled if deemed necessary by site staff to achieve or 
maintain acceptable glycaemic control.
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5.3.3
Counselling (intensive behaviour therapy)
The intensive behaviour therapy (IBT) will consist of counselling on diet, physical activity and 
other lifestyle modifications. The content of the IBT is based on an abbreviated version of the 
Diabetes Prevention Program (DPP)18 19 employing the 5A counselling framework (Ask, Assess, 
Advise, Agree, Assist)20, 21. IBT will be delivered by a registered dietician or similarly qualified 
healthcare professional according to local standard. The individual performing the IBT is called 
interventionist in this protocol. Interventionists will be trained in obesity and its behavioural 
management, prior to beginning the trial and will be provided on-going assistance and share better 
practice in how to perform IBT during the trial.
Subjects will attend a total of 23 counselling sessions during the 56 weeks period. The structure and 
content of each IBT session is specified in an IBT guide, consisting of an interventionist part and a 
subject hand out. Generally each 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 8.6.2) and the interventionist will 
assist with solving individual problems.
In addition to the above, each 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.
IBT sessions that cannot be completed on-site (because of illness, travel, etc.), may be completed by 
phone. However, this will be allowed only in exceptional cases.
Calorie targets 
Caloric deficit and diet composition are aligned with clinical evidence-based guidelines for 
management of overweight and obesity in adults16.
Daily caloric target throughout the trial for subjects should be based on body weight at 
randomisation:
!
Subjects weighing less than 200 lb (~90 kg) will be prescribed a diet of 1200 kcal/day
!
Subjects weighing between 200 lb and 300 lb (~135 kg) will be prescribed a diet calculated 
as:
 	
	  (	) = 
 ℎ () ∗6 (	/) or 
 	
	  (	) = 
 ℎ () ∗13.23  (	/)
!
Subjects weighing more than 300 lb will be prescribed 1800 kcal/day
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The initial caloric target will be kept throughout the trial. If a subject achieves a body mass index 
(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 advised22.
Subjects will be instructed to record their food and calorie intake daily (see Section 8.6.2).
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 weight22.
Subjects will be instructed to record their physical activity daily, see Section 8.6.1. 18, 20.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, the subject may 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. In this 
case, the investigator must note down the current treatment in the medical record and eCRF. If the 
subject has re-started the trial product, the investigator must note down details in the medical record
and eCRF, 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. 
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 loss23, and 
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combining IBT and pharmacologic treatment leads to more weight loss than pharmacologic 
treatment alone24. 
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be randomised: 400
For Mexico: The estimated number of subjects to be randomised in Mexico is 30.
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. Diagnosed with type 2 diabetes mellitus
3. Treatment with up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor or sulphonylurea)
4. Stable treatment, at the discretion of the investigator, with any basal insulin according to its 
label (no requirement of minimum or maximum dose) for at least 90 days prior to screening
5. HbA1c 6.0-10.0% (both inclusive)
6. BMI ≥ 27 kg/m2
7. Age ≥18 years at the time of signing informed consent
8. Maximum 5 kg self-reported weight loss within the past 90 days since screening
9. 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. Diagnosis of type 1 diabetes mellitus
2. Known hypoglycaemic unawareness as indicated by the investigator according to Clarke’s 
questionnaire question 8 
3. Recurrent severe hypoglycaemic episodes within the last year as judged by the investigator
4. Unable or unwilling to perform self-monitoring of plasma glucose according to the protocol 
and to keep a diabetes diary
5. Treatment with any hypoglycaemic medications other than OADs and basal insulin within 
the past 90 days prior to screening
6. Treatment with a DPP-IV inhibitor within the past 90 days prior to screening
7. 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
8. Hypersensitivity to liraglutide or any product components
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9. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to randomisation
10. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
< 60 ml/min/1.73 m2 as defined by KDIGO 2012 classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening
11. Personal or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine
Neoplasia type 2 (MEN2)
12. 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)
For Germany: Only highly effective methods of birth control are accepted (i.e. one that 
results in less than 1% per year failure rate when used consistently and correctly such as 
implants, injectables, combined oral contraceptives, some intrauterine device), or sexual 
abstinence or vasectomised partner
13. Uncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) > 6 mIU/L or < 
0.4 mIU/L (at screening visit)
14. 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)
15. 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
16. History of pancreatitis (acute or chronic)
17. History of major depressive disorder within the past 2 years since screening
18. Diagnosis of other severe psychiatric disorder (e.g., schizophrenia, bipolar disorder)
19. A Patient Health Questionaire-9 (PHQ-9) score of ≥15 at screening or randomisation
20. Any lifetime history of a suicide attempt
21. Any suicidal behaviour within the past 30 days since screening
22. 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
23. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic 
≥180 mmHg or diastolic ≥110 mmHg)
24. History of malignancy (except for non-melanoma skin cancer) within the past 5 years
25. Any disorder, not covered by any of the other exclusion criteria, which in the investigator’s 
opinion, might jeopardise subject’s safety or compliance with the protocol
26. Known or suspected abuse of alcohol or narcotics
27. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures, including dietary changes and physical activity
28. Subjects from the same household participating in the trial
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29. Participation in any clinical trial with or without an investigational medicinal product within 
the past 90 days before screening
30. 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, adherence to 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 criterion
2. Safety concern (not covered by any of below criteria) or unacceptable intolerability to trial 
product, as judged by the investigator
3. Hypersensitivity to trial product(s). If a hypersensitivity reaction occurs, discontinue trial 
product and other suspect medications
4. More than one episode of severe hypoglycaemia, or repeated episodes of documented 
symptomatic hypoglycaemia (ADA classification), despite lowering of insulin dose (as 
judged by investigator)
5. Pregnancy
6. Intention of becoming pregnant
7. Suspicion of pancreatitis (see Section 8.4.3.2 and 8.8.1)
8. Suspicion of acute gallstone disease (see Section 8.4.3.2 and 8.8.2)
9. Suspicion of drug-induced liver injury (DILI) (see Section 8.4.3.2 and 8.8.4)
10. Calcitonin ≥100 ng/L
11. Psychiatric disorder(s) that cannot be adequately treated with psycho- and/or 
pharmacotherapy (see Section 8.4.3.2, 8.6.5 and 8.8.5)
12. Initiation of anti-obesity medication and/or (plans for) weight loss surgery
13. Initiation of treatment with GLP-1 receptor agonist or DPP-IV inhibitors
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14. 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 8 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. 
For Mexico: Should the subject, his/her family members, parents, or legal representative decide to 
withdraw the consent for participation in the trial, the subject will be entitled to receive appropriate, 
free of charge medical care and/or trial drug during the follow up period of the protocol when it will 
be established with certainty that no untoward medical consequences of the subject´s participation 
in the research occurred.
6.7
Subject replacement
Subjects who discontinue trial product prematurely will not be replaced.
6.8
Rationale for trial population 
Subjects with overweight or obesity and T2DM treated with any basal insulin (with or without up to 
2 OADs) were selected for this trial, in alignment with the trial objective. While previously shown 
to be efficacious and generally well-tolerated in subjects with overweight or obesity and T2DM
treated with 0-3 OADs, as an adjunct to a reduced-calorie diet and increased physical activity, 
liraglutide 3.0 mg has not previously been studied in subjects with overweight or obesity with 
T2DM treated with basal insulin.
Due to insulin resistance, these patients are often difficult to treat and require high insulin doses to 
maintain glycaemic control. Escalating insulin dose results in weight gain and reduced patient 
satisfaction and treatment adherence4. By contrast, weight loss improves insulin sensitivity and 
reduces the use of concomitant diabetes medication (including insulin) and related cost25, but may 
be difficult to achieve by lifestyle intervention alone26.
To reflect clinical practice, all types of basal insulin products are allowed, at any dose and dosing 
regimen. Likewise, OAD commonly used by subjects treated with basal insulin will be allowed as 
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per the inclusion criteria. Subjects are included after treatment with basal insulin for at least 90 days
in order to reach effective dose. Subjects treated with DPP-IV inhibitors are excluded from 
participating in the trial since DPP-IV inhibitors and GLP-1 receptor agonists should not be 
combined. 
Improvement in glycaemic control is not the main focus of this trial (design aimed at achieving 
similar glycaemic control in both treatment arms), but in recognition of the anticipated glucose-
lowering associated with treatment, approximately 1.3% from baseline in the SCALE diabetes 
trial13, a minimum entry HbA1c of 6% is required.
Likewise, a maximum entry HbA1c will allow for inclusion of patients at high unmet need for 
weight loss, improvement in glycaemic control and insulin dose reduction. The anticipated lower 
insulin dose requirement with liraglutide 3.0 mg vs. placebo is expected to further amplify weight 
loss whilst also reducing frequency of hypoglycaemia, both of which reduce exercise-related 
hypoglycaemia27, 28 . These are normally considered barriers to effective and sustainable weight 
management in patients with insulin-treated T2DM.
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7
Milestones
Planned duration of recruitment period 16 weeks.
End of trial is defined as last subject last visit (LSLV).
Recruitment
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects 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 Disclosure29, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)30, the Food and Drug Administration Amendment Act31, European 
Commission Requirements32, 33 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 criteria 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 also note down the date in the medical record and 
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 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) 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, 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-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.
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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 maybe 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
Diabetes history and diabetes complications 
Diabetes history and diabetes complications will be recorded at screening and consists of:
!
Date of diagnosis of T2DM
!
Information regarding diabetes complications including date of onset in case of:
o
Diabetic retinopathy
o
Diabetic neuropathy
o
Diabetic nephropathy
o
Macroangiopathy (including peripheral vascular disease)
Diabetes history and diabetes complications, must be recorded on the designated form.
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8.2.3
Hypoglycaemia unawareness
Information on hypoglycaemia unawareness must be recorded at screening according to Clarke’s 
questionnaire, question 834. The investigator must ask the subject in the following way: “To what 
extent can you tell by your symptoms that your blood glucose is low?” The subject can answer 
never, rarely, sometimes, often or always. Subjects answering ‘never, rarely or sometimes’ are 
considered as having reduced awareness of hypoglycaemia.
8.2.4
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. The disease under investigation (T2DM) should not be entered as it is captured under 
diabetes history and diabetes complications.
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 only be entered on the specific forms.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. This also includes changes 
to diabetes history and diabetes complications. 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.
The specific medical history described below should 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 neoplasm
Information related to history of breast neoplasms must be recorded for all female subjects. 
Information regarding menopausal status, previous mammograms and outcome, first degree 
relatives with breast cancer and predisposing factors (alcohol intake above recommended local 
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guidelines, hormone replacement therapy, age of menarche, number of births, maternal age at first 
birth, and if the subject ever breastfed) should be recorded.
History of colon neoplasm
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.
8.2.5
Concomitant medication
A concomitant medication is any medication, other than the trial product, which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at visit 1. Changes in concomitant 
medication must be recorded at each visit as they occur. The information collected for each 
concomitant medication includes trade name or generic name, indication, start date and stop date or 
continuation. 
The products described as NIMP (see Section 5.3.2) are also recorded as concomitant medication in 
the eCRF. However the adjustments of insulin doses performed during the trial will be recorded in 
the designated form and these must be assessed by the investigator. 
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.
8.2.6
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.
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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
8.2.7
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
8.2.8
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 an average.
8.2.9
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.
8.2.10
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 IBT sessions. The 
interview guide will be available in local language.
8.2.11
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. The 
subjects are expected to fill out the food diary for at least 5 days in the period between screening 
and randomisation. 
8.3
Efficacy assessments
All assessments and samples collected at randomisation will be considered as baseline for efficacy, 
unless otherwise specified.
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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 lbs using the 
same scale throughout the trial. The scale must be calibrated yearly as a minimum.
Body mass index will be calculated by the eCRF from visit 1 data and must be in accordance with 
inclusion criterion #6. 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.
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).
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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
Self-measured plasma glucose
At visit 1, subjects will be provided with a blood glucose (BG) meter including auxiliaries as well 
as instructions for use. Only the BG meter provided by Novo Nordisk should be used for the 
measurements required in the protocol. The subjects will be instructed in how to use the device and 
the instruction should be repeated at regular intervals as needed. 
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma-equivalent glucose values, which will be 
shown on the display. 
Subjects should be instructed in how to record the results of the SMPG values in the diabetes 
diaries. The record of each SMPG value should include date, time and value. This data should not 
be entered into the eCRF.
The SMPGs should be measured to ensure data for insulin adjustment (see Section 5.3.2.2) and to 
record 7-point SMPG profile (see Section 8.3.8). In addition, SMPG values are also measured for 
collecting and reporting hypoglycaemic episodes (see Section 8.4.4). The subject may measure 
additional values at the discretion of the investigator.
8.3.8
7-point SMPG profile
Subjects will be instructed to perform a 7-point SMPG profile prior to randomisation and at selected 
visits as specified in the flow chart (see Section 2).
The 7-point profile should be recorded the day before the site visit. The SMPGs should be measured 
and recorded in the diary at the time points listed in Table 8–1. The record of each SMPG must 
include date, actual time point and the plasma glucose value. Data must be transcribed into the 
eCRF during or following the site visit. If a discrepancy is later detected, the values in the eCRF 
must be corrected.
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Table 8–1
Time points for 7-point SMPG profile
Time point
SMPG measurement
Before breakfast
√
90 min after start of breakfast
√
Before lunch
√
90 minutes after start of lunch
√
Before dinner
√
90 min after start of dinner
√
At bedtime
√
8.3.9
Insulin dose
Subjects will be instructed in how to record the insulin use in the provided diabetes diary. The 
investigator should review the subject’s insulin dose as specified in Section 8.1. Results of the 
subject’s SMPG measurements should be noted in the diabetes diary and total daily injected dose of 
basal/bolus insulin prior to each contact will be transcribed into the eCRF and based on these, dose 
adjustment guidance will be provided. All adjustments of insulin dose level will be captured in the 
eCRF. From visit 2 and until follow-up, the investigator should record the subject’s total daily 
injected dose of insulin (basal/bolus) prior to each visit in the eCRF.
8.3.10
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 the 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 five questionnaires for efficacy are:
Impact of Weight on Quality of Life-Lite for Clinical Trials Version
The Impact of Weight on Quality of Life Lite for Clinical Trials Version (IWQoL-Lite for CT) 
questionnaire is a 22-item modified version of an instrument designed to assess weight-related 
quality of life35.
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)36.
Short Form 36 v2.0 acute
Short Form 36 v2.0 acute (SF-36) is a 36-item, patient-reported survey of patient health. SF-36 
measures the subject’s overall Health Related Quality of Life on 8 domains: physical functioning, 
role functioning, bodily pain, general health, vitality, social functioning, role emotional and mental 
health37.
In addition, SF-36 is included to validate the outcome of IWQoL-Lite for CT and WRSS
questionnaires.
Patients’ global impression of change
The patients’ global impression of change (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 WRSS questionnaire.
Patients’ global impression of status
The patients’ global impression of status (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.
Weight related sign and symptom measure
The WRSS measures the presence and bothersome associated with weight related signs and 
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)36.
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8.4
Safety assessments
All assessments and samples collected at randomisation will be considered as baseline for safety, 
unless otherwise specified.
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, abdomen, gastrointestinal system including mouth, 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 8.2.4).
Physical examination performed at screening will be considered as baseline.
8.4.2
Eye examination
Dilated funduscopy/fundus photography will be performed at the visit specified in the flow chart 
(see Section 2) by the investigator or a local ophthalmologist according to local practice. Result of 
the funduscopy/fundus photography will be interpreted by the investigator. 
If a funduscopy/fundus photography has been performed within 90 days prior to randomisation, the 
procedure does not need to be repeated, unless signs of worsening of visual function have been seen 
since the last examination.
If the fundoscopy/fundus photography is performed before the subject has signed the informed 
consent form, it must be documented in the medical records that the reason for performing the 
procedure was not related to this trial.
It is allowed to perform the visit 1 fundoscopy/fundus photography between visit 1 and visit 2. The 
results must be available prior to randomisation.
Any clinically significant abnormalities found at visit 1 or as part of the screening procedures, 
should be recorded as a concomitant illness.
8.4.3
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12. 
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8.4.3.1
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 hypoglycaemic episode(s) or 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.
8.4.3.2
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 drug-induced liver injury)
In case any of these events fulfil the criteria for a SAE, please report accordingly (see Section 12).
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 (see Section 8.8.3)
!
Diagnostic imaging
!
Pathological examination results
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!
Treatment given for the event
!
Participation in screening programs
!
Relevant risk factors associated with the event
Pancreatitis
If there is suspicion 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 
psychiatric disorder form: 
!
Signs and symptoms of depression, suicidal ideation or behaviour
!
Treatment given for the event
!
Relevant risk factors associated with the event
Hepatic event (suspicion of drug-induced liver injury)
In case of suspicion of drug-induced liver injury (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 8.8.4)
!
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.
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8.4.4
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or,
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms 
should be reported in the diary according to the instructions below throughout the trial from visit 1 
to visit 25. 
Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance with current guidelines34.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 minutes after onset on a hypoglycaemic episode, will by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is >3.9
mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form. SMPG measurements ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic 
symptoms after the 60 minutes period shall trigger the reporting of a new hypoglycaemia episode 
and prompt the subject to fill out a new hypoglycaemic episode form until a succeeding 
measurement is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.
In case of several low SMPG values within the 60 minutes interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode 
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements. 
!
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No)
!
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if 
the subject experiences symptoms later during the episode.
!
Whether the subject was able to treat him/herself  
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!
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode 
should be reported, reflecting the most severe degree of hypoglycaemia.
!
Date, time and dose of last trial product, insulin and OAD administration prior to the 
episode 
!
Date and time of last main meal (not including snacks) prior to the episode
!
Whether the episode occurred in relation to physical activity
!
Change in any concomitant illness
!
Any sign of fever and/or other acute disease 
!
Whether the subject was asleep when the episode occurred
o
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration34. 
Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e., medical person or non-
medical person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e., oral carbohydrates, glucagon, IV glucose 
or other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e., physical activity, missed meal, diet change, 
medication error (i.e., overdose, mix-up between products, incorrect use of device), 
miscalculation of dose of antidiabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms38 (layman term used in the diary 
is specified in brackets if different from the protocol term)? 
!
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
!
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
!
General malaise: headache or malaise (feeling discomfort/unease)
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!
Other symptoms 
The investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes. The subject must be questioned whether any of the low values were severe, i.e., whether 
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported 
as a severe hypoglycaemic episode.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data36, 39.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.  
If the hypoglycaemic episode fulfils the criteria for a SAE, then an AE form and a safety 
information form (SIF) must also be filled in (see Section 12).
8.4.5
Vital signs (pulse)
Pulse (beats/minutes) will be recorded in a sitting position after resting for five minutes at the 
specified visits (see Section 2).
8.4.6
Electrocardiogram
An electrocardiogram (ECG) will be performed at the visits specified in the flow chart (see 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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8.4.7
Patient health questionnaire-9 
The patient health questionnaire-9 (PHQ-9)40 is a 9-item depression module of the patient health 
questionnaire, which is a self-administered diagnostic tool used for assessment of mental disorders. 
The questionnaires 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. The questionnaire takes approximately 10 minutes to complete. A PHQ-9 
score ≥ 15 at screening and randomisation excludes the subject from participation in the trial.
8.4.8
Columbia suicidal severity rating scale 
The Columbia suicidal severity rating scale (C-SSRS)41 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. 
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.
8.4.9
Breast and colon neoplasm 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.
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 8.2.4 and Section 12).
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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). 
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 for biochemistry must be collected at the specified visits (see 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 
clinical laboratory adverse event (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 missed a menstrual period. She should contact the site to come in for a urine 
pregnancy test. Urine pregnancy kits will be supplied by the central laboratory.
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Pregnancy testing will not be required for women not of childbearing potential (see Section 8.2.6).
Biochemistry
Blood samples for biochemistry must be collected at the specified visits (see 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.
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Haematology
Blood samples for haematology must be collected at the specified visits (see Section 2).
!
Haemoglobin
!
Haematocrit
!
Thrombocytes
!
Erythrocytes
!
Leucocytes
8.6
Other assessments
8.6.1
Trial product usage
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 and eCRF.
8.6.2
Food record 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.
The subject will be requested to record number of steps daily using a pedometer provided by Novo 
Nordisk. The subject will be asked to record the steps and minutes of physical activity daily in a 
paper physical activity diary which will be provided at each site visit.
8.6.3
Diabetes diary
Subjects will be provided with a new diabetes diary at each site visit. Investigator should instruct 
the subject how to fill in the diary. The diary will be collected at the following site visit and retained 
as at the site as source data. 
The diabetes diary must be reviewed by the investigator to ensure that AEs, or any overall change 
in health, including medical issues and concomitant medication are reported.  In addition the 
investigator must consider whether the reported values from the SMPG measurements should be 
reported as hypoglycaemic episodes (see section 8.4.4).
The investigator is only allowed to record the following data in the diary:
!
Subjects ID number
!
Site contact details
!
Date and time of the next visit 
!
Prescribed dose of trial product
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!
Doses and values from SMPG measurements from previous diary, if required for the insulin 
adjustment
!
Review signature
The investigator or delegated staff should transcribe data from the diary into the eCRF throughout 
the trial. Safety data from the diary must be handled according to timelines described in Figure 12–
1. If discrepancies are found in entries and clarification in the diary is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject.
The review of the diary must be documented either on the document and/or in the subject’s medical 
record. 
The diaries will contain the below information (filled in by the subject):
!
Date of first trial product injection
!
Date, time and value of SMPG measurements
!
Insulin dose
!
Hypoglycaemic episodes
!
Any medical issues
!
Any changes to concomitant medications(s)
!
Date, time and value of the 7-point profile SMPG at selected visits
8.6.4
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 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 pen-injector the first time, the pen should be primed 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.
8.6.5
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 8.4.3.2 and Section 12).
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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 
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. 
8.8
Additional safety assessments
8.8.1
Suspicion of acute pancreatitis
If pancreatitis is suspected, trial product must 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 must be reported as an AE requiring additional data collection (see Section 8.4.3.2 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 
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. 
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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 the trial 
product. Appropriate treatment and careful monitoring of the subject should be initiated. 
Furthermore, the subject should be encouraged to 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 must 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 must be reported as an AE requiring additional data collection (see Section 8.4.3.2 and 
Section 12).
If acute gallstone disease is confirmed, the trial product must be permanently discontinued. 
However, trial product can be restarted at the investigator´s discretion if cholelithiasis is ruled out or 
the gallbladder has been removed. Appropriate treatment and careful monitoring of the subject 
should be initiated. Furthermore, the subject should be encouraged to remain in the trial (see 
Section 8.1). 
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 8.4.3.2 and Section 12). 
Appropriate treatment and careful monitoring of the subject should be initiated. 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.
8.8.4
Hepatic event (suspicion of drug-induced liver injury)
Please consider discontinuing trial product if :
1) ALT or AST >5xUNL, or
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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.
In case of suspicion of DILI, the trial product must promptly 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 8.4.3.2 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. 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 of DILI is not supported.
8.8.5
Depression, suicidal ideation/behaviour
In case of depression or suicidal ideation/behaviour, 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 
8.4.3.2 and Section 12). 
Appropriate treatment and careful monitoring of the subject should be initiated as per local clinical 
practice. A subject should be referred to a MHP if he/she has: 
1. symptoms of moderate or more severe depression, 
2. or any suicidal behaviour, 
3. 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
Basal and bolus insulin and OADs are considered non-investigational medicinal products (NIMPs), hence will not be 
provided by Novo Nordisk. However, insulins and OADs will be reimbursed if required by the country’s regulatory 
authority or IRB/IEC.
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 1342, 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 
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subject that the direction for use is still available and that the subject is using the trial product 
correctly.
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 
(2°C-8°C/
36°F-46°F)
Do not freeze
Protect from 
light
Store below 30°C
Do not freeze
Protect from light
US:
Store at room 
temperature (59°F-
86°F)
or in refrigerator 
(36°F-46°F)
Canada:
30 days at room 
temperature (not 
above 30°) or in a 
refrigerator (2°C-
8°C)
Use within 1 
month
US:
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.
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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.
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
!
Blood glucose (BG) meter
!
BG auxiliaries including test strips, lancets, instructions and control solution.
Only needles provided by Novo Nordisk must be used for administration of trial product.
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10
Interactive 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 dates 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. In addition, the 
subjects will be stratified between the two arms.
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 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.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of an AE form 8.4.4
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.
Medication errors must be reported on an AE form and a specific event form for medication error
(see Section 8.4.3.1).
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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 safety of the trial product.
The below lists AEs that require completion of specific event forms in the eCRFs (see Section 
8.4.3.2):
!
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)
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 in 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.
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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 completed and 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 
document: 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 GCP 1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and ICH GCP 1, 
unless locally this is an obligation of the investigator.
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 
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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 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial. 
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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 an 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.
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.
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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 newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk electronically 
(e.g., in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e., congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
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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 
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 form 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 -fold overdose (
 mg daily) given for  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.
For the US, please refer to the current approved US Saxenda® prescribing information, for details 
concerning overdose.
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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 
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 a 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 = 4
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 effect of 
liraglutide 3.0 mg relative to placebo 56 weeks after randomisation, as adjunct to reduced caloric 
diet and increased physical activity, in all randomised subjects regardless of adherence to 
randomised treatment.
Efficacy estimand
In addition, an efficacy estimand (de jure) is quantifying the average effect of liraglutide 3.0 mg 
relative to placebo 56 weeks after randomisation, as adjunct to reduced caloric diet and increased 
physical activity, if all randomised subjects had adhered to the assigned treatment regimen for the 
entire planned duration of the trial.
Taxonomy of week 56 assessments being available or missing
A given assessment at week 56 may be available or missing. Table 17–1 describes the taxonomy for 
this. Note that 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).
Table 17–1
Taxonomy of week 56 assessments being available or missing
Assessment
at week 56
On randomised 
treatment 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
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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 and all confirmatory secondary endpoints will be tested in a hierarchical 
order.
The study design is a 1:1 randomisation, stratified by sulphonylurea (yes/no) with 400 subjects in 
total (200 subjects in each arm). The sample size calculation does not take stratification into 
account. 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.
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 assume 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. A 30% discontinuation is assumed based on findings in trial NN8022-1922. 
Based on findings from NN8022-1922, a difference in % weight change between liraglutide 3.0 mg 
and placebo of –4 (–6% vs. –2%, SD= 6) is assumed among completing subjects. Adjusting for 
30% discontinuation and using a mixture distribution, a difference of –2.8 is expected in the 
primary analysis. A sample size of 400 subjects (200 in each arm), gives a marginal power of 
99.5%.
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 49% in the liraglutide 3.0 mg arm and 31% in the placebo arm. With 400 subjects,
this results in a marginal power of 95.7%.
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Given these assumptions, the sample size of 400 subjects (200 in each arm), results in a combined 
power (marginal powers multiplied) of 95.2%.
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 power is 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.
Table 17–3
Assumptions, marginal power and effective power for each confirmatory 
endpoint in the hierarchical testing procedure given an anticipated number of 
400 randomised subjects
Assumed mean (±SD) / 
proportion for completers
liraglutide 3.0 mg      placebo
Expected mean 
(±SD) / proportion 
liraglutide 3.0 mg #
Expected 
difference #
Marginal 
power 
(%)
Effective 
power 
(%)
% weight change
–6.0 (±6.0)
–2.0 (±6.0)
–4.8 (±6.3)
–2.8
99.5
99.5
5% responders
57%
31%
49%
18
95.7
95.2
10% responders
25%
9%
20%
11
89.0
84.7
WC
–6.0 (±5.9)
–3.1 (±5.9)
–5.1 (±6.0)
–2.0
92.4
78.3
HbA1c
–1.4 (±1.0)
–0.5 (±1.0)
–1.1 (±1.1)
0.6
99.9
78.2
Fasting glucose 
–2.2 (±2.0)
–0.4 (±2.0)
–1.7 (±2.2)
1.3
99.9
78.1
sBP
–2.6 (±11.7)
–0.3 (±11.7)
–1.9 (±11.7)
–1.6
27.8
21.7
Physical score *
15.0 (±14.5)
10.6 (±14.5)
13.7 (±14.6)
3.1
55.9
12.1
Mental score *
12.0 (±18.0)
9.6 (±18.0)
11.3 (±18.0)
1.7
15.3
1.9
SD   standard deviation, WC   waist circumference, sBP   systolic blood pressure;
# Adjusted for 30% discontinuation; * IWQoL-Lite Clinical Trial Version;
Assumptions are based on findings from NN9068-3951.
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 principle.
!
The safety analysis set includes all randomised subjects exposed to at least one dose of 
randomised treatment.
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 tretment
Factor
Liraglutide 3.0 mg,  placebo
Sulphonylurea
Factor
Yes, no
Body weight (kg)
Covariate
Not applicable
BMI (kg/m2)
Factor
[27,30[, [30,35[, [35,40[, ≥40
Gender 
Factor
Male, female
Insulin type
Factor
Insulin detemir, other basal insulin
Insulin dose
Covariate
Not applicable
HbA1c
Factor
≤ 8.0%,  > 8.0%
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
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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 is below 0. 
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 was made at screening, 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 
exercise43.  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.
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-
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 
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 Sections 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
arm) 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 80224272 as seed number. 
Sensitivity analyses for the analysis 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 McEvoy44 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 including LAO-OT of body weight as covariate. 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 5644. Similarly, AT subjects 
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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 
are missing the weight measurement at week 56 (MD+MT) are assigned a weight of 0 
(zero).
!
A single imputation approach as done by Sacks45. 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 
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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 
discarded. The MMRM will be fitted using % weight change and the same factors and covariates 
(see 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 and sulphonylurea (yes/no) as the only factors.
17.3.4
Subgroup analyses for primary endpoints
For the effectiveness estimand, subgroup analyses will be done for the factors listed and categorised 
as in Table 17–4. For baseline weight and insulin dose, 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
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 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 are planned to be assessed at week 56 and will be analysed 
using the same MI approach as used for the primary endpoints and to address the effectiveness 
estimand. The statistical models for continuous endpoints will be ANCOVA with factors and 
covariates listed in Table 17–4 with baseline body weight replaced by baseline measurement of 
endpoint to be analysed. The statistical model for 10% responders will be analysed using logistic 
regression in the same way as for 5% responders. 
Sensitivity analyses will be carried out for all confirmatory secondary endpoints. 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 using MMRM as 
described for the primary endpoints. 
17.4.1.1
Description of the 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 model to address the effectiveness 
estimand for primary and confirmatory secondary endpoints
MI  Multiple Imputation;
#   See Table 17–5
Test 
order
Endpoint
Endpoint
type
Statistical 
model
MI 
approach 
Sensitivity analyses #
            Primary endpoint
1
Change in body weight (%) from 
baseline to week 56
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Sacks
Tipping point
Unadjusted 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
Change from baseline to week 56 
in waist circumference (cm) 
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
5
Change from baseline to week 56 
in HbA1c (%)
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
6
Change from baseline to week 56 
in fasting glucose (%)
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 from baseline to week 56 
in impact of Weight on Quality of 
Life-Lite (IWQoL-Lite for CT), 
physical functioning score
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
9
Change from baseline to week 56 
in impact of Weight on Quality of 
Life-Lite (IWQoL-Lite for CT), 
mental/emotional function score
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
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17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
Supportive secondary endpoints are listed in Section 4.2.2.2.
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 
secondary endpoints.
The endpoint mean daytime glucose value will be calculated from the 7-point SMPG profile as area 
under the curve (AUC) divided by length of time-interval. AUC will be calculated using the linear 
trapezoidal method. Missing points in the 7-point SMPG profile are ignored for the calculation.
The statistical model for continuous endpoints will be ANCOVA with factors and 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.
17.4.2.2
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 and hypoglycaemic episodes 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.
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.
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.
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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.
Hypoglycaemic episodes 
All hypoglycaemic episodes will be summarised in terms of N, %, E, rate as on drug (PYE) and in 
trial (PYO) and using same ascertainment window of 14 days as for AEs.
Classification of Hypoglycaemia:
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs during on drug time intervals.
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–2) and the ADA classification of hypoglycaemia (see Figure 17–3).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)20Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–2) in addition to the ADA 
classification:
Severe hypoglycaemia according to the ADA classification11.
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma glucose 
value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma glucose 
value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to the 
ADA classification11 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value <3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
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Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification11 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or 
without symptoms consistent with hypoglycaemia. 
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
Novo Nordisk classification of hypoglycaemia
ADA classification11 of hypoglycaemia
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may 
not be available during an event, but neurological recovery following the return of plasma 
glucose to normal is considered sufficient evidence that the event was induced by a low plasma 
glucose concentration.
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are 
not accompanied by a plasma glucose determination but that was presumably caused by a 
plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
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Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–3
ADA classification of hypoglycaemia
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. 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 in trial observation period similar as in the primary analysis for the 
primary estimand but using the safety analysis.
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.
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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.
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. 
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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.
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 GCP1, applicable regulatory requirements and 
in accordance with the Declaration of Helsinki2.
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.
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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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 8.6.5). 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 present46.  If cholelithiasis is suspected, 
treatment should be discontinued and gallbladder examination and appropriate clinical follow-up 
should be initiated.
Hypoglycaemic episodes 
Overall, the incidence of hypoglycaemia with liraglutide is low. However, a higher incidence and 
severity was seen in the clinical development programme, when liraglutide was combined with 
other anti-glycaemic agents. Subjects blood glucose parameters will be monitored prior to starting 
liraglutide 3.0 mg and during treatment To minimise the risk of hypoglycemia, insulin dose will be 
reduced by 15-20% for subjects with HbA1c ≤ 8% at randomisation. Adjustment of insulin dose 
may be initiated one week after randomisation; however, in the first five weeks of the trial, the basal 
insulin dose should not exceed the pre-trial dose and bolus insulin should not be initiated, unless 
deemed necessary by investigator to control unacceptable hyperglycaemia. In addition, the dose of 
sulphonylurea may be reduced by 50% at investigator’s discretion in patients using this OAD since 
hypoglycaemic events are more frequent when combining liraglutide with sulphonylurea than with 
other OADs.
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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.
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 
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 with a regimen anticipated to be better than or equal to 
the weight management they receive at the time of entry into the trial. Results from the clinical 
development programme demonstrated that liraglutide 3.0 mg, as an adjunct to a reduced-calorie 
diet and increased physical activity, was effective for weight loss in subjects with overweight or 
obesity and T2DM treated with 0-3 OADs (metformin, glitazone, sulphonylurea). The anticipated 
lower insulin requirement in the present trial with liraglutide 3.0 mg vs. placebo is expected to 
further amplify weight loss. Even a modest weight loss may improve glycaemic control and 
decreases the risk of hypertension and premature cardiovascular death in patients with obesity47-49. 
Finally, 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. 
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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 GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. This includes the use of an impartial witness where required 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.
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.
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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 clinical trial report
(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.
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 for all 
visits including the 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.
19.3
Protocol compliance for Mexico
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2. 
The above will include the following responsibilities for the head of the Institution/Health Care 
Establishment, Ethics, Research and, when applicable, Biosafety Committees and sponsor within 
their scope of responsibility: a) Investigation follow-up b) Damages to health arising from the 
investigation development; as well as those arising from interruption or advanced suspension of 
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treatment due to non-attributable reasons to the Subject; c) Timely compliance of the terms in 
which the authorization of a research for health in human beings had been issued; d) To present in a 
timely manner the information required by the Health Authority.
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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
!
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
For sites outside the US:
All investigators outside of the US will not sign FDA form 1572
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 GCP1, 
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).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted 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 publications50. 
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 Disclosure29.
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.
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In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors50 (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.
For Germany: Novo Nordisk accepts liability in accordance with: German Drug Law dated 24 
August 1976 in the version published on 12 Dec 2005 (BGBI. I S. 3394), last amended by Article 3 
of the Law of 04 Apr 2016 (BGBI. I S. 569)
For Mexico: Novo Nordisk carries product liability for its products assumed under the special laws, 
acts/and/or guidelines for conducting trials in any country, including those applicable provisions on 
the Mexican United States. If the subject feels that something goes wrong during the course of this 
trial, the subject should contact the trial staff in the first instance. If during their participation in the 
trial the subject experiences a disease or injury that, according to the trial doctor and the sponsor, is 
directly caused by the trial medication and/or a trial procedure that otherwise would not have been 
part of his/her regular care, the subject will receive from the Institution or Medical Care 
Establishment and free of charge, the appropriate medical treatment as required. In this case, the 
costs resulting from such treatment as well as the costs of any indemnification established by law 
will be covered by the trial sponsor in accordance with the terms provided by all applicable 
regulations; even if the subject discontinues his/her participation in the trial by his own will or by a 
decision from the investigator. By signing the informed consent, the subject will not renounce to 
any compensation or indemnification he/she may be entitled to by law, nor will he/she will incur 
any additional expense as a result of his/her participation in the trial; any additional expense 
resulting from the subject’s participation in the trial will be covered by the trial sponsor.
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38.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
39.
Rewers MJ, Pillay K, de Beaufort C, Craig ME, Hanas R, Acerini CL, et al. ISPAD Clinical 
Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in 
children and adolescents with diabetes. Pediatr Diabetes. 2014;15 Suppl 20:102-14.
40.
Kroenke K, Spitzer RL, Williams JBW. The PHQ-9 - Validity of a brief depression severity 
measure. Journal of General Internal Medicine. 2001;16(9):606-13.
41.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-43.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
UTN: U1111-1177-4903
Status:
Final
EudraCT no.: 2015-005619-33
Page:
123 of 123
42.
European Medicines Agency. Ethical considerations for clinical trials on medicinal products 
with the paediatric population. Recommendations of the Ad hoc group for the development 
of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the 
conduct of clinical trials on medicinal products for human use. 2008.
43.
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat. 2013;23(6):1352-71.
44.
McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6.
45.
Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of 
weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J 
Med. 2009;360(9):859-73.
46.
Erlinger S. Gallstones in obesity and weight loss. Eur J Gastroenterol Hepatol. 
2000;12(12):1347-52.
47.
Pi-Sunyer FX. Weight loss and mortality in type 2 diabetes. Diabetes Care. 
2000;23(10):1451-2.
48.
Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects of modest 
weight reduction. Obes Res. 2000;8(3):270-8.
49.
Kritchevsky SB, Beavers KM, Miller ME, Shea MK, Houston DK, Kitzman DW, et al. 
Intentional weight loss and all-cause mortality: a meta-analysis of randomized clinical trials. 
PLoS One. 2015;10(3):e0121993.
50.
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81.
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-005619-33
Page:
1 of 6
Appendix A
NN8022-4272
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: NN8022-4272
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-005619-33
Page:
2 of 6
Table of Contents
Page
Table of Contents .............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin monitoring...............................................................................................................................4
2.1
Calcitonin ≥ 100 ng/L....................................................................................................................4
2.2
Calcitonin ≥ 50 and < 100 ng/L.....................................................................................................4
2.3
Calcitonin ≥ 10 and <50 ng/L........................................................................................................5
3
References..................................................................................................................................................6
CONFIDENTIAL


Liraglutide
CONFIDENTIAL
Date:
14 September 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-005619-33
Page:
3 of 6
1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with 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: NN8022-4272
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-005619-33
Page:
4 of 6
2
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).
2.1
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.
2.2
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: NN8022-4272
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-005619-33
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.
2.3
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: NN8022-4272
Version:
4.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2015-005619-33
Page:
6 of 6
3
References
1.
Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive value of 
serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 
5817 consecutive patients with thyroid nodules. 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: NN8022-4272
Clinical Trial Report
Appendix 16.1.1
)HEUXDU\

)LQDO
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
2.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
1 of 4
Protocol Amendment
no 1
to Protocol, final version 4.0
dated 14 September 2016
Trial ID: NN8022-4272
SCALETM Insulin
Effect and safety of liraglutide 3.0 mg in subjects with overweight or obesity and type 2 
diabetes mellitus treated with basal insulin
Trial phase: 3b
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
2.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
2 of 4
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Section 2 Flow chart ......................................................................................................................3
2.2
Section 5.3.2.2 Treatment with insulin throughout the trial ..........................................................3
2.3
Section 8.2.5 Concomitant medication..........................................................................................3
2.4
Section 8.3.9 Insulin dose..............................................................................................................3
2.5
Section 8.5.2 Laboratory assessments for safety ...........................................................................4
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
2.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
Rationale for the changes:
!
Addition of bicarbonate as a part of the biochemistry laboratory assessment. The FDA has 
requested that bicarbonate is added as a routine laboratory test in trials where sodium-glucose 
cotransporter-2 (SGLT2) inhibitors are used as background medication, because SGLT2-
inhibitors have been associated with a risk for metabolic acidosis. Hence, serum bicarbonate
assay has been included to collect additional safety information in alignment with other Novo 
Nordisk trials where trial product is add-on to an SGLT2 inhibitor. There is no safety risk for 
those subjects who do not have the bicarbonate assay performed during their treatment.
!
Inconsistent wording in reporting of insulin dose and transcription of insulin dose to eCRF.
!
Discrepancy regarding the time period of an eye examination performed prior to randomisation. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 2 Flow chart
3Only if not available within last 90 days before screeningrandomisation
2.2
Section 5.3.2.2 Treatment with insulin throughout the trial
The insulin dose adjustments recorded in the diabetes diary, must be entered in the electronic case 
report form (eCRF). 
2.3
Section 8.2.5 Concomitant medication
The products described as NIMP (see Section 5.3.2) are also recorded as concomitant medication in 
the eCRF. However the adjustments of insulin doses performed during the trial will be recorded in 
the designated form diabetes diary and these must be assessed by the investigator.
2.4
Section 8.3.9 Insulin dose
Subjects will be instructed in how to record the insulin use in the provided diabetes diary and the
investigator should review the subject’s insulin dose. as specified in Section 8.1. From visit 2 and 
until but not including the follow-up visit, the investigator must record the subject’s basal and 
bolus (if applicable) daily injected doses, respectively, prior to each scheduled visit in the eCRF. 
Results of the subject’s SMPG measurements should be noted in the diabetes diary and total daily 
injected dose of basal/bolus insulin prior to each contact will be transcribed into the eCRF and 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
14 November 2016
Novo Nordisk
Trial ID: NN8022-4272
Version:
2.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
4 of 4
based on these, dose adjustment guidance will be provided. All adjustments of insulin dose level 
will be captured in the eCRF. From visit 2 and until follow-up, the investigator should record the 
subject’s total daily injected dose of insulin (basal/bolus) prior to each visit in the eCRF.
2.5
Section 8.5.2 Laboratory assessments for safety
Biochemistry
Blood samples for biochemistry must be collected at the specified visits (see Section 2).
!
Creatinine
!
Urea (blood urea nitrogen)
!
Uric acid
!
Alanine aminotransaminase (ALT)
!
Aspartate aminotransferase (AST)
!
Alkaline phosphatase (ALP)
!
Albumin
!
Amylase
!
Bicarbonate
!
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.
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 March 2017
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
1 of 5
Protocol Amendment
no 2
to Protocol, final version 6.0
dated 15 November 2016
Trial ID: NN8022-4272
SCALETM Insulin
Effect and safety of liraglutide 3.0 mg in subjects with overweight or obesity and type 2 
diabetes mellitus treated with basal insulin
Trial phase: 3b
Applicable to all countries
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 March 2017
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
2 of 5
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Section 1 Summary........................................................................................................................3
2.2
Section 4.1 Objectives ...................................................................................................................4
2.3
Section 5.1 Type of trial ................................................................................................................5
2.4
Section 5.3.2.1 Oral antidiabetic medication.................................................................................5
2.5
Section 5.3.2.2 Treatment with insulin throughout the trial ..........................................................5
2.6
Section 6.2 Inclusion criteria .........................................................................................................5
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 March 2017
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
3 of 5
1
Introduction including rationale for the protocol amendment
Rationale for the changes:
!
Inclusion criterion 3 updated to allow for two additional oral antidiabetic drug (OAD) classes 
(alpha glucosidase inhibitors and glinides) which are currently not permitted.  There are no 
medical reasons for not including them.
!
Inclusion criterion 4 updated to allow subjects to continue on their standard insulin treatment.
Currently the inclusion criterion states that subjects should be treated with any basal insulin 
according to its label. However, some subjects with type 2 diabetes mellitus and obesity are 
using insulin glargine twice daily (BID), due to the high dose based on the subjects’ high body 
weight. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 1 Summary
Objectives and endpoints
Primary objective
To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on weight loss effectiveness in subjects with overweight or obesity and 
type 2 diabetes mellitus (T2DM) treated with a basal insulin and up to 2 oral antidiabetic (OAD) 
medications (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or 
sulphonylurea).
Secondary objectives
To establish the effects of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on relevant efficacy endpoints in subjects with overweight or obesity 
and T2DM treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor, 
alpha glucosidase inhibitor, glinide or sulphonylurea)
To establish the safety and tolerability of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-
calorie diet and increased physical activity, in subjects with overweight or obesity and T2DM 
treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor, alpha 
glucosidase inhibitor, glinide or sulphonylurea)
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 March 2017
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
4 of 5
Trial design
This is a 56-week randomised, double-blind, multi-national, multi-centre, placebo-controlled and 
two-armed trial in subjects with overweight or obesity and T2DM treated with basal insulin and up 
to two OADs (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or 
sulphonylurea).
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. Diagnosed with type 2 diabetes mellitus
3. Treatment with up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase 
inhibitor, glinide or sulphonylurea),
4. Stable treatment with basal insulin according to its label (no requirement of minimum or 
maximum dose) for at least 90 days prior to screening, as judged by the investigator
5. HbA1c 6.0-10.0% (both inclusive)
6. BMI ≥ 27 kg/m2
7. Age ≥ 18 years at the time of signing informed consent
2.2
Section 4.1 Objectives
Primary objective
To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on weight loss effectiveness in subjects with overweight or obesity and 
type 2 diabetes mellitus (T2DM) treated with a basal insulin and up to 2 oral antidiabetic (OAD) 
medications (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or 
sulphonylurea).
Secondary objectives
!
To establish the effects of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie 
diet and increased physical activity, on relevant efficacy endpoints in subjects with 
overweight or obesity and T2DM treated with basal insulin and up to 2 OADs (metformin, 
glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or sulphonylurea)
!
To establish the safety and tolerability of liraglutide 3.0 mg vs. placebo, as an adjunct to a 
reduced-calorie diet and increased physical activity, in subjects with overweight or obesity 
and T2DM treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 
inhibitor, alpha glucosidase inhibitor, glinide or sulphonylurea)
CONFIDENTIAL


Protocol Amendment no. 2
CONFIDENTIAL
Date:
15 March 2017
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
5 of 5
2.3
Section 5.1 Type of trial
This is a 56-week randomised, double-blind, multi-national, multi-centre, placebo-controlled and 
two-armed trial in subjects with overweight or obesity and T2DM treated with basal insulin and up 
to 2 OADs (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or 
sulphonylurea).
2.4
Section 5.3.2.1 Oral antidiabetic medication
Any approved and marketed metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, 
glinide or sulphonylurea product or combination products are allowed. Subjects treated with 
dipeptidyl peptidase-IV (DPP-IV) inhibitors are excluded from participating in the trial since DPP-
IV inhibitors and GLP-1 receptor agonists should not be combined.
2.5
Section 5.3.2.2 Treatment with insulin throughout the trial
Any approved and marketed basal insulin (NPH insulin or insulin analogue) is allowed, at any dose, 
if used according to its prescribing information at screening. Once-daily or twice-daily dosing is 
allowed, according to dosing schedule at baseline.
2.6
Section 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. Diagnosed with type 2 diabetes mellitus
3. Treatment with up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase 
inhibitor, glinide or sulphonylurea)
4. Stable treatment, at the discretion of the investigator, with any basal insulin according to its 
label (no requirement of minimum or maximum dose) for at least 90 days prior to screening
5. HbA1c 6.0-10.0% (both inclusive)
6. BMI ≥ 27 kg/m2
7. Age ≥ 18 years at the time of signing informed consent
8. Maximum 5 kg self-reported weight loss within the past 90 days since screening
9. Increased physical activity is considered to be safe as judged by the investigator
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
19 February 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
1 of 8
Protocol Amendment
no 3
to Protocol, version 4.0
dated 14 September 2016
Trial ID: NN8022-4272
SCALETM Insulin 
Effect and safety of liraglutide 3.0 mg in subjects with overweight or obesity and type 2 
diabetes mellitus treated with basal insulin
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 3
CONFIDENTIAL
Date:
19 February 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
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 8.4.4 Hypoglycaemic episodes ......................................................................................6
2.6
Section 8.5.2 Laboratory assessments for safety ........................................................................6
2.7
Section 17.1 Sample size calculation .........................................................................................7
2.8
Section 17.4.1.1 Description of the testing procedure to address the effectiveness estimand 
for primary and confirmatory secondary endpoints ....................................................................7
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
19 February 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
3 of 8
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. 
!
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.
2
Changes
2.1
Section 1 Key secondary endpoints 
Change from baseline to week 56 in:
!
Waist circumference
!
Systolic blood pressure 
!
HbA1c
!
Fasting plasma glucose
!
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 physical function domain (5-items) score
!
IWQoL-Lite for CT, mental/emotional functioning score
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Protocol Amendment no 3
UTN: U1111-1177-4903
Date:
19 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN8022-4272
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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
EFFICACY
Vital signs (blood pressure) 
8.3.4 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
SAFETY
Adverse Events 8.4.3 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
Hypoglycaemic episodes 8.4.4
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 3
CONFIDENTIAL
Date:
19 February 2018
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Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
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2.3
Section 4.2.2.1 Confirmatory secondary endpoints
Confirmatory secondary endpoints addressing the secondary efficacy objective:
!
Proportion of subjects losing more than 10% of baseline body weight at week 56
Change from baseline to week 56 in:
!
Waist circumference
!
Systolic blood pressure
!
HbA1c
!
Fasting plasma glucose
!
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 function domain (5-items) score
!
IWQoL-Lite for CT, physical functioning score
!
IWQol-Lite for CT, mental/emotional function score
2.4
Section 4.2.2.2 Supportive secondary endpoints
Supportive secondary efficacy endpoints
Change from baseline to week 56 in:
!
Total daily basal insulin dose (% of pre-trial dose in U)
!
Total daily basal insulin dose (U/kg)
!
Total daily insulin dose (U)
!
Total daily insulin dose (U/kg)
!
7-point self-measured plasma glucose (SMPG) profile, mean daytime glucose value
!
Systolic blood pressure
!
Diastolic blood pressure
!
Lipids (total cholesterol [TC], low density lipoprotein cholesterol [LDL cholesterol], high 
density lipoprotein cholesterol [HDL cholesterol], very low density lipoprotein cholesterol 
[VLDL cholesterol], triglycerides [TG], free fatty acids [FFA])
!
Short Form-36 v2.0 acute (SF-36) (physical component summary (PCS), mental component 
summary (MCS) and subdomains)
!
SF-36 v.2.0 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)
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
19 February 2018
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Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
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o
mental component summary (MCS)
!
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): 
!
HbA1c <7% and weight loss ≥5%
!
HbA1c <7%, weight loss ≥5% and no documented symptomatic hypoglycaemia
!
≥ 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 8.4.4 Hypoglycaemic episodes 
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or, 
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms 
should be reported in the diary according to the instructions below throughout the trial from visit 1
2 to visit 25. 
2.6
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
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Protocol Amendment no 3
CONFIDENTIAL
Date:
19 February 2018
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Trial ID: NN8022-4272
Version:
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UTN: U1111-1177-4903
Status:
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EudraCT No.: 2015-005619-33
Page:
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2.7
Section 17.1 Sample size calculation
Table 17-3 Assumptions, marginal power and effective power for each confirmatory 
endpoints in the hierarchical testing procedure given an anticipated number of 400 
randomised subjects
Assumed mean (±SD) / 
proportion for completers
liraglutide 3.0 mg      placebo
Expected mean 
(±SD) / proportion 
liraglutide 3.0 mg #
Expected 
difference #
Marginal 
power 
(%)
Effective 
power 
(%)
% weight change
–6.0 (±6.0)
–2.0 (±6.0)
–4.8 (±6.3)
–2.8
99.5
99.5
5% responders
57%
31%
49%
18
95.7
95.2
10% responders
25%
9%
20%
11
89.0
84.7
WC
–6.0 (±5.9)
–3.1 (±5.9)
–5.1 (±6.0)
–2.0
92.4
78.3
HbA1c
–1.4 (±1.0)
–0.5 (±1.0)
–1.1 (±1.1)
0.6
99.9
78.2
Fasting glucose 
–2.2 (±2.0)
–0.4 (±2.0)
–1.7 (±2.2)
1.3
99.9
78.1
sBP
–2.6 (±11.7)
–0.3 (±11.7)
–1.9 (±11.7)
–1.6
27.8
21.7
SF-36 PF
3.7 (±8.0)
2.4 (±8.0)
3.3 (±8.0)
0.9
20.5
16.0
IWQoL-Lite for 
CT PF *
15.0 (±14.5)
10.6 (±14.5)
13.7 (±14.6)
3.1
55.9
8.9
Mental score *
12.0 (±18.0)
9.6 (±18.0)
11.3 (±18.0)
1.7
15.3
1.9
SD   standard deviation, WC   waist circumference, sBP   systolic blood pressure; SF-36 PF   Short Form-36 v2.0 acute 
physical functioning score, IWQoL-Lite for CT PF   Physical function domain (5 items) score
# Adjusted for 30% discontinuation; * IWQoL-Lite Clinical Trial Version;
Assumptions are based on findings from NN9068-3951 NN8022-1922
2.8
Section 17.4.1.1 Description of the testing procedure to address the effectiveness 
estimand for primary and confirmatory secondary endpoints
Table 17-6 Hierarchical order and type of statistical model to address the effectiveness 
estimand 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)
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
8
Change from baseline to week 56 
in impact of Weight on Quality of 
Life-Lite (IWQoL-Lite for CT), 
physical functioning domain (5-
items) score
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
9
Change from baseline to week 56 
in impact of Weight on Quality of 
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
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Protocol Amendment no 3
CONFIDENTIAL
Date:
19 February 2018
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Trial ID: NN8022-4272
Version:
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UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
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Life Lite (IWQoL Lite for CT), 
mental/emotional function score
Tipping point
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02963922  
Sponsor trial ID: 
NN8022-4272 
Official title of study: 
Effect and safety of liraglutide 3.0 mg in subjects with 
overweight or obesity and type 2 diabetes mellitus treated with 
basal insulin 
Document date: 
18 February 2019 
 


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
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Version:
Status:
Liraglutide 3.0 mg
Trial ID: NN8022-4272
Clinical Trial Report
Appendix 16.1.9
)HEUXDU\

)LQDO
16.1.9 Documentation of statistical methods
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Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
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Date:
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Trial ID: NN8022-4272
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Statistical Analysis Plan
Trial ID: NN8022-4272
SCALE™ Insulin
Effect and safety of liraglutide 3.0 mg in subjects with overweight or 
obesity and type 2 diabetes mellitus treated with basal insulin
Author:
Name:
Department:
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.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
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Date:
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Trial ID: NN8022-4272
Version:
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EudraCT No.: 2015-005619-33
Page:
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Table of contentsPage
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.2
Scope of the statistical analysis plan..........................................................................................6
2
Statistical considerations .....................................................................................................................6
2.1
Sample size calculation .............................................................................................................8
2.2
Definition of analysis sets........................................................................................................10
2.3.1.1
Statistical model for the primary endpoint % weight change .............11
2.3.1.2
Statistical model for the primary endpoint 5% responders.................11
2.3.2
Handling of missing values for the effectiveness estimand .....................................12
2.3.2.1
Handling of missing values at baseline .............................................12
2.3.2.2
Handling of missing values at week 56.............................................12
2.3.3
Analysis method addressing the efficacy estimand for the primary endpoints..........14
2.3.4
Subgroup analyses for primary endpoints ...............................................................15
2.3.5
Exploratory analysis of change in body weight.......................................................15
2.4
Secondary endpoints ...............................................................................................................17
2.4.1
Confirmatory secondary endpoints.........................................................................17
2.4.2
Description of the testing procedure to address the effectiveness estimand for 
primary and confirmatory secondary endpoints ......................................................18
2.4.3
Supportive secondary endpoints .............................................................................20
2.4.3.1
Efficacy endpoints............................................................................20
2.4.3.2
Safety endpoints...............................................................................20
3
Changes to the statistical analyses planned in the protocol..............................................................25
3.1
Deviation from analyses as described in the protocol...............................................................25
3.2
Additional analyses not described in the protocol ....................................................................27
4
References ..........................................................................................................................................28
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Statistical Analysis Plan
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Date:
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Trial ID: NN8022-4272
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List of abbreviations
AD
available drop-out
AE
adverse event
ANCOVA
analysis of covariance
AT
available on treatment
BMI
body mass index
DBL
Database Lock
ECG
Electrocardiogram
FAS
full analysis set
HbA1c
glycosylated haemoglobin
HDL
high-density lipoprotein
IBT
Intensive behaviour therapy
ITT
intention- to-treat
IWQoL-Lite for CT
Impact of Weight on Quality of Life-Lite for Clinical Trials
LAO
last available observation
LAO-OT
last available observation (of body weight) on randomised treatment 
LLOQ
lower limit of quantification
MCS
mental component summary
MD
missing drop-out
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Multiple Imputation
MMRM
Mixed model for repeated measurements
MT
missing on treatment
OR
odds ratio 
PCS
physical component summary
PYE
patient years of exposure
PYO
patient years of observation
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviations
SF-36
short form-36 version 2.0 acute
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Statistical Analysis Plan
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Date:
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UNL
upper normal limit
UTN
Universal Trial Number
wANCOVA
weighted analysis of covariance  
WC
waist circumference
WRSS
Weight related sign and symptom measure
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Statistical Analysis Plan
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Date:
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Trial ID: NN8022-4272
Version:
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1
Introduction
1.1
Trial information
Trial design
This is a 56-week randomised, double-blind, multi-national, multi-centre, placebo-controlled and 
two-armed trial in subjects with overweight or obesity and T2DM treated with basal insulin and up 
to two OADs (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or 
sulphonylurea).
Subjects will be randomised in a 1:1 manner to receive either liraglutide 3.0 mg or placebo, as an 
adjunct to reduced-calorie diet and increased physical activity delivered as part of a comprehensive 
lifestyle intervention program (in this document referred to as Intensive Behaviour Therapy [IBT]). 
Subjects treated with sulphonylurea will be stratified between the two arms.
It is recommended that the dose of basal insulin is reduced by 15-20 %  for all subjects with HbA1c
≤ 8 % (at the investigator’s discretion) at randomisation, followed by weekly adjustment of insulin 
dose with the aim to achieve same pre-breakfast meal target plasma glucose as well as similar 
glycaemic control in the two treatment arms. Insulin dose should not be reduced for subjects with 
HbA1c > 8% to avoid unacceptable deterioration in glycaemic control.
Primary objective
To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on weight loss effectiveness in subjects with overweight or obesity and 
type 2 diabetes mellitus (T2DM) treated with a basal insulin and up to 2 oral antidiabetic (OAD) 
medications (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or 
sulphonylurea).
Secondary objectives
To establish the effects of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and 
increased physical activity, on relevant efficacy endpoints in subjects with overweight or obesity 
and T2DM treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor, 
alpha glucosidase inhibitor, glinide or sulphonylurea)
To establish the safety and tolerability of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-
calorie diet and increased physical activity, in subjects with overweight or obesity and T2DM 
treated with basal insulin and up to 2 OADs (metformin, glitazone, SGLT-2 inhibitor, alpha 
glucosidase inhibitor, glinide or sulphonylurea)
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Statistical Analysis Plan
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Trial ID: NN8022-4272
Version:
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1.2
Scope of the statistical analysis plan
This SAP is based on the protocol “SCALE™ Insulin. Effect and safety of liraglutide 3.0 mg in 
subjects with overweight or obesity and type 2 diabetes mellitus treated with basal insulin”, version 
4, and amendments 1, 2 and 3.
2
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 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
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Statistical Analysis Plan
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1 if  % weight change ≤ –5%
5% responder = 
0 if  % weight change > –5%
Definition of Estimands
Effectiveness estimand
The primary estimand is an effectiveness estimand (de facto) quantifying the average effect of 
liraglutide 3.0mg relative to placebo 56 weeks after randomisation, as adjunct to reduced caloric 
diet and increased physical activity, in all randomised subjects regardless of adherence to 
randomised treatment.
Efficacy estimand
In addition, an efficacy estimand (de jure) is quantifying the average effect of liraglutide 3.0 mg 
relative to placebo 56 weeks after randomisation, as adjunct to reduced caloric diet and increased 
physical activity, if all randomised subjects had adhered to the assigned treatment regimen for the 
entire planned duration of the trial.
Taxonomy of week 56 assessments being available or missing
A given assessment at week 56 may be available or missing. Table 2–1describes the taxonomy for 
this. Note that 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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Statistical Analysis Plan
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Table 2–1
Taxonomy of week 56 assessments being available or missing
Assessment
at week 56
On randomised 
treatment 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
2.1
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 and all confirmatory secondary endpoints will be tested in a hierarchical 
order.
The study design is a 1:1 randomisation, stratified by sulphonylurea (yes/no) with 400 subjects in 
total (200 subjects in each arm). The sample size calculation does not take stratification into 
account. Please see Table 2–2for general specifications on sample size and power calculation.
Table 2–2
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
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In the following paragraphs treatment differences and standard deviations (SD) are given without 
units.
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 assume 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. A 30% discontinuation is assumed based on findings in trial NN8022-1922. 
Based on findings from NN8022-1922, a difference in % weight change between liraglutide 3.0 mg 
and placebo of –4 (–6% vs. –2%, SD= 6) is assumed among completing subjects. Adjusting for 
30% discontinuation and using a mixture distribution, a difference of –2.8 is expected in the 
primary analysis. A sample size of 400 subjects (200 in each arm), gives a marginal power of 
99.5%.
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 49% in the liraglutide 3.0 mg arm and 31% in the placebo arm. With 400 subjects, 
this results in a marginal power of 95.7%.
Given these assumptions, the sample size of 400 subjects (200 in each arm), results in a combined 
power (marginal powers multiplied) of 95.2%.
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 and 
in the protocol). 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 2–3with underlying assumptions, marginal power and effective power. The effective power 
is 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 
CONFIDENTIAL


Statistical Analysis Plan
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Trial ID: NN8022-4272
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Table 2–3.
Table 2–3
Assumptions, marginal power and effective power for each confirmatory 
endpoint in the hierarchical testing procedure given an anticipated number of 400 
randomised subjects
Assumed mean (±SD) / 
proportion for completers
liraglutide 3.0 mg      placebo
Expected mean 
(±SD) / proportion 
liraglutide 3.0 mg #
Expected 
difference #
Marginal 
power 
(%)
Effective 
power 
(%)
% weight change
–6.0 (±6.0)
–2.0 (±6.0)
–4.8 (±6.3)
–2.8
99.5
99.5
5% responders
57%
31%
49%
18
95.7
95.2
10% responders
25%
9%
20%
11
89.0
84.7
WC
–6.0 (±5.9)
–3.1 (±5.9)
–5.1 (±6.0)
–2.0
92.4
78.3
HbA1c
–1.4 (±1.0)
–0.5 (±1.0)
–1.1 (±1.1)
0.6
99.9
78.2
Fasting glucose 
–2.2 (±2.0)
–0.4 (±2.0)
–1.7 (±2.2)
1.3
99.9
78.1
SF-36 PF
3.7 (±8.0)
2.4(±8.0)
3.3 (±8.0)
0.9
20.5
16.0
IWQoL-Lite for 
CT PF *
15.0 (±14.5)
10.6 (±14.5)
13.7 (±14.6)
3.1
55.9
8.9
SD   standard deviation, WC   waist circumference, SF-36   PF Short Form-36 v2.0 acute physical functioning score, 
IWQoL-Lite for CT PF   Physical function domain (5 items) score
# Adjusted for 30% discontinuation; * IWQoL-Lite Clinical Trial Version;
Assumptions are based on findings from NN8022-1922.
2.2
Definition of analysis sets
Two analysis sets are defined:
!
The full analysis set (FAS) includes all randomised subjects according to the intention-to-
treat principle.
!
The safety analysis set includes all randomised subjects exposed to at least one dose of
randomised treatment.
Any observation excluded from the analysis database will be documented before database lock with 
the reason for exclusion provided.
2.3
Primary endpoints
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The two primary endpoints are as mentioned previously (see start of Section 2)
!
% weight change
!
5% responders
2.3.1
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.
2.3.1.1
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 2–4.
Table 2–4
Factors and covariates for the analysis of the primary endpoints
Factors and covariates at baseline
Type
Categories
Randomised tretment
Factor
Liraglutide 3.0 mg,  placebo
Body weight (kg)
Covariate
Not applicable
BMI (kg/m2)
Factor
[27,30[, [30,35[, [35,40[, ≥40
Gender 
Factor
Male, female
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 is below 0. 
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2.3.1.2
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 2–4. 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.
2.3.2
Handling of missing values for the effectiveness estimand
2.3.2.1
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 was made at screening, the screening value will be used as the 
baseline value.
2.3.2.2
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 
exercise1. 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 Sections 2.3.1.1and 2.3.1.2, 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 2–4(except randomised treatment arm) 
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 80224272 as seed number. 
Sensitivity analyses for the analysis 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 McEvoy2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 2–4(except randomised
treatment arm) with no interactions and including LAO-OT of body weight as 
covariate.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)
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to account for the subjects not returning for assessments at week 5644. 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 are missing the weight measurement at week 56 (MD+MT) are 
assigned a weight of 0 (zero).
!
A single imputation approach as done by Sacks3. 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 2–1and Table 2–5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.
In addition, a model resembling the primary analysis models using the same imputation method 
(jump to reference) including treatment, BMI groups, sex, sulphonylurea(Yes, No), insulin type 
(Insulin detemir, Other basal insulin) and HbA1c groups (<=8%, >8%) as factors and baseline body 
weight in kg and total daily basal insulin dose in U as covariates will be conducted. The imputation 
model (step 1) will be same as for the primary approach.
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For the binary primary endpoint, the risk difference (unadjusted for any factors and covariates) and 
corresponding 95% CI will also be calculated.
2.3.3
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 eight 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 
discarded. The MMRM will be fitted using % weight change and the same factors and covariates 
(see Table 2–4) 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 and sulphonylurea (yes/no) as the only factors.
2.3.4
Subgroup analyses for primary endpoints
For the effectiveness estimand, subgroup analyses will be done for the factors listed and categorised 
as in Table 2–4. 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).
2.3.5
Exploratory analysis of change in body weight
Two exploratory analyses of change in body weight (%) taking into account the change in total 
daily insulin use from baseline (week 0) to week 56 will be conducted. Change in total daily insulin 
dose (U) is calculated by subtracting the total daily basal insulin dose (U) at baseline from the 
average total daily insulin dose (U) from baseline or week 44 to week 56. The change in total daily 
insulin dose will also be grouped into 4 groups based on the median for subjects with a change < 0 
and the median for subjects with a change  ≥ 0. Change in body weight will be analysed using a 
analysis of covariance (ANCOVA) including treatment, gender, BMI group and grouped change in 
total daily insulin as factors and baseline body weight in kg as a covariate and an interaction 
between change in total daily insulin dose and the grouped change in total daily insulin dose.
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Figure 2–1
Illustration of imputation approaches
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 2–5
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 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.
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2.4
Secondary endpoints
2.4.1
Confirmatory secondary endpoints
Confirmatory secondary endpoints are listed in Section in the protocol.
All confirmatory secondary endpoints are planned to be assessed at week 56 and will be analysed 
using the same MI approach as used for the primary endpoints and to address the effectiveness 
estimand. The statistical models for continuous endpoints will be ANCOVA with factors and 
covariates listed in Table 2–4with baseline body weight replaced by baseline measurement of 
endpoint to be analysed. The statistical model for 10% responders will be analysed using logistic 
regression in the same way as for 5% responders. 
Sensitivity analyses will be carried out for all confirmatory secondary endpoints. See Table 2–6for 
details on planned analysis methods, multiple imputation approach and sensitivity analyses.
The efficacy estimand will also be assessed for confirmatory secondary endpoints using MMRM as 
described for the primary endpoints. 
2.4.2
Description of the 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 primary 
endpoints. The test hierarchy is given in Table 2–6. 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 2–6
Hierarchical order and type of statistical model to address the effectiveness 
estimand for primary and confirmatory secondary endpoints
Test 
order
Endpoint
Endpoint
type
Statistical 
model
MI 
approach 
Sensitivity analyses #
            Primary endpoint
1
Change in body weight (%) from 
baseline to week 56
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Sacks
Tipping point
Unadjusted 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
Change from baseline to week 56 
in waist circumference (cm) 
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
5
Change from baseline to week 56 
in HbA1c (%)
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
6
Change from baseline to week 56 
in fasting glucose (%)
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
7
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
8
Change from baseline to week 56 
in impact of Weight on Quality of 
Life-Lite (IWQoL-Lite for CT),
physical function domain (5-
itmes) score
Continuous
ANCOVA
Jump to 
reference
McEvoy
wANCOVA
Tipping point
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MI  Multiple Imputation;
#   See Table 2–5
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2.4.3
Supportive secondary endpoints
2.4.3.1
Efficacy endpoints
Supportive secondary endpoints are listed in Section in the protocol.The questionnaire for 
Weight related sign and symptom (WRSS) measure will not be validated until after DBL. 
Therefore the total score cannot be calculated and the supportive secondary endpoint “Weight 
relatedsign and symptom (WRSS) measure, total score” will not be analysed. Instead frequencies 
for categorical responses will be presented for each item and by visit.
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 
secondary endpoints.
In exception, the endpoints total daily basal insulin dose (% of pretrial dose in U), total daily basal 
insulin dose (U/kg) and total daily insulin dose (U/kg) will not be analysed but only summarised in 
tables. Endpoint at baseline and change of endpoint will be summarised by week and treatment.
The endpoint mean daytime glucose value will be calculated from the 7-point SMPG profile as area 
under the curve (AUC) divided by length of time-interval. AUC will be calculated using the linear 
trapezoidal method. Missing points in the 7-point SMPG profile are ignored for the calculation.
The statistical model for continuous endpoints will be ANCOVA with factors and covariates listed 
in Table 2–4with baseline body weight replaced by baseline measurement of endpoint to be 
analysed. The statistical model for proportions will be analysed using logistic regression.
In addition to the supportive secondary efficacy endpoints regarding IWQoL-Lite for CT listed in 
the protocol, analyses and outputs for the IWQoL-Lite for CT physical domain (not to be confused 
with IWQoL-Lite for CT physical function domain) will be made.
2.4.3.2
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 and hypoglycaemic episodes 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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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.
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.
Hypoglycaemic episodes 
All hypoglycaemic episodes will be summarised in terms of N, %, E, rate as on drug (PYE) and in 
trial (PYO) and using same ascertainment window of 14 days as for AEs.
In addition to summary tables for hypoglycaemic episodes, an analysis and outputs for number of 
hypoglycaemic episodes will be made. The number of hypoglycaemic episodes occurring on-drug 
after 56 weeks of treatment will be analysed using a negative binomial regression model with a log-
link function and the logarithm of the on drug time period as offset. The model will include 
treatment, sex, BMI group and sulphonylurea (Yes, No) as fixed factors and baseline bodyweight 
in kg and HbA1c in % as covariates.”
Classification of Hypoglycaemia:
Treatment emergent:hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs during on drug time intervals. 
Nocturnal hypoglycaemic episodes:are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 2–2) and the ADA classification of hypoglycaemia (see Figure 2–3).
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Status:
Final
EudraCT No.: 2015-005619-33
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Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)20 Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 2–2
Novo Nordisk classification of 
hypoglycaemiaFigure 2–2) in addition to the ADA classification:
Severe hypoglycaemia according to the ADA classification11.
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma glucose 
value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma glucose 
value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to the 
ADA classification11 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value <3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification11 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or 
without symptoms consistent with hypoglycaemia. 
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–2
Novo Nordisk classification of hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 October 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
24 of 28
ADA classification11 of hypoglycaemia
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may 
not be available during an event, but neurological recovery following the return of plasma
glucose to normal is considered sufficient evidence that the event was induced by a low plasma 
glucose concentration.
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia are 
not accompanied by a plasma glucose determination but that was presumably caused by a plasma 
glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–3
ADA classification of hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 October 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
25 of 28
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. 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 in trial observation period similar as in the primary analysis for the
primary estimand but using the safety analysis.
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.
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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 October 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
26 of 28
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. 
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.
3
Changes to the statistical analyses planned in the protocol
3.1
Deviation from analyses as described in the protocol
!
Factors and covariates to be included in the statistical modelling of the efficacy related
endpoints has been reduced to only include treatment, gender and BMI group as factors and
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 October 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
27 of 28
baseline body weight in kg as a covariate to align with the current modelling strategy in 
obesity projects at Novo Nordisk A/S.
The following table (Table 2–4in the protocol):
Factors and covariates at baseline
Type
Categories
Randomised tretment
Factor
Liraglutide 3.0 mg,  placebo
Sulphonylurea
Factor
Yes, no
Body weight (kg)
Covariate
Not applicable
BMI (kg/m2)
Factor
[27,30[, [30,35[, [35,40[, ≥40
Gender 
Factor
Male, female
Insulin type
Factor
Insulin detemir, other basal insulin
Insulin dose
Covariate
Not applicable
HbA1c
Factor
≤ 8.0%,  > 8.0%
has been replaced by:
Factors and covariates at baseline
Type
Categories
Randomised tretment
Factor
Liraglutide 3.0 mg,  placebo
Body weight (kg)
Covariate
Not applicable
BMI (kg/m2)
Factor
[27,30[, [30,35[, [35,40[, ≥40
Gender 
Factor
Male, female
!
A MMRM is used for the efficacy estimand and only assessments from subjects who are
taking the randomised treatment until end of trial or until first discontinuing of trial drug
(either temporarily or permanent) are included. In the protocol, a trial drug pause of more
than two days is defined as a treatment discontinuation, but a treatment discontinuation
should have been defined as a trial drug pause of more than 7 days, which is also the
information collected in the eCRF.
The following text:
”A pause of less than three consecutive days is not regarded as discontinuation for this analysis.”
has been replaced by: 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 October 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
28 of 28
”A pause of less than eight consecutive days is not regarded as discontinuation for this analysis.”
!
Since subgroup analyses are only planned to be done for factors and covariates included in
the statistical modelling of efficacy related endpoints, a subgroup analysis for baseline
insulin dose is no longer required as per protocol.
The following text:
“For baseline weight and insulin dose, categories based on quartiles will be used.”
has been replaced by:
“For baseline weight, categories based on quartiles will be used.“
!
The WRSS questionnaire will not be validated until after DBL. Therefore the total score
cannot be calculated and the supportive secondary endpoint “Weight related sign and
symptom (WRSS) measure, total score” cannot be analysed.
The following text has been added:
“The questionnaire for Weight related sign and symptom (WRSS) measure will not be validated 
until after DBL. Therefore the total score cannot be calculated and the supportive secondary 
endpoint “Weight related sign and symptom (WRSS) measure, total score” will not be analysed. 
Instead frequencies for categorical responses will be presented for each item and by visit.”
!
The following three supportive secondary efficacy endpoint Total daily basal insulin dose
(% of pre-trial dose in U), Total daily basal insulin dose (U/kg) and Total daily insulin dose
(U/kg) will not be analysed but only summarised in tables, as no additional relevant
information will be gained from analysing four endpoints all concerning change in insulin
dose from baseline to week 56
The following text has been added:’
“In exception, the endpoints total daily basal insulin dose (% of pretrial dose in U), total daily
basal insulin dose (U/kg) and total daily insulin dose (U/kg) will not be analysed but only 
summarised in tables. Endpoint at baseline and change of endpoint will be summarised by week and 
treatment.”
3.2
Additional analyses not described in the protocol
The following text has been added:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 October 2018
Novo Nordisk
Trial ID: NN8022-4272
Version:
1.0
UTN: U1111-1177-4903
Status:
Final
EudraCT No.: 2015-005619-33
Page:
29 of 29
“In addition, a model resembling the primary analysis models using the same imputation method 
(jump to reference) including treatment, BMI groups, sex, sulphonylurea (Yes, No), insulin type 
(Insulin detemir, Other basal insulin) and HbA1c groups (<=8%, >8%) as factors and baseline 
body weight in kg and total daily basal insulin dose in U as covariates will be conducted. The 
imputation model (step 1) will be same as for the primary approach.”
“Two exploratory analyses of change in body weight (%) taking into account the change in total 
daily insulin use from baseline (week 0) to week 56 will be conducted. Change in total daily insulin 
dose (U) is calculated by subtracting the total daily basal insulin dose (U) at baseline from the 
average total daily insulin dose (U) from baseline or week 44 to week 56. The change in total daily 
insulin dose will also be grouped into 4 groups based on the median for subjects with a change < 0 
and the median for subjects with a change  ≥ 0. Change in body weight will be analysed using a 
analysis of covariance (ANCOVA) including treatment, gender, BMI group and grouped change in 
total daily insulin as factors and baseline body weight in kg as a covariate and an interaction 
between change in total daily insulin dose and the grouped change in total daily insulin dose.”
“In addition to the supportive secondary efficacy endpoints regarding IWQoL-Lite for CT listed in 
the protocol, analyses and outputs for the IWQoL-Lite for CT physical domain (not to be confused 
with IWQoL-Lite for CT physical function domain) will be made.”
“In addition to summary tables for hypoglycaemic episodes, an analysis and outputs for number of 
hypoglycaemic episodes will be made. The number of hypoglycaemic episodes occurring on-drug 
after 56 weeks of treatment will be analysed using a negative binomial regression model with a log-
link function and the logarithm of the on drug time period as offset. The model will include 
treatment, sex, BMI group and sulphonylurea (Yes, No) as fixed factors and baseline body weight in 
kg and HbA1c in % as covariates.”
4
References
1. Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol
deviation: a framework for relevant, accessible assumptions, and inference via multiple
imputation. J Biopharm Stat. 2013;23(6):1352-71.
2. McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat.
2016;26(1):30-6.
3. Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of
weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J
Med. 2009;360(9):859-73.
CONFIDENTIAL