Clinical trial NCT02964247
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2017-03-03; Completion date: 2018-05-08
Enrollment: 303 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The trial is conducted in Asia, Europe, North America and South America. The aim of the study is to compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor with or without metformin on glycaemic control in subjects with type 2 diabetes mellitus.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: liraglutide intervention 2: placebo
Intervention descriptions: intervention 1: Liraglutide given s.c. once daily, gradually titrated to 1.8 mg/day as an add-on to the subject's stable pre-trial SGLT2 inhibitor ± metformin for 26 weeks intervention 2: Liraglutide placebo given s.c. once daily, gradually titrated to 1.8 mg/day as an add-on to the subject's stable pre-trial SGLT2 inhibitor ± metformin for 26 weeks

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02964247   
Sponsor trial ID: 
NN2211-4315 
Official title of study: 
LIRA-ADD2SGLT2i – liraglutide versus placebo as add-on to 
SGLT2 inhibitors 
Document date: 
26 September 2018 
 


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


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
1 of 94
Protocol
Trial ID: NN2211-4315
LIRA-ADD2SGLT2i – liraglutide versus placebo as add-on to SGLT2 
inhibitors
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 No unpublished information contained herein may be 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 No unpublished information contained herein may be 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:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
2 of 94
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................13
3
Background information and rationale for the trial............................................................................16
3.1
Type 2 diabetes mellitus ..............................................................................................................16
3.2
Liraglutide....................................................................................................................................16
3.3
Rationale for the trial...................................................................................................................17
4
Objectives and endpoints........................................................................................................................18
4.1
Objectives ....................................................................................................................................18
4.1.1
Primary objective.......................................................................................................18
4.1.2
Secondary objective...................................................................................................18
4.2
Endpoints .....................................................................................................................................18
4.2.1
Primary endpoint........................................................................................................18
4.2.2
Secondary endpoints..................................................................................................18
4.2.2.1
Confirmatory secondary endpoints .....................................................18
4.2.2.2
Supportive secondary endpoints..........................................................18
5
Trial design ..............................................................................................................................................20
5.1
Type of trial .................................................................................................................................20
5.2
Rationale for trial design..............................................................................................................21
5.3
Treatment of subjects...................................................................................................................22
5.3.1
Liraglutide and placebo .............................................................................................22
5.3.2
Background medication.............................................................................................23
5.3.2.1
SGLT2 inhibitors.................................................................................23
5.3.2.2
Metformin............................................................................................24
5.3.3
Rescue medication.....................................................................................................24
5.4
Treatment after discontinuation of trial product ..........................................................................24
5.5
Rationale for treatment ................................................................................................................25
6
Trial population.......................................................................................................................................26
6.1
Number of subjects......................................................................................................................26
6.2
Inclusion criteria ..........................................................................................................................26
6.3
Exclusion criteria.........................................................................................................................26
6.4
Rescue criteria..............................................................................................................................28
6.5
Criteria for premature discontinuation of trial product................................................................29
6.6
Withdrawal from trial ..................................................................................................................29
6.7
Subject replacement.....................................................................................................................30
6.8
Rationale for trial population.......................................................................................................30
7
Milestones.................................................................................................................................................31
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
3 of 94
8
Methods and assessments .......................................................................................................................32
8.1
Visit procedures...........................................................................................................................32
8.1.1
Informed consent .......................................................................................................32
8.1.2
Investigator site logs ..................................................................................................32
8.1.3
Screening (visit 1)......................................................................................................32
8.1.4
Re-screening ..............................................................................................................32
8.1.5
Fasting visits ..............................................................................................................32
8.1.6
Missed visits ..............................................................................................................33
8.1.7
Rescue medication visit .............................................................................................33
8.1.8
Premature discontinuation of trial product visit.........................................................33
8.1.9
Withdrawal from trial ................................................................................................33
8.2
Assessments.................................................................................................................................34
8.2.1
Subject related information/assessments ...................................................................34
8.2.1.1
Demography........................................................................................34
8.2.1.2
Diabetes history and diabetes complications.......................................34
8.2.1.3
Concomitant illness and medical history.............................................34
8.2.1.4
Concomitant medication .....................................................................35
8.2.1.5
Childbearing potential.........................................................................35
8.2.1.6
Tobacco use.........................................................................................36
8.2.2
Efficacy assessments..................................................................................................36
8.2.2.1
Body measurements ............................................................................36
8.2.2.2
Vital signs............................................................................................37
8.2.2.3
Self-measured plasma glucose (SMPG)..............................................37
8.2.2.4
7-point self-measured plasma glucose profile.....................................37
8.2.2.5
Glucose metabolism and lipids............................................................38
8.2.3
Safety assessments.....................................................................................................39
8.2.3.1
Physical examination...........................................................................39
8.2.3.2
ECG-12 lead........................................................................................39
8.2.3.3
NYHA .................................................................................................40
8.2.3.4
Urinalysis ............................................................................................40
8.2.3.5
Biochemistry and Haematology..........................................................41
8.2.3.6
Pregnancy test .....................................................................................41
8.2.3.7
Adverse events ....................................................................................42
8.2.3.8
Hypoglycaemic episodes.....................................................................43
8.2.4
Laboratory assessments .............................................................................................45
8.3
Subject training............................................................................................................................46
8.3.1
Diaries........................................................................................................................46
8.3.2
Blood glucose meter ..................................................................................................46
8.3.3
Training in the prefilled pen-injector.........................................................................46
8.4
Subject compliance......................................................................................................................47
9
Trial supplies ...........................................................................................................................................48
9.1
Trial products...............................................................................................................................48
9.2
Labelling......................................................................................................................................48
9.3
Storage .........................................................................................................................................49
9.4
Drug accountability and destruction............................................................................................49
9.5
Auxiliary supplies........................................................................................................................50
10 Interactive voice/web response system ..................................................................................................50
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
4 of 94
11 Randomisation procedure and breaking of blinded codes..................................................................51
11.1
Breaking of blinded codes ...........................................................................................................51
12 Adverse events, and technical complaints and pregnancies................................................................52
12.1
Definitions ...................................................................................................................................52
12.1.1
Adverse event ............................................................................................................52
12.1.2
Serious adverse event.................................................................................................53
12.1.3
Non-serious adverse event.........................................................................................54
12.1.4
Medication errors.......................................................................................................54
12.1.5
Adverse events requiring additional data collection..................................................55
12.1.6
Technical complaints.................................................................................................55
12.2
Reporting of adverse events.........................................................................................................55
12.3
Follow-up of adverse events........................................................................................................57
12.4
Technical complaints and technical complaint samples ..............................................................58
12.4.1
Reporting of technical complaints .............................................................................58
12.4.2
Collection, storage and shipment of technical complaint samples ............................59
12.5
Pregnancies..................................................................................................................................59
12.5.1
Pregnancies in female subjects ..................................................................................59
12.5.2
Pregnancies in female partners of male subjects (for US only) .................................61
12.6
Precautions and/or overdose ........................................................................................................61
12.7
Committees related to safety........................................................................................................62
13 Case report forms....................................................................................................................................62
13.1
Corrections to case report forms..................................................................................................63
13.2
Case report form flow..................................................................................................................63
14 Monitoring procedures ...........................................................................................................................63
15 Data management....................................................................................................................................64
16 Computerised systems.............................................................................................................................65
17 Statistical considerations ........................................................................................................................65
17.1
Sample size calculation................................................................................................................67
17.2
Definition of analysis sets............................................................................................................68
17.3
Primary endpoint..........................................................................................................................71
17.3.1
Primary analysis for the primary estimand ................................................................71
17.3.2
Primary analysis for the secondary estimand.............................................................72
17.3.3
Sensitivity Analysis ...................................................................................................72
17.3.3.1
Pattern mixture models........................................................................73
17.3.3.2
Assessment of sensitivity analyses......................................................74
17.4
Secondary endpoints....................................................................................................................74
17.4.1
Confirmatory secondary endpoints............................................................................74
17.4.2
Supportive secondary endpoints ................................................................................74
17.4.2.1
Efficacy endpoints...............................................................................75
17.4.2.2
Safety endpoints..................................................................................76
18 Ethics........................................................................................................................................................80
18.1
Benefit-risk assessment of the trial..............................................................................................80
18.2
Informed consent .........................................................................................................................81
18.3
Data handling...............................................................................................................................82
18.4
Information to subjects during trial..............................................................................................82
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
5 of 94
18.5
Premature termination of the trial and/or trial site.......................................................................82
19 Protocol compliance................................................................................................................................82
19.1
Protocol deviations ......................................................................................................................82
19.2
Prevention of missing data...........................................................................................................83
20 Audits and inspections ............................................................................................................................83
21 Critical documents ..................................................................................................................................83
22 Responsibilities........................................................................................................................................84
23 Reports and publications........................................................................................................................85
23.1
Communication of results............................................................................................................86
23.1.1
Authorship .................................................................................................................87
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................87
23.2
Investigator access to data and review of results.........................................................................87
24 Retention of clinical trial documentation..............................................................................................88
24.1
Retention of clinical trial documentation.....................................................................................88
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............88
26 Indemnity statement ...............................................................................................................................89
27 References................................................................................................................................................91
Attachment I – Global list of key staff and relevant departments and suppliers 
Attachment II – Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
6 of 94
Table of Figures
Page
Figure 5–1
Schematic overview of the trial design...................................................................................21
Figure 12–1
Reporting of AEs....................................................................................................................56
Figure 17–1
ADA classification of hypoglycaemia....................................................................................79
Table of Tables
Page
Table 8–1
NYHA criteria for functional capacity ...................................................................................40
Table 9–1
Trial products..........................................................................................................................48
Table 9–2
Storage conditions ..................................................................................................................49
Table 17–1
Assumptions used in the sample size calculation...................................................................68
Table 17–2
Marginal powers for meeting individual hypothesis ..............................................................68
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
7 of 94
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
AKD
acute kidney disease 
AKI
acute kidney injury 
ALT
alanine aminotransferase
ANCOVA
analysis of covariance 
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
CCDS
Company Core Data Sheet 
CKD
chronic kidney disease
CKD EPI
Chronic Kidney Disease Epidemiology Collaboration formula
CRF
case report form
DPP-4
dipeptidyl peptidase-4 
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomular filtration rate
EOT
end of treatment
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FDAAA
Food and Drug Administration Amendment Act 
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GIP
glucose-dependent insulinotropic polypeptide 
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
8 of 94
hCG
human chorionic gonadotrophin
HDL
high-density lipoprotein
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
IRB
institutional review board
IWRS
interactive voice/web response system
KDIGO
Kidney Disease Improving Global Outcomes
LDL
low-density lipoprotein
LSFV
last subject first visit
LSLV
last subject last visit
MAR
missing at random
MedRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measurements 
NIMP
non-investigational medicinal product
NYHA
New York Heart Association
OAD
oral antidiabetic drug
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
SDV
source data verification
SGLT2
sodium-glucose co-transporter 2 
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SD
standard deviation
SUSAR
suspected unexpected serious adverse reaction
TE
Treatment effect
TMM
Trial Materials Manual
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
9 of 94
T2DM
Type 2 Diabetes Mellitus
TZD
thiazolidinedione
UACR
urine albumin creatinine ratio
UTN
universal trial number
VLDL
very low density lipoprotein 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
10 of 94
1
Summary
Objective(s) and endpoint(s):
Primary objective 
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ± 
metformin on glycaemic control in subjects with type 2 diabetes mellitus.
Secondary objectives
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ± 
metformin in subjects with type 2 diabetes mellitus with regards to:
!
Body weight related parameters
!
Selected cardiovascular risk factors
!
Safety 
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ± 
metformin weeks in subjects with type 2 diabetes mellitus with regards to:
!
selected glucose metabolism parameters 
Primary endpoint
Change from baseline to week 26 in HbA1c
Confirmatory secondary endpoint
Change from baseline to week 26 in body weight 
Key supportive secondary efficacy endpoints
Change from baseline to week 26 in:
!
Fasting plasma glucose
!
Systolic and diastolic blood pressure
Subjects who after 26 weeks achieve (yes/no):
!
HbA1c <7.0% (53 mmol/mol), American Diabetes Association target
!
HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists target
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c reduction ≥1% (11mmol/mol) and weight loss ≥3%
Key supportive secondary safety endpoints
!
Number of treatment emergent severe or blood glucose confirmed symptomatic 
hypoglycaemic episodes during 26 weeks 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
11 of 94
Trial design:
This is a 26-week, 2:1 randomised, placebo controlled, double blind, multicentre, multinational, 
confirmatory, two arm trial investigating the effect and safety of liraglutide versus placebo as add-
on to an SGLT2 inhibitor with or without metformin in subjects with type 2 diabetes mellitus who 
have not achieved adequate glycaemic control despite stable treatment with SGLT2 inhibitor ± 
metformin.
Eligible subjects will be randomised in a 2:1 manner to receive a once daily dose of either 
liraglutide (1.8 mg) or placebo added to pre-trial SGLT2 inhibitor ± metformin. Randomisation will 
be stratified by metformin use at baseline (yes versus no).
The maximum overall duration of the trial participation including screening and follow up will be
29 weeks.
Trial population:
It is planned to randomise 303 subjects (liraglutide N=202; placebo N=101) in this trial. 
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
!
Male or female, age ≥ 18 years at the time of signing informed consent.
!
Diagnosed with type 2 diabetes mellitus.
!
HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
!
Stable dose of an SGLT-2 inhibitor as monotherapy or in combination (including fixed-dose 
drug combination) with a stable dose of metformin (≥ 1500 mg or maximum tolerated dose) 
for at least 90 days prior to the day of screening. All medications in compliance with current 
local label.
!
Body mass index ≥ 20 kg/m2.
Key exclusion criteria
!
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).
!
History of diabetic ketoacidosis while being treated with SGLT2 inhibitors. 
!
Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of < 60 
mL/min/1.73m2 as defined by KDIGO1 classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening. 
!
Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening. However, short 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
12 of 94
term insulin treatment for a maximum of 14 days during the 90 days prior to screening is 
allowed.
!
Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
!
History or presence of pancreatitis (acute or chronic).
!
Impaired liver function, defined as ALT ≥2.5 times upper normal limit at screening.
!
Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
Assessments:
Efficacy
!
Glucose metabolism
!
Body measurements (body weight and waist circumference)
Safety
!
Adverse events and serious adverse events
!
Hypoglycaemic episodes
!
Biochemistry, haematology and urinalysis
!
Physical examination (including electrocardiogram)
Trial product(s):
Investigational medicinal products:
!
Test product: Liraglutide (Victoza®) 6.0 mg/mL (3 mL prefilled pen-injector for
subcutaneous injection)
!
Reference therapy: Placebo (3 mL prefilled pen-injector for subcutaneous injection)
Other medicinal products:
SGLT2 inhibitors and metformin and fixed-dose combinations of the former are considered 
background medication (non-investigational medicinal products) and will not be provided by Novo 
Nordisk A/S. In countries where it is applicable, SGLT2 inhibitors may be reimbursed by Novo 
Nordisk A/S
CONFIDENTIAL


Protocol
UTN: U1111-1184-8086 
Date:
16 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN2211-4315
EudraCT no.: Not Applicable
Version:
1.0
Page:
13 of 94
2
Flow chart
Trial Periods
Protocol 
section
Screen-
ing 
Random-
isation
Treatment
End of 
treatment
(EOT)
Follow-
up 
Rescue 
medica-
tion 
6.4/8.1.7
Premature 
Discontin-
uation
6.5/8.1.8
Site visit (V) 
Phone contact (P) 
V
V
P
P
P
V
P
V
V
V
V
P
V
V
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
Timing of visit: Weeks
up to -2
0
1
2
3
4
6
8
14
20
268.1.9
278.1.9
Visit window: Days
±3
±3
±3
±3
±5
±5
±5
±5
±5
±3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
8.1.1
X
In/exclusion criteria
6.2/6.3
X
X
Subject compliance
8.4
X
X
X
X
X
X
X
X
X
X
X
Rescue criteria
6.4
X
X
X
X
X
Criteria for premature 
discontinuation  of trial 
product
6.5/ 8.1.7
X
X
X
X
X
X
X
X
Withdrawal criteria
8.1.9
X
X
X
X
X
X
X
X
X
Demography
8.2.1.1
X
Diabetes: diagnosis, 
complications and         
treatment history
8.2.1.2
X
Concomitant illness 
8.2.1.3
X
Medical history
8.2.1.3
X
Concomitant medication
8.2.1.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Child bearing potential
8.2.1.5
X
Tobacco use
8.2.1.6
X
EFFICACY
Height
8.2.2.1
X


Protocol
UTN: U1111-1184-8086 
Date:
16 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN2211-4315
EudraCT no.: Not Applicable
Version:
1.0
Page:
14 of 94
Trial Periods
Protocol 
section
Screen-
ing 
Random-
isation
Treatment
End of 
treatment
(EOT)
Follow-
up 
Rescue 
medica-
tion 
6.4/8.1.7
Premature 
Discontin-
uation
6.5/8.1.8
Site visit (V) 
Phone contact (P) 
V
V
P
P
P
V
P
V
V
V
V
P
V
V
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
Timing of visit: Weeks
up to -2
0
1
2
3
4
6
8
14
20
268.1.9
278.1.9
Visit window: Days
±3
±3
±3
±3
±5
±5
±5
±5
±5
±3
Body weight
8.2.2.1
X
X
X
X
X
X
X
X
X
BMI
8.2.2.1
X
X
X
X
X
X
Waist circumference
8.2.2.1
X
X
X
X
X
Vital signs
8.2.2.2
X
X
X
X
X
X
X
X
X
Self-measured plasma glucose 
(7-point profile)
8.2.2.3/ 
8.2.2.4
X
X
X
X
Fasting C-peptide
8.2.2.5
X
X
X
X
X
Fasting glucagon
8.2.2.5
X
X
X
X
X
Fasting insulin
8.2.2.5
X
X
X
X
X
Fasting plasma glucose
8.2.2.5
X
X
X
X
X
X
X
X
HbA1c
8.2.2.5
X
X
X
X
X
X
X
X
Lipids
8.2.2.5
X
X
X
X
X
SAFETY
Physical examination
8.2.3.1
X
X
X
X
ECG
8.2.3.2
X
X
X
X
NYHA classification
8.2.3.3
X
Urinalysis
8.2.3.4
X
X
X
X
X
X
Biochemistry 1
8.2.3.5
X
X
X
X
Biochemistry 2
8.2.3.5
X
X
X
X
X
X
X
Haematology
8.2.3.5
X
X
X
X
Pregnancy test
8.2.3.6
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
X
X
X
Adverse events
8.2.3.7/12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic episodes
8.2.3.8
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1184-8086 
Date:
16 September 2016
Status:
Final
Novo Nordisk
Trial ID: NN2211-4315
EudraCT no.: Not Applicable
Version:
1.0
Page:
15 of 94
Trial Periods
Protocol 
section
Screen-
ing 
Random-
isation
Treatment
End of 
treatment
(EOT)
Follow-
up 
Rescue 
medica-
tion 
6.4/8.1.7
Premature 
Discontin-
uation
6.5/8.1.8
Site visit (V) 
Phone contact (P) 
V
V
P
P
P
V
P
V
V
V
V
P
V
V
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
Timing of visit: Weeks
up to -2
0
1
2
3
4
6
8
14
20
268.1.9
278.1.9
Visit window: Days
±3
±3
±3
±3
±5
±5
±5
±5
±5
±3
Technical complaints
12.1.6/12.4
X
X
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
IWRS call
10
X
X
X
X
X
X
X
X
X
Dispensing visit
9
X
X
X
X
X
Drug accountability
9.4/10
X
X
X
X
X
X
X
X
REMINDERS
Hand out and  instruct in diary 
8.3.1
X
X
X
X
X
X
Diary collection/review
8.3.1
X
X
X
X
X
X
X
X
Hand out and  instruct in BG 
meter use
8.3.2
X
Training in trial product and 
pen handlinga
8.3.3
X
X
X
X
X
Handout ID card
8.1.3
X
Attend visit fasting
8.1.5
X
X
X
X
X
X
X
X
Footer
Description
a
Dispense directions for use


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
16 of 94
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol,International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
Good Clinical Practice(ICH GCP)2and applicable regulatory requirements, and in accordance with 
the Declaration of Helsinki3. 
In this document, the term investigator refers tothe individual responsible for the overall conduct of 
the clinical trial at a trial site.
In the case of Mexico, 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 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
3.1
Type 2 diabetes mellitus
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disease primarily characterised by 
abnormal glucose and lipid metabolism and associated with a high risk of cardiovascular, 
microvascular, and other complications. The pathogenesis is not fully understood but seems to be 
heterogeneous, involving environmental, lifestyle and genetic factors leading to chronic 
hyperglycaemia associated with insulin resistance and impaired insulin secretion due to abnormal 
beta-cell function4-6. Improvement of long-term glycaemic control(HbA1c) is the treatment goal 
in patients with T2DM in order to prevent long-term complications7, 8.Glucose control in T2DM 
deteriorates progressively over time and patients require a new glucose-lowering intervention on 
average every 3-4 years in order to obtain or retain good control9.
3.2
Liraglutide
Liraglutide is a once-daily human GLP-1 analogue developed by Novo Nordisk and is an active 
ingredient used in the authorised product Victoza®for treatment of adults with T2DM. As of up 
until 30 June 2016,Victoza®is approved in 106countries/regions, includingAustralia,the 
European Union, the United States, Canada, Japan, China, Brazil, Russiaand Mexico10.
The HbA1clowering effect of liraglutide in subjects with T2DM is well established. Liraglutide has 
been tested in severalT2DM treatment scenarios during the phase 3 and phase 4 trial programme, 
as monotherapy and in combination with metformin, sulfonylurea,TZD, basal insulin and 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
17 of 94
combinations hereof11, 12. In each of these treatment scenarios, the efficacy and safety of liraglutide 
has been demonstratedand a positive benefit-risk balance has been established. In addition, 
liraglutide has been shown to be safe and efficacious in patients with T2DM and moderate renal 
impairment13.More recently, liraglutide has shown cardiovascularbenefits in patients with T2DM. 
Information about liraglutide is available in the approved local product label of liraglutide 
(Victoza®) and in the liraglutide(NN2211) abbreviated IB, 17th edition of August 2016or any 
updates hereof14.
For an assessment of benefits and risks of the trial, see Section 18.1.
3.3
Rationale for the trial
T2DMis increasing in incidence and prevalence. Despite compliance with their treatment regimens, 
a large proportion of patients do not reach treatment targets15, indicating that the current available 
treatment modalities are not satisfactory and more treatment options need to be explored 16, 17. This 
includes establishing the benefits of combining available marketed glucose lowering agents in order 
to better optimise individual treatment16, 17.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors were recently established as a new class of 
orallyadministered glucose-lowering drugs (dapagliflozin, canagliflozin and empagliflozin). 
SGLT2 inhibitors lower blood glucose by inhibiting SGLT2 in the proximal tubule of the nephron, 
thereby reducing glucose reabsorption and increasing urinary glucose excretion.This action is 
independent of insulin. On the contrary, SGLT2 inhibitors promote secretionof glucagon, which 
may counteract their glucose lowering effect18, 19. A GLP-1 analogue such as liraglutide acts 
through stimulation of insulin secretion in a glucose-dependent manner. Simultaneously, liraglutide 
lowers inappropriately high glucagon secretion, also in a glucose-dependent manner.Given the 
glucagon lowering effect of liraglutide, there is scientificand therapeutic rationale that in 
combination with SGLT2inhibitor, secretion of glucagon induced by the SGLT2 inhibition may be 
reduced. In additionfor patients with T2DM who have not achieved glycaemic control on an 
SGLT2 inhibitor (with or without metformin), it is hypothesised that by adding liraglutide to their 
treatment, better glycaemic control reflected in HbA1creduction with associated decrease in body 
weight and no increase of hypoglycaemic events may be achieved20. 
Although reports of the use of GLP-1 receptor agonistsin combination with SGLT2 inhibitors 
exist20,there is still no clinical evidenceavailable toguide clinical decision making.Liraglutide is 
not approved for use in combination with SGLT2 inhibitors and the efficacy and safety of 
liraglutide as add-on to a SGLT2 inhibitorhas not been established. Therefore, there is an unmet 
medical need to assess the benefits and risks of liraglutide, a GLP-1 analogue, used in combination 
with SGLT2 inhibitors. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
18 of 94
4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ± 
metformin on glycaemic control in subjects with type 2 diabetes mellitus.
4.1.2
Secondary objective
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ± 
metformin in subjects with type 2 diabetes mellitus with regards to: 
!
Body weight related parameters
!
Selected cardiovascular risk factors
!
Safety 
To compare the effect of liraglutide 1.8 mg/day versus placebo as add-on to an SGLT2 inhibitor ± 
metformin in subjects with type 2 diabetes mellitus with regards to: 
!
selected glucose metabolism parameters 
4.2
Endpoints
4.2.1
Primary endpoint
Change from baseline to week 26 in HbA1c
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
Change from baseline to week 26 in body weight
4.2.2.2
Supportive secondary endpoints
Key supportive secondary endpoints prospectively selected for disclosure (e.g., clinicaltrials.gov 
and EudraCT) are marked with an asterisk (*).
Supportive secondary efficacy endpoints
Change from baseline to week 26 in:
!
Fasting plasma glucose*
!
Self-measured plasma glucose 7-point profile:
–
Mean 7-point profile
–
Mean post prandial increments (over all meals)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
19 of 94
!
Fasting blood lipids (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL 
cholesterol, triglycerides and free fatty acids)
!
Body mass index and waist circumference
!
Systolic and diastolic blood pressure*
Subjects who after 26 weeks achieve (yes/no):
!
HbA1c <7.0% (53 mmol/mol), American Diabetes Association target*
!
HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists target*
!
Weight loss ≥3%
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain*
!
HbA1c <7.0% (53 mmol/mol) and no weight gain
!
HbA1c <7.0% (53 mmol/mol), no weight gain and systolic blood pressure <140 mmHg
!
HbA1c reduction ≥1% (11mmol/mol) 
!
HbA1c reduction ≥1% (11mmol/mol) and no weight gain
!
HbA1c reduction ≥1% (11mmol/mol) and weight loss ≥3%*
Change from baseline to weeks 14 and 26 in:
!
Glucagon, C-peptide and insulin (all fasting)
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events during 26 weeks
!
Number of treatment emergent severe or blood glucose confirmed symptomatic 
hypoglycaemic episodes during 26 weeks*
!
Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia 
episodes during 26 weeks (yes/no)
Change from baseline to week 26 in:
!
Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes
!
Biochemistry: creatinine, creatine kinase, urea, albumin, bilirubins (total), estimated 
glomerular filtration rate, alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, sodium, potassium, calcium (corrected), calcium (total), amylase and lipase
!
Pulse
!
Electrocardiogram category
!
Physical examination
!
Urine albumin creatinine ratio
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
20 of 94
5
Trial design
5.1
Type of trial
This is a 26-week, confirmatory, randomised, double-blind, placebo-controlled, multicentre, 
multinational, two-arm, parallel-group trial, investigating the effect and safety of adding liraglutide 
1.8 mg/day to pre-trial treatment with any SGLT2 inhibitor (as monotherapy or in combination with 
metformin) in subjects with T2DM who have not achieved adequate glycaemic control despite 
stable treatment with SGLT2 inhibitor ± metformin for at least 90 days prior to trial participation.
Subjects will be randomised in a 2:1 manner to receive a once daily dose of liraglutide 1.8 mg or 
placebo applying the standard dose escalation for liraglutide with weekly increments of 0.6 mg/day.
The trial medication will be added-on to the subject’s stable pre-trial SGLT2 inhibitor ± metformin. 
Randomisation will be stratified by metformin use at baseline (yes vs. no). 
Subjects will continue their participation in the trial regardless of premature discontinuation of trial 
product or initiation of rescue medication. Efforts will be made to encourage subjects to continue 
the visit schedule.
The maximum overall duration of the trial participation including screening and follow-up will be
29 weeks: the trial includes a 2-week screening period, followed by 26 weeks of treatment and a    
1-week follow-up period after end of treatment. See Figure 5–1.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
21 of 94
Figure 5–1
Schematic overview of the trial design
5.2
Rationale for trial design
Parallel treatment groups and a randomised double-blind, placebo controlled design werechosen in 
accordance with the trial objectives.
In order to evaluate the safety and effect of liraglutide as add-on to SGLT2 inhibitor± metformin, 
use of any one of three currently marketed SGLT2 inhibitors: Invokana®(canagliflozin)21, Farxiga®
(dapagliflozin)22and Jardiance®(empagliflozin)23at any approved doseas monotherapy or in fixed 
dose-combination together with metformin,will be allowed as pre-trial therapy. Stable pre-trial
treatment with metforminis≥1500 mg/day or atthemaximum tolerated dose. To ensure equal 
distribution and avoid bias arising from difference in metformin usage, randomisation will be 
stratified by metformin use (yes vs. no) at baseline. Randomisation 2:1 was chosen to have as few 
subjects as possible on placebo.
A trial duration of 26 weeks is considered adequate in terms of establishing superiority of 
liraglutide treatment versus placebo on glycaemic control and body weight in subjects with T2DM. 
This duration is in accordance with regulatory guidelines on diabetes9, 24. Furthermore, a 26 week 
trial period has previously been shown to be sufficient to identify the liraglutide safety profile 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
22 of 94
including tolerability and risk of hypoglycaemia.In the liraglutide phase 3b trials NN2211-1842 
and 1860, both safety and efficacy observations from the first 26 weeks of treatment were generally 
confirmed during the extension periods up to 52 weeks(trial 184225-28, trial 186027).The trial 
design is in accordancewith the draft CHMP Guideline on clinical investigation of medicinal 
products in the treatment of diabetes mellitus9.
The follow-up period is 1week to allow for wash-out of liraglutide.
5.3
Treatment of subjects
After screening, the subjects will be randomised in a 2:1 manner to receive treatment with
liraglutide + SGLT2 inhibitor ± metformin or placebo + SGLT2 inhibitor ± metformin. Subjects on 
a fixed dose combination of SGLT2 inhibitor and metformin are allowed to continue this fixed dose 
combination throughout the trial. 
5.3.1
Liraglutide and placebo
Liraglutide and placebo are considered investigational medicinal products (IMPs) and will be 
blinded throughout the trial. Liraglutide and placebo will be provided by Novo Nordisk.
Liraglutide will be available at a concentration of 6 mg/mL, and supplied in a 3 mL prefilled pen-
injector. Liraglutide vehicle will be used as placebo in equivalent volumes.
Liraglutide/placebo should be injected subcutaneously in the thigh, upper arm (deltoid region) or 
abdomen. Injections can be done at any time of the day and irrespective of meals. It is 
recommended that the time of injection is consistent throughout the trial once the most convenient 
timing is established.
When initiating liraglutide treatment, subjects will follow a dose escalation regimen. 
Liraglutide/placebo will be initiated with a starting dose of 0.6 mg/day, with subsequent weekly 
dose escalations of 0.6 mg/day in accordance with the approved dose escalation for liraglutide until 
the maintenance dose of 1.8 mg/day in this trial is reached. Escalation from 0.6 to 1.2 then 1.8 
mg/day can be extended by 7 days in total if subjects do not tolerate an increase in dose during dose 
escalation, at the discretion of the investigator. The liraglutide maintenance dose of 1.8 mg/day 
should remain unchanged throughout the remainder of the trial. In rare situations where a dose of 
1.8 mg/day despite all efforts is not tolerated (e.g, using extra time for dose escalation and 
discussing with/informing the subject that gastrointestinal AEs in general are transient and subside
over time), the dose can be reduced to 1.2 mg/day at the discretion of the investigator.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
23 of 94
5.3.2
Background medication
SGLT2 inhibitors and metformin
After signing the informed consent, subjects must continue their anti-diabetic background 
medication (SGLT2 inhibitor +/-metformin) throughout the entire trial. Fixed dose combinations of 
SGLT2 inhibitors and metformin are allowed. The background medication should be maintained at 
the same dose level as given at trial entrance and with the same frequency during the entire 
treatment period unless rescue medication is needed or a safety concern (e.g., diabetic ketoacidosis, 
lactic acidosis, hospitalisation for surgery or acute serious medical illness) arises, qualifying for 
changes to the background medication.
In addition, all background medication: 
!
is considered to be non-investigational medicinal product (NIMP)
!
will not be provided by Novo Nordisk A/S, except if required by local regulations. In
countries where it is applicable, SGLT2 inhibitors may be reimbursed by Novo Nordisk A/S
!
should be used in accordance with standard of care and current approved label in the
individual country
!
should not exceed the maximum approved dose in the individual country
5.3.2.1
SGLT2 inhibitors 
Three SGLT2inhibitors (dapagliflozin,22canagliflozin21and empagliflozin23) are currently 
approved for use either as monotherapy in metformin intolerant patients or in combination with 
metformin, sulfonylurea (SU), thiazolidinedione (TZD) or insulin. In addition, dapagliflozin is 
approved for use in combination with DPP-4 inhibitors22.There is however, currently no approval 
for any SGLT2 inhibitors to be used in combination with a GLP-1 receptor agonist. 
SGLT2 inhibitors may be used at any stage of T2DM provided renal function is adequate. Besides 
lowering blood glucose, treatment with SGLT2inhibitors also inducesweight loss and lowering of 
systolic anddiastolic blood pressure. Additionally,cardiovascular benefits ofempagliflozin
treatmenthave beenshownpreviouslyin patients with T2DM29. 
As SGLT2 inhibitors possess a diuretic effect, hypotension and symptoms related to volume 
depletion may occur. Therefore they should be used with caution in the elderly, in any patient 
already on a diuretic and in anyone with a tenuous intravascular volume status. Initial increases in 
serum creatinine occur with SGLT2 inhibitors, but generally these are small, reversible changes. 
Due to their MOA, SGLT2 inhibitors are less effective when the eGFR is between 45-60 
mL/min1.73 m230.The FDAand EMAhaveadded warnings to the three SGLT2 inhibitors’ labels
regarding diabeticketoacidosis (normoglycemic), urosepsis and pyelonephritis. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
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Information about SGLT2 inhibitorsincluding any benefits and/or any side effects,is available in 
the approved local label documents31. 
5.3.2.2
Metformin
Metformin should be used in accordance with standard of care in the individual country at the
discretion of the investigator. Metformin dose may only be increased at the discretion of the 
investigator if used as rescue treatment (see Section 6.4).
Metformin is a biguanide with anti-hyperglycaemic effects, lowering both basal and postprandial 
plasma glucose. It does not stimulate insulin secretion and therefore, the risk of hypoglycemia under 
normal circumstances is low. Metformin may act via 3 mechanisms:
1. reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
2. in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation
3. delay of intestinal glucose absorption.
In humans, independentof its action on glycaemia, metformin has a favourableeffect on lipid 
metabolism. Lactic acidosis is a rare, but serious (high mortality in the absence of prompt
treatment) metabolic complication that can occur due to metformin hydrochloride accumulation. 
Reported cases of lactic acidosis in patients on metformin hydrochloride have occurred primarily in 
diabetic patients with significant renal failure.Information about metformin including any benefits 
and/or any side effects,is available in the approved local label documents32.
5.3.3
Rescue medication
Rescue criteria (see Section 6.4) for subjects experiencing persistent and unacceptable
hyperglycaemia have been implemented to ensure subjects’ safety and in attempt to improve the 
retention of randomised subjects in the trial and thereby obtain additional safety data. 
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end of treatment visit (visit 11, see 
Section 2) or if trial product is discontinued prematurely, the subject should be switched to a 
suitable marketed product at the discretion of the investigator and in accordance with 
ADA/European Association for the Study of Diabetes.
For Brazil only: At the end of the trial, all subjects will be assured access to the best proved 
prophylactic, diagnostic and therapeutic methods identified during the study (national Council of 
Health Resolution 466/12).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
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5.5
Rationale for treatment
In this trial,any locally approved SGLT2 inhibitordosed at any locally approved dose and dosage
as individually required is applicable. A rangeof SGLT2 inhibitortypesand dosagesis selectedto 
establish the effectand safety of liraglutide as “add-on treatment” to SGLT2 inhibitors (with or 
without metformin) in general.
For metformin treated subjects a minimum dose of metformin of 1500 mg/day or maximum 
tolerated dosehas been applied in order to establish the effectand safety of liraglutide as add-on 
treatment to SGLT2 inhibitors with or without metformin for the two metformin strata (metformin 
y/n at screening).
Administration of liraglutide will be similar to previous phase 3 and 4T2DMtrials and in 
accordance with locally approved labels. The liraglutide dose selected for the trial (1.8 mg/day) is 
the maximum recommended human dosefor T2DM. In previous clinical trials, more subjects on 
this dose reached theAmerican Diabetes Association (ADA)glycaemic target of HbA1c<7.0% and 
experienced weight reductionin comparisonto subjects treated with lower doses. The use of 
liraglutide1.8 mg/day maintenance dose in this trial will ensurethe safe use of liraglutide in 
combination with SGLT2 inhibitors with or without metformin.
The duration (26 weeks) and the dose of the randomised treatment are considered adequate for 
obtaining meaningful information on effect and safety in accordance with the trial objectives14.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 551
Number of subjects planned to be randomised: 303
For Mexico only: Approximately 40 subjects are planned to be randomized/started on trial 
product(s) in Mexico.
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial. 
2. Male or female, age ≥ 18 years at the time of signing informed consent.
3. Diagnosed with type 2 diabetes mellitus.
4. HbA1c of 7.0-9.5% (53-80 mmol/mol) (both inclusive).
5. Stable dose of an SGLT-2 inhibitor as monotherapy or in combination (including fixed-dose 
drug combination) with a stable dose of metformin (≥ 1500 mg or maximum tolerated dose) 
for at least 90 days prior to the day of screening. All medications in compliance with current 
local label.
6. Body mass index ≥ 20 kg/m2.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent.
3. 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).
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Brazil: According to resolution 466/12: Regarding exclusion criterion: 'Female who is 
pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not 
using adequate contraceptive methods (adequate contraceptive measures as required by local 
regulation or practice). For women who expressly declare free of the risk of pregnancy, either 
by not engaging in sexual activity or by having sexual activity with no birth potential risk, use of 
contraceptive method will not be mandatory.'
 Receipt of any investigational medicinal product within 90 days before screening.
 Treatment with any medication for the indication of diabetes or obesity other than stated in
the inclusion criteria within the past 90 days prior to the day of screening. However, short
term insulin treatment for a maximum of 14 daysduring the 90 daysprior to the day of
screening is allowed.
 Any disorder which in the investigator’s opinion might jeopardise subject’s safety or
compliance with the protocol.
 History of diabetic ketoacidosiswhile being treated with SGLT2 inhibitors.
 Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid
carcinoma. Family is defined as a first degree relative.
 History or presence of pancreatitis (acute or chronic).
 Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of < 60
mL/min/1.73m2as defined by KDIGO1classification using isotope dilution mass
spectrometry (IDMS) for serum creatinine measured at screening.
 Impaired liver function, defined as ALT ≥2.5 times upper normal limit at screening.
 Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
 Planned coronary, carotid or peripheral artery revascularisation known on the day of
screening.
 Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or
transient ischaemic attack within the past 180 days prior to the day of screening.
 Inadequately treated blood pressure defined as Grade 3 hypertension or higher (systolic
≥180 mmHg or diastolic ≥110 mmHg) at screening. 
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16. Proliferative retinopathy or maculopathy requiring acute treatment according to the
investigator’s opinion.
17. Presence or history of malignant neoplasms within the past 5 years prior to the day of
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
18. Known or suspected abuse of alcohol or drugs.
19. Mental inability, unwillingness or language barrier precluding adequate understanding of or
compliance with trial procedures.
20. Participation in any clinical trial of an approved or non-approved investigational medicinal
product within 90 days before screening.
21. Brazil; According to Resolution 251/97, item III.2.j. Participation in other trials within one
year prior to screening visit (visit 1) unless there is a direct benefit to the research subject at
the Investigator´s discretion.
6.4
Rescue criteria
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. If any fasting plasma glucose (FPG) value measured by the central laboratory
exceeds the limits below and no intercurrent cause of the hyperglycaemia can be identified, the 
subject must be called in for an unscheduled visit and a confirmatory FPG as soon as possible:
!
15.0 mmol/L (270 mg/dl) from week 4 (+/-3 days see Section 2) to end of week 7
!
13.3 mmol/L (240 mg/dl) from start of week 8 to end of week 13
!
11.1 mmol/L (200 mg/dl) from start of week 14 to end of treatment
If the confirmatory FPG (analysed by the central laboratory) exceeds the values described above
and no intercurrent cause can be identified, the subject should attend a rescue medication visit (see 
Sections 2, 6.4 and 8.1.7) as soon as possible. After the completion of the rescue medication visit,
the subject should be offered rescue medication at the discretion of the investigator and in 
accordance with ADA/European Association for the Study of Diabetes16, 17. Rescue medication
excludes any GLP-receptor agonists, DPP-4 inhibitors and/or amylin analogues. Rescue medication 
can include intensification of existing background medication and/or initiation of suitable marketed 
treatment(s). The rescue treatment must be as add-on to the trial products during the remainder of 
the trial and does not constitute discontinuation criteria.
The randomised treatment should be continued and the subject should continue to follow their
protocol-specified visit schedule (see Section 8.1.7). The rescue medication (including changes in 
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background medication) and any changes hereto must be captured on the concomitant medication 
form in the eCRF. Rescue medication will not be provided by Novo Nordisk.
6.5
Criteria for premature discontinuation of trial product 
Efforts must be made so that the subject attends and completes all scheduled visit procedures. The 
subject should stay in the trial irrespective of lack of adherence to randomised treatment, lack of 
adherence to visit schedule or missing assessments. Only subjects who decline any further contact 
with the site in relation to the trial will be 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 any of the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Pregnancy
3. Intention of becoming pregnant
4. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product.
The primary reason for discontinuation of trial product must be specified in the eCRF. If a criterion 
for premature discontinuation of trial product is met, trial product should not be re-initiated but the 
subject should continue with the protocol-specified visit schedule.
See Section 2 for procedures to be performed for subjects discontinuing trial product prematurely.
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.
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.
Only subjects who withdraw consent should be considered as withdrawn from trial.
See Section 8.1.9 for procedures to be performed for subjects withdrawing consent.  
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6.7
Subject replacement
Subjects who are withdrawn or discontinue trial product prematurely will not be replaced.
6.8
Rationale for trial population 
The trial population will include subjects with T2DM who have not achieved adequate glycaemic 
control despite at least 90 days’ treatment with any SGLT2 inhibitor as monotherapy or in 
combination with metformin and for whom additional intensification of treatment is therefore 
necessary. Subjects with renal impairment defined as eGFR < 60 mL/min/1.73m2 and/or history of 
diabetic ketoacidosis while being treated with SGLT2 inhibitors are excluded due to the background 
medications and limitations in their use.
Stable treatment prior to trial enrolment prevents differential effect on trial endpoints, while only 
serious concomitant conditions (e.g., NYHA class IV, history of recent serious cardiac event, 
neoplastic disease, pancreatitis, renal or hepatic impairment in accordance with the current 
Victoza® labelling) which could interfere with trial procedures preclude subjects from entering into 
the trial. The inclusion/exclusion criteria have been chosen to allow for enrolment of a trial 
population as broad as possible to ensure generalisability of trial results to the general population of 
patients with T2DM. The upper limit of HbA1c of 9.5% was chosen due to inclusion of the placebo 
arm in order to avoid increased safety risks for those subjects who are at the higher range out of 
glycaemic control. 
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7
Milestones
Planned duration of recruitment period(FSFV-LSFV): 36 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 in 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 Disclosure33,it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)34, the Food and Drug Administration Amendment Act (FDAAA)35,
European Commission Requirements36, 37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. Refer to the flow chart (Section 2) 
for visit numbers, timing of site visits and phone contacts, visit windows and assessments during the 
trial period. 
8.1.1
Informed consent
Informed consent must be obtained before any trial related activity, see Section 18.2.
8.1.2
Investigator site logs
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one log. 
Only subjects who have signed the informed consent form should be included on the logs. 
8.1.3
Screening (visit 1)
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. At screening, the subject 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. The subject should be instructed to return the card to the investigator at the last trial visit or to 
destroy the card after the last visit.
Screening failures: For screening failures the screening failure form in the eCRF must be 
completed with the reason for not continuing in the trial. Serious adverse events from screening 
failures must be transcribed by the investigator into the eCRF. Follow-up on serious adverse events 
(SAEs) must be carried out according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed. 
8.1.4
Re-screening
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria; this 
includes re-sampling if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters (e.g., HbA1c or ALT).
8.1.5
Fasting visits
The subject should attend fasting visits in a fasting state (see Section 2 for relevant visits). Fasting is 
defined as having consumed only water within the last 8 hours prior to the visit. Glucose lowering 
agents and trial product cannot be taken until after blood sampling has been performed, but other 
prescribed medication should be taken according to prescription.
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If the subject does not attend the visit in a fasting state, completion of procedures except blood 
sampling can be performed. Blood sampling should be re-scheduled, preferably within the visit 
window.
8.1.6
Missed visits
Should a visit be missed, every effort should be made to re-schedule the visit within the allowed
visit window. If this is not possible, the visit should be re-scheduled at the earliest possible date
before the next visit.
8.1.7
Rescue medication visit
A subject eligible to receive rescue medication (see Section 6.4) will be requested to attend the
rescue medication visit (Section 2) prior to initiating any rescue medication (Section 6.4). Hereafter, 
the subject will continue the planned visit schedule including visit 11 (EOT) and visit 12 (Follow-
up) (see Section 2).
8.1.8
Premature discontinuation of trial product visit
A subject who discontinues trial product prematurely (Section 6.5) will be requested to attend the 
premature discontinuation visit (Section 2) prior to discontinuing treatment. Hereafter, the subject 
will continue the planned visit schedule including visit 11 (EOT) and visit 12 (Follow-up) (see 
Section 2).
The subject will be prescribedsuitable marketed treatment(s)at the discretion of the investigator
after discontinuation of trial products. The prescribed medication mustbe captured on the 
concomitant medication form in the eCRF. The primary reason for premature discontinuation of 
trial product must be specified intheend of treatmentformin the eCRF, and final drug 
accountability must be performed. A treatment discontinuation session must be made in the IWRS
(seeSection10).
If after discontinuation of trial product the subject is not willing to attend one or more of the 
scheduled visits, it should be documented in the subject’s medical record. In such case, site visits 
can be replaced by phone contacts in order to retain the subject in the trial. 
8.1.9
Withdrawal from trial
If a subject withdraws consent, the investigator must aim to undertake the same procedures as visit 
11 (EOT; Section 2) as soon as possible. The subject is asked to return the diaries and remainder of 
the trial products. The end-of-trial form and the end of treatment form must be completed and final 
drug accountability must be performed even if the subject is not able to come to the trial site. The 
end-of-trial form question regarding whether the subject has completed the trial period should be 
marked as ‘No’ and the date of withdrawal completed. Although a subject is not obliged to give 
his/her reason(s) for withdrawing consent, the investigator must make a reasonable effort to 
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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. 
A treatment discontinuation session must be performed in the IWRS (Section 10) and the case book 
must be signed by the investigator in the eCRF. If the subject agrees, the follow-up visit 12 (Section 
2) must be completed 1 week after visit 11.
8.2
Assessments
Review of diaries, laboratory reports, electrocardiograms (ECG’s) and the results of physical 
examinations must be documented with the investigator’s or delegated person’s dated signature
either on the front page of the documents or in the subject's medical record. The signed documents 
must be retained at the trial site as source documentation.
If clarification of entries or discrepancies in the diary is needed, the subject must be questioned and 
a conclusion made in the subject’s medical record. Care must be taken not to bias the subject.
8.2.1
Subject related information/assessments 
8.2.1.1
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)
8.2.1.2
Diabetes history and diabetes complications 
Diabetes history and diabetes complications will be recorded in the eCRF at screening (visit 1) and 
consists of:
!
Date of diagnosis of T2DM
!
Information regarding diabetes complications including date of onset of:
–
Diabetic retinopathy (if ‘Yes’ and includes macular oedema, this is to be entered in ‘Further
description of the complication, if applicable’ in the eCRF)
–
Diabetic neuropathy
–
Diabetic nephropathy
–
Macroangiopathy (including peripheral vascular disease) (if ‘Yes’ and includes foot ulcers,
this is to be entered in ‘Further description of the complication, if applicable’ in the eCRF)
8.2.1.3
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial or found as a result of a 
screening procedure or other trial procedures performed before exposure to trial product. Medical 
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history is a medical event that the subject has experienced in the past. Procedures and assessments 
performed at visit 1 and/or visit 2 are considered as screenings procedures.
The information collected for concomitant illness and medical history should be recorded in the 
eCRF and includes the diagnosis, date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE (Section 12).
It must be possible to verify the subject’s medical history in source documents such as the subject’s 
medical record. If a subject is not from the investigators own practice, the investigator must make 
reasonable effort to obtain a copy of the subject’s medical record from a relevant party (e.g.,
primary physician). The investigator must document any attempt to obtain external medical 
information by noting the date(s) when the information was requested and who has been contacted.
8.2.1.4
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 (screening visit; see Section 2). 
Changes in concomitant medication, including antidiabetic treatment and rescue medication, must 
be recorded at each visit as they occur. The eCRF must be updated accordingly.
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date (only start year is applicable if more than one year) and stop date or 
continuation. The total daily dose is only applicable for antidiabetic medication.
If a change 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.
No other treatment with anti-diabetic medication other than those listed in the inclusion criteria is 
allowed for subjects participating in the trial, with the exception of short term insulin treatment (≤ 7 
days in total) in connection with intercurrent illness. If anti-diabetic medication is deemed as 
necessary, this will be considered rescue medication (see Sections 6.4 and 8.1.7). 
8.2.1.5
Childbearing potential  
It must be recorded in the subject’s medical records by the investigator and in the eCRF, whether 
female subjects are of childbearing potential.
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Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.2.3.5. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 1 week after end of treatment.
Female of non-childbearing potential is defined as:
–
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal
ligation
–
Postmenopausal defined as no menses for 12 months without an alternative medical cause
–
Other medical reasons preventing childbearing potential
8.2.1.6
Tobacco use
Details of use of tobacco must be recorded at the first visit. Smoking is defined as smoking at least
one cigarette, cigar or pipe daily. 
–
Smoking status: Never smoked, Previous smoker, Current smoker
8.2.2
Efficacy assessments
8.2.2.1
Body measurements
Height should be assessed without shoes on, in centimetres (cm) or inches (in) and recorded to the 
nearest one decimal place.
Body weight should be assessed without shoes on, wearing only light clothing and is measured and 
recorded as either kilograms (kg) or pounds (lb) to the nearest one decimal place, preferably using 
the same scale throughout the trial. 
Body mass index (BMI) will be calculated automatically in the eCRF once the height and weight 
are entered. 
Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest. It should be recorded to the nearest one decimal 
place using the same non-stretchable measuring tape provided by Novo Nordisk throughout the 
trial.
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing. The subject should be standing, feet together with arms at their side and waist visible. The 
tape should touch the skin but not compress soft tissue and twists in the tape should be avoided. The 
subject should be asked to breathe normally and the measurement should be taken when the subject 
is breathing out gently.
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8.2.2.2
Vital signs
Blood Pressure
At site visits (see Section 2), systolic and diastolic blood pressure should be measured in a sitting 
position after the subject has been resting for at least 5 minutes. Blood pressure must be measured at 
the trial site using a calibrated digital blood pressure monitoring device.
Pulse, resting
Pulse (beats per minute) should be recorded at site visits (see Section 2) after resting for 5 minutes 
in a sitting position. 
8.2.2.3
Self-measured plasma glucose (SMPG)
At visit 1 (see Section 2), the subject will be provided with a blood glucose meter including
auxiliaries (e.g., lancets, plasma calibrated test strips and control solutions) as well as instructions 
for use. The subject will be instructed on how to use the device, including the performance of 
regular calibrations according to the manufacturer’s instructions. As necessary, sites should repeat 
the directions for use to the subject at subsequent visits.
The blood glucose meters use test strips calibrated to plasma values. Therefore, all measurements
performed with capillary blood are automatically calibrated to plasma equivalent glucose values,
as will be shown on the display. Only the blood glucose meter provided by Novo Nordisk should be 
used for the measurements required in the protocol. 
The subject should be instructed how to record the results of the SMPG values in the provided
diaries in case of hypoglycaemic episodes and in order to complete the 7 point profile. The record 
of each SMPG measurement should include the date, time and value. Occasional review by the 
investigator of the values stored in the memory of the blood glucose meter and correct reporting of 
these in the diary is advised in order to ensure adequacy of the data reported in the trial database. 
8.2.2.4
7-point self-measured plasma glucose profile
The subject will be instructed to perform a 7-point SMPG profile two times during the trial,
preferably within one week prior to site visit 2 and site visit 11 (see Section 2), on a day where the 
subject does not anticipate unusual strenuous exercise.
The plasma glucose levels should be measured and recorded in the diary (including date, time and 
value) at the following time points always starting with the first measurement before breakfast.
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Time points for 7-point SMPG profile:
!
Before breakfast
!
90 min after start of breakfast
!
Before lunch
!
90 min after start of lunch
!
Before dinner
!
90 min after start of dinner
!
At bedtime
8.2.2.5
Glucose metabolism and lipids 
Blood samples will be drawn at the site at the time points specified in Section 2 and analysed at the
central laboratory in order to determine levels of the following laboratory parameters:
Glucose metabolism 
!
fasting C-peptide
!
fasting glucagon
!
fasting insulin
!
FPG
!
HbA1c
Fasting plasma glucose 
An 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). 
Low plasma or blood glucose values reported by a laboratory in relation to specific protocol 
assessments should be assessed case by case and should not per default be reported as a 
hypoglycaemic episode on the usual hypoglycaemic episode forms. These should be reported as 
AEs related to the procedure.
Lipids
!
cholesterol
!
free fatty acids (FFA)
!
high density lipoprotein (HDL) cholesterol
!
low density lipoprotein (LDL) cholesterol
!
very low density lipoprotein (VLDL) cholesterol
!
triglycerides
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8.2.3
Safety assessments  
8.2.3.1
Physical examination
A physical examination must be performed and include the following: 
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
!
Lymph node palpation
In addition to the above, the lower left and lower right extremities will be assessed with regards to 
diabetes complications where the evaluation is normal if the subject has no leg or foot ulcers, and 
abnormal if the subject has one or more leg or foot ulcers. If reporting an abnormality, it should be 
specified if the ulcer appears infected or not.
For physical examinations, the evaluations based on investigator’s or delegate’s judgment, must 
follow the categories:
!
Normal
!
Abnormal (any abnormality should be specified in the eCRF free text)
–
Was the result clinically significant? (Yes/No)
8.2.3.2
ECG-12 lead
A 12-lead ECG must be performed (see Section 2) and interpreted locally by the investigator or 
assigned delegate. The evaluations based on the investigator’s or delegate’s judgment, must follow 
the categories:
!
Normal
!
Abnormal (any abnormality should be specified in the eCRF free text)
Was the result clinically significant? (Yes/No)
An ECG performed for any reason unrelated to this trial within 30 days prior to the first visit is 
acceptable providing no clinical signs or symptoms suggestive of cardiac disease have occurred in 
the meantime. If the ECG is performed before the subject has signed the informed consent form, it 
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must be documented in the medical records that the reason for performing the procedure is not 
related to this trial.
Itis allowed to perform the visit 1 ECG between visit 1 and visit 2. The results must be available
prior to randomisation. An ECG performed within 30days before either the rescue medication visit, 
premature discontinuation visit or visit11 (EOT)is acceptable asdatafor the respective visit, 
providing no clinical signs or symptoms suggestive of cardiac disease have occurred after visit 1.
8.2.3.3
NYHA
The functional capacity of subjects with heart disease should be assessed at screening(see Section
2)according to the NYHA classification38and either class I, II, III, IV or ‘none’ should be captured
in the eCRFTable 8–1.
Table 8–1
NYHA criteria for functional capacity
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain.
A. No objective evidence of
cardiovascular disease.
Class II. Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
B. Objective evidence of
minimal cardiovascular disease.
Class III. Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain.
C. Objective evidence of
moderately severe
cardiovascular disease.
Class IV. Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased.
D. Objective evidence of severe
cardiovascular disease.
8.2.3.4
Urinalysis
Urinalysis will be performed at visits specified in Section 2. For these visits, it is preferable that the 
subject collects a morning urine sample on the day of the visit and provides this to the site staff. If 
the subject does not take their sample with them to the site, the urine sample can then be collected 
while at site. Urine samples will be analysed at the central laboratory to determine levels of the 
following safety laboratory parameters: 
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!
Albumin
!
Creatinine
!
Urine albumin creatinine ratio (UACR).
8.2.3.5
Biochemistry and Haematology
Blood samples will be drawn at site at the time points specified in Section 2 and analysed at the
central laboratory in order to determine levels of the following laboratory parameters:
Biochemistry 1
!
Albumin
!
Alanine aminotransferase (ALT)
!
Alkaline phosphatase
!
Aspartate aminotransferase (AST)
!
Amylase
!
Lipase
!
Bilirubins
!
Calcium (total)
!
Calcium corrected
!
Creatine kinase
Biochemistry 2
!
Potassium
!
Sodium
!
Urea
!
Creatinine, usedby central laboratory for calculation of eGFR according totheCKD-EPI
creatinine equationfor adults1. 
Haematology
!
Erythrocytes
!
Haemoglobin
!
Haematocrit
!
Leucocytes
!
Thrombocytes
8.2.3.6
Pregnancy test
For females of child bearing potential; see Sections 2 and 8.2.1.5:
–
presence or absence of serum beta-human chorionic gonadotropin (hCG)
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At visits 1 and 11, a blood pregnancy test will be performed for women of child-bearing potential.
In Section 2 for the period between visits 1 and 11 where marked as (X): for women of childbearing 
potential, a urine-stick pregnancy test must be performed if a menstrual period is missed or 
according to local requirements. If during the phone contact the subject reports a missing menstrual 
period, the subject will have to attend the site for an unscheduled visit as soon as possible to have a 
urine-stick pregnancy test performed.
US only: At the last scheduled visit, male subjects must be asked if their female partner has become 
pregnant (see Section 12.5.2).
Pregnancy testing will not be required (unless required by local law) for women of non-childbearing 
potential (see Section 8.2.1.5).
8.2.3.7
Adverse events
Adverse events (AEs) must be reported at each visit in accordance with the procedures outlined in 
Section 12. 
!
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form 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 and/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.
!
Adverse events requiring additional data collection
For some AEs additional data collection is required and a specific event form (Renal Event) must be 
completed in addition to the AE form. If a renal event is observed during the trial, the following 
additional information must be reported if available:
!
Signs and symptoms of renal failure(acute kidney injury (AKI), acute kidney disease
(AKD)39orchronic kidney disease (CKD)1)
!
Specific laboratory tests supporting the diagnosis
!
Imaging performed supporting the diagnosis
!
Kidney biopsy results
!
Risk or confounding factors identified including exposure to nephrotoxic agents 
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In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section 12.
8.2.3.8
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 recordedby the subject in the diary. These must be transcribed into the eCRF 
(hypoglycaemic episode form) throughout the trial fromvisit 2to visit 12.
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 to current guidelines
An 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 min 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 min 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 of 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
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!
Whether the subject was able to treat him/herself
–
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 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
–
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 concentration41. 
Oral carbohydrates should 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), other
factors not listed or unknown
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms41? 
–
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.
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 data42-44.The subject must be re-
trained in how to report hypoglycaemic episodes if the investigator identifies low SMPG values not 
reported as hypoglycaemic episodes.
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the
hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety information
form must also be filled in, see Section12.
8.2.4
Laboratory assessments
The laboratory analyses(see Sections 8.2.3.4, 8.2.3.5, 8.2.3.6)will be performed by a central 
laboratory.Descriptions of 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 a central laboratory(for central 
laboratorydetails, see attachment I).
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. Laboratory results will be 
sent by the central laboratory to the investigator on an on-going basis.For laboratory report values 
outside the reference range, the investigator must document whether the value is clinically 
significant or not. The investigator must sign and date the reports from the central laboratory or 
document the review in the subject’s medical record on the day of the evaluation. 
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8.2.3.7and Section12.
Laboratory samples will be destroyedno later than thefinalisation of the clinical trial reportor as 
required according tolocal regulations.
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8.3
Subject training
8.3.1
Diaries
The subject must be provided with diaries at the specified visits (Section 2). It is the
responsibility of the investigator to review the diary for the subject’s notes regarding possible AEs,
hypoglycaemic episodes and concomitant medication (see Sections 8.2.1.4, 8.2.3.8, 8.2.3.7 and 12). 
All relevant data must be transcribed into the eCRF during or following the contact with the subject. 
If obtained via phone and a discrepancy is later detected, the values in the eCRF must be corrected.
Each diary dispensed to a subject should be collected at the next clinic visit and retained as source 
data.
The subject should be instructed in recording the following data in the diary according to the 
provided diary instructions:
!
Date of first liraglutide/placebo injection
!
Date and dose of liraglutide/placebo, SGLT2 inhibitor and metformin (if applicable) on the
day prior to each visit
!
7-point SMPG profile including date, actual clock time and SMPG value of all
measurements
!
Details on hypoglycaemic episodes
!
Any medical condition(s) and concomitant medication(s)
8.3.2
Blood glucose meter
See Section 8.2.2.3.
8.3.3
Training in the prefilled pen-injector 
The subject must be trained in how to handle the prefilled pen-injector for liraglutide/placebo, the 
s.c. administration and the gradual increase of the dose at weekly intervals to reach 1.8 mg/day,
when the pre-filled pen injector is handed out (see Section 2 and Section 9.2). Training should be
repeated during the trial at the investigators discretion based on the subjects needs 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
!
Always perform an air shot before the first use of a new prefilled pen
!
The needle should be kept in the skin while counting slowly to 6 after the dose counter has
returned to zero after injection.
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8.4
Subject compliance
Throughout the trial, the investigator will remind the subject to follow the trial procedures and 
requirements to ensure subject compliance. The investigator must assess the compliance of the 
subject at each visit based on a review of glycaemic control, adherence to the visit schedule and 
completion of the subject’s diary including the 7-point SMPG profiles. 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.
Treatment compliance: The doses of metformin (if applicable), SGLT2 inhibitor, liraglutide and 
liraglutide placebo should be reviewed at each site visit by reviewing the previous day’s dose of 
drug in the diary and by monitoring of drug accountability. If a subject is discovered to be 
noncompliant, the investigator must inform the subject of the importance of taking IMP and other 
diabetes treatments as prescribed.
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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. 
Liraglutide or placebo must not be used, if it does not appear clear, 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
Delivery device
Liraglutide 
(IMP, test product)
6 mg/mL
Solution for 
injection
Subcutaneous 
injection (s.c.)
3 mL, prefilled 
pen-injector
Liraglutide placebo
(IMP, reference therapy)
N/A
Liraglutide and placebo are visually identical.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1343,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, see section 2)and at all subsequent dispensing visits.
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9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
Liraglutide 6 mg/mL or
placebo
Store in a 
refrigerator 2°C to 
8°C/36°F to 46°F
Do not freeze
Protect from light
Temperatures 
below 30°C (86ºF)
or in a refrigerator 
2°C to 8°C (36°F -
46°F)
US only: At room 
temperature (59°F -
86°F) or in a 
refrigerator (36°F -
46°F)
Do not freeze
Protect from light
Use within one 
month
US only: Use 
within 30 days
a In-use time starts when the product is taken out of the refrigerator at the home of the subject
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.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
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Drug accountability is performed using the IWRS drug accountability module. The trial products 
must be accounted for at pen level and either recorded as used/partly used, unused or lost. Returned 
pens must be sent for destruction, thus may not be re-allocated to new subjects. 
Subjects must be 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.
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.
The accountability for the NIMP (SGLT2 inhibitor and metformin if applicable) consists of the
recording of the dose and dose frequency at every visit to the site. Dose information must be source 
data verifiable and must be entered in the eCRF.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM:
!
Direction for use for the pen-injector for the trial product
!
Needles for the device ( maximum length to be used is 8 mm)
!
BG meters and BG meter auxiliary supplies
Only needles provided by Novo Nordisk must be used for administration of trial product.
10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone.  
Access to the IWRS must be restricted to and controlled by authorised persons.
IWRS is used for: 
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Dispensing verification (when barcode scanner is used)
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
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IWRSuser manuals will be provided to each trial site.
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.
If a subject requires additional trial product between dispensing visits, the site must perform an 
additional dispensing session intheIWRS.
11 Randomisation procedure and breaking of blinded codes
The trial is a double-blinded trial. A randomisation session will be carried out for all subjects using 
the IWRS. At the randomisation visit (V2), subjects meeting all eligibility criteria will be 
randomised to one of two parallel treatment arms as described in Section 5.1.
Randomisation will be stratified based on baseline metformin use (yes vs. no) to ensure a 2:1 
distribution of the two treatment arms within the two strata. 
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 is allowed to continue in the trial. If the subject must be withdrawn from 
the trial, a withdrawal session must be completed in IWRS.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial 
procedures performed before exposure to trial product (pre-existing conditions should be 
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form 
instead of on an AE form (see Section 8.2.3.8).
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 products:
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
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–
Unlikely - The event is most likely related to aetiology other than the trial product.
•
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported as 
an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
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 an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd.
a. The term “life threatening” in the definition of SAE refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an 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 aminotransferase (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 an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug or use of wrong device. 
–
Use of wrong DUN is not considered a medication error.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the trial 
subject were likely to happen as judged by the investigator, although they did not 
necessarily occur.
Medication errors must be reported on an AE form and a specific event form, see Section 8.2.3.7.
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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. In this trial, details for AEs requiring additional data 
collection and the completion of specific event form (Renal Event) in the eCRF can be found in 
Sections 8.2.3.7, 12.1.5 and 12.2
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 (visit 12). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”
All AEs, observed either by the investigator or the subject, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.  
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
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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. 
!
SAEs with additional data collection: in addition to above, also the specific event form
within 14 calendar days of the investigator's first knowledge of the AE
!
Non –serious AEs with additional data collection: The AE form, and specific event form 
within 14 calendar days of the investigator’s first knowledge of the event
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. 
AE identified
Does the AE require 
a specific event 
form?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
< 14 calendar days
Is the Adverse Event 
serious or non-
serious?
AE form
<14 calendar days
Non-serious
Serious
No
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines for the completion of forms are 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 
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Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents: Company Core Data Sheet for Victoza® 6.0 mg/mL, 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 GCP2. 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 GCP2,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 
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
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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 an 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. 
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/placebo pen injector
!
Novo Nordisk needles
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 complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
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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.
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:
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1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to
be reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal
death (including spontaneous abortion), and congenital anomalies (including those observed at
gross examination or during autopsy of the foetus), as well as other pregnancy complications
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or
follow-up information to the non-serious AE.
SAEs: 
!
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 newborn infant. If the AE occurred in the foetus or newborn 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.
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12.5.2
Pregnancies in female partners of male subjects (for US only)
Male subjects must be instructed to notify the investigator if their female partner becomes pregnant 
during the trial, except in the screening period. At the last scheduled visit, male subjects must be
asked if their female partner has become pregnant.
If a female partner has become pregnant during the trial, the investigator must follow-up on the 
pregnancy outcome and until the newborn infant is one month of age, irrespective of whether the 
trial is completed or not. The investigator must ask the male subject and assess, if the pregnancy 
outcome is normal or abnormal.
When the pregnancy outcome is normal this information is recorded in the subject’s medical record 
only, no further information is collected and reported to Novo Nordisk. 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), the following 
must be reported by the investigator to Novo Nordisk electronically (e.g. in PDF format) or by fax:
1. Reporting of pregnancy information
Information from the male subject has to be reported on the Paternal Form. Furthermore,
information from the female partner (including information about the pregnancy outcome and
health status of the infant until the age of one month) has to be reported on the Maternal Forms
1A, 1B and 2, after an informed consent has been obtained from the female partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The following AEs in the foetus and newborn infant have to be reported:
!
Non-serious AEs evaluated as possible/probably related to the father’s treatment with the
trial product(s).
!
SAEs in the foetus and newborn infant - whether or not related to the father’s treatment with
the trial product(s). This includes an abnormal outcome - such as foetal death (including
spontaneous abortion) and congenital anomalies (including those observed at gross
examination or during autopsy of the foetus).
Forms and timelines for reporting AEs:
See Section 12.5.1, point 2, “Forms and timelines for reporting AEs”
12.6
Precautions and/or overdose
When initiating treatment with liraglutide, the subject may, in some cases, experience loss of
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fluids/dehydration, e.g., in cases of vomiting, nausea or diarrhoea sometimes with a decrease in
kidney function (see Section 18.1). It is important to avoid dehydration by drinking enough fluids.
From clinical trials and marketed use, overdoses of liraglutide have been reported up to 40 times the 
recommended maintenance dose (72 mg). Events reported included severe nausea, vomiting and 
diarrhoea. None of the reports included severe hypoglycaemia. All patients recovered without
complications. In the event of overdose, appropriate supportive treatment should be initiated
according to the subject’s clinical signs and symptoms.
12.7
Committees related to safety
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.
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.
The investigator or delegated staff must 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) 
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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.
13.2
Case report form flow
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
At the end of the trial the investigator must ensure that all remaining data has been entered into the 
eCRF no later than 3 days after last subject last visit (LSLV) at the site in order to ensure the 
planned lock of the database.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
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 (SDV) 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 FSFV. 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). 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 
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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 (except for BMI).
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.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries must not be removed from the trial site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
Monitors will review the subject’s medical records and other source data (e.g., the diaries) to ensure 
consistency and/or identify omissions compared to the eCRF. If discrepanies are found, the 
investigator must be questioned about these.
15 Data management
Data management is the responsibility of Novo Nordisk. Appropriate measures, including 
encryption of data files containing person identifiable data, will be used to ensure confidentiality of 
subject data, when they are transmitted over open networks.
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
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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.
17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded data will be performed 
before the database is locked.
Data from all sites will be analysed and reported together. 
In statistical analyses where stratification is included, anti-diabetic background medication at 
screening (metformin use: yes vs no) will be included based on the actual information collected 
through the eCRF. In case of missing eCRF information concerning the stratification, the 
information collected from the IWRS will be used. 
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. The 
number of values below LLoQ by treatment and visit will be summarised if deemed relevant.
Results from a statistical analysis will, at a minimum be presented by the estimated treatment 
contrasts for the comparison between liraglutide and placebo with associated two-sided 95% 
confidence intervals and p-values corresponding to two-sided tests of no difference.
Primary and secondary estimands
Two estimands addressing different aspects of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand:
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1. Primary estimand
!
de-facto treatment difference at week 26 for all randomised subjects
The primary de-facto estimand assesses the average glycaemic benefit in a future population with 
T2DM with inadequate glycaemic control that results from adding treatment with liraglutide to a 
stable regimen of either SGLT2 inhibitor monotherapy or in combination with metformin including 
potential rescue medication(s) as compared to a continuing stable regimen of either SGLT2 
inhibitor monotherapy or in combination with metformin including potential rescue medication(s). 
Generalisation of this estimand depends among other things on the extent to which the use of rescue 
medication and treatment adherence in this trial reflects clinical practice. All post-baseline 
scheduled visit data will be included in the analysis, including data collected after discontinuation 
of trial product or initiation of rescue medication(s).
2. Secondary estimand
!
de-jure treatment difference at week 26 for all randomised subjects if all subjects adhered to
treatment and did not initiate rescue medication
The secondary de-jure estimand assesses the glycaemic benefit a future subject with inadequate 
glycaemic control is expected to achieve if adding treatment with liraglutide to a stable regimen of 
either SGLT2 inhibitormonotherapy or in combination with metformin as compared to astable 
regimen of either SGLT2 inhibitormonotherapy or in combination with metformin. It is considered 
a clinically relevant estimand as it provides information to treating clinicians about the expected 
glycaemic efficacy of liraglutide compared to placebo for purposes of treating individual subjects. 
Generalisation of this estimand depends among other things on the extent to which the compliance 
to trial product administration in this trial reflects clinical practice. Only post-baseline scheduled 
visit data collected prior to discontinuation of trial product or initiation of rescue medication will be 
included in the analysis. This will avoid confounding from rescue medication. 
Missing data considerations at week 26
When estimating the primary estimand, the proportion of missing data, (i.e.,data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication(s)), is expected to beat amaximum 10% based onprevious experience in T2DM 
trialNN2211-405945. Missing data will mainly be due to withdrawal from trial or loss to follow-up. 
The proportion of missing data when estimating the secondary estimand is expected to be higher 
(25%),since data collected after discontinuation of trial product or initiation of rescue medication(s) 
will be set to missing. Thisassumption of25% missing datais based on previous observationsin
theT2DM trial NN2211-405945. Across treatment arms,the main reasons for missing data are 
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expected to be:early treatment discontinuation due to GI AEs and initiation of rescue medication. 
Initiation of rescue medication is expected to be more frequent in the placebo arm, whereas a higher 
proportion of subjects are expected to discontinue treatment due to AEs in the liraglutide armwhen
compared to the other treatment arm. Overall,the frequency of missing data is expected to be 
similar across treatment arms.
To document the extent and reason for missing data, descriptive summaries and graphical 
representation of extent, reason(s) for and pattern of missing data will be presented by treatment 
arm.
17.1
Sample size calculation
The primary endpoint is change frombaseline to week 26 in HbA1c. The confirmatory secondary 
endpoint is change from baseline to week 26 in body weight. 
The sample size has been determined in order to demonstrate superiority of liraglutide vs. placebo 
both as add-on to SGLT2 inhibitor+/-metformin, with respect to both the primary and 
confirmatory secondary endpoints. The two pre-specified confirmatory tests are assumed to be 
independent. Since the tests are expected to be positively correlated, the assumption of 
independence is viewed as conservative. The hypotheses and testing procedureare described in 
Section 17.2.
The sample size assumptions for treatment effects, adjusted treatment effects and the standard 
deviations (SD) are given in Table 17–1. These are based on results from previous trials in the 
liraglutide Phase 3a clinical development program46-51, and are supported bytrialNN2211-405945. 
They are as follows:
!
Change in HbA1c: a minimal treatment effect (TE) of 0.5% for liraglutide vs. placebo both
as add-on to SGLT2i +/- metformin; standard deviation (SD) assumed to be 1.1%.
!
The proportion of subjects either discontinuing treatment, initiating rescue medication, or
not completing the week 26 HbA1c assessment is expected to be 25% equally distributed
among the two treatment arms. The TE among these 25% of subjects is expected to be
0.25%, leading to an adjusted TE of 0.4375% in the entire trial population.
!
Change in body weight: a minimal treatment effect of 2.0 kg for liraglutide vs. placebo both
as add-on to SGLT2i +/- metformin; SD assumed to be 4.0 kg.
!
Similarly as for HbA1c, the TE among the 25% of subjects either discontinuing treatment,
initiating rescue medication, or not completing the week 26 body weight assessment is
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expected to be reduced to 1.0 kg, leading to an adjusted TE of 1.75 kg in the entire trial 
population.
Table 17–1
Assumptions used in the sample size calculation
Liraglutide vs. placebo 
HbA1c
Body weight
TE
-0.50%
-2.0 kg
Adjusted TE
-0.4375%
-1.75 kg
SD
1.1%
4.0 kg
* TE: treatment effect
Based on these assumptions, the sample size is set to 202 in the liraglutide arm and 101 in the 
placebo arm for the full analysis set in order to achieve 90% power to confirm superiority in 
reducing HbA1c of liraglutide vs. placebo. Marginal powers for individual hypotheses are presented 
in Table 17–2. The planned total sample size in the trial will be 303 subjects.
Table 17–2
Marginal powers for meeting individual hypothesis
Statistical test
HbA1c superiority
Body weight superiority
Power (%)
90%
95%
17.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
period they were on treatment. This will be referred to as contributing to the evaluation “as treated”. 
Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion must 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
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Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including the follow-up visit (visit 
12).
Subjects and data to be used in an analysis will be selected in a two-step manner.
!
Firstly, subjects will be selected based on the specified analysis set 
!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period
Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. The in-trial 
observation period starts at randomisation (as registered in the IWRS) and ends at the date of: 
!
the last direct subject-site contact, which is scheduled to take place 7 days after planned last 
dose of trial product at the follow-up visit (visit 12) for subjects completing the trial
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
death for subjects who die before any of the above
On-treatment: This observation period represents the time period where subjects are considered 
treated with the trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Three slightly different end dates will be needed to 
cover all assessments appropriately:
For AEs, the observation period ends at the first date of:
–
the follow-up visit (visit 12)
–
the last date on trial product + 1 day (hypoglycaemic episodes only)
–
the last date on trial product + 10 days (all AEs excluding hypoglycaemic episodes). The
follow-up visit is scheduled to take place 7 days after the last date on trial product. The visit 
window for the follow-up visit is +/-3 days. 
–
the end-date for the in-trial observation period 
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A different end date is specified for hypoglycaemic episodes to ensure specificity of reversible 
effects of treatment, as well as to ensure consistency across the liraglutide phase 3b clinical 
development programme.
For efficacy and other safety assessments (laboratory assessments, physical examination and 
vital signs) the observation period ends at the last date on trial product + 3 days. This will be 
used in order to ensure specificity of reversible effects of treatment.
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. Specifically it starts at date of first dose of trial product and the observation 
period ends at the first date of:
!
the last dose of trial product + 3 days
!
initiation of rescue medication
The in-trial observation period will be the primary observation period when estimating the primary 
estimand. The on-treatment without rescue observation period will be the primary observation 
period when estimating the secondary estimand. The on-treatment observation period will be 
considered supportive for evaluating efficacy. Safety will be evaluated based on the in-trial and the 
on-treatment observation periods. For hypoglycaemic episodes, a sensitivity analysis will also be 
performed using the on-treatment period specified for all other AEs (last date on trial product + 10 
days).
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period.
Confirmatory hypotheses
For the primary HbA1c endpoint and the secondary confirmatory body weight endpoint, the 
following hypotheses are planned to be tested:
!
Superiority in reducing HbA1c of liraglutide 1.8 mg/day vs. placebo  after 26 weeks
!
Superiority in reducing body weight  of liraglutide 1.8 mg/day vs. placebo after 26 weeks
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A hierarchical testing procedure is used to control the overall type-1 error at a nominal two-sided 
5% level. The primary endpoint and the confirmatory secondary endpoint will be analysed in the 
following order:
A. Primary endpoint (HbA1c)
B. Confirmatory secondary endpoint (Body weight)
In order to be able to conclude significance for the confirmatory secondary endpoint, a significant 
difference in favour of the liraglutide group must be found both for the primary endpoint and the 
confirmatory secondary endpoint.
17.3
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
17.3.1
Primary analysis for the primary estimand
The primary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The primary statistical analysis will be a pattern mixture model using 
multiple imputation to handle missing data assuming that the missing data mechanism is missing at 
random (MAR) within the groups used for imputation. Imputation of missing data at week 26 will 
be done within 4 groups of subjects defined by randomised treatment arm, and whether subjects at 
week 26; (i) have discontinued treatment or initiated rescue medication or (ii) are still on treatment 
and have not initiated rescue medication. It is hereby assumed that the likely values of what the 
missing data would have been if available are best described by information from subjects who at 
week 26 are similar in terms of randomised treatment arm and treatment adherence/rescue status.
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with country and the stratification factor (metformin 
use at baseline: yes vs no) as categorical fixed effects and baseline HbA1c measurement as a 
covariate will be fitted to observed values of the change from baseline at week 26 in HbA1c.
!
The estimated parameters for location and dispersion, as well as the variability of these 
estimates, will be used to impute values for each subject with missing week 26 data based 
on stratification factor and country and baseline HbA1c. Thus, 1000 complete data sets will 
be generated including observed and imputed values.
Analysis used for confirming superiority versus placebo at week 26:
For each of the 1000 (now complete) imputed data sets the change in HbA1c from baseline to week 
26 will be analysed using an ANCOVA with treatment, country and the stratification factor 
(metformin use at baseline: yes vs. no) as categorical fixed effects and baseline HbA1c as covariate. 
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The results obtained from analysing the datasets will be combined using Rubin’s rule52to draw 
inference.
From this analysis theestimated treatment difference between liraglutide and placebo together with
two-sided 95% CI and p-value for the test of nodifferencein effectwill be presented.
17.3.2
Primary analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using post-baseline measurements up 
to and including week 26 from the on-treatment without rescue observation period. The primary 
analysis for the secondary estimand will be performed using a Mixed Model for Repeated 
Measurements (MMRM). A restricted maximum likelihood (REML) will be used in fitting this 
model. The model will include change from baseline in HbA1c measurements collected at scheduled 
visits up to and including week 26 as dependent variables. The independent effects included in the 
model will be treatment, country and the stratification factor (metformin use at baseline: yes vs. no) 
as categorical fixed effects and baseline HbA1c as a covariate, all nested within visit. An 
unstructured covariance matrix for HbA1c measurements within the same subject will be employed, 
assuming measurements from different subjects are independent.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is MAR. Under this assumption the 
statistical behaviour of the missing data (given the observed responses and model fixed effects and 
covariates) is assumed to be the same as for the observed data.
17.3.3
Sensitivity Analysis
To investigate the sensitivity of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line withtheEuropean Medicines 
Agency(EMA)recommendations53,and the US National Research Council54data. 
The evaluation of the robustness of the primary analysis results will primarily be based on a pattern 
mixture model approach using multiple imputation. An overview of the sensitivity analyses for each 
of the estimands are specified below followed by a more detailed description of the three different 
pattern mixture models used.
Sensitivity analyses for the primary estimand
The estimation of the primary estimandwill be repeated using the following sensitivity analyses: 
!
A placebo multiple imputation analysis based on FAS using the in-trial observation period.
!
A placebo multiple imputation analysis differentiating between reasons for discontinuing
treatment prematurely based on FAS using the in-trial observation period.
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!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation 
period.
!
An MMRM analysis (the primary analysis for the secondary estimand) based on FAS using 
the in-trial observation period.
Sensitivity analyses for the secondary estimand
The estimation of the secondary estimand will be repeated using the following sensitivity analyses: 
!
A placebo multiple imputation analysis based on FAS using the on-treatment without rescue 
medication observation period.
!
A placebo multiple imputation analysis based on FAS using the on-treatment observation 
period. This sensitivity analysis aims to compare liraglutide versus placebo for subjects who 
adhere to treatment regardless of whether or not rescue medication has been initiated. 
!
A placebo multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the on-treatment without rescue medication 
observation period.
!
A tipping-point multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period.
17.3.3.1
Pattern mixture models
All three pattern mixture model sensitivity analyses aim to stress-test the primary HbA1c results by 
changing the assumptions for part or all missing data in the liraglutide treatment arm, while 
maintaining the missing at random data assumption for the placebo arm:
!
Placebo multiple imputation analysis: In this sensitivity analysis, missing data at week 26 
for  subjects in both treatment arms will be imputed to resemble the distribution of the week 
26 values observed in the placebo arm. In effect, this imputation approach removes the 
treatment difference between liraglutide and placebo for subjects randomised to liraglutide
with missing data at week 26, given that liraglutide is better in reducing HbA1c than placebo.
!
Placebo multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely: In this sensitivity analysis, only missing data at week 26 for subjects 
who discontinue liraglutide treatment due to treatment related AE(s) will be imputed to 
resemble the distribution of the week 26 values observed in the placebo arm. For subjects 
who discontinue liraglutide treatment for reasons other than treatment related AE(s), missing 
data at week 26 will be imputed as in the primary analysis. Treatment related AEs are 
defined as AEs classified as possible or probable related to trial product as reported by the 
investigator. In effect, this imputation approach removes the treatment difference between 
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liraglutide and placebo for this selected group of subjects randomised to liraglutide. This 
sensitivity analysis is less conservative as compared to the above sensitivity analysis.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will 
first be imputed according to the primary analysis. Second, for the liraglutide arm a penalty 
will be added to the imputed values at week 26. The approach is to gradually increase this 
penalty until the confirmed HbA1c conclusion from the primary analysis is reversed. For 
each hypothesis tested the specific value of the penalty that reverses the conclusion will be 
used to evaluate the robustness of the primary analysis results. 
17.3.3.2
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c. Due to the inherent conservative nature of the sensitivity analyses, it will not 
be a requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results. 
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
Change from baseline to week 26 in body weight will be a confirmatory secondary endpoint. 
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint. Baseline body weight will be used as a covariate instead of baseline 
HbA1c in both the imputation and analysis model. From the analyses, the estimated treatment 
differences between liraglutide and placebo will be presented together with associated two-sided 
95% CIs and p-values for testing no difference from zero. Sensitivity analyses similar to the ones 
pre-specified for testing superiority for the primary HbA1c endpoint will be made to evaluate the 
robustness of the body weight results.
17.4.2
Supportive secondary endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
!
the primary estimand based on FAS using the in-trial observation period
!
the secondary estimand based on FAS using the on-treatment without rescue medication 
observation period
No sensitivity analyses are planned for these.
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17.4.2.1
Efficacy endpoints
Continuous efficacy endpoints
Change from baseline to week 26 in:
!
Fasting Plasma Glucose (FPG)
!
Self-Measured Plasma Glucose (SMPG): 7-point profile:
–
Mean 7-point profile
–
Mean post prandial increments (over all meals)
!
Fasting blood lipids (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL 
cholesterol, triglycerides and free fatty acids)
!
BMI and waist circumference
!
Systolic and diastolic blood pressure
BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height (m) × height (m)) or (kg/m2 = [lb/in2 × 703])
Change from baseline to weeks 14 and 26 in:
!
Glucagon, C-peptide and insulin (all fasting)
The above continuous endpoints will be analysed separately using similar modeling approaches as 
for the primary endpoint with the associated baseline response as a covariate. Fasting lipid profile 
endpoints will be log-transformed prior to analysis with the associated log-transformed baseline 
value as a covariate.
Binary efficacy endpoints
Subjects who after 26 weeks achieve (yes/no):
!
HbA1c <7.0% (53 mmol/mol), American Diabetes Association target
!
HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists target
!
Weight loss ≥3%
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!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic
hypoglycaemia episodes and no weight gain
!
HbA1c <7.0% (53 mmol/mol) and no weight gain
!
HbA1c <7.0% (53 mmol/mol), no weight gain and systolic blood pressure <140 mmHg
!
HbA1c reduction ≥1% (11mmol/mol)
!
HbA1c reduction ≥1% (11mmol/mol) and no weight gain
!
HbA1c reduction ≥1% (11mmol/mol) and weight loss ≥3%
Handling of missing data for the response status of the above binary endpoints will be determined 
from the imputed continuous responses. A total of 1000imputed data sets will be created based on 
the same models as used to analyse HbA1cand body weight. For the secondary estimand the 
MMRM based analysis will be implemented in a multiple imputationsetting. The imputed complete 
data sets will be analysed using a logistic regression model with treatment, stratification factor and 
country as categorical fixed effects and baseline response as covariate (i.e. baseline HbA1cfor 
binary HbA1cendpoints, baseline weight for binary weight endpoints and both baseline HbA1cand 
body weight for the binary endpoints that combines both parameters). Inference comparing 
treatments will be drawn using Rubin’s rule52.
17.4.2.2
Safety endpoints
!
Number of treatment emergent AEs during 26 weeks
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding. 
A treatment emergent AE is defined as an AE with onset in the on-treatment observation period (see 
definition of observation periods in Section 17.2).
Treatment emergent AEs will be summarised 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 1000 patient years of observation time (R) for the on-treatment observation period. 
Supportive summaries of AEs will be made for the in-trial observation period. The development 
over time in gastrointestinal AEs will be evaluated by the use of graphical methods. 
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Other safety endpoints
Change from baseline to week 26 in:
!
Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes
!
Biochemistry: creatinine, creatine kinase, urea, albumin, bilirubins (total), estimated
glomerular filtration rate, alanine aminotransferase, aspartate aminotransferase, alkaline
phosphatase, sodium, potassium, calcium (corrected), calcium (total), amylase and lipase
!
Pulse
!
ECG category
!
Physical examination
!
UACR
The above safety endpoints will be summarised descriptively by treatment arm and visit. 
Categorical safety endpoints will be summarised as counts and relative frequencies.
Classification of Hypoglycaemia:
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent:hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 17.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.   
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification ofhypoglycaemia (seeFigure 17–1).
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)55. 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 in addition to the ADA classification(see Figure 
17–1): 
!
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.
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!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according
to the ADA classification40or BG confirmed by a plasma glucose value <3.1 mmol/L (56
mg/dL) with symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA
classification56or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with
or without symptoms consistent with hypoglycaemia. 
ADA classification40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
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1
ADA classification of hypoglycaemia
Data on treatment emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG confirmed symptomatic hypoglycaemic endpoints
The number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
will be analysed using a negative binomial regression model with a log-link function and the 
logarithm of the duration of the subject’s on-treatment observation period as offset. The model will 
include factors for treatment, stratification factor and country as fixed factors and baseline HbA1c as 
covariate.
The binary endpoint showing whether a subject has at least one treatment emergent severe or BG 
confirmed symptomatic hypoglycaemic episode will be analysed using a logistic regression model 
with treatment, stratification factor and country as fixed factors and baseline HbA1c as covariate.
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18 Ethics
The trial will be conducted in compliance with ICH GCP2and applicable regulatory requirements,
and in accordance with the Declaration of Helsinki3.
18.1
Benefit-risk assessment of the trial
Inclusion and exclusion criteria have been defined in order to ensure that subjects are eligible for 
trial participation.Subjects will be treated within a regimen anticipated to be better than or equal to 
the treatment they receive at the time of entry into the trial. It is expected that all subjects 
participating in the trial will benefit from participation through close contact tothetrial site, 
frequent visits and thereby an intensified evaluation of their diabetes. 
Two thirdsof the subjects will be randomised to receive liraglutide 1.8 mg/day. Asliraglutide has
beenshown to be effective in lowering blood glucose levels, it canbe expected that thesesubjects 
will experienceimproved glucose control during the trial. Subjects may benefit from the effect of 
treatment on weight, as has been previously demonstrated for liraglutide. 
Hyperglycaemic rescue criteria have been defined to ensure that subjects will be offered additional 
glucose lowering rescue treatment should the level of glycaemic control exceed acceptable limits 
during trial participation. Treatment discontinuation criteria have been definedin order to ensure 
subject safetythroughout the trial. 
The trial drugs may be associated with AEs, howeverrelevant precautions have been implemented 
in the design and planned conduct of the trial in order to minimise the risks and inconveniences of 
trialparticipation. Furthermore, subjects will be fully informed about possible AEs and 
inconveniences and will be instructed to contact the investigatorin case of any concerns regarding 
the trial participation. 
Acute kidney injuryis a focus with regards to safety of trial products: 
!
In subjects treated with GLP-1 analogues including liraglutide, gastrointestinal AEs such as
nausea, vomiting and diarrhoea may lead to significant dehydration and secondary acute
kidney injury.
!
SGLT2 inhibitors have also been associated with volume depletion related to AEs, and
ketoacidosis as a result of severe dehydration has been reported during treatment with
SGLT2 inhibitors.
!
Impaired renal function may increase the risk of metformin associated lactic acidosis when
GLP-1 analogues are co-administered with metformin.
The investigator should encourage subjects with gastrointestinal AEs to drink plenty of fluids in 
order to avoid volume depletion and to monitor renal function for signs and symptoms of fluid loss 
during therapy. As a precaution, serum creatinine and other markers of kidney function will be 
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measured regularly. In subjects treated with metformin who experience prolonged or severe nausea 
and vomiting, the investigator should monitor serum creatinine, and if clinically indicated, withhold 
metformin until resolution of renal dysfunction. 
Safety information on Victoza® can be found in the approved local label for Victoza® and in the 
liraglutide (NN2211) abbreviated IB, 17th edition of August 2016or any updates hereof14. Safety 
information of any oral antidiabetic drug (OAD(s))used in this trial can be found in the approved 
local label of the individual OAD.
The subject hasthe right to withdraw from the trial at any time, without giving a specific reason. 
Novo Nordisk will be entitled to retain anydatathat wascollected.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP2and the requirements in the Declaration of 
Helsinki3.
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.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.  
The responsibility for seeking informed consent must remain withthe investigator, but the 
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. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
All written information to subjects 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.
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. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
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Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
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 know the implications of participating in the trial. 
Close 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 secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g., re-training of site staff).
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.
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)
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!
Signed receipt of Investigator’s brochure (if applicable), signed receipt of Victoza® SmPC
or similar labelling (according to local regulations)
!
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
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
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 GCP2
applicable regulatory requirements and the Declaration of Helsinki3. 
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.
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-
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related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
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 
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obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
Twoinvestigatorswill be appointed by Novo Nordisk to reviewand sign the clinical trial report 
(signatory investigators) on behalf of all participating investigators. The signatory investigatorswill 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for researchpublications57.
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 Disclosure33.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trialreport is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
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Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications shouldbe in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors57(sometimes referred to as the 
Vancouver Criteria).
Novo Nordisk will appoint investigator(s) to prepare publications in collaboration with Novo 
Nordisk. 
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems
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.  
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 
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Brochure, or Victoza® SmPC or similar labelling, unexpected SAEs where a causal relationship 
cannot be ruled out, protocol amendments according to local requirements, deviations to the 
protocol implemented to eliminate immediate hazards to the subjects, new information that may 
affect adversely the safety of the subjects or the conduct of the trial (including new benefit-risk 
analysis in case it will have an impact on the planned follow-up of the subjects), annually written 
summaries of the trial status, and other documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
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 
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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. 
Russia: Federal Law of 12 April 2010 No. 61-FZ "On Medicinal Drugs' Circulation" and the Civil 
Code of the Russian Federation.
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27 References
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Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. Liraglutide versus 
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Pratley R, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. One year of 
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Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, 
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Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
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Local SmPC for metformin, current version. 2008.
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33.
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De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
35.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007.
36.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 1 May 
2001.
37.
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 
Official Journal of the European Communities. 2004.
38.
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. Boston: Mass: Little, Brown & Co; 
1994 1994. p. 253-6.
39.
KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
supplements. 2012;2(1):1-138.
40.
Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005;28(5):1245-9.
41.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
42.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
43.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D(2010) 
3374). 3 February 2010.
44.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. Avaliable from: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf. 2009.
45.
Bailey T TR, Tinahones FJ, Rao P, Tsoukas GM, Thomsen AB, Kaltoft MS aMM. Efficacy 
and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-
SWITCH™): a randomized, double-blind, double-dummy, active-controlled 26-week trial. 
Diabetes, Obesity and Metabolim 2016.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
16 September 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086 
Status:
Final
EudraCT no.: Not Applicable
Page:
94 of 94
46.
Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, et al. Liraglutide, a 
once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces 
greater improvements in glycaemic and weight control compared with adding rosiglitazone 
or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-78.
47.
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and Safety 
Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, 
in Type 2 Diabetes The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes 
Care. 2009;32(1):84-90.
48.
Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, 
et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a 
randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 
2009;373(9662):473-81.
49.
Zinman B, Gerich J, Buse J, et al. Efficacy and safety of the human GLP-1 analog 
liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus 
(LEAD-4 Met + TZD). Diabetes Care. 2009;32:1224-30.
50.
Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs 
insulin glargine and placebo in combination with metformin and sulfonylurea therapy in 
type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 
2009;52(10):2046-55.
51.
Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once 
a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-
group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47.
52.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
53.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 
Rev. 1). 2 Jul 2010.
54.
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
55.
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.
56.
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.
57.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
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


Protocol Amendment
CONFIDENTIAL
Date:
26 October 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
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Protocol Amendment
no 01
to Protocol, final version 1.0
dated 16 September 2016
Trial ID:NN2211-4315
LIRA-ADD2SGLT2i – liraglutide versus placebo as add-on to SGLT2
inhibitors
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:
26 October 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
2 of 5
Table of contents   "Double click to update Table of Content" 
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Section 4.2.2.2: Supportive secondary endpoints (Page 19 of 94) ................................................4
2.2
Section 8.2.3.5: Biochemistry and Haematology (Page 41 of 94).................................................4
2.3
Section 17.4.2.2: Safety endpoints (Page 76 of 94).......................................................................4
2.4
Section 17.4.2.2: Safety endpoints (Page 77 of 94).......................................................................4
2.5
Section 17.4.2.2: Safety endpoints (Page 79 of 94).......................................................................5
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
26 October 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
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1
Introduction including rationale for the protocol amendment
Rationale for the changes:
1. 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, where the 
SGLT2 inhibitor is background medication. There is no safety risk for those subjects who do not 
have the bicarbonate assay performed during their treatment. 
2. Minor changes in the statistical section have been made in order to ensure clarity and alignment 
across trials. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
26 October 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
4 of 5
2
Changes
2.1
Section 4.2.2.2: Supportive secondary endpoints (Page 19 of 94)
Supportive secondary safety endpoints
Change from baseline to week 26 in:
!
Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes
!
Biochemistry: serum bicarbonate, creatinine, creatine kinase, urea, albumin, bilirubins 
(total), estimated glomerular filtration rate, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, sodium, potassium, calcium (corrected), calcium 
(total), amylase and lipase
2.2
Section 8.2.3.5: Biochemistry and Haematology (Page 41 of 94)
Biochemistry 2
!
Serum bicarbonate
!
Potassium
!
Sodium 
!
Urea
!
Creatinine
2.3
Section 17.4.2.2: Safety endpoints (Page 76 of 94)
The safety endpoints will be evaluated based on SAS using the on-treatment and in-trial observation 
periods unless otherwise stated. The following endpoints are used to support the safety objective:
Adverse events
!
Number of treatment emergent AEs during 26 weeks
2.4
Section 17.4.2.2: Safety endpoints (Page 77 of 94)
Other safety endpoints
Change from baseline to week 26 in:
!
Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes
!
Biochemistry: serum bicarbonate, creatinine, creatine kinase, urea, albumin, bilirubins (total), 
estimated glomerular filtration rate, alanine aminotransferase, aspartate aminotransferase, 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
26 October 2016
Novo Nordisk
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
5 of 5
alkaline phosphatase, sodium, potassium, calcium (corrected), calcium (total), amylase and 
lipase
!
Pulse
!
ECG category
!
Physical examination
!
UACR
The above safety endpoints will be summarised descriptively by treatment arm and visit. 
Categorical safety endpoints will be summarised as counts and relative frequencies.
The above safety endpoints will be evaluated based on SAS using the on-treatment and in-trial 
observation periods. Continuous endpoints will be summarised descriptively by treatment arm and 
visit. Categorical safety endpoints will be summarised as counts and relative frequencies.
Hypoglycaemia
!
Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes during 26 weeks*
!
Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia episodes 
during 26 weeks (yes/no)
2.5
Section 17.4.2.2: Safety endpoints (Page 79 of 94)
Analysis of severe or BG confirmed symptomatic hypoglycaemic endpoints
The number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
will be analysed for the on-treatment period using a negative binomial regression model with a log-
link function and the logarithm of the duration of the subject’s on-treatment observation period as 
offset. The model will include factors for treatment, stratification factor and country as fixed factors 
and baseline HbA1c as covariate.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
1 of 10
Protocol Amendment
no 02
to Original Protocol, version 1.0, dated 16 September 2016 and
Global Protocol Amendment 01, version 1.0, dated 26 October 2016 (All countries) and
Protocol final version 2.0 dated 26 October 2016
Trial ID:NN2211-4315
LIRA-ADD2SGLT2i – liraglutide versus placebo as add-on to SGLT2
inhibitors
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:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
2 of 10
Table of contents   "Double click to update Table of Content" 
Page
1
Introduction including rationale for the protocol amendment...........................................................3
2     Changes ................................................................................................................................................4
2.1
Section 2: Flow Chart (page 14 of 94) .......................................................................................4
2.2
Section 2: Flow Chart (page 15 of 94) .......................................................................................5
2.3
Section 5.3.2: Background medication (page 23 of 94) ..............................................................6
2.4
Section 5.3.2.1: SGLT2 inhibitors (page 23 of 94).....................................................................6
2.5
Section 8.2.2.4: 7-point self-measured plasma glucose profile (page 37 of 94)...........................7
2.6
Section 8.3.1: Diaries (page 45 of 94)........................................................................................7
2.7
Section 17: Statistical considerations (page 65 of 94).................................................................8
2.8
Section 17.3.1: Primary analysis for the primary estimand (page 71 of 94).................................9
2.9
Section 17.3.3: Sensitivity Analysis (page 72 of 94) ..................................................................9
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
3 of 10
1
Introduction including rationale for the protocol amendment
Rationale for the changes:
1. Parentheses added around the flowchart ‘Pregnancy test’ assessment ‘X’ at premature 
discontinuation of trial product visit and rescue medication visit (X) to indicate that for 
women of childbearing potential, a urine-stick pregnancy test must be performed if a 
menstrual period is missed or according to local requirements.
2. ‘X’ removed from the flowchart rescue medication visit ‘IWRS call’ as IWRS is not used 
for this in this protocol.
3. Minor change in the background medication section (5.3.2), removing the bullet describing 
reimbursement of background medication as is already described in the summary section 1, 
so as not to be repetitive and to avoid ambiguity.
4. Information is added regarding SGLT2 inhibitor lower limb amputation warnings in section 
5.3.2.1 to ensure comprehensive information is provided after recent label updates.
5. Addition of the description of the requirement for 7-point self-measured plasma glucose 
profiles at the rescue medication and premature discontinuation of trial product visits 
included in section 8.2.2.4 as previously described only in the flowchart (section 2).
6. Removed the capture of date and dose of background medication in diary section 8.3.1 as 
this is not collected in the diaries but only in the eCRF concomitant medications form so as 
to avoid collecting the same information twice. 
7. Minor change in statistical section 17 has been made in order to ensure clarity.
8. The imputation of missing data has been modified such that missing values for all patients 
will be modelled after patients who discontinue or initiated rescue therapy.  
9. An ANCOVA allowing for unequal variances has been included as a sensitivity analysis to 
evaluate the robustness of the primary analysis, in particular, the assumption of equal 
variances between treatment groups. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
UTN: U1111-1184-8086
Date:
21 September 2017
Status:
Final
Novo Nordisk
Trial ID: NN2211-4315
EudraCT No.: Not Applicable
Version:
2.0
Page:
4 of 10
2     Changes
2.1
Section 2: Flow Chart (page 14 of 94)
SAFETY
Physical examination
8.2.3.1
X
X
X
X
ECG
8.2.3.2
X
X
X
X
NYHA classification
8.2.3.3
X
Urinalysis
8.2.3.4
X
X
X
X
X
X
Biochemistry 1
8.2.3.5
X
X
X
X
Biochemistry 2
8.2.3.5
X
X
X
X
X
X
X
Haematology
8.2.3.5
X
X
X
X
Pregnancy test
8.2.3.6
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
X
(X)
(X)
Adverse events
8.2.3.7/12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic episodes
8.2.3.8
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Periods
Protocol 
section
Screen-
ing 
Random-
isation
Treatment
End of 
treatment
(EOT)
Follow-
up 
Rescue 
medica-
tion 
6.4/8.1.7
Premature 
Discontin-
uation 
6.5/8.1.8
Site visit (V) 
Phone contact (P) 
V
V
P
P
P
V
P
V
V
V
V
P
V
V
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
Timing of visit: Weeks
up to -2
0
1
2
3
4
6
8
14
20
268.1.9
278.1.9
Visit window: Days
±3
±3
±3
±3
±5
±5
±5
±5
±5
±3
SUBJECT RELATED
INFO/ASSESSMENTS


Protocol Amendment
UTN: U1111-1184-8086
Date:
21 September 2017
Status:
Final
Novo Nordisk
Trial ID: NN2211-4315
EudraCT No.: Not Applicable
Version:
2.0
Page:
5 of 10
2.2    Section 2: Flow Chart (page 15 of 94)
Technical complaints
12.1.6/12.4
X
X
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
IWRS call
10
X
X
X
X
X
X
X
X
X
Dispensing visit
9
X
X
X
X
X
Drug accountability
9.4/10
X
X
X
X
X
X
X
X
Trial Periods
Protocol 
section
Screen-
ing 
Random-
isation
Treatment
End of 
treatment
(EOT)
Follow-
up 
Rescue 
medica-
tion 
6.4/8.1.7
Premature 
Discontin-
uation 
6.5/8.1.8
Site visit (V) 
Phone contact (P) 
V
V
P
P
P
V
P
V
V
V
V
P
V
V
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
Timing of visit: Weeks
up to -2
0
1
2
3
4
6
8
14
20
268.1.9
278.1.9
Visit window: Days
±3
±3
±3
±3
±5
±5
±5
±5
±5
±3
SUBJECT RELATED
INFO/ASSESSMENTS


Protocol Amendment
CONFIDENTIAL
Date:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
6 of 10
2.3
Section 5.3.2: Background medication (page 23 of 94)
SGLT2 inhibitors and metformin
After signing the informed consent, subjects must continue their anti-diabetic background 
medication (SGLT2 inhibitor +/-metformin) throughout the entire trial. Fixed dose combinations of 
SGLT2 inhibitors and metformin are allowed. The background medication should be maintained at 
the same dose level as given at trial entrance and with the same frequency during the entire 
treatment period unless rescue medication is needed or a safety concern (e.g., diabetic ketoacidosis, 
lactic acidosis, hospitalisation for surgery or acute serious medical illness) arises, qualifying for 
changes to the background medication. 
In addition, all background medication: 
!
is considered to be non-investigational medicinal product (NIMP) 
!
will not be provided by Novo Nordisk A/S, except if required by local regulations. In 
countries where it is applicable, SGLT2 inhibitors may be reimbursed by Novo Nordisk A/S
!
should be used in accordance with standard of care and current approved label in the 
individual country 
!
should not exceed the maximum approved dose in the individual country 
2.4
Section 5.3.2.1: SGLT2 inhibitors (page 23 of 94) 
Three SGLT2 inhibitors (dapagliflozin,22 canagliflozin21 and empagliflozin23) are currently 
approved for use either as monotherapy in metformin intolerant patients or in combination with 
metformin, sulfonylurea (SU), thiazolidinedione (TZD) or insulin. In addition, dapagliflozin is 
approved for use in combination with DPP-4 inhibitors22. There is however, currently no approval 
for any SGLT2 inhibitors to be used in combination with a GLP-1 receptor agonist. 
SGLT2 inhibitors may be used at any stage of T2DM provided renal function is adequate. Besides 
lowering blood glucose, treatment with SGLT2 inhibitors also induces weight loss and lowering of 
systolic and diastolic blood pressure. Additionally, cardiovascular benefits of empagliflozin 
treatment have been shown previously in patients with T2DM 29. 
As SGLT2 inhibitors possess a diuretic effect, hypotension and symptoms related to volume 
depletion may occur. Therefore they should be used with caution in the elderly, in any patient 
already on a diuretic and in anyone with a tenuous intravascular volume status. Initial increases in 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
7 of 10
serum creatinine occur with SGLT2 inhibitors, but generally these are small, reversible changes. 
Due to their MOA, SGLT2 inhibitors are less effective when the eGFR is between 45-60 
mL/min1.73 m2 30. The FDA and EMA have added warnings to the three SGLT2 inhibitors’ labels 
regarding diabetic ketoacidosis (normoglycemic), urosepsis and pyelonephritis. The FDA has added 
a warning only to the canagliflozin label regarding lower limb amputation, while EMA has added 
this warning to all three SGLT2 inhibitors’ labels.  
Information about SGLT2 inhibitors including any benefits and/or any side effects, is available in 
the approved local label documents31. 
2.5
Section 8.2.2.4: 7-point self-measured plasma glucose profile (page 37 of 94)
The All subjects will be instructed to perform a 7-point SMPG profile two times during the trial, 
preferably within one week prior to site visit 2 and site visit 11 (see Section 2), on a day where the 
subject does not anticipate unusual strenuous exercise.
Subjects who attend a rescue medication visit or a premature discontinuation of trial product visit, 
will also be instructed to perform a 7-point SMPG profile within one week prior to the visit. 
The plasma glucose levels should be measured and recorded in the diary (including date, time and 
value) at the following time points always starting with the first measurement before breakfast.
Time points for 7-point SMPG profile:
!
Before breakfast
!
90 min after start of breakfast
!
Before lunch
!
90 min after start of lunch
!
Before dinner
!
90 min after start of dinner
!
At bedtime
2.6
Section 8.3.1: Diaries (page 45 of 94)
The subject must be provided with diaries at the specified visits (Section 2). It is the responsibility 
of the investigator to review the diary for the subject’s notes regarding possible AEs, 
hypoglycaemic episodes and concomitant medication (see Sections 8.2.1.4, 8.2.3.8, 8.2.3.7 and 12). 
All relevant data must be transcribed into the eCRF during or following the contact with the subject. 
If obtained via phone and a discrepancy is later detected, the values in the eCRF must be corrected. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
8 of 10
Each diary dispensed to a subject should be collected at the next clinic visit and retained as source 
data. 
The subject should be instructed in recording the following data in the diary according to the 
provided diary instructions:
!
Date of first liraglutide/placebo injection
!
Date and dose of liraglutide/placebo, SGLT2 inhibitor and metformin (if applicable) on the 
day prior to each visit
!
7-point SMPG profile including date, actual clock time and SMPG value of all 
measurements
!
Details on hypoglycaemic episodes
!
Any medical condition(s) and concomitant medication(s)
2.7
Section 17: Statistical considerations (page 65 of 94)
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded data will be performed 
before the database is locked.
Data from all sites will be analysed and reported together. 
In statistical analyses where stratification is included, anti-diabetic background medication at 
screening randomisation (metformin use: yes vs no) will be included based on the actual 
information collected through the eCRF. In case of missing eCRF information concerning the 
stratification, the information collected from the IWRS will be used. 
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. The 
number of values below LLoQ by treatment and visit will be summarised if deemed relevant.
Results from a statistical analysis will, at a minimum be presented by the estimated treatment 
contrasts for the comparison between liraglutide and placebo with associated two-sided 95% 
confidence intervals and p-values corresponding to two-sided tests of no difference.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
9 of 10
2.8
Section 17.3.1: Primary analysis for the primary estimand (page 71 of 94)
The primary estimand will be estimated based on the FAS using week 26 measurements from the
in-trial observation period. The primary statistical analysis will be a pattern mixture model using
multiple imputation to handle missing data assuming that the missing data mechanism is missing at
random (MAR) within the groups used for imputation. Imputation of missing data at week 26 will
be done within 4 groups of subjects defined by randomised treatment arm, and whether subjects at
week 26; (i) have discontinued treatment or initiated rescue medication or (ii) are still on treatment
and have not initiated rescue medication. Imputation of missing data at week 26 for all subjects will 
be based on patients who discontinue or initiate rescue therapy within each randomised treatment 
arm, respectively. It is hereby assumed that the likely values of what the missing data would have 
been if available are best reasonably described by information from subjects on the same treatment 
arm who at week 26 had discontinued or initiated rescue therapy. are similar in terms of 
randomised treatment arm and treatment adherence/rescue status.
Missing values for each group will be imputed as follows:
! An analysis of covariance (ANCOVA) with country and the stratification factor (metformin
use at baseline: yes vs no) as categorical fixed effects and baseline HbA1c measurement as 
a covariate will be fitted to observed values of the change from baseline at week 26 in 
HbA1c.
! The estimated parameters for location and dispersion, as well as the variability of these
estimates, will be used to impute values for each subject with missing week 26 data based
on stratification factor and country and baseline HbA1c. Thus, 1000 complete data sets will
be generated including observed and imputed values.
2.9
Section 17.3.3: Sensitivity Analysis (page 72 of 94)
To investigate the sensitivity of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line with the European Medicines 
Agency (EMA) recommendations53, and the US National Research Council54 data. 
The evaluation of the robustness of the primary analysis results will primarily be based on a pattern 
mixture model approach using multiple imputation. An overview of the sensitivity analyses for each 
of the estimands are specified below followed by a more detailed description of the three different 
pattern mixture models used.
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analyses: 
!
A placebo multiple imputation analysis based on FAS using the in-trial observation period.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
21 September 2017
Novo Nordisk
Trial ID: NN2211-4315
Version:
2.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
10 of 10
!
A placebo multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the in-trial observation period.
!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation 
period.
!
An MMRM analysis (the primary analysis for the secondary estimand) based on FAS using 
the in-trial observation period.
!
A multiple imputation analysis similar to the primary analysis, but instead using ANCOVA 
allowing for unequal variances between the two treatment groups based on FAS using the 
in-trial observation period. This sensitivity analysis aims to evaluate the assumption of 
equal variances implicit in the ANCOVA model for the primary analysis.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02964247   
Sponsor trial ID: 
NN2211-4315 
Official title of study: 
LIRA-ADD2SGLT2i – liraglutide versus placebo as add-on to 
SGLT2 inhibitors 
Document date: 
26 September 2018 
 


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CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
1 of 22
Statistical Analysis Plan
Trial ID: NN2211-4315
LIRA-ADD2SGLT2i – liraglutide versus placebo as add-on to 
SGLT2 inhibitors
Author:
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.
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.
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.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
2 of 22
Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................4
2
Statistical considerations .....................................................................................................................4
2.1
Sample size calculation .............................................................................................................6
2.2
Definition of analysis sets..........................................................................................................7
2.3
Primary endpoint.....................................................................................................................10
2.3.1
Primary analysis for the primary estimand..............................................................10
2.3.2
Primary analysis for the secondary estimand ..........................................................11
2.3.3
Sensitivity Analysis ...............................................................................................11
2.3.3.1
Pattern mixture models.....................................................................13
2.3.3.2
Assessment of sensitivity analyses....................................................13
2.4
Secondary endpoints ...............................................................................................................14
2.4.1
Confirmatory secondary endpoints.........................................................................14
2.4.2
Supportive secondary endpoints .............................................................................14
2.4.2.1
Efficacy endpoints............................................................................14
2.4.2.2
Safety endpoints...............................................................................16
3
Changes to the statistical analyses planned in the protocol..............................................................19
4
References ..........................................................................................................................................21
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
3 of 22
List of abbreviations
ADA 
American Diabetes Association
AE
adverse event
ANCOVA
analysis of covariance
BG 
blood glucose
BMI
body mass index
CI
confidence interval
CRF
case report form
CTR
clinical trial report
ECG 
electrocardiogram
eCRF
electronic case report form
eGFR 
estimated glomular filtration rate
EoT
end-of-text
FAS
full analysis set
GI
gastro-intestinal
HbA1c
glycosylated haemoglobin
HDL 
high-density lipoprotein
IWRS
interactive voice/web response sytem
LDL 
low-density lipoprotein
LLoQ
lower limit of quantification
LOCF
last observation carried forward
MAR            missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM        mixed model repeated measurements
PD
pharmacodynamics
PK
pharmacokinetics
PP
per protocol
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SD
standard deviation
SE
standard error
SGLT2
sodium-glucose co-transporter 2
SMPG 
self-measured plasma glucose
T2DM
type 2 diabetes mellitus
TE
Treatment effect
VLDL 
very low density lipoprotein
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
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EudraCT No.: Not Applicable
Page:
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1
Introduction
1.1
Trial information
This is a 26-week, 2:1 randomised, placebo controlled, double blind, multicentre, multinational, 
confirmatory, two arm trial investigating the effect and safety of liraglutide versus placebo as addon 
to an SGLT2 inhibitor with or without metformin in subjects with type 2 diabetes mellitus who have 
not achieved adequate glycaemic control despite stable treatment with SGLT2 inhibitor ± 
metformin. Refer to the protocol for further details.
1.2
Scope of the statistical analysis plan
This Statistical Analysis Plan (SAP) is based on the statistical analyses of NN2211-4315 as planned 
in the trial protocol. 
Changes to the statistical methods proposed in this SAP and the reason for the change must be 
reported in the clinical trial report (CTR).
This SAP is based on the protocol version 3.0 (dated 01 September 2017).
2
Statistical considerations
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded data will be performed 
before the database is locked.
Data from all sites will be analysed and reported together. 
In statistical analyses where stratification is included, anti-diabetic background medication at 
randomisation (metformin use: yes vs no) will be included based on the actual information collected 
through the eCRF. In case of missing eCRF information concerning the stratification, the 
information collected from the IWRS will be used. 
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. The 
number of values below LLoQ by treatment and visit will be summarised if deemed relevant.
Results from a statistical analysis will, at a minimum be presented by the estimated treatment 
contrasts for the comparison between liraglutide and placebo with associated two-sided 95% 
confidence intervals and p-values corresponding to two-sided tests of no difference.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
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Primary and secondary estimands
Two estimands addressing different aspects of the trial objective will be defined; a primary de-facto 
(effectiveness) estimand and a secondary de-jure (efficacy) estimand:
1.
Primary estimand
!
de-facto treatment difference at week 26 for all randomised subjects
The primary de-facto estimand assesses the average glycaemic benefit in a future population with 
T2DM with inadequate glycaemic control that results from adding treatment with liraglutide to a 
stable regimen of either SGLT2 inhibitor monotherapy or in combination with metformin including 
potential rescue medication(s) as compared to a continuing stable regimen of either SGLT2 
inhibitor monotherapy or in combination with metformin including potential rescue medication(s). 
Generalisation of this estimand depends among other things on the extent to which the use of rescue 
medication and treatment adherence in this trial reflects clinical practice. All post-baseline 
scheduled visit data will be included in the analysis, including data collected after discontinuation 
of trial product or initiation of rescue medication(s).
2.
Secondary estimand 
!
de-jure treatment difference at week 26 for all randomised subjects if all subjects adhered to 
treatment and did not initiate rescue medication
The secondary de-jure estimand assesses the glycaemic benefit a future subject with inadequate 
glycaemic control is expected to achieve if adding treatment with liraglutide to a stable regimen of 
either SGLT2 inhibitor monotherapy or in combination with metformin as compared to a stable 
regimen of either SGLT2 inhibitor monotherapy or in combination with metformin. It is considered 
a clinically relevant estimand as it provides information to treating clinicians about the expected 
glycaemic efficacy of liraglutide compared to placebo for purposes of treating individual subjects. 
Generalisation of this estimand depends among other things on the extent to which the compliance 
to trial product administration in this trial reflects clinical practice. Only post-baseline scheduled 
visit data collected prior to discontinuation of trial product or initiation of rescue medication will be 
included in the analysis. This will avoid confounding from rescue medication. 
Missing data considerations at week 26
When estimating the primary estimand, the proportion of missing data, (i.e., data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication(s)), is expected to be at a maximum 10% based on previous experience in T2DM 
trial NN2211-40591. Missing data will mainly be due to withdrawal from trial or loss to follow-up. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
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The proportion of missing data when estimating the secondary estimand is expected to be higher 
(25%), since data collected after discontinuation of trial product or initiation of rescue medication(s) 
will be set to missing. This assumption of 25% missing data is based on previous observations in 
the T2DM trial NN2211-40591. Across treatment arms, the main reasons for missing data are 
expected to be: early treatment discontinuation due to GI AEs and initiation of rescue medication. 
Initiation of rescue medication is expected to be more frequent in the placebo arm, whereas a higher 
proportion of subjects are expected to discontinue treatment due to AEs in the liraglutide arm when 
compared to the other treatment arm. Overall, the frequency of missing data is expected to be 
similar across treatment arms.
To document the extent and reason for missing data, descriptive summaries and graphical 
representation of extent, reason(s) for and pattern of missing data will be presented by treatment 
arm.
2.1
Sample size calculation
The primary endpoint is change from baseline to week 26 in HbA1c. The confirmatory secondary 
endpoint is change from baseline to week 26 in body weight. 
The sample size has been determined in order to demonstrate superiority of liraglutide vs. placebo 
both as add-on to SGLT2 inhibitor +/- metformin, with respect to both the primary and 
confirmatory secondary endpoints. The two pre-specified confirmatory tests are assumed to be 
independent. Since the tests are expected to be positively correlated, the assumption of 
independence is viewed as conservative. The hypotheses and testing procedure are described in 
Section 2.2.
The sample size assumptions for treatment effects, adjusted treatment effects and the standard 
deviations (SD) are given in Table 2–1. These are based on results from previous trials in the 
liraglutide Phase 3a clinical development program234567, and are supported by trial NN2211-40591. 
They are as follows:
!
Change in HbA1c: a minimal treatment effect (TE) of 0.5% for liraglutide vs. placebo both 
as add-on to SGLT2i +/- metformin; standard deviation (SD) assumed to be 1.1%.
!
The proportion of subjects either discontinuing treatment, initiating rescue medication, or 
not completing the week 26 HbA1c assessment is expected to be 25% equally distributed 
among the two treatment arms. The TE among these 25% of subjects is expected to be 
0.25%, leading to an adjusted TE of 0.4375% in the entire trial population.
!
Change in body weight: a minimal treatment effect of 2.0 kg for liraglutide vs. placebo both 
as add-on to SGLT2i +/- metformin; SD assumed to be 4.0 kg.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
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!
Similarly as for HbA1c, the TE among the 25% of subjects either discontinuing treatment, 
initiating rescue medication, or not completing the week 26 body weight assessment is 
expected to be reduced to 1.0 kg, leading to an adjusted TE of 1.75 kg in the entire trial 
population.
Table 2–1
Assumptions used in the sample size calculation
Liraglutide vs. placebo 
HbA1c
Body weight
TE
-0.50%
-2.0 kg
Adjusted TE
-0.4375%
-1.75 kg
SD 
1.1%
4.0 kg
* TE: treatment effect
Based on these assumptions, the sample size is set to 202 in the liraglutide arm and 101 in the 
placebo arm for the full analysis set in order to achieve 90% power to confirm superiority in 
reducing HbA1c of liraglutide vs. placebo. Marginal powers for individual hypotheses are presented 
in Table 2–2. The planned total sample size in the trial will be 303 subjects.
Table 2–2
Marginal powers for meeting individual hypothesis
Statistical test
HbA1c superiority
Body weight superiority
Power (%)
90%
95%
2.2
Definition of analysis sets
The following analysis sets will be defined:
Full analysis set (FAS): includes all randomised subjects. Subjects in the FAS will contribute to 
evaluation “as randomised”.
Safety analysis set (SAS): includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
period they were on treatment. This will be referred to as contributing to the evaluation “as treated”. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
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Exclusion of data from analyses will be used restrictively and normally no data should be excluded 
from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion must 
be documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
Data selections and observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including the follow-up visit (visit 
12).
Subjects and data to be used in an analysis will be selected in a two-step manner.
!
Firstly, subjects will be selected based on the specified analysis set 
!
Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period
Definition of the observation periods:
In-trial: This observation period represents the time period where subjects are considered to be in 
the trial, regardless of discontinuation of trial product or initiation of rescue medication. The in-trial 
observation period starts at randomisation (as registered in the IWRS) and ends at the date of: 
!
the last direct subject-site contact, which is scheduled to take place 7 days after planned last 
dose of trial product at the follow-up visit (visit 12) for subjects completing the trial
!
withdrawal for subjects who withdraw their informed consent
!
the last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
death for subjects who die before any of the above
On-treatment: This observation period represents the time period where subjects are considered 
treated with the trial product. The observation period is a subset of the in-trial observation period. It 
starts at the date of first dose of trial product. Three slightly different end dates will be needed to 
cover all assessments appropriately: 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
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EudraCT No.: Not Applicable
Page:
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For AEs, the observation period ends at the first date of:
-
the follow-up visit (visit 12)
-
the last date on trial product + 1 day (hypoglycaemic episodes only)
-
the last date on trial product + 7 days (all AEs excluding hypoglycaemic episodes). The 
follow-up visit is scheduled to take place 7 days after the last date on trial product. the end-
date for the in-trial observation period 
A different end date is specified for hypoglycaemic episodes to ensure specificity of reversible 
effects of treatment, as well as to ensure consistency across the liraglutide phase 3b clinical 
development programme.
For efficacy and other safety assessments (laboratory assessments, physical examination and 
vital signs) the observation period ends at the last date on trial product + 1 day. This will be 
used in order to ensure specificity of reversible effects of treatment.
On-treatment without rescue medication: This observation period is a subset of the on-treatment 
observation period, where subjects are considered treated with trial product, but have not initiated 
any rescue medications. Specifically it starts at date of first dose of trial product and the observation 
period ends at the first date of:
!
the last dose of trial product + 1 day
!
initiation of rescue medication
The in-trial observation period will be the primary observation period when estimating the primary 
estimand. The on-treatment without rescue observation period will be the primary observation 
period when estimating the secondary estimand. The on-treatment observation period will be 
considered supportive for evaluating efficacy. Safety will be evaluated based on the in-trial and the 
on-treatment observation periods. For hypoglycaemic episodes, a sensitivity analysis will also be 
performed using the on-treatment period specified for all other AEs (last date on trial product + 7
days).
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period.
Confirmatory hypotheses
For the primary HbA1c endpoint and the secondary confirmatory body weight endpoint, the 
following hypotheses are planned to be tested:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
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EudraCT No.: Not Applicable
Page:
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!
Superiority in reducing HbA1c of liraglutide 1.8 mg/day vs. placebo after 26 weeks
!
Superiority in reducing body weight  of liraglutide 1.8 mg/day vs. placebo after 26 weeks
A hierarchical testing procedure is used to control the overall type-1 error at a nominal two-sided 
5% level. The primary endpoint and the confirmatory secondary endpoint will be analysed in the 
following order:
A. Primary endpoint (HbA1c)
B. Confirmatory secondary endpoint (Body weight)
In order to be able to conclude significance for the confirmatory secondary endpoint, a significant 
difference in favour of the liraglutide group must be found both for the primary endpoint and the 
confirmatory secondary endpoint.
2.3
Primary endpoint
The primary endpoint is change from baseline to week 26 in HbA1c.
2.3.1
Primary analysis for the primary estimand
The primary estimand will be estimated based on the FAS using week 26 measurements from the 
in-trial observation period. The primary statistical analysis will be a pattern mixture model using 
multiple imputation to handle missing data assuming that the missing data mechanism is missing at 
random (MAR) within the groups used for imputation. Imputation of missing data at week 26 for all 
subjects will be based on patients who discontinue or initiate rescue therapy within each randomised 
treatment arm, respectively. It is hereby assumed that the values of what the missing data would 
have been if available are reasonably described by information from subjects on the same treatment 
arm who at week 26 had discontinued or initiated rescue therapy. 
Missing values for each group will be imputed as follows:
!
An analysis of covariance (ANCOVA) with country and the stratification factor (metformin 
use at baseline: yes vs no) as categorical fixed effects and baseline HbA1c measurement as a 
covariate will be fitted to observed values of the change from baseline at week 26 in HbA1c.
!
The estimated parameters for location and dispersion, as well as the variability of these 
estimates, will be used to impute values for each subject with missing week 26 data based 
on stratification factor and country and baseline HbA1c. Thus, 1000 complete data sets will 
be generated including observed and imputed values.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
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EudraCT No.: Not Applicable
Page:
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In case there is an insufficient number of  patients who discontinue or initiate rescue medication 
within each levels of country or strata,  an analysis of covariance (ANCOVA)  with baseline HbA1c 
measurement as a covariate alone will be fitted to observed values of the change from baseline at 
week 26 in HbA1c. 
Analysis used for confirming superiority versus placebo at week 26:
For each of the 1000 (now complete) imputed data sets the change in HbA1c from baseline to week 
26 will be analysed using an ANCOVA with treatment, country and the stratification factor 
(metformin use at baseline: yes vs. no) as categorical fixed effects and baseline HbA1c as covariate. 
The results obtained from analysing the datasets will be combined using Rubin’s rule8 to draw 
inference.
From this analysis the estimated treatment difference between liraglutide and placebo together with
two-sided 95% CI and p-value for the test of no difference in effect will be presented.
2.3.2
Primary analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using post-baseline measurements up 
to and including week 26 from the on-treatment without rescue observation period. The primary 
analysis for the secondary estimand will be performed using a Mixed Model for Repeated 
Measurements (MMRM). A restricted maximum likelihood (REML) will be used in fitting this 
model. The model will include change from baseline in HbA1c measurements collected at scheduled 
visits up to and including week 26 as dependent variables. The independent effects included in the 
model will be treatment, country and the stratification factor (metformin use at baseline: yes vs. no) 
as categorical fixed effects and baseline HbA1c as a covariate, all nested within visit. An 
unstructured covariance matrix for HbA1c measurements within the same subject will be employed, 
assuming measurements from different subjects are independent.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is MAR. Under this assumption the 
statistical behaviour of the missing data (given the observed responses and model fixed effects and 
covariates) is assumed to be the same as for the observed data.
2.3.3
Sensitivity Analysis
To investigate the sensitivity of the primary analysis results, complementary and separate analyses 
will be performed for the primary and secondary estimand. In line with the European Medicines 
Agency (EMA) recommendations9, and the US National Research Council10 data. 
The evaluation of the robustness of the primary analysis results will primarily be based on a pattern 
mixture model approach using multiple imputation. An overview of the sensitivity analyses for each 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
01 June 2018
1RYR1RUGLVN
Trial ID: NN2211-4315
Version:
1.0
UTN: U1111-1184-8086
Status:
Final
EudraCT No.: Not Applicable
Page:
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of the estimands are specified below followed by a more detailed description of the three different 
pattern mixture models used.
Sensitivity analyses for the primary estimand
The estimation of the primary estimand will be repeated using the following sensitivity analyses: 
!
A placebo multiple imputation analysis based on FAS using the in-trial observation period.
!
A placebo multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the in-trial observation period.
!
A tipping-point multiple imputation analysis based on FAS using the in-trial observation 
period.
!
An MMRM analysis (the primary analysis for the secondary estimand) based on FAS using 
the in-trial observation period.
!
A multiple imputation analysis similar to the primary analysis, but instead using ANCOVA 
allowing for unequal variances between the two treatment groups based on FAS using the 
in-trial observation period. This sensitivity analysis aims to evaluate the assumption of equal 
variances implicit in the ANCOVA model for the primary analysis.
Sensitivity analyses for the secondary estimand
The estimation of the secondary estimand will be repeated using the following sensitivity analyses: 
!
A placebo multiple imputation analysis based on FAS using the on-treatment without rescue 
medication observation period.
!
A placebo multiple imputation analysis based on FAS using the on-treatment observation 
period. This sensitivity analysis aims to compare liraglutide versus placebo for subjects who 
adhere to treatment regardless of whether or not rescue medication has been initiated. 
!
A placebo multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely based on FAS using the on-treatment without rescue medication 
observation period.
!
A tipping-point multiple imputation analysis based on FAS using the on-treatment without 
rescue medication observation period.
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Statistical Analysis Plan
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2.3.3.1
Pattern mixture models
All three pattern mixture model sensitivity analyses aim to stress-test the primary HbA1c results by 
changing the assumptions for part or all missing data in the liraglutide treatment arm, while 
maintaining the missing at random data assumption for the placebo arm:
!
Placebo multiple imputation analysis: In this sensitivity analysis, missing data at week 26 
for  subjects in both treatment arms will be imputed to resemble the distribution of the week 
26 values observed in the placebo arm. In effect, this imputation approach removes the 
treatment difference between liraglutide and placebo for subjects randomised to liraglutide 
with missing data at week 26, given that liraglutide is better in reducing HbA1c than placebo.
!
Placebo multiple imputation analysis differentiating between reasons for discontinuing 
treatment prematurely: In this sensitivity analysis, only missing data at week 26 for subjects 
who discontinue liraglutide treatment due to treatment related AE(s) will be imputed to 
resemble the distribution of the week 26 values observed in the placebo arm. For subjects 
who discontinue liraglutide treatment for reasons other than treatment related AE(s), missing 
data at week 26 will be imputed to resemble the distribution of the week 26 values observed 
within each treatment arm. Treatment related AEs are defined as AEs classified as possible 
or probable related to trial product as reported by the investigator. In effect, this imputation 
approach removes the treatment difference between liraglutide and placebo for this selected 
group of subjects randomised to liraglutide. This sensitivity analysis is less conservative as 
compared to the above sensitivity analysis.
!
Tipping-point multiple imputation analysis: In this sensitivity analysis, missing data will 
first be imputed according to the primary analysis. Second, for the liraglutide arm a penalty 
will be added to the imputed values at week 26. The approach is to gradually increase this 
penalty until the confirmed HbA1c conclusion from the primary analysis is reversed. For 
each hypothesis tested the specific value of the penalty that reverses the conclusion will be 
used to evaluate the robustness of the primary analysis results. 
2.3.3.2
Assessment of sensitivity analyses
The results from the sensitivity analyses will be collectively used to interpret the robustness of the 
trial results for HbA1c. Due to the inherent conservative nature of the sensitivity analyses, it will not 
be a requirement that all confirmatory hypotheses are consistently confirmed across the sensitivity 
analyses. Thus, no absolute success criteria will be pre-defined for each sensitivity analysis. The 
sensitivity results in totality will be used to substantiate the credibility of the trial results. 
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2.4
Secondary endpoints
2.4.1
Confirmatory secondary endpoints
Change from baseline to week 26 in body weight will be a confirmatory secondary endpoint. 
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint. Baseline body weight will be used as a covariate instead of baseline 
HbA1c in both the imputation and analysis model. From the analyses, the estimated treatment 
differences between liraglutide and placebo will be presented together with associated two-sided 
95% CIs and p-values for testing no difference from zero. Sensitivity analyses similar to the ones 
pre-specified for testing superiority for the primary HbA1c endpoint will be made to evaluate the 
robustness of the body weight results.
2.4.2
Supportive secondary endpoints
The below supportive secondary efficacy endpoints will be evaluated for:
!
the primary estimand based on FAS using the in-trial observation period
!
the secondary estimand based on FAS using the on-treatment without rescue medication 
observation period
No sensitivity analyses are planned for these.
2.4.2.1
Efficacy endpoints
Continuous efficacy endpoints
Change from baseline to week 26 in:
!
Fasting Plasma Glucose (FPG)
!
Self-Measured Plasma Glucose (SMPG): 7-point profile:
-
Mean 7-point profile
-
Mean post prandial increments (over all meals)
!
Fasting blood lipids (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL 
cholesterol, triglycerides and free fatty acids)
!
BMI and waist circumference
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!
Systolic and diastolic blood pressure
BMI will be calculated based on body weight and height based on the formulae:
BMI kg/m2 = body weight (kg)/(height (m) × height (m)) or (kg/m2 = [lb/in2 × 703])
Change from baseline to weeks 14 and 26 in:
!
Glucagon, C-peptide and insulin (all fasting)
The above continuous endpoints will be analysed separately using similar modeling approaches as 
for the primary endpoint with the associated baseline response as a covariate. Fasting lipid profile 
endpoints as well as fasting glucagon, C-peptide and insulin endpoints will be log-transformed prior 
to analysis with the associated log-transformed baseline value as a covariate.
Binary efficacy endpoints
Subjects who after 26 weeks achieve (yes/no):
!
HbA1c <7.0% (53 mmol/mol), American Diabetes Association target
!
HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists target
!
Weight loss ≥3%
!
HbA1c <7.0% (53 mmol/mol) without severe or blood glucose confirmed symptomatic 
hypoglycaemia episodes and no weight gain
!
HbA1c <7.0% (53 mmol/mol) and no weight gain
!
HbA1c <7.0% (53 mmol/mol), no weight gain and systolic blood pressure <140 mmHg
!
HbA1c reduction ≥1% (11mmol/mol) 
!
HbA1c reduction ≥1% (11mmol/mol) and no weight gain 
!
HbA1c reduction ≥1% (11mmol/mol) and weight loss ≥3%
Handling of missing data for the response status of the above binary endpoints will be determined
from the imputed continuous responses. A total of 1000 imputed data sets will be created based on 
the same models as used to analyse HbA1c and body weight. The imputed complete data sets will be 
analysed using a logistic regression model with treatment, stratification factor and country as 
categorical fixed effects and baseline response as covariate (i.e. baseline HbA1c for binary HbA1c
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UTN: U1111-1184-8086
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endpoints, baseline weight for binary weight endpoints and both baseline HbA1c and body weight 
for the binary endpoints that combines both parameters). Inference comparing treatments will be 
drawn using Rubin’s rule8.
For the secondary estimand the binary endpoints will be determined from the continuous responses 
and response status for missing values at week 26 will be determined from MMRM predicted 
values. The complete data set will analysed using a logistic regression model with treatment, 
stratification factor and country as categorical fixed effects and baseline response as covariate.
2.4.2.2
Safety endpoints
The safety endpoints will be evaluated based on SAS using the on-treatment and in-trial observation 
periods unless otherwise stated. The following endpoints are used to support the safety objective:
Adverse events
!
Number of treatment emergent AEs during 26 weeks
All AEs will be coded using version 20.1 of the Medical Dictionary for Regulatory Activities 
(MedDRA) coding. 
A treatment emergent AE is defined as an AE with onset in the on-treatment observation period (see 
definition of observation periods in Section 2.2).
Treatment emergent AEs will be summarised 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 1000 patient years of observation time (R) for the on-treatment observation period. 
Supportive summaries of AEs will be made for the in-trial observation period. The development 
over time in gastrointestinal AEs will be evaluated by the use of graphical methods. 
Other safety endpoints
Change from baseline to week 26 in:
!
Haematology: haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes
!
Biochemistry: serum bicarbonate, creatinine, creatine kinase, urea, albumin, bilirubins 
(total), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, sodium, 
potassium, calcium (corrected), calcium (total)
!
Pulse
!
ECG category
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Statistical Analysis Plan
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Date:
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UTN: U1111-1184-8086
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!
Physical examination
The above safety endpoints will be evaluated based on SAS using the on-treatment and in-trial 
observation periods. Continuous endpoints will be summarised descriptively by treatment arm and 
visit. Categorical safety endpoints will be summarised as counts and relative frequencies.
Ratio to baseline from week 26 in:
Amylase, lipase, estimated glomerular filtration rate, all urinalysis assessments.
Furthermore, these endpoints will be summarised by geometric means instead of arithmetic means, 
and will be plotted on logarithmic scale.
Hypoglycaemia
!
Number of treatment emergent severe or blood glucose confirmed symptomatic 
hypoglycaemic episodes during 26 weeks*
!
Treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemia 
episodes during 26 weeks (yes/no)
Classification of Hypoglycaemia:
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only.
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 2.2).
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.   
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 2–1).
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)11. 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 in addition to the ADA classification (see Figure 2–
1): 
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Statistical Analysis Plan
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Date:
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!
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.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification12 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia. 
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification13 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with 
or without symptoms consistent with hypoglycaemia. 
ADA classification12 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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Statistical Analysis Plan
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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
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–1
ADA classification of hypoglycaemia
Data on treatment emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG confirmed symptomatic hypoglycaemic endpoints
Because the number of hypoglycaemic episodes are expected to be very low in this trial, statistical 
analyses of severe or BG-confirmed symptomatic hypoglycaemia will not be performed.
3
Changes to the statistical analyses planned in the protocol
The following changes from the protocol are implemented in this SAP.
On-treatment observation period
The on-treatment period is changed from treatment start date to treatment end date + 3 days to 
treatment start date to treatment end date + 1 day for efficacy laboratory parameters and from 
treatment start date to treatment end date + 10 days to treatment start date to treatment end date + 7 
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Statistical Analysis Plan
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Date:
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UTN: U1111-1184-8086
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days. The on-treatment period is consistent with the PSPS ensuring consistency across the 
liraglutide phase 3b clinical development programme. 
Pattern mixture model with multiple imputation
The strategy for the multiple imputation is specified in case only few subjects discontinue trial 
product or initiate rescue medication. If there is an insufficient number of patients who discontinue 
or initiate rescue medication for any level of country and strata, an analysis of covariance 
(ANCOVA) with baseline HbA1c measurement as a covariate will be fitted to observed values of 
the change from baseline at week 26 in HbA1c. For the placebo multiple imputation differentiating 
between reasons for discontinuing treatment prematurely, it has been further clarified that for 
subjects with reasons other than treatment related AE(s), missing data at week 26 will be imputed 
to resemble the distribution of the week 26 values observed within each treatment arm. 
Responder analyses for the secondary estimand
For the responder analyses for the secondary estimand, binary endpoints will be determined from 
the continuous responses. For missing values at week 26 the binary endpoints will be determined 
from MMRM predicted values.   
MedDRA version
It has been clarified that MedDRA version 20.1 is used for this trial. 
Log-transformation
Further description is added on which assessments are treated as lognormally distributed. Fasting 
lipid profile endpoints, fasting glucagon, C-peptide and insulin will be analysed on the logarithmic 
scale. Amylase, lipase, estimated glomerular filtration rate and urinalysis assessments will be 
presented in ratio to baseline from week 26 and summarised by geometric means instead of 
arithmetic means. 
Analyses of hypoglycaemic episodes
The pre-specified analyses of severe or BG-confirmed symptomatic hypoglycaemic episodes will 
not be performed due to sparse data. Following text was removed from the statistical considerations 
section:
The number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
will be analysed for the on-treatment period using a negative binomial regression model with a log-
link function and the logarithm of the duration of the subject’s on-treatment observation period as 
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Statistical Analysis Plan
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Date:
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offset. The model will include factors for treatment, stratification factor and country as fixed factors 
and baseline HbA1c as covariate.
The binary endpoint showing whether a subject has at least one treatment emergent severe or BG 
confirmed symptomatic hypoglycaemic episode will be analysed using a logistic regression model 
with treatment, stratification factor and country as fixed factors and baseline HbA1c as covariate.
4
References
                                               
1.   Bailey T TR, Tinahones FJ, Rao P, Tsoukas GM, Thomsen AB, Kaltoft MS aMM. Efficacy and      
safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes 
(LIRASWITCH™): a randomized, double-blind, double-dummy, active-controlled 26-week trial. 
Diabetes, Obesity and Metabolim 2016.
2.  Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, et al. Liraglutide, a 
once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater 
improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in 
subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-78. 
3.  Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and Safety 
Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 
2 Diabetes The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care. 
2009;32(1):84-90.
4.  Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et 
al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 
52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473-81.
5.  Zinman B, Gerich J, Buse J, et al. Efficacy and safety of the human GLP-1 analog liraglutide in 
combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD -4 Met + 
TZD). Diabetes Care. 2009;32:1224-30.
6. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin 
glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes 
mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046-55.
7. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a 
day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallelgroup, 
multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47. 
8. Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987.
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9. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 Rev. 1). 2 
Jul 2010.
10. National Academy of Sciences (NAS). The Preventio n and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010. 
11. 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.
12. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005;28(5):1245-9.
13. 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. 
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