Clinical trial NCT02730377
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2016-03-28; Completion date: 2019-08-12
Enrollment: 1991 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of the trial is to investigate efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to metformin background treatment vs. OADs as add-on to metformin background treatment for 104 weeks of treatment in subjects with type 2 diabetes.

Detailed description:

Arms: arm 1: Add-on to metformin arm 2: Add-on to metformin. Treatment with one OAD selected at the discretion of the investigator. Subjects randomised to the OAD arm must remain on the same OAD throughout the trial.
Interventions: intervention 1: liraglutide intervention 2: alpha-glucosidase inhibitors intervention 3: DPP-4 inhibitors intervention 4: meglitinides intervention 5: SGLT-2 inhibitors intervention 6: sulphonylurea intervention 7: thiazolidinediones
Intervention descriptions: intervention 1: Trial product will be prescribed by the investigator and dispensed by pharmacy or similar. intervention 2: Trial product will be prescribed by the investigator and dispensed by pharmacy or similar. intervention 3: Trial product will be prescribed by the investigator and dispensed by pharmacy or similar. intervention 4: Trial product will be prescribed by the investigator and dispensed by pharmacy or similar. intervention 5: Trial product will be prescribed by the investigator and dispensed by pharmacy or similar. intervention 6: Trial product will be prescribed by the investigator and dispensed by pharmacy or similar. intervention 7: Trial product will be prescribed by the investigator and dispensed by pharmacy or similar.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02730377 
Sponsor trial ID: 
NN2211-4232 
Official title of study: 
LIRA-PRIME: Efficacy in controlling glycaemia with 
Victoza® (liraglutide) as add-on to metformin vs. OADs as 
add-on to metformin after up to 104 weeks of treatment in 
subjects with type 2 diabetes inadequately controlled with 
metformin monotherapy and treated in a primary care setting 
Document date: 
14 January 2020 
 


Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol Amendment 01 -Global......................................................................................................
Protocol Amendment 02 -US............................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
/LUDJOXWLGH
Trial ID:NN2211-4232
Clinical Trial Report
Appendix 16.1.1
 January 2020
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
1 of 67
Protocol
Trial ID:NN2211-4232
LIRA-PRIME: Efficacy in controlling glycaemia with Victoza® (liraglutide) as 
add-on to metformin vs. OADs as add-on to metformin after up to 104 weeks of 
treatment in subjects with type 2 diabetes inadequately controlled with 
metformin monotherapy and treated in a primary care setting
A 104-week randomised, phase 4, two-arm, open-label, active-controlled, multicentre, 
multinational, parallel-group trial
Trial phase: 4
Protocol originators
Clinical trial management
Novo Nordisk A/S
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:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
2 of 67
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures and Tables ............................................................................................................................5
List of abbreviations.........................................................................................................................................6
1
Summary....................................................................................................................................................7
2
Flow chart ................................................................................................................................................10
3
Background information and rationale for the trial............................................................................13
3.1
Background information..............................................................................................................13
3.2
Rationale for the trial...................................................................................................................13
4
Objectives and endpoints........................................................................................................................14
4.1
Objectives ....................................................................................................................................14
4.2
Endpoints .....................................................................................................................................14
4.2.1
Primary endpoint........................................................................................................14
4.2.2
Secondary endpoints..................................................................................................15
4.2.2.1
Supportive secondary endpoints..........................................................15
5
Trial design ..............................................................................................................................................16
5.1
Type of trial .................................................................................................................................16
5.2
Definition of primary care ...........................................................................................................16
5.3
Rationale for trial design..............................................................................................................17
5.4
Treatment of subjects...................................................................................................................17
5.5
Treatment after discontinuation of trial product ..........................................................................18
5.6
Rationale for treatment ................................................................................................................18
6
Trial population.......................................................................................................................................19
6.1
Number of subjects......................................................................................................................19
6.2
Inclusion criteria ..........................................................................................................................19
6.3
Exclusion criteria.........................................................................................................................19
6.4
Withdrawal criteria ......................................................................................................................20
6.5
Subject replacement.....................................................................................................................20
6.6
Rationale for trial population.......................................................................................................20
6.7
Pre-trial HbA1c .............................................................................................................................21
7
Milestones.................................................................................................................................................21
8
Methods and assessments .......................................................................................................................21
8.1
Visit procedures...........................................................................................................................21
8.1.1
Informed consent .......................................................................................................21
8.1.2
Investigator site logs ..................................................................................................22
8.1.3
Screening ...................................................................................................................22
8.1.4
Randomisation ...........................................................................................................22
8.1.5
Withdrawals...............................................................................................................22
8.1.6
Site visits....................................................................................................................22
8.1.7
Visits attended fasting................................................................................................23
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
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8.1.8
Missed visits ..............................................................................................................23
8.2
Subject related information..........................................................................................................23
8.2.1
Concomitant illness and medical history...................................................................23
8.2.2
Concomitant medication............................................................................................23
8.2.3
Demography...............................................................................................................24
8.2.4
Diabetes details..........................................................................................................24
8.2.5
Smoking status...........................................................................................................24
8.3
Assessments.................................................................................................................................24
8.3.1
Body measurements...................................................................................................24
8.3.2
Vital signs ..................................................................................................................24
8.3.3
Hypoglycaemic episodes ...........................................................................................25
8.3.4
Self-measured blood glucose (SMBG)......................................................................26
8.3.5
Diaries........................................................................................................................26
8.3.6
Pregnancy test............................................................................................................27
8.4
Laboratory assessments ...............................................................................................................27
8.5
Subject compliance......................................................................................................................28
9
Trial supplies ...........................................................................................................................................29
9.1
Trial products...............................................................................................................................29
9.2
Labelling......................................................................................................................................29
9.3
Storage .........................................................................................................................................30
9.4
Drug accountability and destruction............................................................................................30
9.5
Auxiliary supplies........................................................................................................................31
10 Interactive web response system............................................................................................................31
11 Randomisation procedure ......................................................................................................................32
12 Adverse events, technical complaints and pregnancies .......................................................................32
12.1
Definitions ...................................................................................................................................32
12.2
Reporting of adverse events.........................................................................................................36
12.3
Follow-up of adverse events........................................................................................................38
12.4
Technical complaints and technical complaint samples ..............................................................40
12.4.1
Reporting of technical complaints .............................................................................40
12.4.2
Collection, storage and shipment of technical complaint samples ............................41
12.5
Pregnancies..................................................................................................................................41
12.5.1
Pregnancies in female subjects ..................................................................................41
12.5.2
Pregnancies in female partners of male subjects (Applicable to US only)................43
12.6
Precautions and/or overdose ........................................................................................................44
12.7
Committees related to safety........................................................................................................44
12.7.1
Novo Nordisk safety committee ................................................................................44
13 Case report forms....................................................................................................................................44
13.1
Corrections to case report forms..................................................................................................45
13.2
Case report form flow..................................................................................................................45
14 Monitoring procedures ...........................................................................................................................45
15 Data management....................................................................................................................................46
16 Computerised systems.............................................................................................................................46
17 Statistical considerations ........................................................................................................................47
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
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17.1
Sample size calculation................................................................................................................47
17.2
Definition of analysis sets............................................................................................................48
17.3
Primary endpoint..........................................................................................................................49
17.4
Secondary endpoints....................................................................................................................49
17.4.1
Supportive secondary endpoints ................................................................................49
17.4.1.1
Efficacy endpoints...............................................................................49
17.4.1.2
Safety endpoints..................................................................................51
18 Ethics........................................................................................................................................................56
18.1
Benefit-risk assessment of the trial..............................................................................................56
18.2
Informed consent .........................................................................................................................56
18.3
Data handling...............................................................................................................................57
18.4
Information to subject during trial...............................................................................................57
18.5
Premature termination of the trial and/or trial site.......................................................................57
19 Protocol compliance................................................................................................................................58
20 Audits and inspections ............................................................................................................................58
21 Critical documents ..................................................................................................................................59
22 Responsibilities........................................................................................................................................60
23 Reports and publications........................................................................................................................61
23.1
Communication of results............................................................................................................61
23.1.1
Authorship .................................................................................................................62
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................62
23.2
Investigator access to data and review of results.........................................................................63
24 Retention of clinical trial documentation..............................................................................................63
24.1
Retention of clinical trial documentation.....................................................................................63
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............64
26 Indemnity statement ...............................................................................................................................64
27 References................................................................................................................................................66
Attachment I – Global list of key staff and relevant departments and suppliers
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
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Table of Figures and Tables
Page
Figure 5–1
Schematic overview of the trial design...................................................................................16
Figure 12–1
Initial reporting of AEs..........................................................................................................38
Table 17–1
Sample size calculations for different scenarios – total number of randomised subjects......48
Figure 17–1
Novo Nordisk classification of hypoglycaemia.....................................................................54
Figure 17–2
ADA classification of hypoglycaemia....................................................................................55
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
6 of 67
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
BG
blood glucose
CRF
case report form
DPP-4
Dipeptidyl peptidase 4,
eCRF
electronic case report form
FAS
full analysis set
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
IEC
independent ethics committee
IRB
institutional review board
IWRS
interactive web response system
MESI
medical event of special interest
OAD
oral antidiabetic drug
SAE
serious adverse event
SGLT-2
Sodium/glucose cotransporter 2
SDV
source data verification
SmPC
summary of product characteristics
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes
UTN
Universal Trial Number
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
7 of 67
1
Summary
Objectives and endpoints:
Primary objective:
To compare the efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to 
metformin vs. oral antidiabetic drugs (OADs) as add-on to metformin after up to 104 weeks of 
treatment in subjects with type 2 diabetes (T2D) treated in primary care, inadequately controlled 
with metformin monotherapy.
Secondary objective:
To compare efficacy and safety of Victoza® as add-on to metformin vs. OADs as add-on
to metformin after up to 104 weeks of treatment in subjects with type 2 diabetes (T2D) treated in
primary care, inadequately controlled with metformin monotherapy.
Primary endpoint:
Time to inadequate glycaemic control defined as HbA1c > 7.0% (53 mmol/mol) at two scheduled 
consecutive visits after the first 26 weeks of treatment and up to 104 weeks.
Key supportive secondary endpoints:
!
Number of subjects who at 104 weeks or at premature treatment discontinuation achieve 
(Yes/No):
o
HbA1c ≤ 6.5% (48 mmol/mol) 
o
HbA1c ≤7.0% (53 mmol/mol) without weight gain
!
Change from baseline at 104 weeks or at premature treatment discontinuation in:
o
Fasting plasma glucose (FPG)
o
Body weight
Trial design:
This is a 104-week randomised, two-arm, open-label, active-controlled, multicentre, multi-national, 
parallel-group, phase 4 trial.
Trial population:
It is planned to randomise 1994 subjects.
Key inclusion criteria:
!
Male or female ≥ 18 years of age at the time of signing informed consent.
!
Subjects diagnosed (clinically) with type 2 diabetes ≥90 days prior to the screening visit.
!
Stable daily dose of metformin as monotherapy ≥ 1500 mg or maximum tolerated dose 
within 60 days prior to the screening visit.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
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!
HbA1c 7.5-9.0% (59-75 mmol/mol) (both inclusive) and measured within the last 90 days 
prior to the screening visit.
Key exclusion criteria:
!
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).
!
Receipt of any investigational medicinal product within 30 days before the screening visit.
!
Treatment with any medication for the indication of diabetes other than metformin in a 
period of 60 days before the screening visit. An exception is short-term treatment (≤7 days 
in total) with insulin in connection with intercurrent illness.
!
Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
Definition of primary care:
This trial will be conducted in a primary care environment which is defined as a non-
endocrinologist, non-diabetologist clinic/practice/surgery or equivalent that provides continuing 
care to persons with any undiagnosed sign, symptom or health concern not limited by problem 
origin (biological, behavioural or social), organ system or diagnosis. The primary care practice may 
be the patient’s first point of contact with the health care system. 
The doctors/physicians that work in primary care are often referred to as general practitioners 
(GPs), primary care doctors/physicians and family doctors/physicians. The primary care practice 
may include a team of physicians and other health care professionals.
The definition of primary care is adapted from the definition used by the American Academy of 
Family Physicians (AAFP)1. 
Assessments:
!
HbA1c
!
Fasting plasma glucose
!
Body weight
!
Hypoglycaemic episodes
Trial products:
Victoza®:
!
Victoza® (liraglutide 3.0 mL;6.0 mg/mL)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
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Oral antidiabetic drugs (OADs):
!
Alpha-glucosidase inhibitors
!
DPP-4 inhibitors
!
Meglitinides
!
SGLT-2 inhibitors
!
Sulphonylureas  
!
Thiazolidinediones
CONFIDENTIAL


Protocol
UTN: U1111-1170-7035
Date:
04 September 2015
Status:
Final
Novo Nordisk
Trial ID: NN2211-4232
EudraCT no.: 2015-002417-29 
Version:
1.0
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2
Flow chart
Trial Periods
Screening1 
Random
isation
Treatment
End of 
treatment
Follow up
Visit type
S
S
P/S2
S
S
S
S
S
S
S
S
S
P
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
Timing of visit, Weeks
Up to -2
0
2
4
16
26
38
52
65
78
91
104
105
Visit window, Days
±7
±4
±10
±10
±10
±10
±10
±10
±10
±4
+4
Informed consent
x
In/exclusion criteria
x
Randomisation
x
IWRS session
x
x
Withdrawal criteria3
x
x
x
x
x
x
x
x
x
x
Medical history /Concomitant 
illness
x
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography
x
Diagnosis of diabetes
x
Diabetes complications
x
x
x
Diabetes treatment history
x
Smoking status
x
Pregnancy urine test
x
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
x
Handout ID card
x
Height
x
Body weight
x
x
x
x
x
x
x
x
x
x
Blood sampling
x
x
x
x
x
x
x
x
x
x
- Fasting plasma glucose
x
x
x
x
x
- HbA1c
x
x
x
x
x
x
x
x
x
- Lipids
x
x
x
- Biochemistry
x
x
x
- Haematology
x
x
x
Attend visit fasting
x
x
x
x
x


Protocol
UTN: U1111-1170-7035
Date:
04 September 2015
Status:
Final
Novo Nordisk
Trial ID: NN2211-4232
EudraCT no.: 2015-002417-29 
Version:
1.0
Page:
11 of 67
Trial Periods
Screening1 
Random
isation
Treatment
End of 
treatment
Follow up
Visit type
S
S
P/S2
S
S
S
S
S
S
S
S
S
P
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
13
Timing of visit, Weeks
Up to -2
0
2
4
16
26
38
52
65
78
91
104
105
Visit window, Days
±7
±4
±10
±10
±10
±10
±10
±10
±10
±4
+4
Systolic and diastolic blood 
pressure, sitting
x
x
x
x
x
x
x
x
x
x
Pulse, sitting
x
x
x
x
x
x
x
x
x
x
Handout diary and instruct in 
use5
x
x
x
x
x
x
x
x
x
Handout blood glucose meter 
and instruct in use
x
Prescription of trial product
x
x
x
x
x
x
x
x
x
Information about trial 
product handling
x
(x)4
(x)4
(x)4
(x)4
(x)4
(x)4
(x)4
(x)4
(x)4
Drug accountability
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
Hypoglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
Technical complaints
x
x
x
x
x
x
x
x
x
x
End of treatment
x
End of trial
x
Sign off Casebook
x
Abbreviations: IWRS: Interactive web response system; P/S: Phone contact/Site visit; S: Site visit; P: Phone contact
1 Procedures and assessments relating to visit 1 may be conducted at visit 2 prior to randomisation. Trial related procedures (including 
requesting the subject to be fasting) are not allowed before signing of informed consent
2 Visit 3 can be performed as either a phone contact or a site visit at the discretion of the investigator.
3 Subjects withdrawing from the trial should attend end of treatment visit as soon as possible.


Protocol
UTN: U1111-1170-7035
Date:
04 September 2015
Status:
Final
Novo Nordisk
Trial ID: NN2211-4232
EudraCT no.: 2015-002417-29 
Version:
1.0
Page:
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4 Information about and training in trial product handling to be given at the discretion of the investigator.
5 Diaries should be reviewed at every visit. Relevant data should be reported into the eCRF.


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
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EudraCT no.: 2015-002417-29 
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3
Background information and rationale for the trial
3.1
Background information
The trial will be conducted in compliance with this protocol, ICH GCP2 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.
Information about Victoza® (liraglutide) (hereafter referred to as Victoza®) and oral antidiabetic 
drugs (OAD’s) used as comparators is available in the approved local label documents.
The HbA1c lowering effect of Victoza® in subjects with type 2 diabetes (T2D) is well established. 
The completed phase 3 and phase 4 trials with Victoza® have tested Victoza® in most treatment 
scenarios used for patients with T2D including combination with metformin4. In all these treatment 
scenarios the efficacy of Victoza® was demonstrated and there were no major safety concerns. 
Furthermore, Victoza® has been shown to be safe and efficacious in subjects with moderate renal 
impairment5.
For an assessment of benefits and risks of the trial, see section 18.1.
3.2
Rationale for the trial
The deterioration of glycaemic control over time in T2D, driven by progressive deterioration of 
pancreatic β-cell function, may require continuous intensification of antidiabetic treatment in order 
to provide optimal glycaemic care. In addition, in patients suffering from chronic diseases such as 
T2D, non-compliance to prescribed treatment can be associated with poor treatment outcomes. 
Generally, treatment compliance and adherence decrease with increasing complexity of the 
treatment regimen, e.g. add-on of a third antidiabetic drug6. Thus, the durability of the glycaemic 
control of the antidiabetic drugs added when metformin monotherapy no longer provides adequate 
glycaemic control is important. GLP-1 receptor agonists (RAs) are recommended as a potential 
second line treatment in the American Diabetes Association (ADA) and the European Association 
for the study of Diabetes (EASD) position statement7. However, the durability of the glucose-
lowering effect of GLP-1 receptor agonists is not described in the position statement.
Data have suggested that GLP-1 may increase β-cell mass and function in animal models8,9. 
Further, GLP-1 RAs may improve β-cell function and growth in human subjects. One trial reported 
that in patients with T2D Victoza® provided robust enhancement of β-cell function that was 
sustained over 48 weeks10. Therefore, early introduction of Victoza® may promote durability of 
glycaemic control.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
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The majority of patients with T2D are treated in the primary care setting, however, most clinical 
trials are conducted in secondary care units. This may make the generalisability of the trial results -
ie. whether the results can be reasonably applied to routine primary care practice -  challenging11,12.  
The objective of this trial is to compare the efficacy in controlling glycaemia with Victoza® as add-
on to metformin vs. OADs as add-on to metformin after up to 104 weeks of treatment in subjects 
with type 2 diabetes treated in primary care, inadequately controlled with metformin monotherapy.
4
Objectives and endpoints
4.1
Objectives
Primary objective:
To compare the efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to 
metformin vs. OADs as add-on to metformin after up to 104 weeks of treatment in subjects with 
T2D treated in primary care, inadequately controlled with metformin monotherapy.
Secondary objective:
To compare efficacy and safety of Victoza® as add-on to metformin vs. OADs as add-on
to metformin after up to 104 weeks of treatment in subjects with type 2 diabetes (T2D) treated in
primary care, inadequately controlled with metformin monotherapy.
4.2
Endpoints
4.2.1
Primary endpoint
Time to inadequate glycaemic control defined as HbA1c > 7.0% (53 mmol/mol) at two scheduled 
consecutive visits after the first 26 weeks of treatment and up to 104 weeks.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT no.: 2015-002417-29 
Page:
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4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary endpoints
!
Time to premature treatment discontinuation (for any reason including inadequate glycaemic 
control)
!
Change from baseline in HbA1c at 104 weeks or at premature treatment discontinuation
!
Number of subjects who at 104 weeks or at premature treatment discontinuation achieve 
(Yes/No):
o
HbA1c ≤ 6.5% (48 mmol/mol) *
o
HbA1c ≤7.0% (53 mmol/mol) without weight gain *
o
HbA1c ≤7.0%  (53 mmol/mol) without treatment emergent severe hypoglycaemic 
episodes or blood glucose confirmed symptomatic hypoglycaemic episodes
o
HbA1c ≤7.0% (53 mmol/mol) without weight gain and no treatment emergent severe 
hypoglycaemic episodes or blood glucose confirmed symptomatic hypoglycaemic 
episodes
!
Change from baseline at 104 weeks or at premature treatment discontinuation will be 
evaluated for:
o
Fasting plasma glucose (FPG) *
o
Body weight *
o
BMI
o
Systolic and diastolic blood pressure
!
Number of severe hypoglycaemic episodes
!
Number of severe or blood glucose confirmed symptomatic hypoglycaemic episodes
!
Number of documented symptomatic hypoglycaemic episodes (ADA)
!
Number of serious adverse events (SAEs)
!
Number of AEs leading to permanent discontinuation of trial product
!
Change from baseline at 104 weeks or at premature treatment discontinuation will be 
evaluated for:
o
Lipids
o
Biochemistry
o
Haematology
o
Pulse
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov 
and EudraCT)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
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5
Trial design
5.1
Type of trial
This is a 104-week randomised, two-arm, open-label, active-controlled, multicentre, multi-national, 
parallel-group, phase 4 trial.
The trial will be conducted in the primary care setting. Please refer to definition in section 5.2
Subjects’ eligibility is based on the subjects’ medical history including HbA1c, measured up to 90 
days before screening. 
Subjects will be randomised to one of two treatment arms: Victoza® or OAD. The OAD (see list 
below in section 5.4) will be chosen at the discretion of the investigator. Trial product will be 
prescribed by the investigator and dispensed by pharmacy or similar (see section 9).
The maximum trial duration for the individual subjects will be up to approximately 107 weeks. The 
trial includes an up to 2-week screening period, followed by an up to 104-week randomised 
treatment period and a 1-week follow up period after end of treatment. Please see Figure 5–1 for a 
schematic overview of the trial.
Figure 5–1
Schematic overview of the trial design
5.2
Definition of primary care 
This trial will be conducted in a primary care environment which is defined as a non-
endocrinologist, non-diabetologist clinic/practice/surgery or equivalent that provides continuing 
care to persons with any undiagnosed sign, symptom or health concern not limited by problem 
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
Status:
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origin (biological, behavioural or social), organ system or diagnosis. The primary care practice may 
be the patient’s first point of contact with the health care system. 
The doctors/physicians that work in primary care are often referred to as general practitioners 
(GPs), primary care doctors/physicians and family doctors/physicians. The primary care practice 
may include a team of physicians and other health care professionals.
The definition of primary care is adapted from the definition used by the American Academy of 
Family Physicians (AAFP)1
5.3
Rationale for trial design
A randomised, parallel-group trial design with two treatment arms has been chosen to avoid bias. A 
104-week duration has been chosen as this was deemed appropriate for assessing time to inadequate 
glycaemic control. Due to the duration of the trial and the prescription of trial drug by the 
investigator an open-label design has been chosen as a double-dummy design was deemed 
unfeasible.
5.4
Treatment of subjects
After randomisation, subjects in the Victoza® arm will initiate treatment with 0.6 mg/day with 
subsequent dose escalation according to approved local label up to final dose of 1.8 mg/day at the 
discretion of the investigator. A maintenance dose of 1.2 mg is accepted if the subject’s HbA1c is <
7.0% (53 mmol/mol), however, escalation to 1.8 mg should be attempted if the subjects’ HbA1c is ≥
7% (53 mmol/mol). 
Subjects randomised to the OAD arm will initiate treatment with one OAD selected at the discretion 
of the investigator and, if relevant for the specific OAD, will escalate the dose to the maximum 
approved or maximum tolerated dose according to approved local label at the discretion of the 
investigator. A maintenance dose below the maximum approved or maximum tolerated dose is 
acceptable if the subject’s HbA1c is < 7.0% (53 mmol/mol). However, escalation to the maximum 
approved or maximum tolerated dose should be attempted, at the discretion of the investigator, if 
the subjects’ HbA1c is ≥ 7% (53 mmol/mol). Subjects randomised to the OAD arm must remain on 
the same OAD throughout the trial. 
After randomisation, subjects must remain on the same antidiabetic drugs throughout the trial.
Subjects will receive Victoza® or the OAD treatment for a maximum of 104 weeks.
Victoza® and the OADs will be handled and dispensed by local pharmacies or similar means in 
accordance with local regulations and will be reimbursed by Novo Nordisk throughout the 
individual subject´s trial participation.
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Trial ID: NN2211-4232
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Subjects can receive the following antidiabetic drugs:
!
Victoza®
!
Oral antidiabetic drugs: The OADs included in this trial are:
–
Alpha-glucosidase inhibitors
–
Dipeptidyl peptidase 4 (DPP-4) inhibitors
–
Meglitinides
–
Sodium/glucose cotransporter 2 (SGLT-2) inhibitors
–
Sulphonylureas
–
Thiazolidinediones
Victoza® and OADs must be used in accordance with approved local labels at the discretion of the 
investigator. Fixed dose antidiabetic combination products (e.g. metformin plus DPP-4 inhibitor 
combinations) are not allowed in this trial. 
Subjects should start the treatment they are randomised to as soon as possible and preferably no 
later than 5 days after randomisation. 
Background medication: Metformin is considered background medication. The background 
metformin treatment must be maintained at the pre-trial dose and frequency during the entire trial
treatment period unless there is a safety concern. Metformin is not provided or reimbursed by Novo 
Nordisk.
5.5
Treatment after discontinuation of trial product
Subjects meeting any withdrawal criteria must be withdrawn from the trial and stop treatment with 
trial product. After trial discontinuation the investigator is responsible for further treatment of the 
subject. Novo Nordisk will not provide or reimburse treatment after trial discontinuation.
5.6
Rationale for treatment
Victoza® and OADs will be used according to local approved labels in order to compare the real life 
efficacy in the two treatment arms. The OAD will be chosen at the discretion of the investigator in 
order to compare Victoza® to the OADs most relevant for the individual patient. 
Background metformin has been chosen as this is the recommended first line treatment for type 2 
diabetes. Metformin treatment must be maintained at the pre-trial dose and frequency during the 
trial treatment period in order to be able to compare the efficacy of Victoza® and OADs.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be randomised: 
1994
Number of subjects expected to complete the trial (defined as treated with trial product for 104 
weeks):
462
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 ≥ 18 years of age at the time of signing informed consent.
3. Subjects diagnosed (clinically) with type 2 diabetes ≥90 days prior to the screening visit.
4. Stable daily dose of metformin as monotherapy ≥ 1500 mg or maximum tolerated dose within 
60 days prior to the screening visit. 
5. HbA1c 7.5-9.0% (59-75 mmol/mol) (both inclusive) and measured within the last 90 days prior 
to the screening visit.
6. Patients in which Victoza® and OAD treatment are indicated according to approved local label.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered "no".
1. Previous participation in this trial. Participation is defined as signed informed consent.
2. 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).
3. Receipt of any investigational medicinal product within 30 days before the screening visit.
4. Treatment with any medication for the indication of diabetes other than metformin in a period of 
60 days before the screening visit. An exception is short-term treatment (≤7 days in total) with 
insulin in connection with intercurrent illness.
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5. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6.4
Withdrawal criteria
The subject may withdraw at will at any time. The subject´s request to discontinue must always be 
respected. The subject may be withdrawn from the trial at the discretion of the investigator due to a 
safety concern.
The subject must be withdrawn from the trial if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria.
2. Pregnancy or intention of becoming pregnant.
3. Participation in another clinical trial throughout the trial
4. Use of any antidiabetic medication during the trial other than background metformin, and 
randomised antidiabetic treatment except short-term insulin (≤7 days in total) treatment in 
connection with intercurrent illness.
5. Inadequate glycaemic control defined as HbA1c > 7.0% (53 mmol/mol) at two scheduled 
consecutive visits after the first 26 weeks of treatment. First possible discontinuation due to this 
criterion is at week 38.
If a subject becomes pregnant or intends to become pregnant, trial products must be discontinued 
immediately and the subject should attend the end of treatment visit. 
6.5
Subject replacement
Subjects who are withdrawn from the trial will not be replaced.
6.6
Rationale for trial population 
Subjects with T2D who are inadequately controlled on metformin monotherapy are eligible for the 
trial. Subjects on metformin monotherapy are chosen since this is the current first line treatment of 
T2D recommended by the ADA and EASD. 
The inclusion criteria are chosen to include a population of patients with T2D treated with 
metformin monotherapy, who are inadequately controlled and may benefit from treatment with 
Victoza® or an OAD in addition to metformin treatment. Stable pre-trial treatment prevents recent 
dose changes affecting trial endpoints. A minimum of exclusion criteria is chosen in order to reflect 
a real life setting.
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Trial ID: NN2211-4232
Version:
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6.7
Pre-trial HbA1c
For evaluating whether a subject meets inclusion criterion 5, the requirements for documentation 
are:
!
The most recent available HbA1c obtained by a health care professional and documented in
the medical records.
!
Only HbA1c measured within the last 90 days prior to the screening visit can be used.
Informed consent must be obtained prior to performing any trial related HbA1c measurement.
7
Milestones
Planned duration of recruitment period: 52 weeks
End of trial is defined as Last Subject Last Visit.
Recruitment:
All investigators will be notified immediately when the recruitment period ends, after which no 
subjects may be screened.
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 Disclosure13, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)14, the Food and Drug Administration Amendment Act (FDAAA)15, 
European Commission Requirements16,17 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.
8
Methods and assessments
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see section 2) along with their timing.
8.1
Visit procedures
8.1.1
Informed consent
Informed consent must be obtained before any trial related activity; see section 18.2.
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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 list. 
8.1.3
Screening
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit. A screening session must be performed in IWRS (see section 10). Each subject will be 
assigned a unique 6-digit subject number which will remain the same throughout the trial.
For screening failures the screening failure form in the electronic case report form (eCRF) must be 
completed with the reason for not continuing in the trial. Serious adverse events from screening 
failures must be transcribed by the investigator into the eCRF. Follow-up of serious adverse events 
(SAEs) must be carried out according to section 12.
A screening failure session must be made in the IWRS. The case book must be signed. 
8.1.4
Randomisation
A randomisation session must be performed in IWRS (see section 10).
8.1.5
Withdrawals
If a subject is withdrawn from the trial, the investigator must aim to undertake procedures similar to 
those for visit 12 as soon as possible if acceptable to the subject. The end-of-trial form must be 
completed, and final drug accountability must be performed even if the subject is not able to come 
to the trial site. In addition the follow-up telephone contact (visit 13) should be completed 
approximately 1 week after the early treatment discontinuation visit if possible. After that the case 
book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
subject’s rights. Where the reasons are obtained, the primary reason for not completing the trial 
must be specified on the end-of-trial form in the eCRF.
8.1.6
Site visits 
It is the responsibility of the investigator to have an appointment with the subjects for the site visits. 
If a site visit is missed and it is not possible to re-schedule, the investigator should ensure that 
relevant information is collected for example over the phone.
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8.1.7
Visits attended fasting 
At the time points specified in section 2, subjects must attend the visits fasting for blood sampling.
Fasting is defined as at least eight hours without food and liquids, except for water and any 
prescribed medication other than trial products and background metformin treatment. 
8.1.8
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.
8.2
Subject related information 
8.2.1
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. Medical history is a medical event that the subject has experienced in the 
past.
Procedures and assessments performed at visit 1 and/or 2 are considered screening procedures. The 
results of these procedures should be considered pre-existing conditions and should be reported as 
medical history or concomitant illness
Relevant concomitant illness/medical history related to diabetes should be transcribed to the eCRF. 
The information collected for concomitant illness/medical history should include diagnosis, date of 
onset and date of resolution or continuation, as applicable.
Any relevant 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, if the event meets the 
SAE criteria or is an AE leading to permanent treatment discontinuation according to section 12.2.
8.2.2
Concomitant medication
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, including the screening and the follow-up period.
Concomitant medications used to treat an SAE, an AE leading to permanent treatment 
discontinuation or diabetes must be recorded in the eCRF. Details of diabetes medication must be 
recorded at the first visit. Changes in concomitant medication must be recorded at each visit as they 
occur. 
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Trial ID: NN2211-4232
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The information collected for each concomitant medication includes trade name or generic name, 
indication, total daily dose and unit, start date and stop date or continuation. 
If a change is due to an SAE or an AE leading to permanent treatment discontinuation, then this 
must be reported according to section 12. If the change influences the subject’s eligibility to 
continue in the trial, the monitor must be informed.
8.2.3
Demography
The following demographic data must be recorded:
!
Date of birth
!
Sex
!
Race
!
Ethnicity
Investigators must document whether females are of childbearing potential.
8.2.4
Diabetes details
Details regarding diagnosis of diabetes (diabetes type and date of diagnosis), diabetes complications 
and diabetes treatment history (dose, start and stop date of current diabetes treatment) must be 
recorded in the eCRF at visit 1.
8.2.5
Smoking status
Details of smoking status must be recorded at the first visit. Smoking is defined as smoking at least 
one cigarette, cigar or pipe daily. The collected information should include whether or not the 
subject smokes or has smoked.
8.3
Assessments 
8.3.1
Body measurements
Height should be assessed without shoes in centimetres or inches and recorded to nearest half 
centimeter or ¼ inch.
Body weight should be assessed in light clothes without shoes. It should be recorded in kg or lb and 
preferably using the same scale throughout the trial. 
8.3.2
Vital signs
Diastolic blood pressure, systolic blood pressure and pulse should be assessed according to normal 
site procedures while the subject is sitting.
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8.3.3
Hypoglycaemic episodes
Blood 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) when they occur in conjunction with hypoglycaemic symptoms
should be recorded by the subject. These must be transcribed into the eCRF (hypoglycaemic 
episode form) throughout the trial from visit 2 to visit 13. 
The record should include the following information:
!
Date and time of hypoglycaemic episode
!
The plasma glucose level before treating the episode (if available) 
!
Whether the episode was symptomatic 
!
Whether the subject was able to treat him/herself
!
Date and time of last antidiabetic treatment administration prior to episode 
!
Type and dose of last antidiabetic treatment administration prior to episode 
!
Date and time of last main meal prior to episode
!
Whether the subject was asleep when the episode occurred
–
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration10. 
Oral carbohydrates should not be given if the subject is unconscious.
If the question "Was subject able to treat him/herself?" is answered "No", the following information 
should be recorded:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. family/friend/co-worker or 
similar, paramedic, doctor or other, please specify)
!
Where the treatment was administered (i.e. at home/at friends/at work or similar, in an 
ambulance, emergency room/hospital or other, please specify)
!
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or 
other, please specify)
!
Were symptoms alleviated after administration of treatment?
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!
Factors contributing to the episode (i.e. physical activity, missed meal, diet changed, 
medication error (i.e. overdose, mix-up between products), other factors not listed, please 
specify or none)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms? 
–
Autonomic: sweating, trembling, hunger or palpitations
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination
–
General malaise: headache or malaise
!
Did the subject experience other symptoms? Please specify
!
Description of the episode, if applicable 
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety information 
form must also be filled in, see section 12.
8.3.4
Self-measured blood glucose (SMBG)
At Visit 2, subjects will be provided with a blood glucose meter including lancets, plasma-
calibrated test strips and control solutions as well as instructions for use. The subjects will be 
instructed on how to use the device, the instruction will be repeated as necessary during the trial. 
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, 
which will be shown on the display. 
Subjects should be instructed on how to record the results of the SMBGs in the diaries and to only 
record them in the diaries in case of hypoglycaemic episodes. All relevant data from the diary must 
be transcribed into the eCRF during or following the contact. If obtained via phone and a 
discrepancy is later detected, the values in the eCRF should be corrected.
8.3.5
Diaries
The subject must be provided with diaries at the specified visits (section 2). During the trial subjects 
should use the diary for the below: 
!
to record their blood glucose values in case of hypoglycaemic episodes
!
to record any new concomitant medication during the trial
!
to record dose changes to metformin, Victoza® or OAD treatment (date of change, new trial 
product dose and reason for dose change)
!
to record any adverse events experienced by the subject
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In addition, subjects should be instructed to note the date, time and blood glucose value (if 
available) if they experience a hypoglycaemic episode where they are not able to treat themselves. 
Subjects are requested to bring the diary to each visit. The diary must be collected and retained at 
the site as source data, and the subject will receive a new diary.
The investigator must review the subject diaries to ensure the relevant entries are transcribed to the 
eCRF. If clarification of entries or discrepancies is needed, the subject must be questioned and a
conclusion made in the medical record. Care must be taken not to bias the subject. To verify that the 
data have been reviewed, the investigator must sign and date the diaries or ensure the review is
documented in the subject’s medical record.
8.3.6
Pregnancy test
Sites will be provided with urine pregnancy test kits (urine-sticks). For female subjects who are of 
child-bearing potential (at the discretion of the investigator), a pregnancy test must be performed on 
site at screening. For females of child-bearing potential pregnancy test should be repeated at end of
treatment and at any time during the trial, if a menstrual period is missed or pregnancy is suspected 
or as required by local regulations. The date and result of the pregnancy tests must be recorded in 
the subject’s medical record and the results must be transcribed to the eCRF.
8.4
Laboratory assessments
The laboratory analyses listed below must be performed at a central laboratory and the results will 
be made available for the investigators. The investigator must sign and date the reports from the 
laboratory, to verify that the results have been reviewed, or ensure the review is documented in the 
subject’s medical record. The laboratory report and evaluation are retained at the investigator’s site 
as source documentation.
For laboratory report values outside the reference range, the investigator must specify whether the 
value is or is not clinically significant. 
Laboratory materials, flow charts and a laboratory manual will be provided to each site. The 
documents will include instruction on handling, transportation and storage of the blood samples, as 
well as contact information for the laboratory.
The laboratory analyses are:
Glucose metabolism
!
Fasting plasma glucose
!
HbA1c
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Lipids
!
Cholesterol
!
High density lipoprotein (HDL) cholesterol
!
Low density lipoprotein (LDL) cholesterol
!
Triglycerides
Biochemistry
!
Creatinine
!
eGFR (calculated value)
!
Alanine aminotransferase (ALT)
!
Aspartate Aminotransferase (AST)
!
Potassium
!
Bilirubin
!
Lipase
!
Amylase
Haematology
!
Haemoglobin
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.
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 adverse events and report these according to this protocol see section 
12.2. 
8.5
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
investigator will remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed.
Treatment compliance: Treatment compliance will not be measured as the trial is designed to 
reflect everyday practice.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Trial products must not be used by any 
person not included in the trial. 
9.1
Trial products
Trial products used in this trial are:
Victoza®:
!
Victoza® (liraglutide 3.0 mL;6.0 mg/mL)
Oral antidiabetic drugs (OADs):
!
Alpha-glucosidase inhibitors
!
DPP-4 inhibitors
!
Meglitinides
!
SGLT-2 inhibitors
!
Sulfonylureas  
!
Thiazolidinediones
Trial products will be commercial products dispensed from pharmacies or similar means in 
accordance with local regulation/practice and hence trial product will not be supplied by Novo 
Nordisk. Dispensing of trial products will be based on Investigator prescriptions. The prescription 
must be in accordance with subject randomisation to either Victoza® or OAD treatment arm. Trial 
products will be reimbursed by Novo Nordisk throughout the individual subject´s trial participation.
It is the responsibility of the investigator that the patient is instructed in the use of trial drug during 
the trial and the expected adverse events.
Further information for trial products is available in approved local labels and package inserts.
Metformin is background treatment in this trial hence not trial product and will neither be supplied 
nor reimbursed by Novo Nordisk.
9.2
Labelling
Applicable for Russia, Serbia and Turkey
In accordance with local regulation the commercially supplied trial products will have a dispensing 
label with particulars added to the original container without obscuring the original labelling:
For Serbia the following particulars will be added:
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!
Name of sponsor
!
Trial ID 
!
Subject number (this allows identification of the trial site, investigator and trial subject)
!
For clinical trial use only
For Russia the following particulars will be added:
!
Name of sponsor
!
Trial ID
!
Subject number (this allows identification of the trial site, investigator and trial subject)
!
Investigator information
!
For clinical trial 
!
Dispensing unit number (allocated by the pharmacy)
For Turkey the following particulars will be added:
!
Name of sponsor
!
Trial ID
!
Subject number (this allows identification of the trial site, investigator and trial subject)
!
Site number
!
Investigator information
!
For clinical trial use only
!
Keep out of reach and sight of the children
Adding the dispensing label will be carried out by health care professional/trained specialist at a 
pharmacy or similar and documented.  
Further information will be available in a country specific document describing the local process.
Applicable for Canada, India, Latvia, Lebanon and US
Commercially supplied trial products will not have any additional labelling.   
9.3
Storage 
Trial products are supplied commercially and hence will not be stored at site. 
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the investigator.
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Drug accountability will be performed based on prescribed trial product by investigator. At each 
visit (except for visit number 3) the Investigator will prescribe trial product and at the next visit the 
subject will return to the site used, partly used and not used trial products dispensed from the 
pharmacy. At the site it will be documented what was prescribed and what the subject returned to 
the investigator at the next visit. 
Through this procedure the investigator can verify that correct trial product has been dispensed. 
Applicable for Canada, India, Latvia, Lebanon, Russia, Serbia and Turkey
Trial product (used/partly used or unused including empty packaging material) returned to the site 
can be stored without temperature monitoring. 
Destruction of trial products must be documented.
Applicable for US 
No requirement with regard to documentation of destruction of trial product
9.5
Auxiliary supplies
Auxiliary supplies to the subjects are:
!
Blood glucose meters including lancets, plasma-calibrated test strips and control solutions. 
This will be provided by Novo Nordisk. User manual will be provided along with the blood 
glucose meter.
For subjects randomised to Victoza®, needles for pre-filled Victoza® pens will be supplied to 
subjects from pharmacies or similar means along with Victoza® and will be reimbursed by Novo 
Nordisk
10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet. Access to 
the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
IWRS user manuals will be provided to each trial site.
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11 Randomisation procedure 
The IWRS must be used for randomisation. Only eligible subjects are allowed to be randomised.
12 Adverse events, technical complaints and pregnancies
12.1
Definitions
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form 
instead of on an AE form, see section 8.3.3.
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.
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Causality 
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
!
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 sequelae meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved with 
sequelae" or "not recovered/not resolved". An AE with fatal outcome must be reported as an 
SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd. 
Suspicion of transmission of infectious agents via the trial product must always be considered 
an SAE. 
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a.
The term "life threatening" in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
b. The term "hospitalisation" is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social 
purposes 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 dyscrasias or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below
defined MESI criteria.
Medication errors concerning trial products:
–
Administration of wrong drug. 
–
Wrong route of administration, such as intramuscular instead of subcutaneous.
–
Administration of an overdose with the intention to cause harm (e.g. suicide attempt).
–
Accidental administration of a lower or higher dose than intended, however the 
administered dose must deviate from the intended dose to an extent where clinical 
consequences for the trial subject were likely to happen as judged by the investigator, 
although they did not necessarily occur.
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Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in labelling 
text)
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
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12.2
Reporting of adverse events
All events meeting the definition of an SAE (see section 12.1), MESI (see section 12.1), AEs 
leading to permanent discontinuation of trial product and pregnancies (see section 12.5) must be 
collected and reported. This includes events from first trial related activity after the subject has 
signed the informed consent until the end of trial (visit 13). 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 investigator, the subject must be asked about AEs, for example by
asking: “Have you experienced any problems since the last contact?” AEs are either observed by 
the investigator or reported by the subject.
The investigator will evaluate the need for reporting of AEs. The investigator must report the 
following AEs in the eCRF:
!
All SAEs
!
AEs leading to permanent discontinuation of investigational product
!
MESIs
The investigator should report the diagnosis, if available. If no diagnosis is available, the 
investigator should record each sign as individual AEs using separate AE forms. The investigator 
must evaluate the severity and causality for each event.
For SAEs that could have resulted from hypoglycaemia (for example sudden death, seizure, trauma, 
fractures, fall, motor vehicle accident etc), the narrative should include information whether 
hypoglycaemia could have contributed to these events.
!
The investigator must enter the AE in the eCRF and tick the seriousness box within 24 hours of 
obtaining knowledge of the SAE
!
The safety information form must be completed within 5 days of obtaining knowledge of the 
SAE
If for some reason the eCRF is unavailable, the AE information should be reported to Novo Nordisk 
by fax, telephone, e-mail or courier within the same timelines.
Contact details (fax, telephone, e-mail and address) are provided to each site.
All SAEs, MESIs and AEs leading to permanent treatment discontinuation observed either by the 
investigator or the subject, must be reported by the investigator and evaluated. Novo Nordisk 
assessment of expectedness is performed according to the following reference documents: 
!
Company core data sheet (CCDS), Victoza®, 6.0 mg/mL, version 17.0 or any updates 
thereto
!
Non Novo Nordisk A/S marketed products: European summary of product characteristics or 
other relevant labelling, current version or any updates thereto. 
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All SAEs, MESIs, AEs leading to permanent treatment discontinuation and AEs in connection with 
pregnancies must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs.
MESIs, regardless of seriousness, must be reported using both AE form, safety information form 
and a medication error form. The medication error form is a form tailored to collect specific 
information related to the individual MESI. The AE form for a non-serious AE not fulfilling the 
MESI criteria should be signed when the event is resolved or at the end of the trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator's first knowledge of the SAE. Both forms must be signed within 7 
calendar days from the date the information was entered in the eCRF. 
!
SAEs fulfilling the MESI criteria: In addition to above, the medication error form within 
14 calendar days of the investigator's first knowledge of the AE. 
!
Non-serious AE fulfilling the MESI criteria: The AE form, safety information form and 
medication error 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 paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.
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An AE is 
observed and 
reported 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
!
AE form
Fulfilling 
seriousness 
criteria?
MESI 
(medication 
error)?
MESI 
(medication 
error)?
It is a medication error 
(MESI)
Complete:
!
SIF
!
Medication Error form
both ≤ 14 calendar days
No additional 
forms 
to be completed
It is a medication error 
(MESI)
Complete:
!
SIF
!
Medication Error form
both ≤ 14 calendar days
Yes
No
Yes
No
Yes
No
AE: Adverse Event
SIF: Safety Information Form
MESI: Medical Event of Special Interest (medication errors)
All timelines are from the investigator’s first knowledge of the event
Figure 12–1
Initial reporting of AEs 
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP.1 In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including European Medicines Agency (EMA), of trial product-related SUSARs. In addition, Novo 
Nordisk will inform the IRBs/IECs of trial product-related SUSARs in accordance with local 
requirement and GCP1, unless locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication:
If a SAE and/or MESI is considered to have a causal relationship with a Novo Nordisk marketed 
product used as concomitant medication in the trial, it is important that the suspected relationship is 
reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. 
Novo Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF. 
Follow-up information must be reported to Novo Nordisk according to the following:
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!
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 leading to permanent treatment discontinuation: Non-serious AEs 
must be followed until the outcome of the event is “recovering/resolving”, 
“recovered/resolved” or “recovered/resolved with sequelae” or until the end of the follow-up 
period stated in the protocol, whichever comes first, and until all queries related to these 
AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at time of 
death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the subject has completed the follow-up period and 
is expected by the investigator to recover.
!
Non-serious AE fulfilling the MESI criteria: Non-serious AEs must be followed until the 
outcome of the event is “recovering/resolving”, “recovered/resolved” or “recovered/resolved 
with sequelae” or until the end of the follow-up period stated in the protocol, whichever 
comes first and until all queries related to these AEs have been resolved. Cases of chronic 
conditions, cancer or AEs ongoing at time of death (where death is due to another AE) may 
be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed 
the follow-up period and is expected by the investigator to recover.- Follow-up information 
on MESIs should only include new (e.g. corrections or additional) information and must be 
reported within 14 calendar days of the investigator’s first knowledge of the information. 
This is also the case for previously reported non-serious AEs which subsequently fulfil the 
MESI criteria. 
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow up with re-
assessment of severity and/or seriousness of the event.
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.
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12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following Novo Nordisk products:
!
Victoza® 
!
Needles for Liraglutide (Victoza®) prefilled pen-injector
!
Repaglinid (NovoNorm® /Prandin® / GlucoNorm®) tablet
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.
All technical complaints on any non-Novo Nordisk OAD products:
!
Alpha-glucosidase inhibitors
!
DPP-4 inhibitors
!
Meglitinides 
!
SGLT-2 inhibitors
!
Sulfonylureas  
!
Thiazolidinediones
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. In addition 
the technical complaint should be reported to the Marketing Authorisation Holder via the pharmacy, 
or similar, where the product was obtained.
Contact details (fax, e-mail and address) for reporting to Novo Nordisk are provided in Attachment 
I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs, SAEs, and/or 
MESI.
Technical complaints must be reported on a separate technical complaint form. A technical 
complaint form for each batch 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:
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!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample for all Novo Nordisk products and 
notify the monitor within 5 calendar days of obtaining the sample at trial site. The monitor must 
coordinate the shipment to Customer Complaint Center, Novo Nordisk (the address is provided in 
Attachment I) and ensure that the sample is sent as soon as possible. A print or copy of the technical 
complaint form must be sent with the sample.
The investigator must ensure that the technical complaint sample contains the batch or lot number.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
For non- Novo Nordisk OADs the sample should be returned to the Marketing Authorisation Holder 
via the pharmacy, or similar, where the product was obtained.
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: 
–
Paper AE form* within 14 calendar days of the investigator's first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
–
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE.
–
Paper safety information form within 5 calendar days of the investigator's first knowledge 
of the SAE.
–
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator's first knowledge of the follow-up information.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
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12.5.2
Pregnancies in female partners of male subjects (Applicable to 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:
Please see section 12.5.1, point 2, "Forms and timelines for reporting AEs:". 
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Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
When initiating treatment with Victoza®, the subject may, in some cases, experience loss of 
fluids/dehydration, e.g., in cases of vomiting, nausea or diarrhoea sometimes with a decrease in 
kidney function. It is important to avoid dehydration by drinking enough fluids.
From clinical trials and marketed use, overdoses have been reported up to 40 times the 
recommended maintenance dose (72 mg). One case of a 
-fold overdose (
 mg daily) given for  
has been reported. Generally, the patients reported severe nausea, vomiting and diarrhoea, 
but recovered without complications. None of the patients reported severe hypoglycaemia. In the 
event of overdose, appropriate supportive treatment should be initiated according to the patient’s 
clinical signs and symptoms.
For non Novo Nordisk marketed products please consult the EU summary of product characteristic 
and US prescribing information for information on precautions and/or overdose. 
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal Victoza® safety committee to perform ongoing safety 
surveillance.
13 Case report forms 
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
In addition paper AE forms, Safety information forms and Technical complaint forms will be 
provided. These must be used when access to the eCRF is revoked or if the eCRF is unavailable. 
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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.
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 and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 8 weeks during recruitment and 12 
weeks after end of recruitment for sites with subjects between Visit 1 and Visit 13.
The monitor must be given direct access to source documents (original documents, data and 
records) including documentation for pre-trial HbA1c (see section 6.7). Direct access includes 
permission to examine, analyse, verify and reproduce any record(s) and report(s) that are important 
to the evaluation of the trial. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the monitor with signed and dated printouts. In addition the relevant trial 
site staff should be available for discussions at monitoring visits and between monitoring visits (e.g.
by telephone).
All data must be verifiable in source documentation other than the eCRF.
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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 returned diaries must be filed with source documents.
The monitor will ensure that the CRFs are completed.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent
Monitors must review the subject's medical records and other source data (e.g. the diaries) to ensure 
consistency and/or identify omissions compared to the eCRF. If discrepancies are found, the 
investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
15 Data management
Data management is always 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.
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
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17 Statistical considerations
Results from the statistical analyses will generally be presented by two-sided confidence intervals 
with a confidence level of 95%. 
The full analysis set (FAS) will be used in the analysis of the efficacy endpoints. For the safety 
endpoints, the safety analysis set (SAS) will be used. 
The main statistical analyses and summaries will be based on assessments taken while the subject is 
on treatment. With exception for AEs (see Section 17.4.1.2), the period in which a subject will be 
considered to be on treatment extends to one day after last administration of trial product.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.  
17.1
Sample size calculation
The sample size calculation is based on the objective to detect a difference in the time to inadequate 
glycaemic control between the Victoza® arm and the OAD arm, using a two-sided log rank test at a 
5% significance level. The power is set to 90%.
The distributions of event time for the two treatment arms are derived from a model of the 
continuous HbA1c measurements. In this model, the post-baseline measurements for each subject 
are assumed to be normally distributed and, conditional on a random subject effect, independent 
between assessment times. Based on data from another Novo Nordisk trial (NN2211-1860), the 
mean HbA1c in the Victoza® arm is anticipated to be at a constant post-baseline level of 6.9% and 
the standard deviation of the within-subject error is anticipated to be 0.85%. The latter is in reality 
an estimate of the standard deviation of the total error and is therefore a conservative estimate of the 
within-subject standard deviation. 
A mean treatment difference in HbA1c of 0.3% is considered clinically relevant and is therefore 
used as the assumption in the model18. The HbA1c levels in the two treatment arms are assumed to 
diverge after the visit at 65 weeks, when the mean in the OAD arm is assumed to increase in one 
step from 6.9% to 7.2%. Otherwise, the means are assumed to be constant during the observation 
period between 26 and 104 weeks.
Based on previous trials, the anticipated percentage of subjects who discontinue treatment 
prematurely (are withdrawn from the trial) without having inadequate glycaemic control is 20% in 
both treatment arms. As a conservative assumption, these subjects are assumed to discontinue 
before the week 26 visit and thus not give any contribution to the statistical analysis.
Based on the assumptions above, the required sample size is found to be 1994 subjects. The 
anticipated percentage of subjects who have had inadequate glycaemic control after 104 weeks is 
66% in the Victoza® arm and 76% in the OAD arm. The number of subjects who complete the trial 
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without premature treatment discontinuation (for any reason including inadequate glycaemic 
control) is expected to be 462.
In order to investigate the influence of the values of the model parameters on the calculation, 
sample sizes have been calculated for different alternative scenarios, assuming the mean post-
baseline HbA1c level in the Victoza® arm to be 6.8%, 6.9% or 7.0%, the standard deviation to be 
0.7% or 0.85%, the treatment difference to be 0.2% or 0.3% and the divergence time to be 52 or 65 
weeks. The results are presented in Table 17–1 with the adopted sample size marked in bold.
Table 17–1
Sample size calculations for different scenarios – total number of randomised 
subjects
Divergence time
52 weeks
65 weeks
Standard deviation
Standard deviation
Mean HbA1c in 
Victoza® arm
Treatment 
difference
0.7%
0.85%
0.7%
0.85%
6.8%
0.2%
1138
1782
2394
3840
0.3%
492
776
1010
1636
6.9%
0.2%
1332
2042
2948
4608
0.3%
588
902
1272
1994
7.0%
0.2%
1668
2456
3948
5868
0.3%
752
1098
1736
2566
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guideline.
FAS: includes all randomised subjects who have received at least one dose and have any post 
randomisation data. The statistical evaluation of the FAS will follow the intention-to treat principle 
and subjects will contribute to the evaluation “as randomised”.
SAS: includes all subjects exposed to at least one dose of trial product. Subjects in the SAS will 
contribute to the evaluation “as treated”.
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Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude a subject or single observations from the statistical analysis is the joint responsibility of the 
trial statistician, the international trial manager and the medical specialist. 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.
17.3
Primary endpoint
The primary endpoint is the time to inadequate glycaemic control defined as HbA1c > 7.0% (53 
mmol/mol) at two scheduled consecutive visits after the first 26 weeks of treatment and up to 104 
weeks. First possible occurrence is at week 38. 
The time to inadequate glycaemic control will be compared between the Victoza® arm and the OAD 
arm using a two-sided nonparametric test at a 5% significance level. The test will be a generalised 
log rank test for interval censored failure time data19. The analysis will not be based on any model 
assumptions such as proportional hazards. The possible event times will be considered as a discrete 
set of time points corresponding to the scheduled visits. An alternative but technically equivalent 
model would be to view the event time as a continuous variable which can only be observed to lie 
in the interval between the visit when inadequate glycaemic control is established and the previous 
scheduled visit. Subjects who complete the trial without an event of inadequate glycaemic control 
will be censored after the last visit at 104 weeks, which means that the event time is only observed 
to be greater than 104 weeks. Subjects who discontinue treatment before 104 weeks without having
an event of inadequate glycaemic control will be censored immediately after the last visit which 
they attended while on treatment. In particular, subjects changing antidiabetic drug after 
randomisation will be discontinued from the trial and in relation to the primary endpoint be 
considered as censored and not having had an event of inadequate glycaemic control.
The result of the log rank test will be presented as the asymptotic p-value obtained from a chi-
square distribution. If the asymptotic p-value is not considered a valid approximation based on the 
Mantel-Fleiss criterion20, then the exact p-value will be calculated.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
Time to premature treatment discontinuation (for any reason including inadequate glycaemic 
control)
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The time to premature treatment discontinuation will be analysed using the same type of generalised 
log rank test as for the primary endpoint with the difference that subjects who discontinue treatment 
before 104 weeks without having an event of inadequate glycaemic control will not be considered 
as censored but as meeting the endpoint. For these discontinued subjects, the event will be 
considered to have occurred in the interval between the last attended visit on treatment and the next 
planned visit.
Change from baseline in HbA1c at 104 weeks or at premature treatment discontinuation
The change from baseline in HbA1c will be evaluated using an analysis of covariance (ANCOVA) 
model where the last post-baseline measurement taken on treatment will enter as the dependent 
variable, treatment arm and country as factors and baseline HbA1c as a covariate. The estimated 
differences between Victoza® and OAD will be presented together with the corresponding 95% 
confidence intervals and two-sided p-values.
To further describe the effects of Victoza® compared to OAD with respect to the change from 
baseline in HbA1c, supportive analyses will be performed using a mixed model for repeated 
measurements (MMRM) where all post-baseline measurements taken on treatment will enter as the 
dependent variable, treatment arm as a factor and baseline HbA1c as a covariate. The factor and the 
covariate will be nested within visit. An unstructured covariance matrix for the measurements 
within subject will be employed. From this analysis, the differences between Victoza® and OAD at 
different visits will be estimated.
The purpose of the MMRM analysis is to estimate the treatment effects that would have been 
observed if all subjects had remained on treatment and completed all visits, instead of dropping out. 
The analysis relies on the assumption that data are missing at random (MAR), which means that 
given the observed data, the events that lead to data being missing are independent of the 
unobserved data. This is a reasonable assumption also for subjects discontinuing treatment due to 
inadequate glycaemic control since it can be explained by the observed data obtained prior to
discontinuation.
Categorical endpoints related to HbA1c
Secondary categorical efficacy endpoints are subjects who at 104 weeks or at premature treatment 
discontinuation achieve (Yes/No):
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!
HbA1c ≤ 6.5%
!
HbA1c ≤ 7.0% without weight gain
!
HbA1c ≤ 7.0% without treatment emergent severe hypoglycaemic episodes or BG confirmed 
symptomatic hypoglycaemic episodes
!
HbA1c ≤ 7.0% without weight gain and no treatment emergent severe hypoglycaemic 
episodes or BG confirmed symptomatic hypoglycaemic episodes
These endpoints will be analysed separately using the same type of logistic regression model. In the 
calculation of the responses, the last post-baseline measurements of HbA1c and body weight which 
were taken on treatment will be used. The model will include treatment arm as a factor and baseline 
HbA1c as a covariate. The results will be described by the odds ratio for the comparison of Victoza®
versus OAD and the associated 95% confidence interval and two-sided p-value.
Other efficacy endpoints
The change from baseline at 104 weeks or at premature treatment discontinuation will be evaluated 
for:
!
FPG
!
Body weight
!
BMI
!
Systolic and diastolic blood pressure
These endpoints will be analysed using the same type of ANCOVA as for HbA1c but with the 
baseline measurement of the corresponding endpoint as covariate instead of baseline HbA1c. The 
corresponding supportive analyses to estimate treatment differences at different visits will also be 
performed. 
BMI will be derived at each visit with a body weight measurement by using the body weight from 
the corresponding visit and the height measured at screening.
17.4.1.2
Safety endpoints
The following secondary endpoints are used to support the safety objectives: 
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!
Number of severe hypoglycaemic episodes
!
Number of severe or blood glucose confirmed symptomatic hypoglycaemic episodes
!
Number of documented symptomatic hypoglycaemic episodes (ADA)
!
Number of SAEs
!
Number of AEs leading to permanent discontinuation of trial product
!
Change from baseline at 104 weeks or at premature treatment discontinuation:
o
Lipids
o
Biochemistry
o
Haematology
o
Pulse
Adverse events
The collected AEs will be coded using the most recent version of the Medical Dictionary for 
regulatory Activities (MedDRA) coding. A treatment emergent adverse event (TEAE) is defined as 
an event that has onset date (or increase in severity) on or after the first day of trial product 
administration and no later than seven days after the last day of trial product administration.
AE data will be displayed in terms of the number of subjects with at least one event, the percentage 
of subjects with at least one event, the number of events and the event rate per 1000 patient years of 
exposure. The main AE summaries will only contain TEAEs. Non-treatment emergent AEs will be 
included in listings and overview summaries. 
Hypoglycaemic episodes
The endpoints involving hypoglycaemic episodes will be analysed separately using a negative 
binomial regression model with the number of treatment emergent episodes as response, the 
logarithmic function as link function and the logarithm of the time period in which episodes are 
considered treatment emergent as offset. The model will include treatment arm as factor and 
baseline HbA1c as a covariate. The results will be described by the rate ratio for the comparison of 
Victoza® versus OAD and the associated 95% confidence interval and two-sided p-value.
The hypoglycaemic episodes will also be summarised descriptively in a similar way as the AEs in 
terms of the number of subjects with at least one event, the percentage of subjects with at least one 
event, the number of events and the event rate per 1000 patient years of exposure. 
Classification of Hypoglycaemia:
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of trial product administration, and no later than the day 
after the last day of trial product administration.
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Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–2) and the ADA classification of hypoglycaemia (see Figure 17–3).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL).21 Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–2) in addition to the ADA 
classification:
!
Severe hypoglycaemia according to the ADA classification22.
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value < 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value < 3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification22 or BG confirmed by a plasma glucose value < 3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia. 
!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value 
< 3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification22 or BG confirmed by a plasma glucose value < 3.1 mmol/L (56 mg/dL) with
or without symptoms consistent with hypoglycaemia. 
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Figure 17–2
Novo Nordisk classification of hypoglycaemia 
ADA classification22 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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Figure 17–3
ADA classification of hypoglycaemia 
Laboratory assessments
Lipids, biochemistry and haematology will be summarised and evaluated by descriptive statistics. 
Amylase and lipase will be analysed with the same type of statistical methods as for HbA1c but with 
the baseline value of the corresponding endpoint as covariate instead of baseline HbA1c. The 
response as well as the baseline value will be log transformed in the analysis.
eGFR will be derived from serum creatinine using the modification of diet in renal disease (MDRD) 
formula.
Pulse
Pulse will be summarised descriptively as well as analysed with the same type of statistical methods 
as for HbA1c but with baseline pulse as covariate instead of baseline HbA1c.
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18 Ethics
18.1
Benefit-risk assessment of the trial
The trial will be conducted in compliance with ICH GCP2 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki3.
Inclusion and exclusion criteria have been defined in order to ensure that subjects are eligible for 
trial participation. Furthermore, a withdrawal criterion has been defined to ensure that subjects that 
in whom glycaemic treatment intensification may be warranted are withdrawn from the trial.
All subjects included in the trial will continue their pre-trial treatment with metformin throughout 
the trial. During the trial, Victoza® or a marketed OAD will be added. All trial medications have 
been approved and have shown efficacy in lowering blood glucose levels. It is expected that the 
majority of subjects entering the trial will achieve an improved glucose control during the trial.
The trial drugs may be associated with AEs, but relevant precautions have been implemented in the 
design and planned conduct of the trial in order to minimise the risks and inconveniences of 
participating in the trial. 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.
Safety information on Victoza® can be found in the approved local label for Victoza®. Safety 
information of the OADs used in this trial can be found in the approved local label of the individual 
OAD. 
The subjects have the right to withdraw from the trial at any time, without giving a specific reason. 
Novo Nordisk will be entitled to keep the data 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.
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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.
18.3
Data handling
If the subject is withdrawn from the trial or lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subject during 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 a trial is suspended or prematurely terminated, the investigator must inform the subjects promptly 
and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must also 
promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
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Version:
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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
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical database. 
Documentation on protocol deviations must be kept in the investigator's trial master file and 
sponsor trial master file.
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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CONFIDENTIAL
Date:
04 September 2015
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Trial ID: NN2211-4232
Version:
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21 Critical documents
Before a trial site is allowed to start screening subjects, the following documents must be available 
to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s 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)
Only applicable for US trial sites: 
!
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
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Date:
04 September 2015
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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.
By signing the protocol, each investigator agrees to comply fully with ICH GCP2, applicable 
regulatory requirements and the Declaration of Helsinki3. 
By signing the protocol, 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. If any tasks are delegated, 
the investigator must maintain a log of appropriately qualified persons to whom he/she has 
delegated specified trial-related duties. The investigator must ensure that there is adequate training 
for all staff participating in the conduct of the trial. It is the investigator's responsibility to supervise 
the conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data
produced) in the investigator trial master file. The documents including the subject identification 
code list should be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
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04 September 2015
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Version:
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Status:
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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 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications23.
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 
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Protocol
CONFIDENTIAL
Date:
04 September 2015
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Version:
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disclosure by other means. 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.
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 Disclosure13.
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.
Novo Nordisk will analyse and report data from all sites together. In a multi-centre trial, any 
publication of results in a journal article must acknowledge all trial sites. Where required by the 
journal, the investigator from each trial site will be named in an acknowledgement or in the 
supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors23 (sometimes referred to as the Vancouver 
Criteria).
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
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CONFIDENTIAL
Date:
04 September 2015
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
Status:
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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.
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 as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
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Date:
04 September 2015
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
Status:
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator's Brochure
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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 September 2015
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
Status:
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Novo Nordisk accepts liability in accordance with:
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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04 September 2015
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27 References
1 Definition of primary care. American Academy of Family Physicians (AAFP) 
(http://www.aafp.org/about/policies/all/primary-care.html).  2015. 
2 ICH Harmonised Tripartite Guideline. International Conference on Harmonisation. ICH 
Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6 (R1), Step 4. 10-
Jun-1996. 1996.
3 World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. 64th WMA General Assembly, Fortaleza. 1 Oct 2013. 2013.
4 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. Diabetes Care 2009; 32(1):84-90.
5 Davies M, Atkin S, Bavin SC, Scott D., Rossing P, Shamkhalova M et al. Efficacy and Safety 
of Liraglutide vs. Placebo as Add-on to Existing Diabetes Medication in Subjects with Type 2 
Diabetes (T2DM) and Moderate Renal Impairment (LIRA-RENAL). Diabetes 2014; 
63(Supplement 1):A212-A343.
6 Rubin RR. Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. The 
American Journal of Medicine 2005; 118(5, Supplement):27-34.
7 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management 
of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position 
statement of the American Diabetes Association and the European Association for the Study 
of Diabetes. Diabetologia 2015; 58(3):429-442.
8 Buteau J, Foisy S, Joly E, Prentki M. Glucagon-Like Peptide 1 Induces Pancreatic +¦-Cell 
Proliferation Via Transactivation of the Epidermal Growth Factor Receptor. Diabetes 2003; 
52(1):124-132.
9 Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di MU et al. Glucagon-like peptide-1 
promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002; 
143(11):4397-4408.
10 Retnakaran R, Kramer CK, Choi H, Swaminathan B, Zinman B. Liraglutide and the 
Preservation of Pancreatic +¦-Cell Function in Early Type 2 Diabetes: The LIBRA Trial. 
Diabetes Care 2014; 37(12):3270-3278.
11 Wilson S, Delaney BC, Roalfe A, Roberts L, Redman V, Wearn AM et al. Randomised 
controlled trials in primary care: case study. BMJ 2000; 321(7252):24-27.
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Date:
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
Status:
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12 Chalkidou K, Tunis S, Whicher D, Fowler R, Zwarenstein M. The role for pragmatic 
randomized controlled trials (pRCTs) in comparative effectiveness research. Clinical Trials 
2012; 9(4):436-446.
13 Novo Nordisk. http://www.novonordisk-trials.com/website/content/how-we-disclose-trial-
information.aspx.  2015. 
14 De Angelius 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; 351:1250-1251.
15 Food and Drug Administration Amendments Act of 2007. 11 Oct 2007.
16 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 May 2001.
17 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities April 2001.
18 Guidance (draft) for Industry Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. Food and Drug Administration, February 2008.  
19 SUN JIAN. A non-parametric test for interval-censored failure time data with applications to 
AIDS studies. Statist Med 1996; 15(13):1387-1395.
20 Mantel L, Fleiss JL. Minimum Expected Cell Size Requirements for the Mantel-Haenszel 
One-Degree-of-Freedom Chi-Square Test and a Related Rapid Procedure. American journal 
of epidemiology 12, 129-134. 1980. 
21 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):777-781.
22 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; 36:1384-1395.
23 International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. Dec 2014.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide
Trial ID: NN2211-4232
Clinical Trial Report
Appendix 16.1.1
 January 2020
1.0
Final
CONFIDENTIAL


Protocol Amendment 1
CONFIDENTIAL
Date:
30 May 2016
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
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EudraCT No.: 2015-002417-29
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Protocol Amendment
no 1
to Protocol, final version 1
dated 04 September 2015
Trial ID:NN2211-4232
LIRA-PRIME: Efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to 
metformin vs. OADs as add-on to metformin after up to 104 weeks of treatment in subjects 
with type 2 diabetes inadequately controlled with metformin monotherapy and treated in a 
primary care setting
Trial phase: 4
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 1
CONFIDENTIAL
Date:
30 May 2016
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No.: 2015-002417-29
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Table of Contents...........................................................................................................................3
2.2
Section 5.1 Type of trial ................................................................................................................3
2.3
Section 6.2 Inclusion criteria .........................................................................................................3
2.4
Section 6.7 Pre-trial HbA1c ............................................................................................................4
2.5
Section 8.2.1 Concomitant illness and medical history .................................................................4
2.6
Section 9.1 Trial products..............................................................................................................4
2.7
Section 9.2 Labelling.....................................................................................................................4
2.8
Section 9.4 Drug accountability and destruction ...........................................................................4
2.9
Section 12.2 Reporting of adverse events......................................................................................4
2.10
Section 12.2 Reporting of adverse events......................................................................................5
2.11
Section 17.1 Sample size calculation.............................................................................................6
2.12
Section 17.2 Definition of analysis sets.........................................................................................6
2.13
Section 17.3 Primary endpoint.......................................................................................................6
2.14
Section 17.3 Primary endpoint.......................................................................................................6
Table of Figures   
Page
Figure 12.1 Initial reporting of AEs ...................................................................................................................5
CONFIDENTIAL


Protocol Amendment 1
CONFIDENTIAL
Date:
30 May 2016
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Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
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1
Introduction including rationale for the protocol amendment
The reason for initiating this protocol amendment is that the current protocol text on drug 
accountability does not allow the subjects to keep unused and partly used trial product during the 
trial. In this trial the trial products are handed out by pharmacies or similar. Since some subjects 
may not be able to collect new trial product from the pharmacy on the same day as they attend a site 
visit and hand in the trial product that were prescribed at the previous site visit, this means that 
these subjects may risk being without trial product for one or more days unless the current protocol 
text on drug accountability is changed. Therefore, the protocol text regarding drug accountability 
has been revised as described below.
This protocol amendment will include new wordings in order to prevent potential cases of patients 
using trial products that have exceeded the expiry date. In addition this amendment will include 
clarifications of the randomisation ratio, sample size calculation and specific statistical analyses in 
line with suggestions from FDA.
Columbia has been included in the trial after the finalisation date of protocol version 1.0 and 
therefore country specific issues for Columbia has been added.
Finally, this protocol amendment will include updates and clarifications to wordings that may be 
confusing in their current form. This includes removal of a sentence in protocol section 6.7, 
rewording of section 8.2.1, updating figure 12.1 describing the initial reporting of AEs to align this
with the remaining text in the protocol and other minor changes. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Table of Contents
Attachment II – Country list of key staff and relevant departments
2.2
Section 5.1 Type of trial
Subjects will be randomised in a 1:1 manner to one of two treatment arms: Victoza® or OAD.
2.3
Section 6.2 Inclusion criteria
4. Stable daily dose of metformin as monotherapy ≥ 1500 mg or maximum tolerated dose within for
≥60 days prior to the screening visit.
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Protocol Amendment 1
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30 May 2016
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Version:
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2.4
Section 6.7 Pre-trial HbA1c
Informed consent must be obtained prior to performing any trial related HbA1c measurement.
2.5
Section 8.2.1 Concomitant illness and medical history
Procedures and assessments performed at visit 1 and/or 2 are considered screening procedures. The 
results of these procedures should be are considered pre-existing conditions and should be reported 
as medical history or concomitant illness.
Type 2 diabetes mellitus and diabetes complications present at screening must be reported in the 
diabetes module.  All other Rrelevant concomitant illness/medical history not related to diabetes 
should be transcribed to the eCRF. entered in the concomitant illness/medical history module.
2.6
Section 9.1 Trial products
It is the responsibility of the investigator that the patient is instructed in the use of trial drug during 
the trial and the expected adverse events. The investigator should remind the subject to be aware of 
trial product expiration.  
2.7
Section 9.2 Labelling
Applicable for Canada, Columbia, India, Latvia, Lebanon and US
2.8
Section 9.4 Drug accountability and destruction
Drug accountability will be performed based on prescribed trial product by the investigator. At each 
visit (except for visit number 3) the Iinvestigator will prescribe trial product and at the next visit the 
subject will return to the site used, and partly used and not used trial products including empty 
packaging material dispensed from the pharmacy. Subjects are allowed to keep partly used and 
unused trial products. At the site it will be documented what was prescribed and what the subject 
returned to the investigator at the next visit. 
Through this procedure the investigator can verify that correct trial product has been dispensed. 
Subjects are instructed to return all used, partly used and unused trial product including empty 
packaging material at the latest at their final site visit.
Applicable for Canada, Columbia, India, Latvia, Lebanon, Russia, Serbia and Turkey 
2.9
Section 12.2 Reporting of adverse events
!
Company core data sheet (CCDS), Victoza®, 6.0 mg/mL, version 17.0 or any updates thereto
!
Company core data sheet (CCDS) for Novo Nordisk A/S OAD: NovoNorm®/GlucoNorm®, 
version 13.0 or any updates thereto.
CONFIDENTIAL


Protocol Amendment 1
CONFIDENTIAL
Date:
30 May 2016
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
Status:
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!
Non Novo Nordisk A/S marketed products: European summary of product characteristics or
other relevant labelling, current version or any updates thereto.
2.10
Section 12.2 Reporting of adverse events
Figure 12.1 Initial reporting of AEs 
(Old figure 12.1)
An AE is 
observed and 
reported 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
!
AE form
Fulfilling 
seriousness 
criteria?
MESI 
(medication 
error)?
MESI 
(medication 
error)?
It is a medication error 
(MESI)
Complete:
!
SIF
!
Medication Error form
both ≤ 14 calendar days
No additional 
forms 
to be completed
It is a medication error 
(MESI)
Complete:
!
SIF
!
Medication Error form
both ≤ 14 calendar days
Yes
No
Yes
No
Yes
No
AE: Adverse Event
SIF: Safety Information Form
MESI: Medical Event of Special Interest (medication errors)
All timelines are from the investigator’s first knowledge of the event
(Updated figure 12.1)
An AE is 
observed and 
reported 
It is an SAE
Complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE 
leading to permanent 
treatment 
discontinuation 
Complete:
!
AE form
Fulfilling 
seriousness 
criteria?
MESI 
(medication 
error)?
MESI 
(medication 
error)?
It is a medication error 
(MESI)
Complete:
!
Medication Error form
   ≤ 14 calendar days
No additional 
forms 
to be completed
It is a medication error 
(MESI)
Complete:
!
SIF
!
Medication Error form
both ≤ 14 calendar days
Yes
No
Yes
No
Yes
No
AE: Adverse Event
SIF: Safety Information Form
MESI: Medical Event of Special Interest (medication errors)
All timelines are from the investigator’s first knowledge of the event
CONFIDENTIAL


Protocol Amendment 1
CONFIDENTIAL
Date:
30 May 2016
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No.: 2015-002417-29
Page:
6 of 6
2.11
Section 17.1 Sample size calculation
Based on the assumptions above, the required sample size is found to be 1994 subjects. The 
anticipated number percentage of subjects who have had inadequate glycaemic control after 104 
weeks is 526 66% in the Victoza® arm and 606 76% in the OAD arm. In each arm, 200 subjects are 
expected to discontinue treatment prematurely without having inadequate glycaemic control. The 
number of subjects who complete the trial without premature treatment discontinuation (for any 
reason including inadequate glycaemic control) is expected to be 462.
2.12
Section 17.2 Definition of analysis sets
FAS: includes all randomised subjects who have received at least one dose and have any post 
randomisation data. The statistical evaluation of the FAS will follow the intention-to-treat principle 
and subjects will contribute to the evaluation “as randomised”.
2.13
Section 17.3 Primary endpoint
The test will be a generalised log rank test for interval censored failure time data19. The analysis 
will not be based on any model assumptions such as proportional hazards and it will not adjust for 
any covariates.
2.14
Section 17.3 Primary endpoint
Subjects who complete the trial without an event of inadequate glycaemic control will be censored 
after the last visit at 104 weeks, which means that the event time is only observed to be greater than 
104 weeks. If a subject has an HbA1c measurement above 7.0% at the week 26 visit or later but 
discontinues treatment before the next planned visit, the last observation will be carried forward 
and the subject will be considered to have had an event of inadequate glycaemic control at the next 
planned visit. Otherwise, sSubjects who discontinue treatment before 104 weeks without having an
confirmed event of inadequate glycaemic control will be censored immediately after the last visit 
which they attended while on treatment. In particular, subjects changing antidiabetic drug after 
randomisation will be discontinued from the trial and in relation to the primary endpoint be 
considered as censored and not having had an event of inadequate glycaemic control.
CONFIDENTIAL


Protocol Amendment US_1
CONFIDENTIAL
Date:
18 January 2017
Novo Nordisk
Trial ID: NN2211-4232
Version:
2.0_US
UTN: U1111-1170-7035
Status:
Final
EudraCT No.: 2015-002417-29
Page:
1 of 3
Protocol Amendment Local US
no 2
to Protocol, final version 2.0
dated 01 June 2016
Trial ID:NN2211-4232
LIRA-PRIME: Efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to 
metformin vs. OADs as add-on to metformin after up to 104 weeks of treatment in subjects 
with type 2 diabetes inadequately controlled with metformin monotherapy and treated in a 
primary care setting
Trial phase: 4
Applicable to US only
Amendment originator:
Clinical Trial Management
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 US_1
CONFIDENTIAL
Date:
18 January 2017
Novo Nordisk
Trial ID: NN2211-4232
Version:
2.0_US
UTN: U1111-1170-7035
Status:
Final
EudraCT No.: 2015-002417-29
Page:
2 of 3
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Section 6.7 Pre-trial HbA1c...........................................................................................................3
CONFIDENTIAL


Protocol Amendment US_1
CONFIDENTIAL
Date:
18 January 2017
Novo Nordisk
Trial ID: NN2211-4232
Version:
2.0_US
UTN: U1111-1170-7035
Status:
Final
EudraCT No.: 2015-002417-29
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
The reason for initiating this protocol amendment is that the current protocol inclusion criteria does
not allow for an HbA1c reading to be obtained assessing eligibility prior to screening. Some subjects 
may not have an HbA1c reading in their charts from within the past 90 days which prevents them 
from being screened for inclusion into the trial. Therefore, the protocol text regarding timing of 
HbA1c readings has been revised as described below.
This protocol amendment will include new wordings in order to allow subjects to have an HbA1c
reading measured and evaluated prior to screening.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 6.7 Pre-trial HbA1c
For evaluating whether a subject meets inclusion criterion 5, the requirements for documentation
are:
!
The most recent available HbA1c obtained by a health care professional and documented in
the medical records.
!
Only HbA1c measured within the last 90 days prior to the screening visit can be used.
If there is no documented HbA1c value measured within the last 90 days prior to the screening visit 
available, the investigator may obtain a pre-screening consent from the potential subject and 
hereafter obtain an HbA1c value, which must be analysed locally. The result must be available and 
evaluated prior to screening.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02730377 
Sponsor trial ID: 
NN2211-4232 
Official title of study: 
LIRA-PRIME: Efficacy in controlling glycaemia with 
Victoza® (liraglutide) as add-on to metformin vs. OADs as 
add-on to metformin after up to 104 weeks of treatment in 
subjects with type 2 diabetes inadequately controlled with 
metformin monotherapy and treated in a primary care setting 
Document date: 
14 January 2020 
 


Link
List of contents
Statistical Programming Specification.............................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Liraglutide
Trial ID: NN2211-4232
Clinical Trial Report
Appendix 16.1.9
 January 2020
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
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Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
1 of 42
Statistical Programming Specification
Trial ID: NN2211-4232
LIRA-PRIME: Efficacy in controlling glycaemia with Victoza® (liraglutide) as
add-on to metformin vs. OADs as add-on to metformin after up to 104 weeks of
treatment in subjects with type 2 diabetes inadequately controlled with
metformin monotherapy and treated in a primary care setting
Authors:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
2 of 42
Table of contents   
Table of contents.........................................................................................................................................2
1
Introduction .........................................................................................................................................5
1.1
Purpose.....................................................................................................................................5
1.2
Acronyms .................................................................................................................................5
1.3
Study data standards and dictionary inventory ...........................................................................6
1.4
Source data used for analysis dataset creation............................................................................7
1.5
Trial folder structure and naming standards ...............................................................................7
1.5.1
Naming standard......................................................................................................7
1.5.1.1
Naming of instances...........................................................................7
1.5.1.2
Output programs and outputs..............................................................7
1.5.1.3
ADaM programs ................................................................................7
1.5.1.4
Macros...............................................................................................8
2
Protocol description.............................................................................................................................8
2.1
Protocol number and title ..........................................................................................................8
2.2
Protocol design in relation to ADaM concepts ...........................................................................8
2.3
Period definitions and transitions...............................................................................................9
2.3.1
Transition rules........................................................................................................9
2.3.2
In-trial period.........................................................................................................10
2.3.3
On-treatment period...............................................................................................11
3
Analysis considerations related to multiple analysis datasets...........................................................12
3.1
Comparison of SDTM and ADaM content...............................................................................12
3.2
Core variables .........................................................................................................................12
3.3
Treatment variables.................................................................................................................13
3.4
Subject issues that require special analysis rules ......................................................................14
3.4.1
Subjects receiving wrong treatment........................................................................14
3.4.2
Subjects randomised but not exposed to trial product..............................................14
3.4.3
Subjects excluded from the full analysis set............................................................14
3.4.4
Subjects switching sites..........................................................................................15
3.5
Use of visit windowing, unscheduled visits, and record selection.............................................15
3.5.1
Visit windowing or reallocation .............................................................................15
3.5.2
Re-test ...................................................................................................................15
3.6
Imputation and derivation methods..........................................................................................15
3.6.1
Date imputations....................................................................................................15
3.6.2
Imputations in relation to analyses .........................................................................17
3.6.3
Missing baseline ....................................................................................................17
3.6.4
Definition of treatment/trial completers..................................................................18
3.6.5
Treatment emergent events ....................................................................................18
3.6.6
Durations...............................................................................................................19
3.6.7
Age........................................................................................................................19
3.6.8
Body Mass Index (BMI) ........................................................................................20
3.6.9
Rounding...............................................................................................................20
3.6.10
Fasting status.........................................................................................................20
3.6.11
Laboratory lower and upper limit of quantification.................................................20
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
3 of 42
3.6.12
Time-to-event endpoints ........................................................................................21
3.6.12.1
Primary endpoint - Time to inadequate glycaemic control.................21
3.6.12.2
Secondary endpoint - Time to premature treatment 
discontinuation (for any reason including inadequate glycaemic 
control) ............................................................................................23
3.6.13
Dose data categorization ........................................................................................23
4
Analysis data creation and processing issues ....................................................................................25
4.1
Split datasets...........................................................................................................................25
4.2
Data dependencies...................................................................................................................25
4.2.1
Execution order......................................................................................................25
4.2.1.1
Execution order of datasets...............................................................25
4.3
Intermediate datasets...............................................................................................................27
4.3.1
AXNR – Normal ranges lab data............................................................................27
4.3.2
ADTRTEV – Planned or actual treatment for events ..............................................28
4.3.3
ADTRTVIS – Planned or actual treatment for findings...........................................28
5
Analysis datasets descriptions ...........................................................................................................29
5.1
Overview ................................................................................................................................29
5.2
Analysis Datasets....................................................................................................................29
5.2.1
ADSL – Subject Level Analysis.............................................................................29
5.2.2
ADSLSF – Subject level screening failures ............................................................29
5.2.3
ADAE – Adverse events analysis...........................................................................29
5.2.4
ADCM - Concomitant medication analysis ............................................................30
5.2.5
ADEX -- Exposure analysis set ..............................................................................30
5.2.6
ADEC -- Exposure analysis set ..............................................................................30
5.2.7
ADHBA1C – HbA1c .............................................................................................30
5.2.8
ADHYPO – Hypoglycaemic episode analysis ........................................................31
5.2.9
ADHYPOEN – Hypoglycaemic episode analysis endpoint.....................................31
5.2.10
ADLB - Lab Analysis ............................................................................................32
5.2.11
ADMH – Medical History Analysis .......................................................................33
5.2.12
ADVS - Vital Signs Analysis .................................................................................33
5.2.13
ADTTE – Time-to-Event Analyses ........................................................................34
5.2.14
ADRESP – Responder Analysis.............................................................................34
6
Data conformance summary..............................................................................................................36
7
Submission of Programs ....................................................................................................................37
8
Specification of output .......................................................................................................................38
9
References ..........................................................................................................................................39
Appendix A
Table shells location .........................................................................................................39
Appendix B
Good Specification Practice for Data Derivations...........................................................40
Appendix C
Table of converted units applied......................................................................................41
10
Change Log ........................................................................................................................................42
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
4 of 42
Table of Figures
Figure 1
Identification of interval (t1, t2]..........................................................................................22
Table of Tables
Table 1
Acronyms ............................................................................................................................5
Table 2
Versions of standards and dictionaries used..........................................................................6
Table 3
Naming of instances.............................................................................................................7
Table 4
Transition rules for each period in APHASE ........................................................................9
Table 5
Core variables in NN2211-4232 .........................................................................................12
Table 6
Values for treatment variables ............................................................................................13
Table 7
Subjects excluded from full analysis set..............................................................................14
Table 8
Date variables and related imputation methods ...................................................................16
Table 9
Duration variables and related period definitions ................................................................19
Table 10
Definition of AAGEG1BL and AAGEG1BN .....................................................................19
Table 11
Definition of AAGEG2BL and AAGEG2BN .....................................................................19
Table 12
Definition of BMIG1BL and BMIG1BLN..........................................................................20
Table 13
Defined daily dose for oral antidiabetics.............................................................................24
Table 14
Dataset dependencies and execution order ..........................................................................26
Table 15
Derived hypoglycaemic endpoints......................................................................................32
Table 16
Parameters included in ADRESP dataset ............................................................................34
Table 17
Table shells location...........................................................................................................39
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
5 of 42
1
Introduction
1.1
Purpose
This Statistical Programming Specification (SPS) describes decisions for programming and output 
generation for the trial.
Like the ADRG, the SPS also provides context for the analysis datasets and terminology that 
benefit from additional explanation beyond the data definition document, define.xml. 
Documents referred to in this trial are:
PSPS: nn2211-phase3b-4-project-statistical-programming-specification version 1.0, novoDOCS
object ID
Table shells: version 1.0 located on P:\nn2211\nn2211-
4232\current\stats\document\0300_programming\0310_statistical_programming_specification, and 
archived in novoDOCS. A list of novoDOCS object IDs can be found in Appendix A
The specifications for the programming of this trial are described in the NN2211-PSPS (see above). 
Any deviations from and additions to the specifications in the PSPS are described in this document.
1.2
Acronyms
Table 1
Acronyms
Acronym
Translation
ADaM
Analysis Data Model
ADRG
Analysis Data Reviewers Guide
AE
Adverse event
ALCOA (C)
Attributable, Legible, Contemporaneous, Original, Accurate, 
Complete
BDS
Basic Data Structure
BMI
Body Mass Index
CRF
Case report form
CTR
Clinical trial report
DDD
Defined daily dose
DPP-4
Dipeptidyl peptidase 4
FAS
Full Analysis Set
FPG
Fasting plasma glucose
HbA1c
glycosylated haemoglobin
MedDRA
Medical Dictionary for Regulatory Activities
MMA
Metadata Management Application
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
6 of 42
NN
Novo Nordisk
OAD
Oral Antidiabetic Drug
PD
Protocol deviation
PSPS
Project Statistical Programming Specification
SAS
Statistical Analysis System
SDTM
Study Data Tabulation Model
SGLT-2
Sodium/glucose cotransporter 2
SPS
Statistical Programming Specification 
TEAE
Treatment emergent adverse event
WHO
World Health Organization
1.3
Study data standards and dictionary inventory
Table 2 gives an overview of versions used for data definitions and documentation.
Table 2
Versions of standards and dictionaries used
Standard or 
Dictionary
Versions Used
SDTM
SDTM v1.3/SDTM IG v3.1.3
ADaM
ADaM Model Document 2.1
ADaM Implementation Guide v1.1
ADAM Basic Data Structure for Time-to-Event Analysis v1.0
ADaM Structure for Occurrence Data (OCCDS) v1.0
ADaM Supplement to the TAUG-Diabetes v1.0  
Controlled 
Terminology
ADaM 2014-09-26
Data Definitions
Define.xml version 2.0
Platform
HP-UX HP IPF B.11.31 U ia64
Software
SAS v9.4 (TS1M2)
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
Novo Nordisk
Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
7 of 42
Standard or 
Dictionary
Versions Used
Date of reference 
(Software specific)
1 January 1960
MedDRA
22.0
WHO
WHODrug Global/B3 1 Mar 2019
1.4
Source data used for analysis dataset creation
The SDTM datasets of the trial are to be used as source data.
1.5
Trial folder structure and naming standards
1.5.1
Naming standard
1.5.1.1
Naming of instances
Electronic record (ER) instances will be used for the CTR instance (at the time of report review 
Committee (RRC)) and for any output delivered to authorities.
Table 3
Naming of instances
Instance
Name
DBL, RM
Zzz,yyymmdd
Where zzz = {dbl, rm,..}
CTR
ctr_yyyymmdd_er
1.5.1.2
Output programs and outputs
Output programs and output names should not contain capital letters or spaces and should follow 
the following naming standard to the extent possible:
[t|l|f|a|s]_[domain]_[subset]_[sub-subset]_[population].sas
Where t, l, f, a, and s denote tables, listings, figures, analyses and sensitivity analyses, respectively.
1.5.1.3
ADaM programs
The naming of ADaM programs (hereafter referred to as mk-files) should follow the following 
naming standard:
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
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Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
Status:
Final
EudraCT No: 2015-002417-29
Page:
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mk_ssss_adxxxxen.sas
Where (1) is a number so that the mk-files are sorted in the order of execution in UNIX SCE, (2) is 
a name 2-6 characters long that corresponds to the domain that the data originates from and (3) is a 
suffix of “en” if the dataset contains endpoints. If (1) is the same for two or more programs, it is 
assumed that these can be executed in parallel.
1.5.1.4
Macros
Macro names should not contain capital letters or spaces. The names should include “adam” as 
prefix if they are used in the production of ADaM data.
2
Protocol description
2.1
Protocol number and title
This SPS is applicable to the NN2211-4232 trial, ‘LIRA-PRIME: Efficacy in controlling glycaemia 
with Victoza® (liraglutide) as add-on to metformin vs. OADs as add-on to metformin after up to 
104 weeks of treatment in subjects with type 2 diabetes inadequately controlled with metformin 
monotherapy and treated in a primary care setting’, protocol version 2.0 dated 01-JUN-2016.
2.2
Protocol design in relation to ADaM concepts
The trial is a 104-week, randomised, phase 4, two-arm, open-label, active-controlled, multicentre, 
multinational, parallel-group trial, comparing the efficacy in controlling glycaemia with Victoza® as 
add-on to metformin vs. OADs as add-on to metformin after up to 104 weeks of treatment in 
subjects with type 2 diabetes treated in primary care setting, inadequately controlled with 
metformin monotherapy.
Subjects will be randomised in a 1:1 manner to receive a once daily dose of liraglutide 1.8 mg or 
OAD (i.e. Alpha-glucosidase inhibitors, Dipeptidyl peptidase 4 (DPP-4) inhibitors, Meglitinides, 
Sodium/glucose cotransporter 2 (SGLT-2) inhibitors, Sulphonylureas and Thiazolidinediones will 
be chosen at the discretion of the investigator) applying the standard dose escalation for liraglutide 
with 0.6 mg/day with subsequent dose according to approved local label up to final dose of 1.8 
mg/day at the discretion of the investigator. Subjects randomised to the OAD arm must remain on 
the same OAD throughout the trial. After randomisation, subjects must remain on the same 
antidiabetic drugs throughout the trial.
Metformin is considered background medication. The background metformin treatment must be 
maintained at the pre-trial dose and frequency during the entire trial treatment period unless there is 
a safety concern.
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
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Trial ID: NN2211-4232
Version:
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UTN: U1111-1170-7035
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EudraCT No: 2015-002417-29
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The maximum overall duration of the trial participation including screening and follow-up will be 
105 weeks: the trial includes a 2-week screening period, followed by 104 weeks of treatment and a 
1-week follow-up period after end of treatment.
APHASE
APHASEN
APERIOD
APERIODC
Screening
10
Treatment
30
30
Treatment
Follow-up 
90
2.3
Period definitions and transitions
2.3.1
Transition rules
The treatment period defined in APHASE and APERIODC are aligned. For all datasets the 
APHASE and APERIOD are linked to visit dates, except for all datasets not related to visits, e.g. 
ADAE, and ADHYPO, where the treatment periods are linked to the treatment emergent definition. 
See with transition rules below Table 4.
Table 4
Transition rules for each period in APHASE
APHASE
Period ID
Transition Rules linked to 
visits
Transition rules linked to AEs 
and Hypos
Start
End
Start
End
Screening
SCREENING
Date of 
screening visit
Date of first 
occurring visit 
after the 
screening visit 
Date of 
screening visit
Date of first 
occurring visit 
after the 
screening visit 
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
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Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
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Final
EudraCT No: 2015-002417-29
Page:
10 of 42
minus 1 day.
minus 1 day.
Treatment Liraglutide 1.8 
mg
OAD
(see section 8)
Date of 
randomisation 
visit.
Date of last 
visit in 
treatment 
period
Start date on 
randomised 
trial product
End date on 
randomised 
trial product+x 
days;
7 days for AEs 
and 1 day for 
hypos
Follow-up
FOLLOW-UP
Date of last 
visit in 
treatment 
period plus 1 
day 
Visit date for 
follow-up 1.
End date on 
randomised 
trial 
product+y 
days;
8 days for 
AEs and 1
day for hypos
Visit date for 
follow-up.
2.3.2
In-trial period
The in-trial observation period is data collected in the time period from randomisation until:
!
The final planned visit for subjects who did not die or withdraw consent and was not lost to 
follow-up. 
!
The time of death for subjects who die before the final planned visit. 
!
The time of 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.
The end date of the in-trial period will be in the variable EOSDT.
The variable INTRFL will be used to define all records in the trial period. INTRFL will be in all 
datasets with visit structure (BDS).
All baseline assessments (ABLFL = “Y”) eligible for analyses and taken prior to trial product
initiation will be included in in-trial period (INTRFL = “Y”). 
CONFIDENTIAL


Statistical Program. Specification
CONFIDENTIAL
Date:
10 September 2019
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Trial ID: NN2211-4232
Version:
1.0
UTN: U1111-1170-7035
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EudraCT No: 2015-002417-29
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2.3.3
On-treatment period
In accordance with protocol on-treatment definition as follows: the on-treatment period is defined 
as the observations occurring from when subject initiates randomised treatment (treatment start 
date) to 
!
Efficacy parameters, safety lab and hypos: 1 day after last dose of randomised treatment 
(both days included)
!
AEs: 7 days after last dose of randomised treatment (both days included)
For missing date of last dose see section 3.6.1.
For subjects in the safety analysis set (SAFFL = “Y”), the baseline assessments (ABLFL = “Y”) in 
the in-trial period (INTRFL = “Y”) will be included in the on-treatment period (ONTRTFL = “Y”). 
The variable ONTRTFL are used to define periods on-treatment. ONTRTFL will be ‘Y’ for all 
records in the period on-treatment and ‘N’ at other periods. The ONTRTFL will be included in all 
datasets with visit structure (BDS).
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3
Analysis considerations related to multiple analysis datasets
3.1
Comparison of SDTM and ADaM content
Screening failures
Subject information, demographics and reason for violation of inclusion/exclusion/randomisation 
criteria for screening failures are included in a separate ADAM dataset ADSLSF. Other data from 
screening failures will not be included in ADAM datasets, but can be found in SDTM datasets.
A screening failure is defined as a subject withdrawn before randomisation and without any 
investigational medical product intake. 
Age
Age is calculated based on birth date and a given visit and described in variables related to AAGE
(refer section 3.6.7). 
3.2
Core variables 
Core variables include treatment assignments, key demographic variables and baseline assessments 
incl. baseline value of primary endpoint and confirmatory secondary endpoints. Baseline value of 
non-confirmatory endpoints will not be considered core.
The core variables are the following:
Table 5
Core variables in NN2211-4232
Variable name
Variable description
STUDYID
Study identifier used for this protocol
USUBJID
Unique subject identifier
SUBJID
Subject identifier
SITEID
Site identifier
REGION1
Geographic region 1
REGION1N
Geographic region 1 (N)
COUNTRY
Country
AGE
Age from SDTM
AGEU
Age unit from SDTM
AAGE
Derived age
AAGEG1BL
Age group 1 
AAGEG1BN
Age group 1 (N)
SEX
Gender
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Variable name
Variable description
RACE
Race
RACEOTH
Race other
ETHNIC
Ethnicity
RANDDT
Date of Randomization
TRTSDT
Date of First Exposure to Treatment
TRTEDT
Date of Last Exposure to Treatment
RANDFL
Randomized population flag. 
FASFL
Full analysis set flag. ‘Y’ indicates inclusion in the set.
SAFFL
Safety analysis set flag. ‘Y’ indicates inclusion in the set.
TRTP
Planned treatment
TRTPN
Planned treatment (N)
TRTA
Actual treatment [conditional]
TRTAN
Actual treatment (N) [conditional]
HBA1CBL
Baseline HbA1c (%) 
HBA1CSBL
Baseline HbA1c (mmol/mol) 
DIABDURY
Duration of Diabetes (years)
SMOKER
Smoking Status
3.3
Treatment variables
The subject level treatment variable TRT30P represents the randomised (planned) treatment for the 
period “treatment” and can be found in the ADSL dataset. 
In all other ADAM datasets, the record level treatment variable, TRTP is used. TRTP should be 
non-missing showing randomised treatment. 
The values of the individual treatment variables are given in Table 6. 
Table 6
Values for treatment variables
Treatment variable
Pre-specified values (based on naming from previous trials)
ARM
Liraglutide 1.8 mg, OAD
TRT30P/ TRTP
Lira 1.8 mg, OAD
TRTPN
1, 2
Note that ARM is defined as “Label” in the MMA and TRT30P is defined as “Short label” in MMA.
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3.4
Subject issues that require special analysis rules
This section should include descriptions of any situation that affects the analysis of an individual 
subject and how it was handled. A sub-section should only be included in case a violation in the 
given subsection is done
Guidance to handling violations is given below:
3.4.1
Subjects receiving wrong treatment
The subject receiving treatment different than from the randomised treatment will be included in his 
randomised treatment arm for efficacy analysis and in the treatment received arm for safety 
analysis.
The subject randomised in OAD arm and switching to a different OAD during the course of trial 
will be considered in the OAD he started with after randomisation for all analyses.
3.4.2
Subjects randomised but not exposed to trial product
The subjects are included in the full analysis set, but excluded from safety analysis set 
(SAFFL=’N‘), and in e.g. the ADAE dataset there will not be any events in the treatment period.
3.4.3
Subjects excluded from the full analysis set
The subjects listed below are excluded from full analysis set for the reasons mentioned.
Table 7
Subjects excluded from full analysis set
Site
Subject ID
Reason for exclusion
For this subject, casebooks are not signed with the legally binding PI 
signature according to the ALCOA(C) principles as the site is closed 
due to death of the PI
For this subject, casebooks are not signed with the legally binding PI 
signature according to the ALCOA(C) principles as the site is closed 
due to death of the PI
For this subject, casebooks are not signed with the legally binding PI 
signature according to the ALCOA(C) principles as the site is closed 
due to death of the PI
For this subject, casebooks are not signed with the legally binding PI 
signature according to the ALCOA(C) principles as the site is closed 
due to death of the PI
For this subject, casebooks are not signed with the legally binding PI 
signature according to the ALCOA(C) principles as the site is closed 
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due to extenuating circumstances
For this subject, casebooks are not signed with the legally binding PI 
signature according to the ALCOA(C) principles as the site is closed 
due to extenuating circumstances
3.4.4
Subjects switching sites
Subjects switching sites will keep their original subject ID and site and will be analysed 
accordingly.
3.5
Use of visit windowing, unscheduled visits, and record selection
The analysis flag ANELFL is used to define records selected for summaries and analyses. E.g. if 
several measurements exist for a parameter at a visit then ANELFL will be ‘Y’ for the measurement 
used for analysis and ‘ ’ for the other measurements. The variable ANELREA will be filled in with 
a description for all ANELFL=’ ’ and kept empty when ANELFL=’Y’.
The ANELFL and ANELREA will be included in all datasets with visit structure (BDS datasets). 
The ANELFL is created before deriving other flags as e.g. baseline flag to ensure only one baseline 
measurement for a given parameter.
3.5.1
Visit windowing or reallocation
Visit reallocation will not be performed. All data will be used for all analyses. 
3.5.2
Re-test
See PSPS version 1.0 for general rules.
For the following assessment tests and re-tests the subjects are required to be fasting according to 
the protocol:
!
Fasting plasma glucose (FPG) at visits: 2, 4, 6, 8, and 12
If these assessments are taking with fasting status ‘Not fasting’ the values are considered not valid
(ANELFL = ‘’).
3.6
Imputation and derivation methods
All imputations of AVAL are indicated in the variable DTYPE at record level in all ADaM datasets.
3.6.1
Date imputations
Date and time are captured in the ISO 8601 format in SDTM and follows the pattern: 
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yyyy-mm-ddTHH:MM:SS.
Table 8
Date variables and related imputation methods
Description
Variable
Imputation flag
Imputation method
Treatment start date
TRTSDT
TRTSDTF
Actual date of first trail product 
administration or Randomisation date, 
whichever comes later
Treatment end date
TRTEDT
TRTEDTF
Actual date of last trial product 
administration or Date of last visit in 
on-treatment period or Date of last 
trial-related subj-site contact, 
whichever comes first
Medical history/ 
concomitant illness 
Start
ASTDTF
MONTH: Jan
DAY: 1st
A missing start year will not be 
imputed, but for medical history the 
event will be classified to belong to 
the Screening 
Stop
AENDTF
If continuing=”No” 
MONTH: Dec
DAY: Last day of month. 
If imputed date is after randomisation
then Date of randomisation-1 will be 
used 
Concomitant 
medication
Start
ASTDTF
MONTH: Jan
DAY: 1st
If imputed date is before 
randomisation then the Date of 
randomisation will be used
Stop
AENDTF
If continuing=”No” 
MONTH: Dec
DAY: Last day of month. 
If imputed date is after last day in trial 
then Date of last trial-related subj-site 
contact will be used 
Adverse events
Start
ASTDTF
1st of month. 
If imputed date is before TRSTDT 
then TRSTDT date will be used
Stop
AENDTF
Last day of month. 
If imputed date is after last day in trial 
then Date of last trial-related subj-site 
contact will be used
If “not recovered” then AENDTF=”” 
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Hypoglycaemic 
events/ 
Hyperglycaemic 
Events
Start
ASTDTF
DAY: 1st unless: 
(1) Event stop date is non-missing 
where Start date will be stop date -
1
(2) Event occurs in same month as 
TRSTDT, in which case TRSTDT 
is used 
TIME: 00:00
Event date is the same as first drug 
date then time will be time of first 
drug intake, if possible, or 24:00
Stop
AENDTF
DAY: The day after hypo start date
TIME: 24:00
For all date variables that can be imputed (listed in Table 8) the imputation flag can take values “ ” 
(blank), D, M and Y and are set as described below. The imputation flag variable is only included if 
any dates/times are imputed.
3.6.2
Imputations in relation to analyses
The variable DTYPE will be used to mark imputed values. Imputation of missing data will be based 
on the measurements included in the analysis.
3.6.3
Missing baseline
For any missing baseline value, the last value prior to baseline visit should be used. However, any 
measurements assigned to a visit at or before baseline, but with an assessment date after first drug 
date will not be used as a baseline measurement. 
The value will be assigned to the baseline visit and the record will be marked with 
DTYPE=’LVPD’ (Last Value Prior Dosing). If no value exists prior to the baseline visit, the 
baseline value should be kept as missing.
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The values assigned to a baseline visit will be included in the in-trial period 
(APHASE/APERIODC=”Treatment” and INTRFL=’Y’), even though the sample date will be prior 
to randomisation.
For subjects who are randomised at another date than the randomisation visit date the randomisation 
date will be set to the randomisation visit date. 
3.6.4
Definition of treatment/trial completers
Treatment and trial completers are defined directly in the CRF by the investigator. A subject has 
completed trial if subject completes 104 weeks of treatment.
3.6.5
Treatment emergent events
A Treatment Emergent Adverse Event (TEAE) is defined as an event with onset or increase in 
severity on or after the time of first trial product administration and no later than seven days (7 
times 24 hours) after the time of last trial product administration. 
A Treatment Emergent hypoglycaemic episode is defined as an event with onset on or after the time 
of first trial product administration and no later than one day (24 hours) after the time of last trial 
product administration. 
If the date and datetime of the event is not missing or is partial, the exact number of hours since trial 
product administration is used to determine if the event is treatment emergent. This also means that 
an event on the same date as trial product administration will not be treatment emergent if the time 
of the event is before time of trial product administration.
However, if the start-date and datetime for the adverse event or hypoglycaemic episode is missing 
or partial, and an imputed date or datetime can result in an onset of the event that is within the 
treatment emergent period, then the event is defined as treatment emergent. Otherwise it is defined 
as non-treatment emergent. Following partial date and datetime rules should be applied:
!
If the time of the event is partially observed such that only the hours are observed, the event is 
regarded as treatment emergent if the date and hour of the event is the same as for the trial 
product administration or if the treatment-emergent window extends to at least the beginning of 
the given hour.
!
If the time (hours) of the event is missing the event is regarded as treatment emergent if it 
occurs on the date of trial product administration or no later than the specified amount of time 
after this date. 
!
If date is missing or partial missing the event is not regarded as treatment emergent.  
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3.6.6
Durations
Durations are calculated as Duration (in years) =
End of period	 
 	
 + 1
.
Table 9
Duration variables and related period definitions
Duration periods
Flag
Start of period
End of period
Duration variable
Exposure
TRTSDT
TRTEDT
TRTDURY
In trial 
(Observation 
time)
INTRFL
RANDDT
EOSDT
INTRDURY
On treatment
ONTRTFL
TRTSDT
TRTEDT
ONTRDURY
Duration of AE
ASTDT
AENDT
AEDURN, 
AEDURU
Duration of 
diabetes
Diagnosis of 
diabetes
RANDDT
DIABDURY
3.6.7
Age
AGE is the age in SDTM, and AAGE is the calculated age:
AAGE = Date of visit - Date of birth + 1
365.25
The age group 1 defined by the two variables AAGEG1BL and AAGEG1BN is defined as 
described in Table 10.
Table 10
Definition of AAGEG1BL and AAGEG1BN
AAGEG1BL
AAGEG1BN
18 ≤ age < 45 years
10
45 ≤ age < 55 years
20
55 ≤ age < 65 years
30
65 ≤ age < 75 years
40
75 ≤ age < 85 years
50
85 ≤ age
60
The age group 2 for EudraCT is defined by the two variables AAGEG2BL and AAGEGE2BN is 
defined as described in Table 11.
Table 11
Definition of AAGEG2BL and AAGEG2BN
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AAGEG2BL
AAGEG2BN
18 ≤ age < 65 years
10
65 ≤ age < 85 years
20
85 ≤ age
30
3.6.8
Body Mass Index (BMI)
BMI will be calculated as: Weight(kg) / Height2(m2) even if the BMI is collected on the CRF.
Table 12
Definition of BMIG1BL and BMIG1BLN
BMIG1BL (kg/m^2)
BMIG1BLN
< 25
10
25 - <30
20
30 - <35
30
35 - <40
40
>= 40
50
3.6.9
Rounding
Data points stored in numeric variables in datasets will not in any circumstances be rounded. 
Rounding will only occur if numeric variables are converted to character information, e.g. in CTR 
outputs as a final step when presenting numeric data. In this case, number of decimal points will 
follow the table shells.
3.6.10
Fasting status
According to the protocol fasting plasma glucose (FPG) at visit 2, 4, 6, 8, and 12 are required to be 
taken when subjects are fasting. 
Any of the above measurements taken when the subjects are non-fasting will be excluded from the 
analyses and have ANELFL =’’ and ANELREA=’Record was excluded due to subject being non-
fasting’. 
All other assessments do not require a fasting status.
3.6.11
Laboratory lower and upper limit of quantification
When laboratory data are below the lower limit of quantification (LLOQ), i.e. the collected value 
contains “<”, the reported value is converted to half of the LLOQ value. Laboratory values above 
In the age calculation, no rounding should be done to preserve the precision of days. 
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upper limit of quantification (ULOQ), collected value containing “>”, is set to the ULOQ value. 
The variable DTYPE will be used to mark converted laboratory data, ‘LOQHALF’ and ‘ULOQ’.
Any analysis imputations (see section 3.6.2) will be made on the converted numeric data.
3.6.12
Time-to-event endpoints
3.6.12.1
Primary endpoint - Time to inadequate glycaemic control
The primary endpoint is the time to inadequate glycaemic control defined as HbA1c > 7.0% (53 
mmol/mol) at two scheduled consecutive visits after first 26 weeks of treatment and up to 104 
weeks. First possible occurrence is at week 38.
The data will inherently be interval censored, since HbA1c is only measured at the scheduled visits 
while subjects may reach an HbA1c > 7.0% at any time between 2 visits. The possible failure times 
will be viewed as continuous variable which can only be observed to lie in the interval between the 
visit when the treatment failure is established and the previous scheduled visit.
In order to perform the analysis, interval (t1, t2] will be identified where t1 is the time of the last 
visit at which an event has not occurred for the subject and t2 is the time of the visit at which the 
event occurs.
HbA1c records will be extracted from the laboratory analysis dataset (ADHBA1C) with a selection 
on non-missing measurements which were taken while on treatment at the scheduled visits 5, 6, 7, 
8, 9, 10, 11 and 12 which correspond to weeks 16, 26, 38, 52, 65, 78, 91 and 104.
The first post-baseline HbA1c assessment was done at visit 5 (Week 16). However, for determining 
consecutive visits, assessments from visit 6 onwards will be considered.
Visits with only non-missing measurements of HbA1c will be considered to determine whether visits 
are consecutive or whether a visit is the last visit on treatment. For example, if there are HbA1c 
measurements at visit 6 and visit 8 but it is missing at visit 7, then visit 6 and 8 will be considered 
as two consecutive visits.
The interval (t1, t2] will be identified as below.
1) If the subject discontinued treatment before Week16, subject is censored with t1 as time of 
visit at Week 0 and t2 as missing.
LOQ can be identified by LB.LBORRES containing “<” or “>”. The conversion should happen in ADaM by 
updating AVAL based on the rule and setting DTYPE = “LOQHALF” or DTYPE=”ULOQ1”. AVALC should be 
left empty for these records. LBORRES and LBORRESU should be included in the dataset for traceability.
Comment: 
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2) If the subject discontinued treatment between Week 16 and Week 26, then subject is 
censored with t1 as time of visit at Week 16 and t2 as missing.
3) If the subject does not have any non-missing HbA1c measurements on treatment, subject is 
censored with t1 as time of visit at Week 0 and t2 as missing.
4) If there are two consecutive measurements of HbA1c > 7.0% taken at Week26 or later, then 
event has occurred with t1 as time of first measurement of HbA1c > 7.0% and t2 as time of 
second measurement of HbA1c > 7.0%.
5) If last available HbA1c measurement is at Week 26 or later but before Week104 and the 
value is > 7.0%, then the event has occurred with t1 as time of last available measurement 
and t2 as time of next visit. If the next visit has not happened then, t2 will be time of next 
planned visit as per protocol defined intervals between the visits.
6) If last available HbA1c is between Week 26 and Week 104 and the value is ≤ 7.0%, then the 
subject is censored with t1 as time of last available measurement and t2 as missing.
7) If last available HbA1c is at Week 104 and there are no consecutive visits with HbA1c > 
7.0%, then the subject is censored with t1 as time of visit at Week104 and t2 as missing.
Figure 1
Identification of interval (t1, t2]
The time to inadequate glycaemic control will be compared between the Victoza® arm and the OAD 
arm using a two-sided non-parametric test at a 5% significance level. The test will be a generalised 
log rank test for interval censored failure time data, not based on any model assumptions such as 
proportional hazards or adjusted for any covariates.
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The result of the log rank test will be presented as the asymptotic p-value obtained from a chi-
square distribution.
3.6.12.2
Secondary endpoint - Time to premature treatment discontinuation (for 
any reason including inadequate glycaemic control)
The secondary endpoint is the time to premature treatment discontinuation (for any reason including 
inadequate glycaemic control).
The data will inherently be interval censored, since the criteria for treatment discontinuation is 
primarily checked at the scheduled visits while subjects may have discontinued treatment at any 
time between 2 visits. The possible event time will be considered as a continuous variable.
For subjects that discontinued treatment before Week 104, due to inadequate glycaemic control, 
interval (t1, t2] will be identified as mentioned in the section 3.6.12.1 .
For subjects that discontinued treatment before Week 104, due to any other reason, interval (t1, t2] 
will be identified where t1 is the time of the last attended visit on treatment and t2 is the time of the 
next planned visit. 
The subjects that completed the treatment for Week 104 and did not meet inadequate glycaemic 
control criteria before Week 104 will be considered as censored, 
The time to premature discontinuation (for any reason including inadequate glycaemic control) will 
be compared between the Victoza® arm and the OAD arm using a two-sided non-parametric test at 
a 5% significance level. The test will be a generalised log rank test for interval censored failure time 
data, not based on any model assumptions such as proportional hazards or adjusted for any 
covariates.
3.6.13
Dose data categorization
The defined daily dose (DDD) is the assumed average maintenance dose per day for a drug used for 
its main indication in adults.
The DDD is a unit of measurement and does not necessarily reflect the recommended or prescribed 
daily dose.
The oral antidiabetic and Liraglutide dose data will be categorised as <=DDD and >DDD for each 
drug.
For Liraglutide, as per WHO, DDD is 1.2 mg.
For Metformin, 1500 mg will be considered as DDD and doses will be categorised as <DDD and 
>=DDD.
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Values of DDD mentioned below are taken from WHO website. Please refer to 
https://www.whocc.no/ddd/definition_and_general_considera/for more information.
Table 13
Defined daily dose for oral antidiabetics
Type of OAD
ATC code
Name  
DDD
Unit
Sulfonylureas
A10BB01
glibenclamide
7
mg
Sulfonylureas
A10BB02
chlorpropamide
0.375
g
Sulfonylureas
A10BB03
tolbutamide
1.5
g
Sulfonylureas
A10BB05
tolazamide
0.5
g
Sulfonylureas
A10BB07
glipizide
10
mg
Sulfonylureas
A10BB08
gliquidone
60
mg
Sulfonylureas
A10BB09
gliclazide
60
mg
Sulfonylureas
A10BB12
glimepiride
2
mg
Alpha glucosidase inhibitors
A10BF01
acarbose
0.3
g
Alpha glucosidase inhibitors
A10BF02
miglitol
0.3
g
Alpha glucosidase inhibitors
A10BF03
voglibose
0.6
mg
Thiazolidinediones
A10BG02
rosiglitazone
6
mg
Thiazolidinediones
A10BG03
pioglitazone AT
30
mg
Dipeptidyl peptidase 4 (DPP-4) inhibitors
A10BH01
sitagliptin
0.1
g
Dipeptidyl peptidase 4 (DPP-4) inhibitors
A10BH02
vildagliptin
0.1
g
Dipeptidyl peptidase 4 (DPP-4) inhibitors
A10BH03
saxagliptin
5
mg
Dipeptidyl peptidase 4 (DPP-4) inhibitors
A10BH04
alogliptin
25
mg
Dipeptidyl peptidase 4 (DPP-4) inhibitors
A10BH08
teneligliptin
20
mg
Dipeptidyl peptidase 4 (DPP-4) inhibitors
A10BH05
linagliptin
5
mg
Sodium-glucose co-transporter 2 (SGLT2) 
inhibitors
A10BK01
dapagliflozin
10
mg
Sodium-glucose co-transporter 2 (SGLT2) 
inhibitors
A10BK02
canagliflozin
0.2
g
Sodium-glucose co-transporter 2 (SGLT2) 
inhibitors
A10BK03
empagliflozin
17.5
mg
Other blood glucose lowering drugs, excl. 
insulins
A10BX02
repaglinide
4
mg
Other blood glucose lowering drugs, excl. 
insulins
A10BX03
nateglinide
0.36
g
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4
Analysis data creation and processing issues
4.1
Split datasets 
Datasets larger than 5GB should be split
4.2
Data dependencies
4.2.1
Execution order
The execution order of some data derivations is crucial. The following selected data derivation rules 
apply in the given order:
!
Partial date/time imputation.
!
Laboratory LLOQ/ULOQ conversion.
!
Reference range indicators
!
Define ANELFL based on
o
Fasting status
o
Visit reallocation 
o
Re-test
!
Last observed value before or at first drug date carried forward to baseline
!
Setting observation period record flags, and other period variables
In the datasets with a visit structure (BDS) there should only be one record per subject per visit per 
parameter after the data derivations at this time (for ANELFL=’Y’).
!
Endpoints calculation: BMI, , hypoglycaemia etc. 
!
Trial specific endpoints calculation
!
Calculate values for variables relative to baseline
!
Imputations in relation to analyses, e.g. Last values carried forward
In case of several derivations for a given parameter at a given visit, the DTYPE will be the last 
derivation in the order above. The variable DDCOM will show all derivations for the given 
parameter and visit, as e.g. ‘LOQHALF | LOCF from AVISITN=110’.
4.2.1.1
Execution order of datasets
For execution order of dataset, the below Table 14 shows the dependencies between datasets and 
the macros or functions applied to create the datasets. 
!
Data located in same batch are independent of each other. 
!
A batch depends on previous batches.
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Table 14
Dataset dependencies and execution order
Table of data dependencies including application of macros and functions
Batch 
Data set
Macros or functions applied to create data
1
ADSL (version 1)
ADSLSF
ADHBA1C
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
ADLB
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
ADVS
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
ADEC
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
2
ADSL (version 2)
ADHBA1C
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
ADLB
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
ADVS
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
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ADEC
!
External NN library: GCMD.topic_cd_def
!
External metadata: ADM.plnd_flowch_item_coll
ADEX
!
External NN library: GCMD.topic_cd_def
ADAE
ADCM
ADMH
ADHYPO
ADHYPOEN
!
External NN library: GCMD.topic_cd_def
ADTRTEV
ADTRTVIS
!
External metadata: ADM.plnd_flowch_item_coll
AXNR
ADRESP
!
External NN library: GCMD.topic_cd_def
ADTTE
!
External NN library: GCMD.topic_cd_def
4.3
Intermediate datasets
4.3.1
AXNR – Normal ranges lab data
Dataset containing normal ranges from the laboratory, that can be obtained from the central NN 
library GCMD.lab_range where lab=’4232_ICON’. Normal range data will be applied in ADLB 
and listings.
Reference ranges for all the parameters in converted units is obtained using the 
SDTMMAP.SDTM_UNIT_CONVERSION dataset.
All lab parameters are identified from lab variable ‘quest’ uniquely corresponding to topic code and 
the dataset will add-on the ADaM analysis parameter variables PARAMCD, PARAM, and 
PARCAT1 obtained from the central NN library GCMD.topic_cd_def (see section 3.3 for definition 
of the variables). 
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4.3.2
ADTRTEV – Planned or actual treatment for events
ADTRTEV contains start and end dates for the events. It is based on the dataset SDTM.SE.
4.3.3
ADTRTVIS – Planned or actual treatment for findings
ADTRTVIS contains all the scheduled visits with start and end date and it is based on the 
SDTM.SV.
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5
Analysis datasets descriptions 
5.1
Overview
The ADAM datasets support all the statistical analyses of the efficacy and safety specified in the 
protocol and SPS. They are structured such that the statistical analyses can be performed with 
minimal programming. ADAM datasets are not generated specifically for outputs such as listings 
and other non-analytical displays.
5.2
Analysis Datasets
5.2.1
ADSL – Subject Level Analysis
The ADSL contains data from all randomised subjects, and the data will support all analyses, 
baseline characteristics, and disposition analyses. Data is built from SDTM DM and DS including 
also information from SUPPDM, SUPPSU, MH, SUPPMH, SV, CM, and EC.
ADSL data is built in two steps (batch 1 and 3 in Table 14). First version builds the ADSL data 
without baseline variables of HbA1c, FPG, BMI, weight, systolic blood pressure and diastolic blood 
pressure. Second step of ADSL add-on the listed baseline variables from lab (HbA1C and FPG) and 
vital sign assessments. Only the baseline variables in standard units is added to ADSL. 
In the ADSL the date of randomisation is set to the date of visit 2, and not the randomisation date 
from IWRS. This has been chosen as there are some subjects with a randomisation visit (visit 2) 
date different from the randomisation date in IWRS. 
5.2.2
ADSLSF – Subject level screening failures
The ADSLSF contains data from subjects not randomised (screening failure subjects in SDTM.DM) 
and reason for not being randomised.
Information from inclusion/exclusion SDTM data (SDTM.IE) is transposed and in case of multiple 
records per subject concatenated into an inclusion variable and an exclusion variable. 
ADSLSF is the only dataset including subjects not enrolled.
5.2.3
ADAE – Adverse events analysis
ADAE contains all reported events for randomised subjects. All 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 are included. Data is built on SDTM data AE, SUPPAE, RELREC, and information from 
ADSL.
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5.2.4
ADCM - Concomitant medication analysis 
The ADCM contains all collected concomitant medication observations in SDTM.CM from 
randomised subjects. Information from SDTM.SUPPCM and SDTM.TS is added.
The continuation flag (CONTINFL) indicating if the concomitant medication is ongoing or not, 
relative to the treatment period, is set as “Y” when CM.CMENRF is equal to “ONGOING” 
otherwise it is set to blank.
The status relative to screening date (ASCRF) is set as “COMPLETED BEFORE” when analysis 
start date (ASTDT) and analysis end date (AENDT) is less than the screening date. ASCRF is set as 
“STARTED AFTER” when ASTDT is greater than the screening date. Finally, ASCRF is set as 
“ONGOING” when ASTDT is less or equal to the screening date and AENDT is greater or equal to 
the screening date or missing.
The status relative to baseline (ABLRF) is set as “COMPLETED BEFORE” when analysis start 
date (ASTDT) and analysis end date (AENDT) is less than the randomisation date 
(ADSL.RANDDT). ABLRF is set as “STARTED AFTER” when ASTDT is greater than the 
randomisation date. Finally, ABLRF is set as “ONGOING” when ASTDT is less or equal to the 
randomisation date and AENDT is greater than or equal to the randomisation date.
When AENDT is greater than or equal to the last visit date, ACRF or ABLRF is set to 
“ONGOING” based on ASTDT and AENDT is set to missing.
5.2.5
ADEX -- Exposure analysis set
The ADEX contains data of exposure to trial product for all randomised subjects. Data is built on 
SDTM.EX. There is an observation for each new dose for each subject.
5.2.6
ADEC -- Exposure analysis set
The ADEC contains data of exposure to trial product for all randomised subjects. Data is built on 
SDTM.EC and information from SDTM.SUPPEC is added. There is an observation for each new 
dose for each subject at each visit. 
5.2.7
ADHBA1C – HbA1c
The ADHBA1C contains data for HbA1c assessments for all randomised subjects. Converted lab 
assessments also included in this dataset, see Appendix C.
The ADHBA1C is built in two steps and based on the SDTM datasets LB, and XL where 
LBTESTCD = “HBA1C”, and add information from SUPPLB, AXNR, and ADBR. First version 
builds the complete ADHBA1C without the core efficacy and safety baseline variables. The second 
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version depends on the completed ADSL dataset and add-on the efficacy and safety core baseline 
variables.
5.2.8
ADHYPO – Hypoglycaemic episode analysis
The ADHYPO contains data on all reported hypoglycaemic episodes for randomised subjects. All 
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 are included. Data is built on SDTM data XH, SUPPXH, 
RELREC, and information from ADSL.
The ONTRTFL defines the on-treatment period for hypoglycaemic episodes as described in section 
2.3.3. The TRTEMFL defined the on-treatment period with an addition of 1 more day (section 
3.6.5).
The variables ACAT1 contains the analysis category 1 of ADA hypoglycaemic classification
described in protocol. Each of the ADA classification categories are also marked in the variable 
flags ADASYMFL, ADDOCSFL, ADPROBFL, ADPSEUFL, ADSEVFL, ADUNCLFL, 
ADUNNSFL.
The variables ACAT2 contains the analysis category 1of NN hypoglycaemic classification
described in protocol. Each of the NN classification categories and merged categories are also 
marked in the variable flags NNASCOFL, NNCONFL, NNSECOFL, NNSEVFL, NNSYCOFL, 
NNSYSEFL, NNUNCLFL.
The date-time imputations follow the derivation rules in 3.6.1, and note that missing time 
information imputed to 00:00 implies that the hypoglycaemic episodes are imputed to occur during 
day-time.
5.2.9
ADHYPOEN – Hypoglycaemic episode analysis endpoint
The ADHYPOEN contains data on the number of treatment emergent severe hypoglycaemic 
episodes for all FAS subjects. 
The counts are made over two periods: on-treatment or on-treatment+1 day, corresponding to 
ONTRFL=’Y’ and TRTEMFL=’Y’, respectively, in ADHYPO. This results in two rows per 
subject; one with the count for the on-treatment period with ONTRFL=’Y’ and TRTEMFL=’’ and 
one with the count for the on-treatment+1 day period with ONTRFL=’’ and TRTEMFL=’Y’.
A binary variable indicating whether there are >0 or 0 episodes are also included using the 
CRIT1/CRIT1FL structure.
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Table 15
Derived hypoglycaemic endpoints
Endpoint
Topic code (PARAMCD)
Technical details
Severe hypoglycaemic 
episodes
HYPO_N_TE_SEVERE
(SEV_HYPO)
Sum of records with 
ADHYPO.ADSEVFL=”Y” 
and
ADHYPO.TRTEMFL=”Y” 
Severe or blood glucose 
confirmed symptomatic 
hypoglycaemic episodes
HYPO_N_TE_NNSBCFL
(HYCNFSEX)
Sum of records with 
ADHYPO.NNSECOFL=”Y” 
and
ADHYPO.TRTEMFL=”Y” 
Documented symptomatic 
hypoglycaemic episodes
(ADA)
HYPO_N_TE_DOC_SYMP
(DOC_HYPO)
Count of records where 
ADHYPO.TRTEMFL = "Y"
and ADHYPO.ACAT1 = 
"Documented symptomatic
hypoglycaemia"
5.2.10
ADLB - Lab Analysis  
The ADLB contains data for safety lab assessments for lipids, biochemistry, haematology, and 
pregnancy test, and the efficacy lab assessments for FPG for all randomised subjects. Converted lab 
assessments is also included in this dataset for a list of lab assessments which have been reported in 
multiple units, see PSPS Appendix 4.
The ADLB is built in two steps and based on the SDTM datasets LB, XL, SUPPLB, AXNR, and 
information from ADBR. Data for HbA1c measurements are excluded. First version builds the 
complete ADLB without the core efficacy and safety baseline variables. The second version 
depends on the completed ADSL dataset and add-on the efficacy and safety core baseline variables. 
Parameters with character values are presented in AVALC and include topic codes of urine 
pregnancy test and information on whether urine or blood samples were collected. All other 
parameters are in nature numeric and their values are presented in AVAL. For numeric values 
truncated by a lower or upper limit of quantification the value in AVAL is derived as described in 
section 3.6.11. The SDTM variable LB.LBSTRESC is kept in ADLB for traceability of all values.
The analysis eligibility flag, ANELFL, is defined in accordance with rules described in section 3.5. 
The parameter , fasting plasma glucose  is required to be assessed when the subject is fasting. For 
non-fasting subjects these assessments have ANELFL =’’ (Section 3.6.10). All unscheduled 
(VISITNUM=29500) and non-visits (VISITNUM = 29999) have ANELFL = ‘’.
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In LB data LDL measurements calculated using Friedwald equation are reported with the topic code 
“CALC_LDL_CHOL_SERUM”. If the triglycerides were >4.52 mmol/L, then the direct LDL 
cholesterol measurement is reported with topic code “LDL_CHOL_SERUM”. In such cases a new 
row in entered in ADLB with CALC_LDL_CHOL_SERUM = LDL_CHOL_SERUM and dtype as 
derived.
5.2.11
ADMH – Medical History Analysis 
The ADMH contain all general medical history and history of diabetic complications, from 
SDTM.MH for randomised subjects. Information from SDTM.SUPPMH is added.
The continuation flag (CONTINFL) indicating if the concomitant medication is ongoing or not, 
relative to the treatment period, is set as “Y” when CM.CMENRF is equal to “ONGOING” 
otherwise it is set to blank.
The medical analysis records (ANL01FL) is set to “Y” when (MH.MHOCCUR = 'Y' and 
MH.MHPRESP = 'Y') or when CONTINFL is non-missing. Otherwise the ANL01FL is empty, 
where the ANL01REA states “Does not meet criteria for analysis”.
The status relative to screening date (ASCRF) is set as “COMPLETED BEFORE” when analysis 
start date (ASTDT) and analysis end date (AENDT) is less than the screening date. ASCRF is set as 
“STARTED AFTER” when ASTDT is greater than the screening date. Finally, ASCRF is set as 
“ONGOING” when ASTDT is less or equal to the screening date and AENDT is greater or equal to 
the screening date.
The status relative to baseline (ABLRF) is set as “COMPLETED BEFORE” when analysis start 
date (ASTDT) and analysis end date (AENDT) is less than the randomisation date 
(ADSL.RANDDT). ABLRF is set as “STARTED AFTER” when ASTDT is greater than the 
randomisation date. Finally, ABLRF is set as “ONGOING” when ASTDT is less or equal to the 
randomisation date and AENDT is greater than or equal to the randomisation date.
An illness is defined as a concomitant illness at screening if ASCRF is equal to either “ONGOING” 
or “STARTED AFTER”. Similarly, an illness is a concomitant illness at baseline if ABLRF is equal 
to either “ONGOING” or “STARTED AFTER”.  
5.2.12
ADVS - Vital Signs Analysis
The ADVS contains data on vital sign assessments for all randomised subjects. Converted 
assessments are also included in this dataset for a list of vital sign assessments which have been 
reported in multiple units, see Appendix C.
The ADVS is built in two steps and based on the SDTM datasets VS, XV, SUPPVS, and 
information from ADBR. The first step builds the complete ADVS without the core efficacy and 
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safety baseline variables. The second stepdepends on the completed ADSL dataset and addsthe 
efficacy and safety core baseline variables. 
BMI on CRF is excluded from ADVS and replaced by derived BMI. The BMI is derived at all 
control visits with topic code (topic_cd = “BMI_DERIVED”) and DTYPE is set to “DERIVED”
and where the record is set to ANELFL = “Y”.
Note, that are no entries for investigator comments on the vital sign CRF forms, and therefore no 
ACOMNT variable included in ADVS data.
5.2.13
ADTTE–Time-to-Event Analyses
. The ADTTE contains data on time-to-eventcorresponding to primary and secondary endpoints.
The variables ALBNDDTandARBNDDT are defined in section 3.6.12..
If an event is met,then the CNSR (censoring) is assigned as 0 else 1.
5.2.14
ADRESP – Responder Analysis
ADRESP contains the dichotomous endpoints calculated from observed data in ADHBA1C without 
any imputations.
Table 16
Parameters included in ADRESP dataset
TOPIC_CD
PARAM
PARAMCD
HBA1C_BLOOD_65
HbA1c <=6.5% (IDF)
HBA_BL65
HBA1C_BLOOD_LE70_WO_WEIGHT_
GAIN
HbA1c <=7% without weight gain
HLE7WOW
G
HBA1C_BLOOD_LE70_WO_TE_SEV_
BG_HYPO
HbA1c <=7% without treatment 
emergent sever hypoglycaemic 
episodes or blood glucose confirmed 
symptomatic hypoglycaemic 
episodes
HLE7WOH
Y
HBA1C_BLOOD_LE70_WO_WEIGHT_
GAIN_TE_SEV_BG_HYPO
HbA1c <=7% without weight gain 
and no treatment emergent severe 
hypoglycaemic episodes or blood 
glucose confirmed symptomatic 
hypoglycaemic episodes
HLE7WOW
H
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These endpoints will be derived using the last post-baseline measurements of HbA1c on treatment, 
last measurement of body weight taken on treatment, baseline body weight and the hypoglycaemic 
episodes in period from TRTSDT till Analysis Date.
AVALC will be derived as “Y” or “N” based on the criteria for each topic_cd. 
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6
Data conformance summary
This section will be updated in the Analysis Data Reviewers Guide.
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7
Submission of Programs
This section will be updated in the Analysis Data Reviewers Guide.
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8
Specification of output
See PSPS version 1.0.
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9
References
Appendix A
Table shells location
Table 17
Table shells location
Document
novoDOCS object ID
4232-sec-14-1-demographic-data-statistical-table-shells
4232-sec-14-2-efficacy-data-statistical-table-shells
4232-sec-14-3-1-adverse-events-statistical-table-shells
4232-sec-14-3-2-deaths-saes-statistical-table-shells
4232-sec-14-3-4-abnormal-lab-list-statistical-table-shells
Not Applicable
4232-sec-14-3-5-lab-displays-statistical-table-shells
4232-sec-14-3-6-other-safety-observations-displays-statistical-
table-shells
4232-sec-14-3-7-other-safety-observations-lists-statistical-table-
shells
Not Applicable
4232-sec-16-2-1-discontinued-patients-statistical-table-shells
4232-sec-16-2-3-patients-excluded-from-efficacy-analysis-
statistical-table-shells
Not Applicable
4232-sec-16-2-4-individual-demographic-data-statistical-table-
shells
4232-sec-16-2-5-compliance-and-drug-concentration-data-
statistical-table-shells
Not Applicable
4232-sec-16-2-6-individual-efficacy-response-data-statistical-
table-shells
Not Applicable
4232-sec-16-2-7-adverse-event-listings-statistical-table-shells
4232-sec-16-2-8-listing-individual-lab-measurements-statistical-
table-shells
Not Applicable
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Appendix B
Good Specification Practice for Data Derivations
B.1 Sequence of ANELREA text:
The ANELREA text is prioritized in the following order:
1. “Unscheduled assessment”
2. “Assessment not planned”
3. “Record at baseline visit was excluded due to date after treatment start”
4. “Before in-trial observation period”
5. “After in-trial observation period”
6. “No measurement”
7. “Record was excluded due to subject being non-fasting”
8. “Retest rule 1: Not first value for visit”
9. “Assessment done after starting add on glucose lowering drug”
The ANELREA enters all BDS ADaM datasets.
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Appendix C
Table of converted units applied
Parameter
Topic code
SI unit
Conventional 
unit
(if required)
Conversion factor 
(SI to conventional 
unit) 
Total 
Bilirubin
T_BILIRUBIN_SERU
M
umol/L
mg/dL
0.058466
Creatinine
CREATININE_SERUM
umol/L
mg/dL
0.0113118
Fasting 
Plasma 
Glucose
FPG_PLASMA
mmol/L
mg/dL
18.02
HbA1c
HBA1C_BLOOD
%
mmol/mol
<src>*10.93-23.5
HDL 
Cholesterol
HDL_CHOL_SERUM
mmol/L
mg/dL
38.61
Haemoglobin
HAEMOGLOBIN_BLO
OD
mmol/L
g/dL
1.6125
LDL 
Cholesterol
LDL_CHOL_SERUM
mmol/L
mg/dL
38.61
Calculated 
LDL 
Cholesterol
CALC_LDL_CHOL_SE
RUM
mmol/L
mg/dL
38.61
Potassium
POTASSIUM_SERUM
mmolL
mEq/L
1
Total 
Cholesterol
T_CHOL_SERUM
mmol/L
mg/dL
38.61
Triglycerides
TRIGLYCERIDES_SE
RUM
mmol/L
mg/dL
89
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10 Change Log
Edition no.
1.0
Effective date:
10 Jun 2019
Changes to 
document
First version.
2.0
Effective date:
13 September 2019
Trial specific updates
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