Clinical trial NCT03078478
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2017-03-13; Completion date: 2019-03-04
Enrollment: 1609 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted in Europe and North America. The aim of the trial is to compare the efficacy and safety of insulin degludec and insulin glargine 300 units/mL in subjects with type 2 diabetes mellitus inadequately treated with basal insulin with or without oral antidiabetic drugs. Due to change in glycaemic data collection process, this trial is amended to allow for a full 36 weeks (maintenance 2 period) of the use of the new process.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Insulin degludec intervention 2: Insulin glargine
Intervention descriptions: intervention 1: For subcutaneous (s.c., under the skin) injection once daily intervention 2: For subcutaneous (s.c., under the skin) injection once daily

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03078478 
Sponsor trial ID: 
NN1250-4252 
Official title of study: 
A trial comparing the efficacy and safety of insulin degludec 
and insulin glargine 300 units/mL in subjects with type 2 
diabetes mellitus inadequately treated with basal insulin with or 
without oral antidiabetic drugs 
Document date: 
29 May 2019 
 


Link
Link
Link
Link
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Link
List of contents
Protocol version 2...............................................................................................................................
Protocol version 3...............................................................................................................................
Appendix A .........................................................................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 Serbia ...........................................................................................................
Protocol amendment 2 .......................................................................................................................
Memo analyse of antibodies...............................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
insulin degludec
Trial ID: NN1250-4252
Clinical Trial Report
Appendix 16.1.1
29 May 2019
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
1 of 109
Protocol
Trial ID: NN1250-4252
A trial comparing the efficacy and safety of insulin degludec and 
insulin glargine 300 units/mL in subjects with type 2 diabetes mellitus 
inadequately treated with basal insulin with or without oral anti-
diabetic drugs
Trial phase: 3b
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:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
2 of 109
Table of contents
  
Page
Table of contents...............................................................................................................................................2
Table of figures.................................................................................................................................................6
Table of tables...................................................................................................................................................6
List of abbreviations.........................................................................................................................................6
1
Summary..................................................................................................................................................11
2
Flow chart ................................................................................................................................................14
3
Background information and rationale for the trial............................................................................20
3.1
Background information..............................................................................................................20
3.2
Rationale for the trial...................................................................................................................21
4
Objective(s) and endpoint(s) ..................................................................................................................23
4.1
Objective(s)..................................................................................................................................23
4.2
Endpoint(s)...................................................................................................................................23
4.2.1
Primary endpoint........................................................................................................23
4.2.2
Secondary endpoints..................................................................................................23
4.2.2.1
Confirmatory secondary endpoints .....................................................23
4.2.3
Other endpoints..........................................................................................................23
5
Trial design ..............................................................................................................................................25
5.1
Type of trial .................................................................................................................................25
5.2
Rationale for trial design..............................................................................................................26
5.3
Treatment of subjects...................................................................................................................26
5.4
Treatment after discontinuation of trial product ..........................................................................28
5.5
Rationale for treatment ................................................................................................................28
6
Trial population.......................................................................................................................................29
6.1
Number of subjects......................................................................................................................29
6.2
Inclusion criteria ..........................................................................................................................29
6.3
Exclusion criteria.........................................................................................................................30
6.4
Criteria for premature discontinuation of trial product................................................................31
6.5
Withdrawal from trial ..................................................................................................................32
6.6
Subject replacement.....................................................................................................................33
6.7
Rationale for trial population.......................................................................................................33
7
Milestones.................................................................................................................................................34
8
Methods and assessments .......................................................................................................................35
8.1
Visit procedures...........................................................................................................................35
8.1.1
Screening visit (Visit 1) .............................................................................................35
8.1.1.1
Screening failures................................................................................36
8.1.2
Randomisation visit (V2)...........................................................................................36
8.1.3
Phone contacts ...........................................................................................................37
8.1.4
Fasting visits ..............................................................................................................37
8.1.5
End of Treatment visit (V54).....................................................................................38
8.1.6
Follow up visits..........................................................................................................38
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
3 of 109
8.1.7
Unscheduled site visits...............................................................................................39
8.1.8
Premature discontinuation of trial product ................................................................39
8.1.8.1
eDiary records after premature discontinuation of trial product .........41
8.1.9
Withdrawal from trial ................................................................................................41
8.1.10
Review of results .......................................................................................................41
8.2
Subject related information/assessments .....................................................................................42
8.2.1
Demography...............................................................................................................42
8.2.2
Diabetes history .........................................................................................................42
8.2.3
Hypoglycaemia unawareness.....................................................................................42
8.2.4
Concomitant illness and medical history...................................................................42
8.2.5
Concomitant medication............................................................................................43
8.2.6
Concomitant medication (Diabetes) ..........................................................................43
8.2.7
Childbearing potential................................................................................................44
8.2.8
Tobacco use ...............................................................................................................44
8.3
Efficacy assessments....................................................................................................................44
8.3.1
Self-measured plasma glucose...................................................................................44
8.3.2
Insulin dose................................................................................................................45
8.4
Safety assessments.......................................................................................................................45
8.4.1
Adverse events...........................................................................................................45
8.4.1.1
Medication error..................................................................................45
8.4.1.2
Adverse events requiring additional data collection ...........................46
8.4.2
Hypoglycaemic episodes ...........................................................................................47
8.4.3
Body measurements...................................................................................................50
8.4.4
Vital signs ..................................................................................................................50
8.4.5
Physical examination.................................................................................................50
8.4.6
Eye examination ........................................................................................................51
8.4.7
Electrocardiogram......................................................................................................51
8.5
Laboratory assessments ...............................................................................................................52
8.5.1
Laboratory assessments for efficacy..........................................................................53
8.5.2
Laboratory assessments for safety .............................................................................53
8.6
Other assessments........................................................................................................................54
8.6.1
Training in the pen injector........................................................................................56
8.7
Subject compliance......................................................................................................................56
9
Trial supplies ...........................................................................................................................................58
9.1
Trial products...............................................................................................................................58
9.2
Labelling......................................................................................................................................59
9.3
Storage .........................................................................................................................................59
9.4
Drug accountability and destruction............................................................................................60
9.5
Auxiliary supplies........................................................................................................................60
10 Interactive web response system............................................................................................................61
11 Randomisation procedure ......................................................................................................................62
12 Adverse events, and technical complaints and pregnancies................................................................63
12.1
Definitions ...................................................................................................................................63
12.1.1
Adverse event ............................................................................................................63
12.1.2
Serious adverse event.................................................................................................64
12.1.3
Non-serious adverse event.........................................................................................65
12.1.4
Medication errors.......................................................................................................66
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
4 of 109
12.1.5
Adverse events requiring additional data collection..................................................66
12.1.6
Technical complaints.................................................................................................67
12.2
Reporting of adverse events.........................................................................................................67
12.3
Follow-up of adverse events........................................................................................................69
12.4
Technical complaints and technical complaint samples ..............................................................71
12.4.1
Reporting of technical complaints .............................................................................71
12.4.2
Collection, storage and shipment of technical complaint samples ............................71
12.5
Pregnancies in female subjects ....................................................................................................72
12.6
Precautions and/or overdose ........................................................................................................73
12.7
Committees related to safety........................................................................................................74
12.7.1
Novo Nordisk safety committee ................................................................................74
12.7.2
Event adjudication committee....................................................................................74
13 Case report forms....................................................................................................................................77
13.1
Corrections to case report forms..................................................................................................77
13.2
Case report form flow..................................................................................................................78
13.3
eDiary...........................................................................................................................................78
14 Monitoring procedures ...........................................................................................................................79
15 Data management....................................................................................................................................81
16 Computerised systems.............................................................................................................................81
17 Statistical considerations ........................................................................................................................81
17.1
General considerations.................................................................................................................81
17.2
Sample size calculation................................................................................................................83
17.3
Definition of analysis sets............................................................................................................84
17.4
Primary endpoint..........................................................................................................................85
17.4.1
Primary statistical analysis for the primary estimand................................................85
17.4.2
Sensitivity analyses for the primary estimand ...........................................................85
17.4.3
Statistical analysis for the secondary estimand..........................................................86
17.4.4
Sensitivity analysis for the secondary estimand ........................................................86
17.5
Secondary endpoints....................................................................................................................86
17.5.1
Confirmatory secondary endpoints............................................................................86
17.6
Other endpoints............................................................................................................................87
17.6.1
Efficacy endpoints .....................................................................................................87
17.6.2
Safety endpoints.........................................................................................................87
17.7
Classification of Hypoglycaemia.................................................................................................89
17.8
Health economics and/or patient reported outcomes...................................................................92
18 Ethics........................................................................................................................................................93
18.1
Benefit-risk assessment of the trial..............................................................................................93
18.2
Informed consent .........................................................................................................................94
18.3
Data handling...............................................................................................................................95
18.4
Information to subjects during trial..............................................................................................95
18.5
Premature termination of the trial and/or trial site.......................................................................95
19 Protocol compliance................................................................................................................................96
19.1
Protocol deviations ......................................................................................................................96
19.2
Prevention of missing data...........................................................................................................96
20 Audits and inspections ............................................................................................................................98
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
5 of 109
21 Critical documents ..................................................................................................................................98
22 Responsibilities........................................................................................................................................99
23 Reports and publications......................................................................................................................100
23.1
Communication of results..........................................................................................................100
23.1.1
Authorship ...............................................................................................................101
23.1.2
Site-specific publication(s) by investigator(s) .........................................................101
23.2
Investigator access to data and review of results.......................................................................102
24 Retention of clinical trial documentation and human bio samples...................................................103
24.1
Retention of clinical trial documentation...................................................................................103
24.2
Retention of human bio samples................................................................................................103
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............105
26 Indemnity statement .............................................................................................................................106
27 References..............................................................................................................................................107
Appendix A
Titration Guideline
Attachment I  Global list of key staff and relevant departments and suppliers
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
6 of 109
Table of figures
Page
Figure 5–1
Trial design.............................................................................................................................25
Figure 12–1
Reporting of AEs....................................................................................................................68
Figure 13–1
eDiary data flow .....................................................................................................................79
Figure 17–1
Novo Nordisk classification of hypoglycaemia......................................................................90
Figure 17–2
ADA classification of hypoglycaemia....................................................................................91
Table of tables
Page
Table 2–1
Flow chart – phone contacts ...................................................................................................19
Table 9–1
Trial products..........................................................................................................................58
Table 9–2
Storage conditions ..................................................................................................................59
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event
adjudication ............................................................................................................................66
Table 12–2
Events for adjudication...........................................................................................................74
Table 17–1
Sample sizes for the primary and secondary estimand for combinations of RR and 
event rates to achieve a power of 80% ...................................................................................83
Table 17–2
Marginal power for confirmatory secondary endpoints .........................................................84
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
7 of 109
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AP
alkaline phosphatase
AST
aspartate aminotransferase
BG
blood glucose
BID
Bis In Die/twice daily
CAS
completer analysis set
CCDS
Company Core Data Sheet
CFR
Code of Federal Regulations
CLAE
clinical laboratory adverse event
CRF
case report form
DPP-IVi
dipeptidyl peptidase-4 inhibitor 
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
eGFR
estimated Glomerular Filtration Rate 
EMA
European Medicines Agency
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPFV
first patient first visit
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
8 of 109
FPG
fasting plasma glucose
FU
follow-up
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotropin
IB
investigator’s brochure
ICH
International Conference on 
Harmonisation of Technical 
Requirements for Registration of 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical 
Journal Editors
IDeg
insulin degludec
IEC
independent ethics committee
IGlar
insulin glargine
IMP
investigational medicinal product
IND
Investigational New Drug
ITT
intention-to-treat
IRB
institutional review board
IWRS
interactive voice/web response 
system
LI
label information
LLOQ
lower limit of quantification
LPLV
last patient last visit
MACE
major adverse cardiovascular events
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
9 of 109
NIMP
Non-Investigational Medicinal 
Product 
NPH
insulin Neutral Protamine Hagedorn 
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
OD
once daily
PP
per protocol
PRO
patient reported outcome
PYE
Patient years of exposure
PX
monthly phone contact
RR
rate ratio
SAE
serious adverse event
SAS
safety analysis set
SD
standard deviation
SF-36v2®
short-form 36 health survey version 2
SGLT2i
sodium-glucose co-transporter 2 
inhibitors
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SU
sulfonylureas
SUSAR
suspected unexpected serious adverse 
reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent AE
TIA
transient ischaemic attack 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
10 of 109
TMM
trial materials manual
TRIM-D
Treatment related impact measure -
diabetes 
TRIM-D-Device
Treatment related impact measure -
diabetes device 
TZD
Thiazolidinediones
U
Units
UNL
upper normal limit
UTN
Universal Trial Number
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
11 of 109
1
Summary
Objective(s) and endpoint(s):
Primary objective
To compare the effects of insulin degludec once daily and insulin glargine 300 units/mL once daily 
on hypoglycaemia in subjects with type 2 diabetes mellitus, inadequately treated with basal insulin 
with or without oral anti-diabetic drugs.
Key secondary objectives
To compare insulin degludec and insulin glargine 300 units/mL in terms of basal insulin 
requirement.
To compare insulin degludec and insulin glargine 300 units/mL in terms of safety and parameters of 
glycaemic control.
Primary endpoint
!
Number of severe or blood glucose confirmed symptomatic hypoglycaemic episodes during 
maintenance period (week 16-52)
Confirmatory secondary endpoints:
!
Basal insulin dose (units) at 52 weeks
!
Number of nocturnal, severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes during maintenance period (week 16-52)
!
Number of severe or blood glucose confirmed symptomatic hypoglycaemic episodes during 
52 weeks
!
Number of severe hypoglycaemic episodes during maintenance period (week 16-52)
Other efficacy endpoints:
!
Change in HbA1c from baseline to 52 weeks
Other safety endpoints:
!
Hypoglycaemia
o
Number of nocturnal, severe or blood glucose confirmed symptomatic  
hypoglycaemic episodes during 52 weeks
o
Number of severe hypoglycaemic episodes during 52 weeks
!
Number of adverse events during 52 weeks
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
12 of 109
Trial design:
This is a 52-week, randomised (1:1), open-label, parallel, multi-centre, multi-national, treat-to-
target, active controlled trial comparing the efficacy and safety of insulin degludec 200 units/mL
with insulin glargine 300 units/mL both administered once daily ± oral anti-diabetic drugs in 
subjects with type 2 diabetes mellitus previously treated with basal insulin once or twice daily ± 
oral anti-diabetic drugs excluding sulfonylureas/glinides. Type and dose of any pre-trial oral anti-
diabetic treatment should remain unchanged throughout the trial.
Within each treatment arm, subjects will be randomised 1:1 to morning (from waking up to 
breakfast) or evening dosing (from main evening meal to bedtime). The dosing time will be kept 
throughout the entire treatment period.
Total trial duration for the individual subjects will be up to 58 weeks.
Trial population:
It is planned to randomise 1,590 subjects.
Key inclusion criteria:
!
Male or female, age above or equal to 18 years at the time of signing informed consent.
!
Subjects fulfilling at least one of the below criteriaa:
a.
Experienced at least one severe hypoglycaemic episode within the last year 
(according to the ADA definition, April 2013b).
b. Moderate chronic renal failure, defined as glomerular filtration rate 30 - 59 
mL/min/1.73 m2 per CKD-EPI by central laboratory analysis.
c.
Hypoglycaemic symptom unawarenessc.
d. Treated with insulin for more than 5 years.
e.
Episode of hypoglycaemia (defined by symptoms of hypoglycaemia and/or episode 
with low glucose measurement (≤ 70 mg/dL [≤ 3.9 mmol/L])) within the last 12 
weeks prior to Visit 1(screening).
!
Subjects diagnosed (clinically) with type 2 diabetes mellitus.
!
Treated with basal only insulin (once daily or twice-daily insulin (insulin detemir; insulin 
glargine 100 U/mL, biosimilar of insulin glargine 100 U/mL or insulin Neutral Protamine 
Hagedorn)) ≥ 90 days prior to the day of screening with or without any of the following 
anti-diabetic drugs with stable doses for ≥ 90 days prior to screening:
a
Metformin
b
Dipeptidyl peptidase -4 inhibitor
c
Sodium-glucose co-transporter 2 inhibitor
d
Alpha-glucosidase-inhibitors (acarbose)
e
Thiazolidinediones
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
13 of 109
f
Marketed oral combination products only including the products listed in criteria 5a-
5e
!
HbA1c ≤ 9.5% (80 mmol/mol) at screening by central laboratory analysis.
!
BMI ≤ 45 kg/m2.
aFor this inclusion criterion the aim is to include minimum 80% of individuals with a previous 
episode of hypoglycaemia (criterion e). The remaining subjects will have to fulfil at least one of 
criteria a-d.
bAn 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.
cHistory of impaired autonomic responses (tremulousness, sweating, palpitations, and hunger) 
during hypoglycaemia.
Key exclusion criteria
!
Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria in a period of 90 days before the day of screening.
Key assessments:
!
Hypoglycaemic episodes
!
Insulin dose
!
HbA1c
!
Adverse events
Trial products:
Investigational medicinal products:
!
Test product: Insulin degludec (Tresiba®), 200 U/mL, 3 mL prefilled PDS290 (FlexTouch®) 
pen for subcutaneous injection
!
Reference therapy: Insulin glargine (Toujeo®), 300 U/mL, 1.5 mL prefilled Solostar® pen
for subcutaneous injection
Other medicinal products:
!
Insulin Neutral Protamine Hagedorn (Insulatard®/Prothaphane®/Novolin N™), 100 IU/mL, 
3 mL pre-filled pen for subcutaneous injection (will be provided by sponsor to subjects 
during the wash-out period in order to measure insulin antibodies)
CONFIDENTIAL


Protocol
UTN: U1111-1184-8175
Date:
11 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
2.0
Page:
14 of 109
2
Flow chart
For further description of methods and assessments; see Section 8.
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
SUBJECT 
RELATED 
Informed consent
18.2
X
Inclusion/exclusion 
criteria
6.2 6.3
X
X
Randomisation
8.1.2
X
Premature 
discontinuation of trial 
products
6.4
8.1.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Withdrawal from trial
6.5
8.1.9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography
8.2.1
X
Diabetes history
8.2.2
X
Stop date of current 
diabetes treatment
8.2.2
X
Hypoglycaemia 
unawareness
8.2.3
X


Protocol
UTN: U1111-1184-8175
Date:
11 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
2.0
Page:
15 of 109
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
Concomitant illness 
and medical History
8.2.4
X
Concomitant 
medication
8.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication (Diabetes)
8.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Childbearing potential
8.2.7
X
Tobacco use
8.2.8
X
EFFICACY 
ASSESMENTS
Self-measured plasma 
glucose Once daily 
(pre-breakfast)
8.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting plasma glucose 8.5.1
X
X
X
X
X
X
X
HbA1c
8.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAFETY 
ASSESMENTS
Adverse events
8.4.1
12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic 
episodes 
8.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
8.4.3
X
X
X
X
X
Height
8.4.3
X


Protocol
UTN: U1111-1184-8175
Date:
11 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
2.0
Page:
16 of 109
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
Vital signs
8.4.4
X
X
Physical examination
8.4.5
X
X
Eye examination 
(Fundoscopy or fundus 
photography)
8.4.6
X
X
ECG
8.4.7
X
X
Anti-insulin antibodies 8.5.2
X
X
X
X
X
Biochemistry
8.5.2
X
X
Haematology
8.5.2
X
X
Pregnancy test
8.5.2
X
X
Technical complaints
12.1.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
OTHER 
ASSESSMENTS
SF-36v2® Standard
8.6
X
X
X
TRIM-D
8.6
X
X
X
TRIM-D device
8.6
X
X
Baseline 
hypoglycaemic
Questionnaire (BHQ)
8.6
X
Insulin Pen 
Questionnaire
8.6
X


Protocol
UTN: U1111-1184-8175
Date:
11 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
2.0
Page:
17 of 109
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
Hypoglycaemia 
resource use 
questionnaire
8.6
X
X
X
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
NPH dosing (Date and 
Dose)
8.1.5
X
Dosing (Date, Dose 
and time of trial 
insulin), every day
8.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Date of first dose of 
investigational trial 
product
8.1.2
X
New prescribed dose 
of trial insulin
8.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensing visit
9.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
9.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IWRS session
10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
REMINDERS
Attend visit fasting
8.1.4
X
X
X
X
X
X
X
X
X
X
Confirmation of 
unchanged OAD
8.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1184-8175
Date:
11 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
2.0
Page:
18 of 109
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
Training in trial 
product and pen 
handling
8.6.1
9.2
X
X
Hand-out direction for 
use for the pen 
injectors
9.2
X
Hand-out ID card
8.1.1
X
Hand-out and instruct 
in BG meter
8.1.2
X
X
Hand-out and instruct 
in eDiary
8.1.2. 
8.6
X
eDiary collection
8.6
X
X
Make appointment for 
eye examination
8.4.6
X
End Of Treatment
8.1.5
X
X
End of trial
7
X
X
Sign off Casebook
X


Protocol
UTN: U1111-1184-8175
Date:
11 November 2016
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
2.0
Page:
19 of 109
Table 2–1
Flow chart – phone contacts
NN1250-4252
Phone contacts (P)
Time shown in site visit flow chart
Protocol 
section
P3-P53
PX
Contact window (days)
± 3
± 5
Criteria for premature discontinuation of trial products
6.4
X
Concomitant medication
8.2.5
X
Concomitant medication (Diabetes)
8.2.6
X
X
Self-measured plasma glucose, Once daily (pre-breakfast)
8.3.1
X
First date on trial product
8.3.2
P3
Dosing
8.3.2
X
New prescribed dose of trial insulin
8.3.2
X
Adverse events 
8.4.1 12
X
X
Hypoglycaemic episodes
8.4.2
X
X
Technical complaints
12.4
X
End of Trial
7


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
20 of 109
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
Therapeutic area
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, impaired insulin secretion
and increased hepatic glucose output due to glucagon dysregulation resulting in chronic 
hyperglycaemia3. A number of landmark studies have demonstrated the importance of maintaining 
tight glycaemic control to reduce the risk of long-term complications associated with diabetes4. The 
current treatment cascade follows a stepwise approach comprising lifestyle changes in combination 
with pharmacological intervention. Metformin is recommended as initial pharmacological therapy, 
followed by combination therapy with other oral anti-diabetic drugs (OADs), glucagon-like peptide 
1 receptor agonists (GLP-1) and insulin as the disease progresses5.
Insulin treatment is associated with hypoglycaemia, and fear of hypoglycaemia, especially severe 
hypoglycaemia, is widely acknowledged as the main limiting factor for achieving tight glycaemic 
control. Given the impact on quality of life, the potentially life-threatening consequences of severe 
and nocturnal hypoglycaemia, reducing the risk of hypoglycaemia is critical to the lives of patients.
Information on the hypoglycaemia profile of insulin products is considered an important part of the 
information foundation for health care professionals in considering individualised treatment. Thus it 
is important to compare different insulin analogues in terms of efficacy and safety to be able to 
offer subjects with T2DM in need of insulin treatment the best possible option.
Insulin degludec
Insulin degludec (IDeg) is an insulin analogue with unique pharmacological properties and a long 
duration of action8. IDeg provides similar glycaemic control to comparators with a 14–18% lower 
risk of confirmed hypoglycaemia and a 23–38% lower risk of nocturnal confirmed hypoglycaemia
compared to insulin glargine 100 U/mL (IGlar 100 U/mL) in T2DM (phase 3a trials)6, 7. Moreover, 
in the SWITCH 2 trial (T2DM, phase 3b trial) IDeg was associated with a 23% lower risk of 
overall confirmed symptomatic hypoglycaemia, a 25% lower risk of nocturnal confirmed 
symptomatic hypoglycaemia and a 51% lower risk of severe hypoglycaemia compared to IGlar 
100 U/mL8. The hypoglycaemic risk reduction for IDeg compared to IGlar 100 U/mL was more 
pronounced in the maintenance period in all trials6-8.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
21 of 109
IDeg is developed in two strengths (100 U/mL and 200 U/mL) that are bio-equivalent in clinical 
pharmacology trials. IDeg has been approved in more than 70 countries globally and is indicated for 
treatment of diabetes mellitus as monotherapy, in combination with oral anti-diabetic agents and 
GLP-1, and as part of a basal-bolus insulin regimen in adults and children from the age of 1 year 
(GLP-1 co-usage and paediatric indication <18 years is not an approved indication in all countries
with market authorisation). For further details please refer to the current version of the IDeg 
Investigator’s Brochure (IB)9, of the Tresiba® summary of product characteristics(SmPC)10, U.S. 
Label Information (LI)11 and any updates thereof.
Insulin glargine 300 U/mL
Insulin glargine 300 U/mL (IGlar 300 U/mL), a new long-acting insulin analogue approved in USA,
Canada, EU and Japan, is indicated for treatment of diabetes mellitus as monotherapy, in 
combination with oral anti-diabetic agents and as part of a basal-bolus insulin regimen. The 
development programme established comparable efficacy and safety versus IGlar 100 U/mL12, 13. 
Furthermore, a tendency towards a reduction in the incidence of hypoglycaemia with IGlar 300 
U/mL was found in subjects with T2DM. For further details, please refer to the current version of 
the Toujeo® SmPC14 or local labelling15, 16.
For an assessment of benefits and risks of the trial, see Section 18.1.
3.2
Rationale for the trial
The overall purpose of the trial is to compare the hypoglycaemia profile and the insulin dose 
requirements of IDeg versus IGlar 300 U/mL in subjects with T2DM inadequately controlled on 
basal insulin with or without OADs.
Both IDeg and IGlar 300 U/mL used IGlar 100 U/mL as comparator during the phase 3 
development programme achieving non-inferiority with respect to the glycaemic endpoint measured 
by the reduction in HbA1c from baseline to end of trial. In T2DM patients treatment with IDeg 
showed a consistent hypoglycaemia benefit compared to IGlar 100 U/mL whereas a lower number 
of hypoglycaemic episodes for IGlar 300 U/mL compared to IGlar 100 U/mL was primarily 
observed during the first weeks of treatment13, 17.
IGlar 300 U/mL has a lower bioavailability compared to IGlar 100 U/mL leading to higher mean 
pre-breakfast SMPG values and FPG levels for patients treated with IGlar 300 U/mL compared to 
IGlar 100 U/mL. This is most evident during the first weeks of treatment and makes assessment of a 
possible hypoglycaemic benefit difficult during this time period.
Across the trial programme for IGlar 300 U/mL a 12-17% higher dose usage was needed with IGlar 
300 U/mL to reach the same level of glycaemic control at end of trial compared to IGlar 
100 U/mL12, 18. In the IDeg phase 3a program an overall higher dose of approximately 10% was 
seen for IGlar 100 U/mL compared to IDeg19 and in the SWITCH 2 trial a post hoc analysis 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
22 of 109
demonstrated  significantly lower insulin dose with IDeg compared with IGlar 100 U/mL after 32 
weeks of treatment.
The present trial seeks to confirm the safety of IDeg particularly in the assessment of overall, 
nocturnal and severe hypoglycaemic episodes when similar glycaemic control levels have been 
obtained. Moreover, the trial will provide guidance on insulin dose requirements for achieving 
glycaemic control.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
23 of 109
4
Objective(s) and endpoint(s)
4.1
Objective(s)
Primary objective
To compare the effects of IDeg OD and IGlar 300 U/mL OD on hypoglycaemia in subjects with 
T2DM, inadequately treated with basal insulin with or without OADs.
Secondary objectives
To compare IDeg and IGlar 300 U/mL in terms of basal insulin requirement.
To compare IDeg and IGlar 300 U/mL in terms of safety and parameters of glycaemic control.
4.2
Endpoint(s)
4.2.1
Primary endpoint
!
Number of severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes 
during maintenance period (week 16-52)
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
!
Basal insulin dose (U) at 52 weeks
!
Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes during 
maintenance period (week 16-52)
!
Number of severe or BG confirmed symptomatic hypoglycaemic episodes during 52 weeks
!
Number of severe hypoglycaemic episodes during maintenance period (week 16-52)
4.2.3
Other endpoints
Other efficacy endpoints
!
Change in HbA1c from baseline to 52 weeks
!
Change in fasting plasma glucose (FPG) from baseline to 52 weeks
!
FPG ≤ 7.2 mmol/L (130 mg/dL) at 52 weeks (yes/no)
!
FPG ≤ 5 mmol/L (90 mg/dL) at 52 weeks (yes/no)
!
HbA1c < 7% (53 mmol/mol) at 52 weeks and no severe or BG confirmed symptomatic 
hypoglycaemic episodes during the maintenance period (week 16-52) (yes/no)
!
HbA1c < 7% (53 mmol/mol) at 52 weeks and no nocturnal, severe or BG confirmed 
symptomatic hypoglycaemic episodes during the maintenance period (week 16-52) (yes/no)
!
Change in mean pre-breakfast self-measured plasma glucose used for titration from baseline 
to 52 weeks
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
24 of 109
Other safety endpoints
!
Hypoglycaemia
o
Number of nocturnal, severe or BG confirmed symptomatic  hypoglycaemic episodes 
during 52 weeks
o
Number of severe hypoglycaemic episodes during 52 weeks
!
Number of adverse events during 52 weeks
!
Change in clinical evaluations from baseline to week 52 in terms of:
o
Vital signs (including blood pressure and pulse)
o
Dilated fundoscopy or fundus photography
o
Electrocardiogram (ECG)
!
Change in body weight from baseline to week 52
!
Change in central laboratory assessments from baseline to 52 weeks in terms of
o
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes)
o
Biochemistry (creatinine, alanine aminotransferase , aspartate aminotransferase , 
alkaline phosphatase , sodium, potassium, albumin, total bilirubin)
!
Special laboratory assessment during 52 weeks in terms of
o
Anti-insulin antibodies
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
25 of 109
5
Trial design
5.1
Type of trial
This is a 52-week, randomised (1:1), open-label, parallel, multi-centre, multi-national, treat-to-
target, active controlled trial comparing efficacy and safety of IDeg 200 U/mL with IGlar 300 U/mL
both administered OD ± OADs in subjects with T2DM previously treated with basal insulin OD or 
twice daily (BID) ± OADs excluding sulfonylureas/glinides. Type and dose of any pre-trial OAD 
treatment should remain unchanged throughout the trial.
The trial design is summarised schematically in Figure 5–1. The total trial duration will be 
approximately 58 weeks divided into the following periods:
!
Screening up to two weeks
o
Screening (V1)
o
Randomisation (V2)
!
52-week treatment period consisting of
o
A 16-week titration period
o
A 36-week maintenance period
!
30 days post treatment follow-up period including two follow-up (FU) contacts
o
FU1 (V55) 7-12 days after end of treatment
o
FU2 (V56) 30-35 days after end of treatment
IDeg 200 U/mL OD ± OADsa
IGlar 300 U/mL OD ± OADsa
Randomisation 1:1 
(morning or evening)
Screening
(≤ 2 weeks)
Wash out 1 week for 
antibody measurements
V1                       V2                          V18                                                                 V54  V55 (FU1)     V56 (FU2)
-2                         0                             16                                                                   52     53                   56 weeks
52 weeks treatment period
16 weeks titration + 36 weeks maintenance
Follow-up
(minimum 30 days to FU2)
aOral Anti-diabetic Drugs (OADs): Metformin, Dipeptidyl peptidase-4 inhibitor, Sodium-glucose co-transporter 2 
inhibitor, Alpha-glucosidase-inhibitors (acarbose), Thiazolidinediones, marketed oral combination products only 
including the products listed in inclusion criteria 5a-5e.
IDeg: insulin degludec, IGlar: insulin glargine, OD: once daily, FU: follow-up
Figure 5–1
Trial design
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
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EudraCT no.: 2016-002801-20
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5.2
Rationale for trial design
In this trial an open-labelled trial design is chosen to minimize inconvenience for the subjects since 
a blinded trial due to different pen injector systems would require a double dummy approach.
Subjects with recent severe and non-severe hypoglycaemia, hypoglycaemia symptom unawareness, 
moderate chronic renal failure, or long-term insulin treatment are eligible to participate in this trial. 
Thus, this trial includes a broader population of subjects, compared to previous phase 3a trials with 
IDeg.
For subjects randomised to IDeg OD, the daily basal insulin dose should be reduced by 20% from 
pre-trial dose.
Subjects randomised to IGlar 300 U/mL should switch unit-to-unit, if they prior to randomisation 
received basal insulin once daily. For subjects that prior to randomisation received a BID basal 
insulin regimen, the following applies:
!
US subjects that prior to randomisation received a BID basal regimen with Neutral 
Protamine Hagedorn (NPH) insulin should have their total daily NPH dose reduced by 20% 
and given once daily.
!
US subjects that prior to randomisation received a BID basal regimen with other basal 
insulin types should have their total daily basal insulin dose added up and injected once 
daily.
!
EU subjects that prior to randomisation received a BID basal regimen with any basal  insulin 
type should have their total daily basal insulin dose reduced by 20% and given once daily.
The basal insulin IDeg and IGlar 300 U/mL will be administered in the morning (from waking up to 
breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and should 
be taken at the same time of day throughout the trial.
The 1:1 randomisation to morning or evening dosing of the basal insulin is applied to avoid any 
confounding from injection time on a particular time interval (such as nocturnal) during which 
subjects would be at highest risk of hypoglycaemic episodes.
The trial is conducted with a treat-to-target principle: the insulin dose is adjusted for each individual 
subject with the aim of achieving identical glycaemic targets for IDeg and IGlar 300 U/mL. This 
allows for a valid comparison of safety endpoints such as hypoglycaemia.
5.3
Treatment of subjects
Insulin treated subjects with T2DM can enter the trial if they present with an HbA1c equal to or 
below 9.5% (80 mmol/mol) and have been treated with basal insulin for ≥ 90 days prior to the day 
of screening (V1) with or without OADs (metformin, DPP-4i, SGLT2i, thiazolidinedione, alpha-
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
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glucosidase-inhibitors or marketed oral combination products only including the products listed in 
inclusion criteria 5a-5e), at stable doses for ≥ 90 days prior to V1.
Pre-trial treatment with IDeg or IGlar 300 U/mL is not allowed within 90 days prior to the 
screening visit. Any previous use of bolus insulin, insulin pump or pre-mix insulin excludes 
subjects from the trial, as well as use of any GLP-1 receptor agonist (e.g., exenatide or liraglutide) 
or SU/glinides, all within the 90 days prior to the screening visit.
At randomisation (V2) subjects who met all inclusion criteria and no exclusion criteria will be 
randomly allocated 1:1 into one of two treatment arms:
!
IDeg -200 U/mL OD ± OADs
!
IGlar -300 U/mL OD ± OADs
Within each treatment arm, subjects will be randomised 1:1 to morning (from waking up to 
breakfast) or evening dosing (from main evening meal to bedtime). The dosing time will be kept 
throughout the entire treatment period.
Following randomisation pre-trial insulin treatment must be discontinued and the subject switched 
to randomised treatment.
Type and dose of any pre-trial OAD treatment should remain unchanged throughout the trial and 
subjects should continue pre-trial OAD treatment from screening (V1) to end of trial (V54), unless 
for safety reasons.
The maximum duration of treatment will be 52 weeks. No maximum trial insulin dose is specified. 
Doses are adjusted according to plasma glucose values (see titration guideline; Appendix A).
Surveillance of insulin titration will be performed by Novo Nordisk.
At end of treatment (V54) all subjects will be switched to insulin NPH for at least one week to 
ensure that all IDeg/IGlar is washed out when measuring anti-insulin antibodies.
After End of treatment each subject will have a 30-day safety follow-up period including two 
follow-up contacts (FU1 and FU2).
FU1 (V55) will be at least 7 days after end of treatment (V54). The purpose is to collect all 
treatment emergent adverse events (AEs) including hypoglycaemia and antibody samples.
FU2 (V56) will be at least 30 days after end of treatment (V54). The purpose is to collect 
information on anti-diabetic medication and AEs including hypoglycaemia occurring in the period 
between the two follow-up contacts.
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Date:
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Trial ID: NN1250-4252
Version:
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Status:
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All trial products and insulin NPH are administered subcutaneously and should be injected in the 
thigh, upper arm or abdomen. The injection areas should be consistent throughout the trial, however 
rotation of injection sites within the area is recommended.
For both treatment arms diet and exercise counselling is continued as per the standard of care at the 
investigational site.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end of treatment visit or if trial product is 
discontinued prematurely, the subject will be instructed to switch insulin treatment to the 
intermediate acting insulin NPH until the first follow-up visit (V55). At V55 the subject should be 
switched to a suitable marketed product at the discretion of the investigator. Doses of subsequent 
anti-diabetic treatment should be carefully titrated based on blood glucose measurements, 
considering the long half-life of IMPs.
5.5
Rationale for treatment
The treat-to-target design and consequent visit schedule is used in order to ensure optimal insulin 
titration based on self-measured plasma glucose (SMPG) values and to ensure improvement in 
glycaemic control. The first 16 weeks of treat-to-target is to ensure optimal time to achieve 
improved and stable HbA1c for both treatments when entering the maintenance period (from week 
16-52). A 52-week treatment period has been chosen to optimise the trial treatment regimen and to 
obtain sufficient data for efficacy and safety evaluation.
The switch from trial insulin treatment to the ‘washout’ insulin (NPH) between the end of treatment 
visit (V54) and the 7-day follow-up visit (V55), is done in order to provide basal insulin coverage 
while reducing the level of IDeg/IGlar present at antibody sampling and consequently to reduce the 
possibility for interference with antibody measurements.
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Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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Status:
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6
Trial population
6.1
Number of subjects
Number of subjects planned to be screened: 2,271
Number of subjects planned to be randomised: 1,590
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”.
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male or female, age above or equal to 18 years at the time of signing informed consent.
3. Subjects fulfilling at least one of the below criteriaa:
a.
Experienced at least one severe hypoglycaemic episode within the last year 
(according to the ADA definition, April 2013b)
b. Moderate chronic renal failure, defined as glomerular filtration rate 30 - 59 
mL/min/1.73 m2 per CKD-EPI20, 21 by central laboratory analysis
c.
Hypoglycaemic symptom unawarenessc
d. Treated with insulin for more than 5 years
e.
Episode of hypoglycaemia (defined by symptoms of hypoglycaemia and/or episode 
with low glucose measurement (≤ 70 mg/dL [≤ 3.9 mmol/L])) within the last 12 
weeks prior to Visit 1(screening)
4. Subjects diagnosed with type 2 diabetes mellitus.
5. Treated with basal only insulin (once daily or twice-daily insulin (insulin detemir; insulin 
glargine 100 U/mL, biosimilar of insulin glargine 100 U/mL or NPH)) ≥ 90 days prior to the 
day of screening with or without any of the following anti-diabetic drugs/regimens with 
stable doses for ≥ 90 days prior to screening:
a.
Metformin
b. Dipeptidyl peptidase-4 inhibitor
c.
Sodium-glucose co-transporter 2 inhibitor
d. Alpha-glucosidase-inhibitors (acarbose)
e.
Thiazolidinediones
f.
Marketed oral combination products only including the products listed in criteria 5a-
5e
6. HbA1c ≤ 9.5% (80 mmol/mol) at screening by central laboratory analysis.
7. BMI ≤ 45 kg/m2.
8. Ability and willingness to adhere to the protocol including self-measurement of plasma 
glucose according to the protocol.
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aFor inclusion criterion 3 the aim is to include minimum 80% of individuals with a previous episode
of hypoglycaemia (3e). The remaining subjects will have to fulfil at least one of criteria a-d.
bAn 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.
cHistory of impaired autonomic responses (tremulousness, sweating, palpitations, and hunger) 
during hypoglycaemia.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”.
1. Acute impairment of glycaemic control requiring immediate intensification of treatment to 
prevent severe metabolic dysregulation (e.g. diabetes ketoacidosis) ≤90 days prior to the 
day of the screening.
2. Known or suspected hypersensitivity to trial product(s) or related products.
3. Previous participation in this trial. Participation is defined as signed informed consent.
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice).
For Denmark: Contraceptive measures considered adequate include:
a.
intrauterine devices or hormonal contraception (oral contraceptive pills, implants, 
transdermal patches, vaginal rings or long-acting injections)
For Estonia: Contraceptive measures considered adequate include:
a.
double barrier method (a combination of male condom with either cap, diaphragm or 
sponge with spermicide)
For Germany: The following contraceptive measures are considered adequate: 
a.
combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, transdermal or intravaginal)
b. progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable or implantable)
c.
intrauterine device
d. intrauterine hormone-releasing system
e.
sexual abstinence
f.
vasectomised partner
g. double barrier method (a combination of male condom with either cap, diaphragm or 
sponge with spermicide)
5. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product (IMP) within 30 days prior to screening.
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6. Any of the following: myocardial infarction, stroke or hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and between 
screening and randomisation.
7. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
8. Planned coronary, carotid or peripheral artery revascularization known on the day of 
screening.
9. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
<30 mL/min/1.73 m2 as defined by KDIGO 2012 classification22 using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening.
10. Impaired liver function, defined as ALT or AST ≥2.5 times upper limit of normal at 
screening.
11. Inadequately treated blood pressure as defined as Grade 3 hypertension or higher (Systolic 
≥180 mmHg or diastolic ≥110 mmHg) at screening.
12. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening.
13. Anticipated initiation or change in concomitant medications (for more than 14 consecutive 
days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid 
hormones, or corticosteroids).
14. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
15. Presence or history of malignant neoplasms within the last 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinomas in-situ are allowed.
16. Any condition, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6.4
Criteria for premature discontinuation of trial product
Efforts should be made so that subjects attend and complete all scheduled visit procedures. Subjects 
should stay in the trial irrespective of lack of adherence to randomised treatment, lack of adherence 
to visit schedule or missing assessments. Only subjects who decline any further contact with the site 
in relation to the trial will be considered as withdrawn from the trial (see Section 6.5).
The subject may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
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The subject must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria.
2. Pregnancy.
3. Intention of becoming pregnant.
4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
5. Initiation of concomitant medication(s) for more than 14 calendar days, which in the 
investigator’s opinion could affect weight or glucose metabolism.
6. Lack of efficacy; if all of the fasting SMPG values taken on three consecutive days or if any
of the FPG samples analysed by the central laboratory exceeds the limit of:
a.
13.3 mmol/L (240 mg/dL) from visit 18 to visit 26 (both inclusive)
b. 11.1 mmol/L (200 mg/dL) from visit 26 (not included) to visit 54 (included)
and if no treatable intercurrent cause for the hyperglycaemia has been identified, the subject 
must be called for a confirmatory FPG measurement at a scheduled or unscheduled visit as 
soon as possible. A confirmatory FPG must be obtained and analysed by the central 
laboratory. If this FPG exceeds the limits described above, the trial product must be 
discontinued.
See Section 8.1.8 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.5
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected.
If the subject considers withdrawing consent the investigator must underline to the subject the 
importance of continuing in the trial despite trial product discontinuation. If the subject agrees to 
discontinue trial products but to stay in the trial, procedures described in section 8.1.8 must be 
followed.
Only subjects who decline any further contact with the site in relation to the trial, and hence do not 
agree to provide information concerning morbidities, which are relevant for the assessment of AEs 
and/or other trial endpoints at the planned end of trial, should be withdrawn from trial.
See Section 8.1.9 for procedures to be performed for subjects withdrawing consent.
A subject will be considered lost to follow-up if he/she repeatedly fails to attend the scheduled visits 
and the Investigator is unable to establish contact with the subject.
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Date:
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Trial ID: NN1250-4252
Version:
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The following actions must be taken in relation to a subject who fails to attend the site for a 
required visit:
!
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible.
!
The site must re-train the subject in the importance of maintaining the scheduled visits.
!
In cases in which the subject is deemed lost to follow-up the investigator must make every 
effort to regain contact with the subject (e.g. telephone calls to friends or family members, e-
mails or certified letter to the subject as applicable). These contact attempts must be 
documented in the subject’s medical records. Should the subject continue to be unreachable, 
only then will he/she be considered to have withdrawn from the trial with the primary reason 
being “lost to follow-up”.
6.6
Subject replacement
Subjects who discontinue trial product prematurely will not be replaced.
6.7
Rationale for trial population
A population of insulin-treated subjects with T2DM presenting with an HbA1c equal to or below 
9.5% while treated continuously with basal insulin with or without OADs for at least 90 days and 
who recently have experienced hypoglycaemia or have increased risk of severe hypoglycaemia has 
been chosen for this trial. This population reflects a general T2DM population qualifying for
optimisation of basal insulin treatment. The trial is not excluding individuals at high risk of 
developing hypoglycaemia making the population generalizable for the T2DM population. Subjects 
requiring treatment with basal bolus are not included to avoid the confounding element of bolus 
insulin. Treatment with SUs/glinides and insulin in combination creates an increased risk of 
hypoglycaemia, and therefore, SU/glinides are not allowed as pre-trial, and subsequently trial 
treatment.
A BMI ≤ 45.0 kg/m2 was chosen to include as broad a population as possible, while excluding 
severely insulin resistant subjects in order to secure a rather homogenous population with regard to 
insulin needs.
The inclusion and exclusion criteria applied in this trial should ensure relevance of trial results for a 
broad population of subjects with T2DM.
The 20% reduction of IDeg when transferring from pre-trial insulin regimen, is to reduce the risk of 
subjects experiencing hypoglycaemia in the initial treatment phase and to secure equal and 
comparable levels of glycaemic control initially, given that IGlar 300 U/mL has a known lower 
potency compared to IGlar 100 U/mL and hence also IDeg.
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Protocol
CONFIDENTIAL
Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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7
Milestones
Planned duration of recruitment period, which is from first patient first visit (FPFV)–last patient 
first visit (LPFV): 24 weeks.
End of trial is defined as last patient last visit (LPLV).
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in orderto estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects screened during the recruitment period 
and found eligible for randomisation can be randomised within the timelines specified in the flow 
chart, see Section2.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.govand novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure23it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)24, the Food and Drug Administration Amendment Act25, European 
Commission Requirements26, 27and other relevant recommendations or regulations. If a subject 
requests to be included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo 
Nordisk may disclose the investigator’s contact details to the subject. As a result of increasing 
requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
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Date:
11 November 2016
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Version:
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8
Methods and assessments
8.1
Visit procedures
Timing of assessments and procedures are specified in the flow chart (see Section 2). This section 
includes a description.
Informed consent must be obtained before any trial related activity, see Section 18.2.
8.1.1
Screening visit (Visit 1)
The subjects will attend a screening visit in order to assess eligibility.
Before any trial-related activity, the investigator must give the subject oral and written information 
about the trial in a form that the subject can read and understand. The informed consent process 
must be completed before any trial-related activity.
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 will be obtained 
from the subject before any trial-related activity. The responsibility for seeking informed consent 
must remain with the investigator, but the task may be delegated by the investigator to a medically 
qualified person, in accordance with local requirements. The informed consent form must be signed 
and personally dated by the person who seeks the informed consent.
The investigator should inform the subject's primary physician about the subject's participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. The informed consent will include permission for the investigator to obtain 
information from the subject and/or from his/her primary physician or other healthcare professional 
/next of kin on vital status. The consent will include that this information can be obtained until trial 
completion even if the subject stops the investigational products and/or trial procedures 
prematurely.
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirements and adhere to ICH GCP1 and the Declaration of Helsinki2.
The date of informed consent must be transcribed to the eCRF.
If information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial, the investigator must inform the subject in a timely manner, and a revised 
written informed consent must be obtained.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
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Version:
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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 it after the last visit.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. The first 3 digits indicate the site number and the last 3 digits are unique for the 
subject.
A screening session must be performed in the IWRS, see Section 10.
All assessments related to the inclusion and exclusion criteria must be performed. If any inclusion 
criterion is answered “no” or any exclusion criterion answered “yes”, the subject is a screening
failure and no further assessments should be done. Please refer to the flow chart in section 2 for the 
full list of assessments and procedures to be performed at this visit.
In- or exclusion criteria cannot not be ticked “Yes” or “No” in the electronic case report form 
(eCRF) before source data is available. In this case “Result pending” must be chosen. This is 
particularly relevant for lab samples and in some cases the ECG and eye examination result. 
Subjects cannot be randomized until all results are available.
The subject has to complete the Baseline Hypo Questionnaire at the screening visit.
8.1.1.1
Screening failures
For screening failures the screening failure form in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events from screening failures must be transcribed by the 
investigator into the eCRF. Follow-up on serious adverse events (SAEs) must be carried out 
according to Section 12.
A screening failure session must be made in the IWRS. When data has been monitored and queries 
have been resolved the case book must be signed.
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria, this 
includes re-sampling if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters. Re-sampling is allowed in case the sample is haemolysed, leaked during 
transit etc.
8.1.2
Randomisation visit (V2)
All screening including laboratory results must be available and reviewed and the subject confirmed 
eligible before randomisation can take place. Randomisation should take place as soon as trial 
products are available on site and no later than 14 days after screening visit. A randomisation 
session must be performed in IWRS; see Section 10 and trial product must be dispensed.
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The Investigator should record the following in the eCRF:
!
Last date on pre-trial insulin
!
Total dose of pre-trial insulin administered within the last 24 hours
!
Frequency of pre-trial insulin injections
!
First date on trial product (registered at P3)
!
First dose of trial product (registered at P3)
!
Time point of trial product administered (morning or evening as specified by IWRS)
The subject must attend randomisation visit fasting. For definition of fasting, please see Section 
8.1.4.
At randomisation baseline laboratory values of HbA1c and anti-insulin antibodies will be taken. 
Please refer to the flow chart in section 2 for the full list of assessments and procedures to be 
performed at this visit.
A BG meter and an electronic diary (eDiary) must be provided to the subjects at V2. Subjects must 
be trained in the use of the BG meter. A practice eDiary must be completed before the eDiary can 
be used. Subject must be instructed that entries must be made according to the protocol, see Section 
8.3.1, 8.3.2 and 8.4.2 and instructions provided.
8.1.3
Phone contacts
Before any phone contact, both the Investigator and subject should agree on the timing and 
direction of the call. The Investigator remains responsible for ensuring that the phone contacts occur 
even if it is agreed that the subject should call the site.
A phone contact may be converted to a site visit if needed. For scheduled phone contacts and their 
time points; see Section 2.
8.1.4
Fasting visits
The subjects must attend the visits specified in section 2 in a fasting condition. Fasting is defined as 
at least eight hours without drink or food intake prior to the visit except for water.
No diabetes treatment (neither trial insulin, nor any OADs) is allowed up to eight hours prior to the
blood sampling. Non-anti-diabetic medication is still allowed to be taken.
If a subject attends the visit non-fasting, then the subject’s blood samples should be re-scheduled 
preferable within the next two working days. If blood sampling has already been done before 
realising the subject was not fasting, only the FPG needs to be re-drawn.
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Version:
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8.1.5
End of Treatment visit (V54)
At the end of treatment visit (V54) the treatment with trial product must be stopped and the subjects 
will be instructed to switch insulin treatment to the intermediate acting insulin NPH until the first 
follow-up visit (V55). A completion session must be performed in IWRS, see Section 10. NPH will 
be dispensed as part of the completion session.
Last date on the randomised trial product (basal insulin) must be recorded in the eCRF.
Since NPH insulin is an intermediate acting insulin, it should be administered twice daily. To 
determine the dose of insulin NPH to be taken during the follow-up period, the total daily basal 
dose at end of the treatment period should be reduced by 20% and divided into two doses; one to be 
administered in the morning and one in the evening.
Date and dose of first injection of insulin NPH must be recorded in the eCRF.
Please refer to the flow chart in section 2 for the full list of assessments and procedures to be 
performed at this visit.
8.1.6
Follow up visits
The first follow up visit (V55) is a site visit and must take place 7-12 days after the end of treatment 
visit. Follow-up visit 2 (V56) is a site visit and must take place 30-35 days after end of treatment.
Follow-up visit 1 (V55)
At the first follow up visit (V55) treatment with insulin NPH must be stopped.
The following data will be collected:
!
Date and dose of last injection of insulin NPH
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Technical complaints
!
Antibody sample
The eDiary must be returned by the subject at this visit. Subjects who prematurely discontinue trial 
product should keep the eDiary and not return it until at V54A.
Please refer to the flow chart in section 2 for the full list of assessments and procedures to be 
performed at this visit.
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Protocol
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Date:
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Version:
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Follow-up visit 2 (V56)
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
8.1.7
Unscheduled site visits
If the subject attends the clinic outside the visit schedule, an unscheduled visit form in the eCRF 
should be completed. An unscheduled visit form should not be completed if the subject attends the 
clinic only to obtain additional trial supplies or for re-scheduled visits.
If more trial product is needed an additional dispensing session in the IWRS must be performed.
If blood resampling is needed the laboratory requisition form must be completed with the visit 
number to which the sample belongs.
8.1.8
Premature discontinuation of trial product
If a subject prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for the end of treatment visit (V54) as soon as possible including fasting blood 
sampling and dispensing of wash-out insulin NPH, see Section 8.1.5.
Treatment discontinuation must be performed in the eDiary web portal and in the IWRS.
Furthermore two follow up visits similar to V55 and V56 must be performed 7-12 and 30-35 days
after discontinuation of trial product, respectively.
Follow-up visit 1 (V55)
At the first follow up visit (V55) the subject should be switched to treatment with a suitable 
marketed product at the discretion of the investigator.
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The following data will be collected:
!
Date and dose of last injection of insulin NPH prior to V55
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Technical complaints
!
Antibody sample
Follow-up visit 2 (V56)
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
In addition, subjects prematurely discontinued from trial product should come in for abbreviated 
site visits at week 16 (V18A), week 28 (V30A) and at week 40 (V42A) after randomisation 
depending on when the subject discontinues trial product. The abbreviated site visits can be 
converted to phone contacts if needed.
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Blood sample to measure HbA1c (only if site visit)
In between the abbreviated site visits listed above monthly phone contacts (PX visits) should be 
performed until the originally planned end of treatment.
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
The earliest of the abbreviated site visits or monthly phone contacts (whichever comes first) should 
be scheduled at least 30 days after FU2. If the timing of a monthly phone contact (PX visit) is less 
than two weeks from a planned abbreviated site visit, the phone contact can be omitted.
Subjects prematurely discontinued from trial products should come in for a final visit (V54A) at the 
originally planned end of treatment date to collect:
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!
Date and dose of basal insulin
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Blood sample to measure HbA1c
The eDiary must be returned by the subject at this visit.
The primary reason for premature discontinuation of trial product must be specified in the End-of-
Treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
8.1.8.1
eDiary records after premature discontinuation of trial product
Hypoglycaemic episode information (see Section 8.4.2) should be recorded from V54 and to V54A 
in the eDiary.
8.1.9
Withdrawal from trial
If a subject withdraws consent, the investigator should aim to undertake procedures similar to those 
for the end of treatment visit (V54) as soon as possible. The eDiary must be returned by the subject 
at this visit.
If the subject agrees, the follow up visits (V55 and V56) must be performed 7-12 and 30-35 days 
after discontinuation of trial product.
The End-of-Treatment and End of Trial forms must be completed, and final drug accountability 
must be performed even if the subject is not able to come to the trial site. A treatment 
discontinuation session must be made in the eDiary web portal and in the IWRS. The case book 
must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the End-of-Trial form in the eCRF.
Subjects withdrawing consent during the follow up period will be considered as completers.
8.1.10
Review of results
Review of ECG results, eye examination report, laboratory reports, data entered in the eDiaries, etc. 
must be documented either on the documents, printouts, in the eDiary web portal or in the subject’s 
medical record.
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If clarification of entries or discrepancies in the eDiary is needed, the subject must be questioned 
and a conclusion made in the subject’s medical record. Care must be taken not to bias the subject.
8.2
Subject related information/assessments
8.2.1
Demography
Demography will be recorded at screening, unless not permitted by local regulations, and consists 
of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Diabetes history
Diabetes history will be recorded at screening and consists of:
!
Date of diagnosis of type 2 diabetes
8.2.3
Hypoglycaemia unawareness
Information on hypoglycaemia unawareness will be recorded at screening according to Clarke’s 
questionnaire, question 828.
The investigator must ask the subject in the following way: “To what extent can you tell by your
symptoms that your blood glucose is low?” The subject can answer never, rarely, sometimes, often 
or always.
Subjects answering ‘never, rarely or sometimes’ are considered as having impaired awareness of 
hypoglycaemia.
8.2.4
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit (V1)) 
or found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product.
Date of diagnosis of type 2 diabetes should be reported separately in the Diabetes History Form in 
the eCRF.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be reported.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
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Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.5
Concomitant medication
A concomitant medication is any medication, other than the pre-trial insulin, trial products and 
OADs, which is taken during the trial, from the screening visit (V1) until end of treatment (V54).
Details of any concomitant medication must be recorded at V1. Changes in concomitant medication 
must be recorded at each visit as they occur.
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.6
Concomitant medication (Diabetes)
Any diabetes medication other than the trial product(s) which is taken during the trial, from the 
screening visit (V1) until FU2 (V56) must be recorded in a separate concomitant medication 
(diabetes) form in the eCRF.
At V1 the pre-trial insulin and pre-trial OADs must be recorded including:
!
Trade name or generic name
!
Total daily dose
!
Start date
!
Stop date or continuation
For subjects treated with OADs it is the start date and dose of latest stable OAD dose which should 
be reported.
At the randomisation visit (V2) pre-trial insulin must be discontinued and a stop date recorded in 
the eCRF. For subjects treated with OADs, the investigator should at each weekly contact (V2 until 
V55), confirm with the subject that dose and frequency of OADs has been unchanged. This should 
be documented in the medical records.
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8.2.7
Childbearing potential
It must be recorded in the eCRF whether female subjects are of childbearing potential. Reason for 
not being of childbearing potential must be documented in the medical records.
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.2. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 1 week after end of treatment.
Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation
!
Postmenopausal defined as no menses for 12 months without an alternative medical cause
!
Other medical reasons preventing childbearing potential
8.2.8
Tobacco use
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily.
Smoking status:
!
Never smoked
!
Previous smoker
!
Current smoker
8.3
Efficacy assessments
8.3.1
Self-measured plasma glucose
At V2, subjects will be provided with a BG meter including auxiliaries as well as instructions for 
use. The subjects will be instructed in how to use the device.
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display.
Only the BG meter provided by Novo Nordisk should be used for the measurements required in the 
protocol.
For Serbia: The BG-meter is regarded as an investigational device and should be collected by the 
investigator at FU2 (Visit 56).
Subjects must be instructed to measure their pre-breakfast SMPG daily from V2 toV54 and in how 
to transfer the results of the SMPG values into the eDiary.
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8.3.2
Insulin dose
During the trial, starting at the randomisation visit (V2), the subject should be instructed to report 
date, dose and actual time of basal insulin in the eDiary on a daily basis.
The recommended insulin doses will be calculated in the eDiary web portal on recommendations 
from the Insulin Titration Guideline (see Appendix A). At each visit/phone contact the Investigator 
will titrate the subjects by making prescribed dose adjustments based on the recommendation from 
the eDiary web portal if applicable.
The Investigator should record the following in the eDiary (through the web portal):
!
Prescribed doses of trial products
!
Reason for deviating in dose adjustments from the titration guideline
The subject should report the following in the eDiary:
!
Date, dose and time of trial basal insulin daily
The Investigator should record the following in the eCRF:
!
First date on trial product
!
First dose of trial product
!
Last date on trial product
!
Last dose of trial product
8.4
Safety assessments
All safety assessments are outlined in the flow chart in section 2.
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the concomitant illness form if it is present at screening. Any new abnormal, clinically significant 
finding during the trial and any clinically significant worsening from baseline must be reported as 
an AE.
8.4.1
Adverse events
During each contact (site visits and phone contacts) the subject must be asked about AEs and 
technical complaints, for example by asking: "Have you experienced any problems since the last 
contact?" This must be documented in the subject’s medical record. AEs must be reported at each 
visit in accordance with the procedures outlined in Section 12.
8.4.1.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form:
!
Trial product(s) involved
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!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error
!
Suspected primary reason for the medication error
For definition of medication errors, see Section 12.1.4.
8.4.1.2
Adverse events requiring additional data collection
For some AEs additional data collection is required and specific event forms must be completed in 
the eCRF in addition to the AE form.
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section 12.
Acute coronary syndrome
If an event of Acute Coronary Syndrome (ranging from unstable angina pectoris to myocardial 
infarction) is observed during the trial the following additional information must be reported if 
available on the acute coronary syndrome form:
!
Duration of symptoms
!
Changes in ECG
!
Collection of cardiac biomarkers
!
Cardiac imaging
!
Cardiac stress testing
!
Angiography
!
Use of thrombolytic drugs
!
Revascularisation procedures
Cerebrovascular events
If a cerebrovascular event (e.g. transient ischaemic attack (TIA), stroke, and haemorrhage) is 
observed during the trial the following additional information must be reported if available on the 
cerebrovascular event form:
!
Type of event (e.g. TIA, Stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the event
!
Treatment given for the event
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Neoplasm
All events of benign, pre-malignant/carcinoma in-situ and malignant neoplasm must be reported 
during the trial and the following additional information should be obtained if available as part of 
standard of care on the neoplasm form:
!
Type of neoplasm
!
Symptoms and laboratory results leading to identification of event
!
Diagnostic imaging
!
Pathological examination (outcome and staging)
!
Treatment given for the event
!
Participation in screening programs
!
Relevant risk factors associated to the event
Events for adjudication
Severe hypoglycaemia or hypoglycaemic episodes reported as an SAE and all fatal events will be 
subject to external independent adjudication. For these AEs a (hypoglycaemia) Adjudication Form 
must be completed in the eCRF. For detailed information on event adjudication, please refer to 
Section 12.7.2.
8.4.2
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the eDiary according to the instructions below throughout the trial from visit 2
to visit 56.
Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance to current guidelines29.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 min after onset on a hypoglycaemic episode, will by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is >3.9 
mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form. SMPG measurements ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic 
symptoms after the 60 min period shall trigger the reporting of a new hypoglycaemia episode and 
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prompt the subject to fill out a new hypoglycaemic episode form until a succeeding measurement is 
>3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.
In case of several low SMPG values within the 60 minutes interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
The e-diary will automatically link multiple values within 60 minutes to the same hypoglycaemic 
episode.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No)
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if 
the subject experiences symptoms later during the episode. The subject is therefore to be 
questioned whether there are changes to symptoms for each low SMPG value within the 60 
minutes period or until the subject has confirmed that the hypoglycaemic episode is 
symptomatic.
!
Whether the subject was able to treat him/herself
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode 
should be reported reflecting the most severe degree of hypoglycaemia. The subject is 
therefore to be questioned whether he/she is able to self-treat for each low SMPG value 
within the 60 minutes period or until the subject respond that he/she is not able to self-treat.
!
Date, time and dose of last trial product administration prior to the episode
!
Date and time of last main meal (not including snacks) prior to the episode
!
Whether the episode occurred in relation to physical activity
!
Whether the episode related  to a change in a pre-existing disease
!
Any sign of fever and/or other acute disease
!
Whether the subject was asleep when the episode occurred
o
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration29.
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Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-
medical person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose 
or other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, 
medication error (i.e. overdose, mix-up between products, incorrect use of device), 
miscalculation of dose of anti-diabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms30 (layman term used in the diary 
is specified in brackets if different from the protocol term)?
o
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
o
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate 
movement)
o
General malaise: headache or malaise (feeling discomfort/unease)
!
Other symptoms.
The investigator must review the diary data for correct reporting of SMPGs and hypoglycaemic 
episodes. In case of incomplete or incorrect data in the diary, the subject must be questioned 
whether there have been any severe hypoglycaemic episodes since the last visit, i.e. any 
hypoglycaemic episodes where the subject was not able to self-treat. Any severe hypoglycaemic 
episodes must be reported.
In case a subject is not able to fill in the eDiary e.g. in case of a fatal event, the investigator will be 
allowed to report the hypoglycaemic episode in the eDiary web portal.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value, if any symptoms were present and 
whether the subject was able to self-treat due to decreased validity of such data31, 32.
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The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
unreported hypoglycaemic episodes.
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form, a safety information 
form and an adjudication form must also be filled in, see Section 12.
8.4.3
Body measurements
Body weight should be measured in kilogram (kg) or pounds (lb) without coat and shoes wearing 
only light clothing. Body weight will be recorded to one decimal. The body weight should be 
assessed on the same weighing scale equipment throughout the trial, if possible.
Height should be assessed without shoes. Height is measured in inches or meters at visit 1 
(screening) and recorded to one decimal place (inches) or two decimal places (meters) respectively.
From the body weight and height the BMI will be calculated in the eCRF.
8.4.4
Vital signs
Diastolic blood pressure, systolic blood pressure and pulse will be assessed following standard 
clinical practice. Abnormal and clinically significant findings must be recorded as described in 
Section 8.4.
8.4.5
Physical examination
Physical examination will include:
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
The evaluation must follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
Abnormal and clinically significant findings must be recorded as described in Section 8.4.
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8.4.6
Eye examination
Fundus photography or dilated fundoscopy must be performed by the investigator or local 
opthalmologist, or an optometrist according to local practice. The result of the fundus 
photography/dilated fundoscopy will be interpreted by the investigator. To document this, the 
Investigator must sign and date the interpretation in the subject’s medical records.
The evaluation must follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
Abnormal and clinically significant findings must be recorded as described in Section 8.4.
If a fundus photography/dilated fundoscopy have been performed within 90 days prior to V2, and if 
the results are available at V2, then the procedure do not need to be repeated. If performed before 
the subject consents to participate in the trial, it must also be stated in the subject’s medical records 
that this procedure was not performed in relation to the trial.
A subject cannot be randomised without results confirming there is no acute treatment-requiring 
retinopathy.
Eye examination performed within a period of three weeks before end of treatment visit (V54) is 
acceptable, if results are available at the end of treatment visit.
8.4.7
Electrocardiogram
A 12-lead ECG must be performed at the trial site. The ECG must be interpreted by the 
investigator, and documented by Investigator signature and date on the ECG print-out. .
The evaluation must follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
The baseline ECG must be performed at screening (V1) or in the period between screening (V1) 
and randomisation (V2). The result must be available prior to randomisation.
ECGs at the end of treatment visit (V54) should be performed at the day of the visit.
Abnormal and clinically significant findings must be recorded as described in Section 8.4
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8.5
Laboratory assessments
Laboratory analyses will be performed at laboratories contracted by Novo Nordisk. A central 
laboratory will provide all laboratory supplies for the sampling and transportation of all blood 
samples taken during the trial.
A detailed description of the procedures for obtaining the samples, handling, storage, and shipment 
of the samples are specified in a trial-specific laboratory manual provided to the sites by the central 
laboratory. Information regarding laboratory materials such as tubes and labels are also described.
If laboratory samples need to be retaken due to missing result(s) (e.g. haemolysed, sample leaked 
during transit, sample not being conclusive, lost in transit, etc.), the subject should be called in for 
resampling. Please see the laboratory manual for further guidance.
Samples will be coded in order to keep subject’s identity anonymous.
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 AEs and report these according to Section 8.2.4 and Section 12. Review 
of laboratory reports must be documented either on the documents and/or in the subject's medical 
record.
Antibody results will not be provided to the investigator on an ongoing basis, as these results will 
not be used for any clinical evaluation during the trial.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory.
Laboratory samples will be destroyed no later than at end of trial or no later than at finalisation of 
the clinical trial report.
Antibody samples will be stored as described in Section 24.2.
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8.5.1
Laboratory assessments for efficacy
Glucose metabolism
FPG is measured in order to evaluate metabolic control. The subject must attend these visits fasting. 
For definition of fasting, see Section 8.1.4.
A FPG result ≤3.9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as a 
clinical laboratory adverse event (CLAE) at the discretion of the investigator (see Section 12.1.1).
Low plasma or blood glucose values (e.g. FPG) reported by a laboratory in connection to trial 
related visits should NOT be reported as hypoglycaemic episodes; these should be reported as AEs 
related to the procedure at the discretion of the investigator.
Blood samples will be drawn to determine the HbA1c level in order to evaluate metabolic control.
8.5.2
Laboratory assessments for safety
Haematology
Blood samples for haematology will be analysed to determine:
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Erythrocytes
!
Thrombocytes
Biochemistry
Blood samples for biochemistry will be analysed to determine:
!
ALT
!
Albumin
!
AST
!
Alkaline phosphatase
!
Bilirubins, total
!
Creatinine
!
Potassium
!
Sodium
eGFR will be calculated (at screening) by the central laboratory based on the creatinine value using 
the CKD-EPI equation20, 21 in order to assess inclusion criteria 3b.
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Pregnancy testing
For females of childbearing potential (see Section 8.2.7) a blood human Chorion Gonadotropin 
(hCG) test will be performed at screening (V1) and V54. In addition, urine pregnancy tests will be 
performed locally during the trial if pregnancy is suspected or if required by local law. A positive 
urine test should be followed by a confirmatory serum-hCG (central laboratory).
The central laboratory will provide the pregnancy kits for urine testing performed locally at the site.
Anti-insulin antibodies
Antibody samples may be retained and used for further characterisation of antibody responses 
towards drug if required by health authorities, for safety reasons or in relation to exploratory 
analysis, see Section 24.2.
Serum samples will be analysed at a special lab for anti-insulin degludec or anti-insulin glargine 
antibodies. Anti-degludec antibodies and anti-glargine antibodies will be tested for cross-reactivity 
to human insulin.
!
Blood samples will be drawn for determination of antibodies to insulin degludec or insulin 
glargine (including cross-reacting antibodies to human insulin).
The subjects must attend the antibody sampling visits specified in section 2 in a fasting condition. 
Fasting is defined as at least eight hours without drink or food intake prior to the visit except for 
water.
No diabetes treatment (neither trial insulin, nor any OADs) is allowed up to eight hours prior to the 
blood sampling. Non-anti-diabetic medication is still allowed to be taken.
8.6
Other assessments
Patient reported outcome questionnaires
The patient reported outcome (PRO) questionnaires are to be completed by the subject without 
assistance of the site personnel, and should preferably be completed after all fasting-related 
activities are completed, but before any other visit related procedures are conducted. Instructions on 
how to complete the questionnaires will be provided to the subject. The questionnaires will be used 
to investigate the health related quality of life, hypoglycaemic episode experience as well as 
treatment and device satisfaction.
The following PRO questionnaires will be supplied in the site based eDiary in a linguistically 
validated version in all languages relevant for this trial:
!
SF-36v2® The ‘Short-Form 36 Health Survey version 2 is a questionnaire concerning 
various health-related quality-of-life questions. It is a sensitive, validated and widely used 
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instrument which will allow direct comparison with other trials including subjects with 
T2DM. SF-36v2 consists of 36 items grouped into 8 domains
!
TRIM-D measures treatment related impact on subjects of diabetes medication across the 
spectrum of pharmacological treatment over the past two weeks. The TRIM-D consists of 28 
items grouped into five domains. The domains are treatment burden, daily life, diabetes 
management, compliance and psychological health
!
TRIM-DD measures the impact of the treatment delivery system as an eight-item 
instrument. The instrument consists of eight items grouped into two domains: Device 
Function and Device Bother
!
Insulin Pen questionnaire measures how easy or difficult it is to reach the dose button 
when injecting insulin, how easy or difficult it is to use the pen and whether or not the 
subject will recommend the pen to others
!
Baseline Hypo Questionnaire measures the subjects experience with hypoglycaemic 
episodes
Besides the five subject completed questionnaires an investigator interview questionnaire is to be 
completed in the site based eDiary if the subject has reported any hypoglycaemic episode(s) since 
the last visit:
!
Hypoglycaemia resource use is collected as an interview administered questionnaire 
regarding resource use of the latest hypoglycaemic episode within the last four weeks. The 
questionnaire includes questions regarding the length of the hypoglycaemic episode, the 
number of extra blood monitoring, contact to health care professionals, and time missed at 
work
The questionnaires should be completed as specified in the flow chart, see Section 2.
eDiary
An eDiary will be used to capture patient reported data, see Sections 8.3.1, 8.3.2 and 8.4.2. The 
Investigator must carefully instruct the subject in how to use the eDiary. All data entered in the 
eDiary is considered source data. All data from the eDiary will be transferred electronically to the
PRO database. The investigator must review all the data for the subjects belonging to the site
through the eDiary web portal. Review of hypoglycaemic episode confirmation must be 
documented in the web portal, while review of remaining data must be documented in the subject’s 
medical record. The review of data must be performed before or during each visit/phone contact.
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The Investigator should record the following administrative information in the eDiary/web portal:
!
Subject ID
!
Visit confirmation
!
Hypoglycaemic episode confirmation
!
Prescribed doses of trial products or confirm recommended dose
!
Reason for deviation from the recommended dose, if needed
!
Evaluate if a hypoglycaemic episode qualifies as an SAE
Selected titration data (e.g. certain SMPGs and dose data) will only be used during the trial for 
central titration surveillance, to ensure compliance with the titration guideline (Appendix A), and 
will not be reported in the clinical trial report (CTR). All data will be stored by Novo Nordisk (see 
Section 24).
The eDiary should be collected by the Investigator at FU2 (V56).
Subjects who prematurely discontinue trial product should keep the eDiary and not return it until at 
V54A.
8.6.1
Training in the pen injector
The subjects must be trained in how to handle the pen injector when handed out the first time. 
Training must be repeated at V6 in order to ensure correct use of the device. The following should 
be emphasised:
!
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
!
Priming the pen to ensure product flow
!
Injection technique as per DFU
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance.
To ensure treatment compliance, the investigator will at each visit assess the subject’s compliance 
by evaluating the glycaemic control, adherence to the visit schedule and completion of the subject’s 
eDiary including the SMPG measurements, hypoglycaemia reporting and PRO questionnaire 
completion. In addition, subject compliance will be assessed by monitoring of drug accountability 
at specified visits, please refer to the flow chart, see Section 2. The unused amount IMP will be 
assessed against the dispensed amount and, in case of discrepancies, the subject must be asked.
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.
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Treatment compliance: It is important to ensure subjects adhere to treatment. Therefore, during 
the treatment period the investigator must at each weekly contact (visit or phone contact), evaluate 
if the subject has adhered to trial treatment since last contact.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM).
Trial products must not be dispensed to any person not included in the trial.
Trial insulin products (Investigational medicinal product (IMPs)) must not be used, if they do not 
appear clear and colourless.
Insulin NPH product (Non-Investigational Medicinal Product (NIMP)) must not be used if it does 
not appear uniformly white and cloudy after re-suspension.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
Insulin degludec (Tresiba®)
(IMP)
200 U/mL
Solution for 
injection
Subcutaneous
3 mL PDS290
pre-filled pen 
injector
(FlexTouch®)
Insulin glargine (Toujeo®)
(IMP)
300 U/mL
Solution for 
injection
Subcutaneous
1.5 mL
pre-filled pen 
injector(SoloStar®)
Human isophane insulin (NPH)
(Insulatard®/Prothaphane®/Novolin® N)
(NIMP)
100 IU/mL
Suspension for 
injection
Subcutaneous
3 mL
pre-filled pen
injector
(FlexPen®)
The following Non-Investigational Medicinal Products (NIMPs) will not be provided by Novo 
Nordisk:
!
Metformin, tablets for oral use
!
DPP-4i, tablets for oral use
!
SGLT2i, tablets for oral use
!
Thiazolidinedione, tablets for oral use
!
Alpha-glucosidase-inhibitor, tablets for oral use
!
Marketed oral combination products only including the products listed above, tablets for 
oral use
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However, metformin, DPP-IVi, SGLTi, Thiazolidinedione, Alpha-glucosidase-inhibitor or 
marketed combination products only including the products listed in inclusion criteria 5a-5e will be 
reimbursed if required by the country’s regulatory authority or IRB/IEC.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1333, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation.
The investigator must document that direction for use is given to the subject orally and in writing at 
the first dispensing visit (V2). Direction for use can be provided as needed at the following 
dispensing visits.
9.3
Storage
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
Insulin degludec (Tresiba®)
(IMP)
!
Store in refrigerator 
(2°C - 8°C)
!
Protect from light
!
Do not freeze
!
Do not store above 
30°C
!
Protect from light
!
Can be stored in 
refrigerator (2°C - 8°C)
!
Do not freeze
Use within 8 weeks
Insulin glargine (Toujeo®)b
(IMP)
!
Store in refrigerator 
(2°C - 8°C)
!
Protect from light
!
Do not freeze
!
Store below 30°C
!
Protect from light
!
Do not refrigerate
!
Do not freeze
For CA: Store at room 
temperature (15°C – 30°C)
Use within 26 days
Insulin NPH
(Insulatard®/Prothaphane®/
Novolin® N)
(NIMP)
!
Store in refrigerator 
(2°C - 8°C)
!
Protect from light
!
Do not freeze
!
Store below 30°C
!
Protect from light
!
Do not refrigerate
!
Do not freeze 
For US: Use within 14 days
For CA: Use within 4 weeks
For EU: Use within 6 weeks
aIn-use time starts when first dose is taken.
bBefore first use, the Toujeo® pre-filled pen injector must be stored at room temperature at least 1 hour.
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
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product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Subjects are instructed to return all used, partly used and unused trial product at each dispensing 
visit after V2. Please refer to the flowchart, see Section 2 for timing of the dispensing visits.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk:
!
Direction for use for the pen injectors
!
Novo Nordisk needles for prefilled systems
!
MyGlucoHealth Wireless Meter (CE approved) and strips, lancets and control solution for 
BG meters
!
eDiary
Only needles provided by Novo Nordisk must be used for administration of trial product.
For Serbia: The BG-meter is regarded as an investigational device. Technical complaints regarding 
the BG-meter should be reported to the manufacturer of the device (Entra Health Systems). This 
device has been selected in order to have automatic transfer of SMPG data to the eDiary and 
thereby increase the accuracy of SMPG values. It is expected that the better accuracy in SMPG data 
will facilitate an improvement in the insulin titration efforts during the trial.
Please refer to the TMM for further auxiliary supplies’ details.
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10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons.
IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing and Additional Dispensing between scheduled visits
!
Dispensing Verification (when barcode scanner is used)
!
Treatment discontinuation
!
Completion
!
Drug accountability
!
Data change
Notifications generated as a result of sessions performed in the IWRS should be archived in the 
investigator trial file or together with other source documents for the subject.
At any time during the trial only dispensing unit numbers (DUN) allocated by the IWRS are 
allowed to be dispensed to a subject. By doing this it will be ensured that:
!
correct trial product is dispensed to subject
!
stock is available at sites as needed for the subjects
!
no trial product that will expire before the next dispensing visit will be allocated
!
drug accountability can be made in the IWRS
IWRS user manuals will be provided to each trial site.
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11 Randomisation procedure
The IWRS is used for randomisation. Subjects complying with the inclusion- and exclusion criteria 
will be randomised 1:1 into one of the two treatment arms. Within each treatment arm, subjects will 
be randomised 1:1 to morning or evening dosing.
In IWRS this means that there will be four different treatment regimens:
!
IDeg 200 U/mL OD morning dosing ± OADs
!
IDeg 200 U/mL OD evening dosing ± OADs
!
IGlar 300 U/mL OD morning dosing ± OADs
!
IGlar 300 U/mL OD evening dosing ± OADs
Recruitment will be closed as soon as the total number of planned subjects to be randomised is 
achievable, taking the number of screened subjects and the screening failure rate into account. All 
investigators will be notified immediately when the recruitment period ends (estimated to be 24 
weeks), after which no further subjects may be screened and the IWRS will be closed for further 
screening. All subjects included in the screening period and eligible for randomisation can be 
randomised.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial 
procedures performed before exposure to trial product (pre-existing conditions should be 
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
!
Non-serious hypoglycaemia is an AE, but is from V2 until FU1 reported on a 
hypoglycaemic episode form instead of on an AE form, see Section 8.4.2. However, FPG 
results ≤ 3.9 mmol/L (70 mg/dL) should not be reported as hypoglycaemic episodes but as a 
CLAE at the discretion of the investigator.
The following three definitions are used when assessing an AE:
!
Severity
o
Mild – no or transient symptoms, no interference with the subject’s daily activities.
o
Moderate – marked symptoms, moderate interference with the subject’s daily 
activities.
o
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):
o
Probable - Good reason and sufficient documentation to assume a causal 
relationship.
o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
•
Final outcome
o
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.
o
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.
o
Recovered/resolved with sequelae - The subject has recovered from the condition, 
but with lasting effect due to a disease, injury, treatment or procedure. If a sequela 
meets an SAE criterion, the AE must be reported as an SAE.
o
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
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.
o
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
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!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd.
a
The term “life threatening” in the definition of SAE refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it was more severe.
b
The term “hospitalisation” is used when a subject:
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or
o
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 dyscrasia or convulsions that do not result in hospitalisation or 
development of drug dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product
!
risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x upper normal limit (UNL) and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
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12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug or use of wrong device.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. That is a dose lower or 
higher than 20% of the prescribed/intended dose; 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.
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.1.1.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety.
Some events in this trial will be adjudicated by an independent external committee as described in 
Section 12.7.2.
Table 12–1 lists AEs that require completion of specific event forms in the eCRFs and/or are 
subject to event adjudication.
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event 
form
Event 
adjudication
Fatal event
No
Yesa
Acute coronary syndrome (myocardial infarction or 
hospitalisation for unstable angina)
Yes
No
Cerebrovascular event (stroke or transient ischaemic 
attack)
Yes
No
Neoplasm
Yes
No
Severe hypoglycaemia or hypoglycaemic episodes reported 
as an SAE
Nob
Yes
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Event
Specific event 
form
Event 
adjudication
Medication error
Yes
No
aFatal events will be adjudicated as potential hypoglycaemic episodes (Hypoglycaemia Adjudication form to be 
completed).
bHypoglycaemia will be captured in the eDiary by the subject.
For details about specific event forms, see Section 8.4.1.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (V56). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1.
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”.
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs.
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For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator’s first knowledge of the SAE. Both forms must be signed within 7 
calendar days from the date the information was entered in the eCRF.
For SAEs requiring reporting on a specific event form: In addition to the above the 
specific event form within 14 calendar days from the investigator’s first knowledge of the 
AE.
!
Events for Adjudication: The adjudication form should be completed within 14 calendar 
days of the investigator’s first knowledge of the AE, see Section 12.7.2. The investigator 
should provide copies of the source documentation preferably within 4 weeks of event 
identification.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF. Contact details (fax, telephone, e-mail and address) are provided in the investigator trial 
master file.
AE identified
AE identified
Does the AE require 
a specific event 
form?
Is the AE subject to 
adjudication and/or 
is the outcome fatal?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs: 
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
Adjudication form
< 14 calendar days
Source data < 4 
weeks
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness
AEs requiring specific event forms are descibed in Section 12.1.4 and 12.1.5
AEs for adjudication are described in Section 12.7.2
No additional action
No additional action
AE: Adverse event   SIF: Safety information form
Serious
Yes
Yes
Non-serious
No
No
Figure 12–1
Reporting of AEs
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Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of expectedness is performed according to the current versions and any 
updates of the following reference documents:
!
IDeg IB9
!
IGlar 300 U/mL SmPC14 or local labelling15, 16
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and ICH GCP1, 
unless locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as
non-investigational medicinal product (Insulatard®/Prothaphane®/Novolin N™) or 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.
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Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. 
Cases of chronic conditions, cancer or AEs ongoing at time of death (where death is due to 
another AE) may be closed with the outcome “recovering/resolving” or “not recovered/not 
resolved”. Cases can be closed with the outcome of “recovering/resolving” when the subject 
has completed the follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of 
the information. This is also the case for previously non-serious AEs which subsequently 
become SAEs.
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until 
the end of the follow-up period stated in the protocol, whichever comes first, and until all 
queries related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs 
ongoing at time of death (where death is due to another AE) may be closed with the 
outcome “recovering/resolving” or “not recovered/not resolved”. Cases can be closed with 
the outcome of “recovering/resolving” when the subject has completed the follow-up period 
and is expected by the investigator to recover.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
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12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following products:
!
Insulin degludec 3ml PDS290 pen injector (FlexTouch®)
!
Insulin glargine (Toujeo®)1.5ml prefilled pen (SoloStar®)
!
Insulin NPH (Insulatard®/Prothaphane®/Novolin N™) 3ml prefilled pen (FlexPen®)
!
Novo Nordisk needles for pre-filled pen systems
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs and/or SAEs.
Technical complaints must be reported on a separate technical complaint form:
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each 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:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
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The investigator must ensure that the technical complaint sample contains the batch or lot number 
and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.
12.5
Pregnancies 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 new-born infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the new-born infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
new-born infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the new-born infant(s) 
has to be reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, 
further information has to be reported for the female subject on Maternal Form 2. In 
addition, information from the male partner has to be reported on the Paternal Form, after an 
informed consent has been obtained from the male partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus 
and new-born infant(s). The SAEs that must be reported include abnormal outcome, such as 
foetal death (including spontaneous abortion), and congenital anomalies (including those 
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observed at gross examination or during autopsy of the foetus), as well as other pregnancy 
complications fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs:
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or 
follow-up information to the non-serious AE.
SAEs:
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Safety information form within 5 calendar days of the investigator’s first knowledge of the 
SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or new-born infant. If the AE occurred in the foetus or new-born infant, 
the AE can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
During treatment with insulin, there is a risk of hypoglycaemia (see Section 8.4.2). Symptoms 
usually occur suddenly and may include cold sweat, nervousness or tremor, anxious feelings, 
unusual tiredness, confusion, difficulty in concentration, excessive hunger, temporary vision 
changes, headache, nausea and palpitation. Prolonged or severe hypoglycaemia can lead to a loss of 
self-control, spasms, and/or unconsciousness and, in extreme cases, death.
Hypoglycaemic episodes should be treated following best practice at the discretion of the 
investigator. As with all long-acting insulin preparations, their prolonged effect may delay recovery 
from a hypoglycaemic episode.
Asymptomatic hypoglycaemia and symptoms of hypoglycaemia should be treated with 
carbohydrates. Mild to moderate symptoms can be treated by ingestion of carbohydrate (for 
example juice). Severe hypoglycaemia resulting in loss of consciousness should be treated with 
parenteral glucose, glucagon or dextrose.
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For further details, please refer to current versions and any updates of the following:
!
IDeg IB9
!
IGlar 300 U/mL SmPC14 or local labelling15, 16
!
NPH SmPC34 or local labelling35, 36
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal IDeg safety committee to perform ongoing safety 
surveillance.
The IDeg safety committee may recommend un-blinding of any data for further analysis, and in this 
case an independent ad hoc group will be established in order to maintain the blinding of the trial 
personnel.
12.7.2
Event adjudication committee
An independent external event adjudication committee is established to perform validation of 
selected AEs according to pre-defined diagnostic criteria. The validation is based on review of pre-
defined clinical data related to the specific AE.
The events are reviewed by the event adjudication committee in a blinded manner. The EAC will 
have no authorisations to impact on trial conduct, trial protocol or amendments. The EAC is 
composed of permanent members covering required medical specialities. The EAC members must 
disclose any potential conflicts of interest and must be independent of Novo Nordisk.
The AEs for adjudication are listed in Table 12–2.
Table 12–2
Events for adjudication
Event
Description of events in scope for 
adjudication
Adjudication Outcome
Fatal event
All cause death
Severe hypoglycaemia
Severe hypoglycaemia or 
hypoglycaemic episodes reported as 
an SAE
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 episode, but neurological 
recovery following the return of 
plasma glucose to normal is 
considered sufficient evidence that the 
event episode was induced by a low 
plasma glucose concentration
Severe hypoglycaemia
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Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
The following describes the ways events are captured for adjudication:
Direct reporting by investigator:
AEs for adjudication must be reported according to Section 12.2 and Table 12–1. In addition the 
specific adjudication form should be completed within 14 calendar days of the investigator’s first 
knowledge of the AE, and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual.
Hypoglycaemic episodes will be reported by the subject in the eDiary. For severe hypoglycaemic 
episodes the adjudication form must be completed by the investigator in the eCRF. If a 
hypoglycaemic episode fulfils the criteria as an SAE as well as for all fatal events the AE, SIF and 
adjudication forms must be completed.
Screening of AEs:
All AEs will be screened to detect potential missed events for adjudication. If needed, the 
investigator will be requested to provide additional information such as an alternative aetiology, 
underlying cause(s) and/or clinical details.
Based on the information provided, the Event Adjudication supplier or Event Adjudication 
Committee can decide to have an AE adjudicated even if not initially reported as an event for 
adjudication by the investigator. If so, the investigator must complete the Adjudication form and 
upload source data, when they receive the request from Novo Nordisk or the Event Adjudication 
supplier.
EAC identified events:
During the review of source data, the EAC may identify additional events relevant for adjudication, 
not reported as for such by the investigator. In case an additional event is identified, the site will be 
informed and asked to consider reporting the event. If the site does not report the event, it may still 
be adjudicated.
For all events for adjudication, the source documentation should be anonymised by investigator 
according to the Event Adjudication Site Manual. Prior to submitting the source documentation to 
the EAC, the Event Adjudication supplier will ensure translation into English.
For each source document the investigator should specify/indicate on the adjudication form when/if 
the required documents will be available. If a document is unobtainable this needs to be specified. If 
no source data are available, a clinical narrative should be provided.
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For further details regarding event adjudication, please refer to the Event Adjudication Site Manual.
The assessment made by the event adjudication committee will be included in the clinical trial 
report as well as the assessments made by the investigator. However, the adjudication made by the 
event adjudication committee, given its independent analysis of each event, will be attributed with 
greater importance of the two.
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
The investigator must ensure that all relevant questions are answered, and that no empty data field 
exists. If a test or an assessment has not been done and will not be available, or if the question is 
irrelevant (e.g. is not applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms
!
Safety information forms
!
Technical complaint forms (also to be used to report complaints that are not subject related 
(e.g. discovered at trial site before allocation)
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
Corrections to the data in the paper CRFs should be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that were crossed out. Each 
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correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff.
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. Queries will be generated on an ongoing basis and 
investigator must ensure that queries are resolved as soon as possible, preferable within 5 calendar 
days.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
13.3
eDiary
An eDiary will be used to capture patient reported data, see Sections 8.3.1, 8.3.2 and 8.4.2. The 
Investigator must carefully instruct the subject in how to use the eDiary. All data entered in the 
eDiary is considered source data. All data from the eDiary will be transferred electronically to the 
electronic patient reported outcomes (ePRO) database. Data in the ePRO database will be viewable 
to investigator and Novo Nordisk personnel on a secure, password protected eDiary web portal.
The investigator must review all the data for the subjects belonging to the site through the eDiary 
web portal. The review of hypoglycaemic episode confirmation must be documented in the web 
portal, while review of remaining data must be documented in the subject’s medical record. The 
review of data must be performed before or during each visit/phone contact.
In case of corrections to transferred data are needed, a query flow must be initiated by the 
investigator. Upon review by Novo Nordisk, data will be corrected accordingly by the vendor. An 
audit trail will be maintained.
The Investigator should record the following administrative information in the eDiary/web portal:
!
Subject ID
!
Visit confirmation
!
Hypoglycaemic episode confirmation
!
Prescribed doses of trial products or confirm recommended dose
!
Reason for deviation from the recommended dose, if needed
!
Evaluate if a hypoglycaemic episode qualifies as an SAE
Data will be transferred to the Novo Nordisk trial database at defined intervals. For details on 
eDiary data flow, see Figure 13–1.
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Figure 13–1
eDiary data flow
Selected titration data (e.g. certain SMPGs and dose data) will only be used during the trial for 
central titration surveillance, to ensure compliance with the titration guideline (Appendix A), and 
will not be reported in the clinical trial report (CTR). All data will be stored by Novo Nordisk (see 
Section 24).
The eDiary should be collected by the Investigator at FU2 (V56).
Subjects who prematurely discontinue trial product should keep the eDiary and not return it until at 
V54A.
14 Monitoring procedures
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks until LPLV at the trial site.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
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).
Oracle Clinical
ePRO Vendor
Investigator site
Subject
Novo Nordisk
ePRO database
eDiary device
Web Portal
Trial Team
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All data must be verifiable in source documentation other than the eCRF, except for:
!
Age and BMI which are calculated by the EDC system
During the trial the eDiary database will be considered source for data recorded directly in the 
eDiary/web portal.
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 monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
!
Screen Failure Form/Reason
!
SAEs
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk.
Appropriate measures, including encryption of data files containing 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.
The eDiary software and hardware implementation are compliant with the requirements of FDA 21 
CFR Part 11 and ICH E6 (EU directive for personal data protection). After trial finalisation, Novo 
Nordisk and each site will be supplied with long-life DVDs. These DVDs will contain site-specific 
subject records including the subject’s eDiary data and audit trail as well as any data additions and 
corrections made on each form. The eDiary vendor will furthermore retain and securely store copies 
of all archived documents and data for 50 years or as required by local data retention laws for trial 
data.
17 Statistical considerations
17.1
General considerations
For subjects withdrawing from the trial as well as for subjects not discontinuing randomised 
treatment prematurely, the trial period completion is at visit 54. For subjects who prematurely 
discontinue randomised treatment but do not withdraw, the trial period completion is at visit 54A. 
Treatment period completion is defined as the date when randomised treatment is discontinued.
All efficacy, PRO and hypoglycaemic endpoints will be summarised using the full analysis set 
(FAS) and safety endpoints excluding hypoglycaemic endpoints will be summarised using the 
safety analysis set (SAS).
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All statistical analysis of efficacy and safety endpoints will be based on the FAS unless otherwise 
specified. Confirmatory analysis addressing the primary estimand will include on-treatment data 
and not available retrieved (V54A) data.
The primary objective is to compare the effects of IDeg OD and IGlar 300 U/mL OD on the rate of 
hypoglycaemia in subjects with type 2 diabetes mellitus, inadequately treated with basal insulin 
with or without oral anti-diabetic drugs. The primary estimand is the treatment difference between 
IDeg and IGlar 300 U/mL assuming that all randomised subjects adhered to the randomised 
treatment, that is a de jure estimand. The primary estimand addresses the treatment difference for 
subject that can be long-term treated with either of the two insulins. Data collected after premature 
treatment discontinuation will not be used when addressing the primary estimand. With the aim of 
comparing a safety endpoint this estimand is considered the most relevant as it compares the 
occurrence of a safety endpoint that is caused by the drug during exposure to the drug. The 
confirmatory endpoints will additionally be investigated with a de-facto estimand, other endpoints 
will be analysed only with a de jure estimand to support the primary analysis of the primary 
endpoint.
The secondary estimand is the treatment difference between IDeg and IGlar 300 U/mL regardless of 
whether subjects adhered to the randomised treatment throughout the trial, that is a treatment policy 
estimand. For this de-facto estimand, data collected after premature discontinuation will be used.
In accordance with guidance37 endpoints will be assessed at frequent visits and also for subjects 
who prematurely discontinue treatment. The baseline value is defined as the value from the 
randomisation visit. If this value is missing the last recorded value before randomisation visit will 
be used.
The severe hypoglycaemia episodes included in the statistical analysis are all events adjudicated 
with the outcome severe hypoglycaemia.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
The primary and secondary endpoints will be tested in a hierarchical order to control the family 
wise Type I error in the strong sense. Inferences will be based on the primary estimand.
Presentation of results from a statistical analysis will include the estimated treatment means as well 
as estimated mean treatment difference (or ratio) together with the two-sided 95% confidence 
interval and corresponding two-sided p-value.
In the statistical models explanatory factors will be categorized as follows:
1. Treatment: IDeg, IGlar 300 U/mL
2. Pre-trial 0 OADs, 1OAD, ≥2 OADs
3. Region: Europe , North America
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Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
83 of 109
4. Sex: male, female
5. Dosing time: morning, evening
17.2
Sample size calculation
The sample size is based on the primary objective and the primary endpoint, number of 
hypoglycaemic episodes during maintenance treatment.
For the sample size calculations it is assumed that the true treatment rate ratio (RR) is 0.75 
corresponding to a 25% reduction in rate of hypoglycaemia in maintenance period with IDeg OD 
compared to IGlar 300 U/mL OD. Sample size is determined based on a negative binomial model 
with log-offset equal to exposure time in maintenance. The observed rate of severe or BG 
confirmed symptomatic hypoglycaemia for IDeg is assumed to be 1.8 per patient years of exposure 
(PYE) and the dispersion parameter in the negative binomial distribution is assumed to be 3.1. 
Furthermore it is assumed that 4% of subjects will withdraw before starting the maintenance period 
and therefore have no on-treatment data for the maintenance period. For these 4% the treatment 
ratio is set to 1. Rate assumptions are based on experience from SWITCH 2 (NN1250-3998), which 
has similar inclusion criteria. Dispersion parameter assumptions are based on experience from the 
Degludec phase 3a and 3b program. Assumptions concerning withdrawal are similarly based on the 
Degludec phase 3a and b program and increased focus on retention.
From these assumptions, and based on a 1:1 randomisation, the sample size is set to 795 subjects 
per treatment arm; in total 1,590 subjects will be randomised. This will ensure a nominal power of 
at least 80% for detecting a difference in favour of IDeg. The power equals 80% with 1,584 subjects 
and the assumptions above.
Power calculations for the secondary estimand are based on the same assumptions, except a 
treatment ratio of 1 is assumed for all 13% of the subjects that are assumed not to complete the trial 
on treatment.
Table 17–1
Sample sizes for the primary and secondary estimand for combinations of RR 
and event rates to achieve a power of 80%
Yearly event rate
1.5
1.8
2.0
RR
Adjusted RR
Primary
Secondary
Primary
Secondary
Primary
Secondary
0.80
0.808/0.826
2738
3412
2638
3286
2588
3224
0.75
0.76/0.7825
1642
2062
1584
1988
1556
1952
0.70
0.712/0.739
1066
1350
1030
1302
1010
1278
The marginal power for detecting a difference between IDeg OD and IGlar 300 U/mL OD with 795 
subjects per treatment arm assuming a one-sided t-test at the 2.5% significance level for the 
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Date:
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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confirmatory secondary endpoints is shown below. The assumptions are based on data from 
NN1250-3998 with respect to hypoglycaemic episodes and the phase 3a+b program for the dose-
difference.
Table 17–2
Marginal power for confirmatory secondary endpoints
Assumptions
Endpoint
True ratio
Adjusted RR
CV/
Over dispersion
Rate in IDeg 
treatment arm
Power
Number of nocturnal, severe or 
BG confirmed symptomatic 
hypoglycaemic episodes during 
maintenance
0.7
0.712
3.1
0.55
84%
Insulin dose (U)
0.90
0.904
0.65
-
92%
Number of severe or BG 
confirmed symptomatic
hypoglycaemic episodes during
52 weeks
0.75
0.75
3.1
2.2
87%
Number of severe 
hypoglycaemic episodes during 
maintenance
0.6
0.616
3.1
0.03
32%
17.3
Definition of analysis sets
Full analysis set (FAS): includes all randomised subjects. In exceptional cases, subjects may be 
eliminated from the full analysis set. In such cases the elimination will be justified and documented. 
In the statistical evaluation of the full analysis set subjects contribute "as treated" when addressing 
the primary estimand and "as randomised" when addressing the secondary estimand".
Safety analysis set (SAS): includes all subjects receiving at least one dose of the investigational 
product or comparator. Subjects in the safety set will contribute to the evaluation “as treated”.
Randomised subjects who are lost to follow up and where no exposure information of the 
investigational product or comparators is available after randomisation will be handled as 
unexposed.
Before data are released for statistical analysis, a review of all data will take place to identify 
protocol deviations that could potentially affect the results. In exceptional cases a decision to 
exclude any subject or observation from the statistical analysis can be made. This is the joint 
responsibility of the members of the study group. The subjects or observations to be excluded, and 
the reasons for their exclusion must be documented before database lock. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report.
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Date:
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Trial ID: NN1250-4252
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17.4
Primary endpoint
17.4.1
Primary statistical analysis for the primary estimand
The primary estimand will be estimated based on information from the maintenance period 
collected when subjects use randomised treatment (on-treatment data). Subjects that discontinue 
randomised treatment during the maintenance period will contribute with the available on treatment
data from the maintenance period. For subjects that discontinue randomised treatment during the 16 
week titration period, the number of events in the maintenance period will be imputed based on data
from the same arm from the maintenance period for subjects that discontinued randomised 
treatment during the maintenance period. Missing data within each group will be imputed as 
follows:
!
First 1000 samples from the posterior distribution of model parameters will be extracted. 
The model will be fitted to the on-treatment maintenance data for subjects that discontinued 
randomised treatment during the maintenance period. This will be done using a Bayes 
negative binomial log-link model with the factors descried in section 17.1 (except 
treatment), age as covariate, and log of exposure time as offset.
!
For each sample of model parameters, the total number of hypoglycaemia events for 
subjects that discontinued randomised treatment in the titration period will be imputed as a 
random number of events from a negative binomial distribution using the sampled 
parameters.
Having 1000 complete data sets that have maintenance period data for all randomised subjects, the 
mean treatment ratio will be estimated using a negative binomial model with all the factors 
described in section 17.1, age as covariate and log exposure time as offset. The estimates and 
standard deviations will be pooled to one estimate and associated standard deviation using Rubin’s 
formula. From these the 95% confidence intervals for the treatment ratio and the associated p-value 
will be calculated.
If the above model cannot fit due to sparse data, the model in step 1 above is fitted to the on-
treatment data for subjects that discontinued randomised treatment during either titration or 
maintenance. If this model cannot fit either, factors will be left out one by-one in the model using 
data from all subjects discontinuing randomised treatment in the following order, until a model fits: 
!
sex
!
region
!
previous OAD treatment
17.4.2
Sensitivity analyses for the primary estimand
To investigate missing not at random scenarios, a tipping point analysis of the hypothesis that IDeg 
is superior to IGlar 300 U/mL will be performed for the primary estimand. In this analysis the event 
rates for subjects that discontinued randomised treatment in the IDeg OD arm during either titration 
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or maintenance is gradually increased until the difference between the two treatments is no longer 
statistically significantly different. If the penalty found by this method is evaluated to be clinically 
plausible the sensitivity analysis does not support the primary analysis. If the penalty is not 
considered plausible the sensitivity analysis supports the primary analysis.
To investigate the potential influence of subjects with high number of events, the analysis of the 
primary estimand will be repeated on data where the maximal number of events in the maintenance 
period is truncated at three. The value three is based on data from SWITCH 2 (NN1250-3998) 
where three hypos correspond to the 95% percentile in the IDeg arm.
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses.
17.4.3
Statistical analysis for the secondary estimand
The secondary estimand will be estimated based on information from the maintenance period 
collected regardless of whether subjects used randomised treatment or not, i.e. including data after 
premature discontinuation.
Missing data for withdrawn subjects will be imputed based on off-treatment data from the same arm 
from the maintenance period for subjects that discontinued randomised treatment during the 
maintenance period. The imputations and the analysis will be made using the same method as for 
the primary estimand.
17.4.4
Sensitivity analysis for the secondary estimand
The same sensitivity analysis as the sensitivity analysis for the primary estimand will be performed.
17.5
Secondary endpoints
17.5.1
Confirmatory secondary endpoints
Provided that IDeg OD is superior to IGlar 300 U/mL OD for the primary endpoint using the 
primary estimand, the confirmatory secondary endpoints will be tested for superiority of IDeg OD 
over IGlar 300 U/mL OD using the primary estimand.
The confirmatory secondary endpoints are given below; the order of the endpoints defines the 
testing sequence. The hierarchical testing strategy will control the family wise type 1 error in the 
strong sense at 5% (two sided).
1. Basal insulin dose (U) after 52 weeks
2. Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes during 
maintenance, week 16-52
3. Number of severe or BG confirmed symptomatic hypoglycaemic episodes during 52 weeks
4. Number of severe hypoglycaemic episodes during maintenance, week 16-52
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The hypoglycaemic endpoints will be analysed with the same analysis method as the primary 
endpoint and with similar sensitivity analysis.
Basal insulin dose after 52 weeks will be analysed as follows: A basal insulin dose at every titration, 
maintenance and end of treatment visit mentioned in the flow chart will be calculated as a mean of 
the insulin doses in the 7 day period before the visits. These doses will be analysed on log-scale 
with an MMRM with the factors described in section 17.1 and age at baseline and pre-trial insulin 
dose as covariate.
Insulin dose will also be analysed with a de-facto estimand, i.e. including using insulin dose 
collected after premature discontinuation. This is done using a pattern mixture model using multiple 
imputation to handle missing data. Imputation of missing data at end of trial will be done within the 
4 groups of subjects defined by randomised treatment and whether subjects discontinued 
randomised treatment or not. Missing data within each group will be imputed as follows:
!
An analysis of covariance model for insulin dose at week 52 with the factors listen in 17.1
(except treatment) and pre-trial insulin dose and age at baseline as covariates will be fitted to 
the observed data.
!
The estimated parameters will be used to impute 1000 values for insulin dose at week 52, 
creating 1000 complete datasets.
Having 1000 complete datasets, each of these will be analysed using an analysis of covariance 
model with all the factors listed in 17.1, pre-trial insulin dose and age at baseline as covariates. The 
estimates and standard deviations will be pooled to one estimate and associated standard deviation 
using Rubin’s formula. From these the 95% confidence intervals for the treatment ratio and the 
associated p-value will be calculated.
17.6
Other endpoints
17.6.1
Efficacy endpoints
Continuous supportive secondary efficacy endpoints will be summarised descriptively by visits and 
by mean plots of observed values and observed change from baseline.
17.6.2
Safety endpoints
Adverse events during 52 weeks
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities.
A treatment-emergent AE (TEAE) is defined as an event that has onset date on or after the first day 
of exposure to randomised treatment and no later than 7 days after the last day of randomised 
treatment, or has onset date before the first day of exposure on randomised treatment and increases 
in severity during the treatment period and until 7 days after the last drug date. Major adverse 
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cardiovascular events (MACEs, defined as all cardiovascular deaths, non-fatal myocardial 
infarctions and non-fatal strokes) are considered treatment-emergent until 30 calendar days after the 
last day of randomised treatment.
TEAEs are summarised descriptively, whereas non-TEAEs are presented in listings. TEAE data 
will be displayed in terms of the number of subjects with at least one event (N), the percentage of 
subjects with at least one event (%), the number of events (E) and the event rate per 100 years of 
exposure (R).
Summaries of TEAEs and of serious TEAEs will be presented as an overview including all AEs, 
serious AEs, number of deaths, AEs by severity, AEs by relation to treatment and AEs leading to 
treatment discontinuation or withdrawal.
Furthermore summary tables based on system organ class and preferred terms are made for:
!
All TEAEs
!
Serious TEAEs
!
TEAEs possibly or probably related to trial product
!
Severe, moderate and mild TEAEs
!
TEAEs with preferred term that are experienced by at least 5% (1%) of the subjects in any 
treatment arm or by at least 5% (1%) of all subjects
Summary tables of SAEs including SAEs reported for subject that discontinue trial product 
prematurely will be presented including summary tables based on system organ class and preferred 
terms.
Hypoglycaemic episodes during 52 weeks
For the definition and classification of hypoglycaemic episodes refer to section 17.7.
Data on treatment-emergent hypoglycaemic episodes are presented in terms of the number of 
subjects with at least one event (N), the percentage of subjects with at least one event (%), the 
number of events (E) and the event rate per 100 years of exposure (R).
Separate summaries are made by severity considering severe or BG confirmed symptomatic 
hypoglycaemic episodes, severe hypoglycaemic episodes, and the ADA classification of 
hypoglycaemia. The summaries are made for all and nocturnal (between 00:01 and 05.59 both 
inclusive) episodes respectively and for the total treatment period (52 weeks) and maintenance 
period only (week 16-52).
Body weight
Body weight (absolute value and change from baseline) will be summarised descriptively by visit.
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Clinical evaluation (ECG, vital signs, eye examination and physical examination) change from 
baseline after 52 weeks
Vital signs, physical examination, eye examination and 12-lead ECG findings will be summarised,
including:
!
Summaries for each visit
!
Shift tables from baseline to after 52 weeks
Laboratory assessments
Biochemistry and Haematology laboratory parameters will be summarised including:
!
Summaries by visit
!
Shift tables from baseline to after 52 weeks
!
Proportion of subjects with measurements outside reference range by treatment and week
!
Box plots by time since randomisation
!
Listings of individual values outside reference ranges (abnormal values)
All laboratory values will be included in listings.
Anti-insulin antibodies will be summarised by visit.
17.7
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 IMP administration, and no later than the 7 days from 
last day on IMP.
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the ADA classification of hypoglycaemia (see Figure 17–2).
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) 38. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
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Novo Nordisk uses the following classification (see Figure 17–1) in addition to the ADA 
classification:
!
Severe hypoglycaemia according to the ADA classification29.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification29or BG confirmed by a plasma glucose value <3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia.
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1
Novo Nordisk classification of hypoglycaemia
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ADA classification29 of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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17.8
Health economics and/or patient reported outcomes
Health economics and/or patient reported outcomes will be analysed after the CTR.
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18 Ethics
18.1
Benefit-risk assessment of the trial
The trial population will consist of insulin-treated subjects with T2DM presenting with an HbA1c
equal to or below 9.5% while treated continuously with basal insulin with or without OADs for at 
least 90 days and who recently have experienced hypoglycaemia or have increased risk of severe 
hypoglycaemia. For all subjects participating in this trial, the anticipated benefits include improved 
glycaemic control. Titration algorithms, specifying recommended adjustments of the basal insulin 
dose at different plasma glucose levels, are used in order to ensure that subjects receive an optimal 
treatment. Subjects will receive intense medical care by means of close contact to the clinical sites 
with at least weekly contacts.
Trial products will be provided by Novo Nordisk free of charge. Subjects will receive IDeg or IGlar 
300 U/mL in prefilled pens and NPH during 7 days follow-up. For a description of risks and 
benefits please refer to current versions and any updates of the following:
!
IDeg IB9
!
IGlar 300 U/mL SmPC14 or local labelling15, 16
!
NPH SmPC34 or local labelling35, 36
The subjects will be provided with a glucose meter including lancets, plasma-calibrated test strips 
and control solutions as well as instructions for use.
The trial products may be associated with side effects, 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. These precautions include thorough information 
regarding the correct administration of the trial product and in handling of low BG measurement.
Furthermore, subjects will be fully informed about possible AEs and inconveniences.
Clinical benefits and risk considerations for the trial
For the individual subjects, the personal health-related benefits are related to the medical 
examination and the benefit from a treatment regimen anticipated being equal to or better than the 
treatment they receive at the time they enter the trial. However, subjects will have to spend some 
extra time monitoring and recording data and on additional visits to the clinic and phone contacts.
The maximum trial duration for each subject is 58 weeks and the treatment duration for a subject is 
planned to be 52 weeks. Subjects will be asked to perform SMPG recording every day.
The very high frequency of contacts between the subject and the investigator and the thorough 
evaluation of SMPG values will provide the opportunity for optimising the titration of basal insulin 
based on SMPG values and thereby may contribute to obtaining improved HbA1c results.
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For the individual subjects, the anticipated side effects associated with the trial products are not 
different from what is seen with other insulins and include hypoglycaemia, hypersensitivity 
reactions, injection site reactions, lipodystrophy and antibody development (for more detailed 
description, please refer to the local labelling for each product). The side effects will be mitigated 
by the close supervision of the subjects and the frequent measurements of BG levels.
All treatments are contraindicated in case of hypersensitivity to the active substances or any of the 
excipients. The risk of hypersensitivity is partly mitigated by excluding subject with known 
hypersensitivity towards any trials products or related products.
Injection site reactions can occur. The nature of the injection site reactions is expected to be mild, 
transient, and more of a visual character and is not expected to be of concern to the subject’s safety. 
Lipodystrophy (including lipohypertrophy, lipoatrophy) at the injection site can occur. Continuous 
rotation of the injection site within the particular injection area may help to reduce the risk of 
developing these reactions.
Conclusion
Subjects in this trial will benefit from a basal insulin treatment in a treat-to-target setting under 
close supervision.
The safety profiles of the trial products are well established.
It is concluded that the clinical benefits from the trial outweigh the potential risks of participating in 
this trial.
18.2
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand.
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.
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The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow up 
visits will be retained by Novo Nordisk, entered into the database and used for the clinical 
trial report.
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain the letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject at the discretion of the investigator. The subject may 
receive a “welcome to the trial letter” and a “thank you for your participation letter” after 
completion of the trial. Further the subject may receive letters during the trial.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation.
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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
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database.
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
A significant proportion of missing data is a potential source of bias when analysing data in clinical 
trials leading to a risk of misinterpretation of the trial results. Missing data may affect both 
estimation of treatment effect and the confidence interval that surrounds it as well as the 
representativeness of the sample size in relation to the target population.
Only absolutely necessary criteria to discontinue trial drug have been stated, see Section 6.4, and a 
process has been set up to follow-up on subjects discontinuing trial drug prematurely, see section 
8.1.8.
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites.
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. In addition, only absolutely necessary 
criteria for premature discontinuation of trial products primarily focusing on subjects safety are 
included and thereby reducing the number of discontinuations and limiting the amount of missing 
data.
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites.
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11 November 2016
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Trial ID: NN1250-4252
Version:
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The subjects must be instructed to complete their eDiary on an ongoing basis according to the 
protocol. Missing data will not be recorded retrospectively due to the decreased validity of such 
data31, 32; however a 7 days’ timeline is applied for reporting of missing hypoglycaemic episode. 
The subject will be retrained in correct completion of the eDiary if missing data is identified.
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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CONFIDENTIAL
Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure, SmPC or similar labelling
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
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Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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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 if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1
applicable regulatory requirements and the Declaration of Helsinki2.
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data.
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11 November 2016
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Trial ID: NN1250-4252
Version:
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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 publications39.
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 
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scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure23.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors39 (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:
11 November 2016
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
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.
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CONFIDENTIAL
Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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24 Retention of clinical trial documentation and human bio samples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs, and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human bio samples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities, for safety reasons or in relation to 
exploratory analysis.
Remaining anti-insulin antibody samples may be used for exploratory investigation of antibodies. 
The analyses will be performed by Immunogenicity Assessment, Novo Nordisk A/S or a laboratory 
assigned by Novo Nordisk A/S. Results will be reported under a separate study and the data 
documented independently from the clinical trial report.
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Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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The samples will be stored at a central bio-repository after end of trial and until marketing 
authorisation approval or until the research project terminates, but no longer than 15 years from end 
of trial after which they will be destroyed.
The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples.
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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CONFIDENTIAL
Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
For Poland only: Novo Nordisk carries liability for the trial exclusively in the scope defined by the 
applicable laws and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 
2001 (uniform version Journal of Laws of 2008 No. 45 item 271 with amendments). In order to 
support potential claims for liability attributable to the trial, Novo Nordisk and the investigators are 
covered by the insurance policy issued according to applicable Polish law.
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CONFIDENTIAL
Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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Date:
11 November 2016
Novo Nordisk
Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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
Yki-Järvinen H, Bergenstal RM, Bolli GB, Ziemen M, Wardecki M, Muehlen-Bartmer I, et
al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin
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antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month
extension. Diabetes Obes Metab. 2015;17(12):1142-9.

Home PD, Bergenstal RM, Bolli GB, Ziemen M, Rojeski M, Espinasse M, et al. NewInsulin 
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Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4).Diabetes Care.2015.
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Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1
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the European Parliament and of the Councill of 4 April 2001on the approximation of the
laws, regulations and administrative provisions of the Member States relating to the
implementation of good clinical practice in the conduct of clinical trials on medicinal
products for human use, article 11. Official Journal of the European Communities. 1 May
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
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726/2004 of the European Parliament and of the Council of 31 March 2004 laying down
Community procedures for the authorisation and supervision of medicinal products for
human and veterinary use and establishing a European Medicines Agency, article 57.
Official Journal of the European Communities. 2004.

Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22.
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Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia
and diabetes: a report of a workgroup of the American Diabetes Association and the
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
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Date:
11 November 2016
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Trial ID: NN1250-4252
Version:
2.0
UTN: U1111-1184-8175
Status:
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
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes.
Diabet Med. 2001;18(9):690-705.
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for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to
Support Labeling Claims. December 2009.
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Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-reported 
outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-42.
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Rewers MJ, Pillay K, de Beaufort C, Craig ME, Hanas R, Acerini CL, et al. ISPAD Clinical
Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in
children and adolescents with diabetes. Pediatr Diabetes. 2014;15 Suppl 20:102-14.

Novo Nordisk A/S. Insulatard® (human isophan insulin), EU Summary of Product
Charateristics. SEP 2015.

Novo Nordisk A/S. NOVOLIN®N, US Prescribing Information (PI). 01-August-2016 2016.

Novo Nordisk A/S. Novolin®ge, CA prescribing Information (PI). 11-March-2016 2016.

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Rev. 1). 2 Jul 2010.

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.
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
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Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version
available at www.icmje.org.
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Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
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Protocol
Trial ID: NN1250-4252
A trial comparing the efficacy and safety of insulin degludec and 
insulin glargine 300 units/mL in subjects with type 2 diabetes mellitus 
inadequately treated with basal insulin with or without oral anti-
diabetic drugs
Updated protocol including:
Protocol, final version 2.0 dated 11 November 2016
Local Protocol Amendment no. 1 in Serbia version 1.0 dated 25 July 2017
Global Protocol Amendment no. 2, version 1.0 dated 22 February 2018
Trial phase: 3b
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:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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Table of contents
Page
Table of contents.........................................................................................................................................2
Table of figures ...........................................................................................................................................6
Table of tables.............................................................................................................................................6
List of abbreviations ...................................................................................................................................6
1
Summary............................................................................................................................................11
2
Flow chart ..........................................................................................................................................14
3
Background information and rationale for the trial.........................................................................24
3.1
Background information..........................................................................................................24
3.2
Rationale for the trial...............................................................................................................25
4
Objective(s) and endpoint(s)..............................................................................................................27
4.1
Objective(s) ............................................................................................................................27
4.2
Endpoint(s) .............................................................................................................................27
4.2.1
Primary endpoint ...................................................................................................27
4.2.2
Secondary endpoints ..............................................................................................27
4.2.2.1
Confirmatory secondary endpoints ...................................................27
4.2.3
Other endpoints......................................................................................................27
5
Trial design ........................................................................................................................................29
5.1
Type of trial ............................................................................................................................29
5.2
Rationale for trial design .........................................................................................................30
5.3
Treatment of subjects ..............................................................................................................31
5.4
Treatment after discontinuation of trial product .......................................................................32
5.5
Rationale for treatment............................................................................................................32
6
Trial population .................................................................................................................................33
6.1
Number of subjects .................................................................................................................33
6.2
Inclusion criteria .....................................................................................................................33
6.3
Exclusion criteria ....................................................................................................................34
6.4
Criteria for premature discontinuation of trial product .............................................................35
6.5
Withdrawal from trial..............................................................................................................36
6.6
Subject replacement ................................................................................................................37
6.7
Rationale for trial population...................................................................................................37
7
Milestones...........................................................................................................................................38
8
Methods and assessments ..................................................................................................................39
8.1
Visit procedures ......................................................................................................................39
8.1.1
Screening visit (Visit 1) .........................................................................................39
8.1.1.1
Screening failures.............................................................................40
8.1.2
Randomisation visit (V2) .......................................................................................40
8.1.3
Phone contacts.......................................................................................................41
8.1.4
Fasting visits..........................................................................................................41
8.1.5
Maintenance 2 initiation visit (V57) .......................................................................41
8.1.6
End of Treatment visit (V54 or V93)......................................................................42
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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8.1.7
Follow up visits .....................................................................................................43
8.1.8
Unscheduled site visits...........................................................................................43
8.1.9
Premature discontinuation of trial product..............................................................44
8.1.10
Withdrawal from trial.............................................................................................45
8.1.11
Review of results ...................................................................................................46
8.2
Subject related information/assessments..................................................................................46
8.2.1
Demography ..........................................................................................................46
8.2.2
Diabetes history .....................................................................................................46
8.2.3
Hypoglycaemia unawareness .................................................................................46
8.2.4
Concomitant illness and medical history.................................................................46
8.2.5
Concomitant medication ........................................................................................47
8.2.6
Concomitant medication (Diabetes)........................................................................47
8.2.7
Childbearing potential............................................................................................48
8.2.8
Tobacco use...........................................................................................................48
8.3
Efficacy assessments...............................................................................................................48
8.3.1
Self-measured plasma glucose................................................................................48
8.3.2
Insulin dose ...........................................................................................................49
8.4
Safety assessments ..................................................................................................................49
8.4.1
Adverse events.......................................................................................................50
8.4.1.1
Medication error...............................................................................50
8.4.1.2
Adverse events requiring additional data collection ..........................50
8.4.2
Hypoglycaemic episodes........................................................................................51
8.4.3
Body measurements...............................................................................................54
8.4.4
Vital signs..............................................................................................................54
8.4.5
Physical examination .............................................................................................54
8.4.6
Eye examination ....................................................................................................54
8.4.7
Electrocardiogram..................................................................................................55
8.5
Laboratory assessments...........................................................................................................55
8.5.1
Laboratory assessments for efficacy.......................................................................56
8.5.2
Laboratory assessments for safety ..........................................................................57
8.6
Other assessments ...................................................................................................................58
8.6.1
Training in the pen injector ....................................................................................59
8.7
Subject compliance .................................................................................................................60
9
Trial supplies......................................................................................................................................61
9.1
Trial products..........................................................................................................................61
9.2
Labelling.................................................................................................................................62
9.3
Storage....................................................................................................................................62
9.4
Drug accountability and destruction ........................................................................................63
9.5
Auxiliary supplies ...................................................................................................................63
10
Interactive web response system........................................................................................................64
11
Randomisation procedure..................................................................................................................65
12
Adverse events, and technical complaints and pregnancies .............................................................66
12.1
Definitions ..............................................................................................................................66
12.1.1
Adverse event ........................................................................................................66
12.1.2
Serious adverse event.............................................................................................67
12.1.3
Non-serious adverse event......................................................................................68
12.1.4
Medication errors...................................................................................................68
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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12.1.5
Adverse events requiring additional data collection................................................69
12.1.6
Technical complaints .............................................................................................69
12.2
Reporting of adverse events.....................................................................................................70
12.3
Follow-up of adverse events....................................................................................................72
12.4
Technical complaints and technical complaint samples............................................................73
12.4.1
Reporting of technical complaints ..........................................................................73
12.4.2
Collection, storage and shipment of technical complaint samples ...........................73
12.5
Pregnancies in female subjects ................................................................................................74
12.6
Precautions and/or overdose....................................................................................................75
12.7
Committees related to safety ...................................................................................................76
12.7.1
Novo Nordisk safety committee .............................................................................76
12.7.2
Event adjudication committee ................................................................................76
13
Case report forms ..............................................................................................................................78
13.1
Corrections to case report forms..............................................................................................78
13.2
Case report form flow .............................................................................................................79
14
Monitoring procedures ......................................................................................................................79
15
Data management ..............................................................................................................................81
16
Computerised systems .......................................................................................................................81
17
Statistical considerations ...................................................................................................................81
17.1
General considerations ............................................................................................................81
17.2
Power calculation....................................................................................................................83
17.3
Definition of analysis sets........................................................................................................84
17.4
Primary endpoint.....................................................................................................................85
17.4.1
Primary statistical analysis for the primary estimand ..............................................85
17.4.2
Sensitivity analyses for the primary estimand.........................................................85
17.4.3
Statistical analysis for the secondary estimand........................................................86
17.4.4
Sensitivity analysis for the secondary estimand ......................................................86
17.5
Secondary endpoints ...............................................................................................................86
17.5.1
Confirmatory secondary endpoints.........................................................................86
17.6
Other endpoints.......................................................................................................................87
17.6.1
Efficacy endpoints .................................................................................................87
17.6.2
Safety endpoints ....................................................................................................87
17.7
Classification of Hypoglycaemia .............................................................................................89
17.8
Health economics and/or patient reported outcomes.................................................................92
18
Ethics..................................................................................................................................................93
18.1
Benefit-risk assessment of the trial ..........................................................................................93
18.2
Informed consent ....................................................................................................................94
18.3
Data handling..........................................................................................................................95
18.4
Information to subjects during trial..........................................................................................95
18.5
Premature termination of the trial and/or trial site....................................................................95
19
Protocol compliance...........................................................................................................................96
19.1
Protocol deviations..................................................................................................................96
19.2
Prevention of missing data ......................................................................................................96
20
Audits and inspections .......................................................................................................................97
21
Critical documents.............................................................................................................................97
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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22
Responsibilities...................................................................................................................................98
23
Reports and publications ...................................................................................................................99
23.1
Communication of results........................................................................................................99
23.1.1
Authorship...........................................................................................................100
23.1.2
Site-specific publication(s) by investigator(s).......................................................100
23.2
Investigator access to data and review of results ....................................................................101
24
Retention of clinical trial documentation and human bio samples.................................................102
24.1
Retention of clinical trial documentation ...............................................................................102
24.2
Retention of human bio samples............................................................................................102
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........104
26
Indemnity statement ........................................................................................................................105
27
References ........................................................................................................................................106
Appendix A
Titration Guideline
Attachment I  Global list of key staff and relevant departments and suppliers
Attachment II Country list of key staff and relevant departments, if applicable for the individual 
country
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Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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Table of figures
Page
Figure 5–1
Trial design........................................................................................................................30
Figure 12–1
Reporting of AEs ...............................................................................................................71
Figure 17–1
Novo Nordisk classification of hypoglycaemia ...................................................................90
Figure 17–2
ADA classification of hypoglycaemia.................................................................................91
Table of tables
Page
Table 2–1
Flowchart – titration and maintenance 1 .............................................................................14
Table 2–2
Flowchart – maintenance 2.................................................................................................19
Table 2–3
Flow chart – phone contacts during titration and maintenance 1..........................................23
Table 2–4
Flow chart – phone contacts during maintenance 2 .............................................................23
Table 9–1
Trial products.....................................................................................................................61
Table 9–2
Storage conditions..............................................................................................................62
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication .......................................................................................................................69
Table 12–2
Events for adjudication.......................................................................................................76
Table 17–1
Power for the primary estimand for combinations of RR and event rates............................83
Table 17–2
Marginal power for confirmatory secondary endpoints .......................................................83
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AP
alkaline phosphatase
AST
aspartate aminotransferase
BG
blood glucose
BID
Bis In Die/twice daily
CAS
completer analysis set
CCDS
Company Core Data Sheet
CFR
Code of Federal Regulations
CLAE
clinical laboratory adverse event
CRF
case report form
DPP-IVi
dipeptidyl peptidase-4 inhibitor 
DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
eGFR
estimated Glomerular Filtration Rate 
EMA
European Medicines Agency
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPFV
first patient first visit
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
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FPG
fasting plasma glucose
FU
follow-up
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotropin
IB
investigator’s brochure
ICH
International Conference on 
Harmonisation of Technical 
Requirements for Registration of 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical 
Journal Editors
IDeg
insulin degludec
IEC
independent ethics committee
IGlar
insulin glargine
IMP
investigational medicinal product
IND
Investigational New Drug
ITT
intention-to-treat
IRB
institutional review board
IWRS
interactive voice/web response 
system
LI
label information
LLOQ
lower limit of quantification
LPLV
last patient last visit
MACE
major adverse cardiovascular events
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
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NIMP
Non-Investigational Medicinal 
Product 
NPH
insulin Neutral Protamine Hagedorn 
NYHA
New York Heart Association
OAD
oral anti-diabetic drug
OD
once daily
PP
per protocol
PRO
patient reported outcome
PYE
Patient years of exposure
PX
monthly phone contact
RR
rate ratio
SAE
serious adverse event
SAS
safety analysis set
SD
standard deviation
SF-36v2®
short-form 36 health survey version 2
SGLT2i
sodium-glucose co-transporter 2 
inhibitors
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SU
sulfonylureas
SUSAR
suspected unexpected serious adverse 
reaction
T2DM
type 2 diabetes mellitus
TEAE
treatment-emergent AE
TIA
transient ischaemic attack 
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Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
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TMM
trial materials manual
TRIM-D
Treatment related impact measure -
diabetes 
TRIM-D-Device
Treatment related impact measure -
diabetes device 
TZD
Thiazolidinediones
U
Units
UNL
upper normal limit
UTN
Universal Trial Number
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
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1
Summary
Objective(s) and endpoint(s):
Primary objective
To compare the effects of insulin degludec once daily and insulin glargine 300 units/mL once daily 
on hypoglycaemia in subjects with type 2 diabetes mellitus, inadequately treated with basal insulin 
with or without oral anti-diabetic drugs.
Key secondary objectives
To compare insulin degludec and insulin glargine 300 units/mL in terms of basal insulin 
requirement.
To compare insulin degludec and insulin glargine 300 units/mL in terms of safety and parameters of 
glycaemic control.
Primary endpoint
!
Number of severe or blood glucose confirmed symptomatic hypoglycaemic episodes during 
maintenance 2 (36 weeks)
Confirmatory secondary endpoints:
!
Basal insulin dose (units) at end of treatment (up to 88 weeks)
!
Number of nocturnal, severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes during maintenance 2 (36 weeks)
!
Number of severe hypoglycaemic episodes during maintenance 2 (36 weeks)
Other efficacy endpoints:
!
Change in HbA1c from baseline to end of treatment (up to 88 weeks)
Other safety endpoints:
!
Hypoglycaemia
o
Number of severe or blood glucose confirmed symptomatic hypoglycaemic episodes 
during treatment (up to 88 weeks)
o
Number of nocturnal, severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes during treatment (up to 88 weeks)
o
Number of severe hypoglycaemic episodes during treatment (up to 88 weeks)
!
Number of adverse events during treatment (up to 88 weeks)
Trial design:
This is a up to 88-week, randomised (1:1), open-label, parallel, multi-centre, multi-national, treat-
to- target, active controlled trial comparing the efficacy and safety of insulin degludec 200 units/mL
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
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with insulin glargine 300 units/mL both administered once daily ± oral anti-diabetic drugs in 
subjects with type 2 diabetes mellitus previously treated with basal insulin once or twice daily ± 
oral anti-diabetic drugs excluding sulfonylureas/glinides. Type and dose of any pre-trial oral anti-
diabetic treatment should remain unchanged throughout the trial.
Within each treatment arm, subjects will be randomised 1:1 to morning (from waking up to 
breakfast) or evening dosing (from main evening meal to bedtime). The dosing time will be kept 
throughout the entire treatment period.
Total trial duration for the individual subjects will be up to 94 weeks.
Trial population:
It is planned to randomise 1,590 subjects.
Key inclusion criteria:
!
Male or female, age above or equal to 18 years at the time of signing informed consent.
!
Subjects fulfilling at least one of the below criteriaa:
a.
Experienced at least one severe hypoglycaemic episode within the last year 
(according to the ADA definition, April 2013b)
b. Moderate chronic renal failure, defined as glomerular filtration rate 30 - 59 
mL/min/1.73 m2 per CKD-EPI by central laboratory analysis
c.
Hypoglycaemic symptom unawarenessc
d. Treated with insulin for more than 5 years
e.
Episode of hypoglycaemia (defined by symptoms of hypoglycaemia and/or episode 
with low glucose measurement (≤ 70 mg/dL [≤ 3.9 mmol/L])) within the last 12 
weeks prior to Visit 1(screening)
!
Subjects diagnosed (clinically) with type 2 diabetes mellitus.
!
Treated with basal only insulin (once daily or twice-daily insulin (insulin detemir; insulin 
glargine 100 U/mL, biosimilar of insulin glargine 100 U/mL or insulin Neutral Protamine 
Hagedorn)) ≥ 90 days prior to the day of screening with or without any of the following 
anti-diabetic drugs with stable doses for ≥ 90 days prior to screening:
a.
Metformin
b. Dipeptidyl peptidase -4 inhibitor
c.
Sodium-glucose co-transporter 2 inhibitor
d. Alpha-glucosidase-inhibitors (acarbose)
e.
Thiazolidinediones
a
Marketed oral combination products only including the products listed in criteria 
5a-5e
!
HbA1c ≤ 9.5% (80 mmol/mol) at screening by central laboratory analysis.
!
BMI ≤ 45 kg/m2.
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Protocol
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Date:
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
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EudraCT no.: 2016-002801-20
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aFor this inclusion criterion the aim is to include minimum 80% of individuals with a previous 
episode of hypoglycaemia (criterion e). The remaining subjects will have to fulfil at least one of 
criteria a-d.
bAn 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.
cHistory of impaired autonomic responses (tremulousness, sweating, palpitations, and hunger) 
during hypoglycaemia.
Key exclusion criteria
!
Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria in a period of 90 days before the day of screening.
Key assessments:
!
Hypoglycaemic episodes
!
Insulin dose
!
HbA1c
!
Adverse events
Trial products:
Investigational medicinal products:
!
Test product: Insulin degludec (Tresiba®), 200 U/mL, 3 mL prefilled PDS290 (FlexTouch®) 
pen for subcutaneous injection
!
Reference therapy: Insulin glargine (Toujeo®), 300 U/mL, 1.5 mL prefilled Solostar® pen
for subcutaneous injection
Other medicinal products:
!
Insulin Neutral Protamine Hagedorn (Insulatard®/Prothaphane®/Novolin N™), 100 IU/mL, 
3 mL pre-filled pen for subcutaneous injection (will be provided by sponsor to subjects 
during the wash-out period in order to measure insulin antibodies)
CONFIDENTIAL


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
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2
Flow chart
Table 2–1
Flowchart – titration and maintenance 1
ONLY applicable until the new glycaemic data collection system (an Abbott BG-meter and paper diary) is available. As soon as the 
new glycaemic data collection system is available the subject should come for a visit 57 to enter maintenance 2 (Table 2–2) 
irrespectively of their current visit. Hence subject should only follow and complete the scheduled maintenance 1 visit plan until the 
new glycaemic data collection system is available.
For further description of methods and assessments; see Section 8.
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance 1
Up to 36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
SUBJECT 
RELATED 
Informed consent
18.2
X
Inclusion/exclusion 
criteria
6.2 6.3
X
X
Randomisation
8.1.2
X
Premature 
discontinuation of trial 
products
6.4
8.1.9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Withdrawal from trial
6.5
8.1.10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography
8.2.1
X


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
15 of 108
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance 1
Up to 36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
Diabetes history
8.2.2
X
Stop date of current 
diabetes treatment
8.2.2
X
Hypoglycaemia 
unawareness
8.2.3
X
Concomitant illness 
and medical History
8.2.4
X
Concomitant 
medication
8.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication (Diabetes)
8.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Childbearing potential
8.2.7
X
Tobacco use
8.2.8
X
EFFICACY 
ASSESMENTS
Self-measured plasma 
glucose Once daily 
(pre-breakfast)
8.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting plasma glucose 8.5.1
X
X
X
X
X
X
X
HbA1c
8.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAFETY 
ASSESMENTS
Adverse events
8.4.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
16 of 108
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance 1
Up to 36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
12
Hypoglycaemic 
episodes 
8.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
8.4.3
X
X
X
X
X
Height
8.4.3
X
Vital signs
8.4.4
X
X
Physical examination
8.4.5
X
X
Eye examination 
(Fundoscopy or fundus 
photography)
8.4.6
X
X
ECG
8.4.7
X
X
Anti-insulin antibodies 8.5.2
X
X
X
X
X
Biochemistry
8.5.2
X
X
Haematology
8.5.2
X
X
Pregnancy test
8.5.2
X
X
Technical complaints
12.1.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
OTHER 
ASSESSMENTS
SF-36v2® Standard
8.6
X
X
X
TRIM-D
8.6
X
X
X


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
17 of 108
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance 1
Up to 36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
TRIM-D device
8.6
X
X
Baseline 
hypoglycaemic
Questionnaire (BHQ)
8.6
X
Insulin Pen 
Questionnaire
8.6
X
Hypoglycaemia 
resource use 
questionnaire
8.6
X
X
X
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
NPH dosing (Date and 
Dose)
8.1.6
X
Dosing (Date, Dose 
and time of trial 
insulin), every day
8.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Date of first dose of 
investigational trial 
product
8.1.2
X
New prescribed dose 
of trial insulin
8.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensing visit
9.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
9.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IWRS session
10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
18 of 108
Trial NN1250-4252
Protocol section
Screening
Randomisation
Titration
16 weeks
Maintenance 1
Up to 36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V1
V2
V6
V10
V14
V18
V22
V26
V30
V34
V38
V42
V46
V50
V54
V55
V56
V18A V30A V42A V54A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P3
P4
P5
P7
P8
P9
P11
P12
P13
P15
P16
P17
P19
P20
P21
P23
P24
P25
P27
P28
P29
P31
P32
P33
P35
P36
P37
P39
P40
P41
P43
P44
P45
P47
P48
P49
P51
P52
P53
Timing of visit 
(weeks)
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
56
16
28
40
52
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
±3
±3
±3
±3
REMINDERS
Attend visit fasting
8.1.4
X
X
X
X
X
X
X
X
X
X
Confirmation of 
unchanged OAD
8.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Training in trial 
product and pen 
handling
8.6.1
9.2
X
X
Hand-out direction for 
use for the pen 
injectors
9.2
X
Hand-out ID card
8.1.1
X
Hand-out and instruct 
in BG meter
8.1.2
X
X
Hand-out and instruct 
in eDiary
8.1.2. 
8.6
X
eDiary collection
8.6
X
X
Make appointment for 
eye examination
8.4.6
X
End Of Treatment
8.1.6
X
X
End of trial
7
X
X
Sign off Casebook
X


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
19 of 108
Table 2–2
Flowchart – maintenance 2
Applicable from when the new glycaemic data collection system (an Abbott BG-meter and paper diary) is available.
Trial NN1250-4252
Protocol section
Maintenance 2
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V57
V61
V65
V69
V73
V77
V81
V85
V89
V93
V94
V95
V57A V69A V81A V93A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P58
P59
P60
P62
P63
P64
P66
P67
P68
P70
P71
P72
P74
P75
P76
P78
P79
P80
P82
P83
P84
P86
P87
P88
P90
P91
P92
Timing of visit 
(maintenance weeks)
0
4
8
12
16
20
24
28
32
36
37
40
0
12
24
36
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
SUBJECT 
RELATED 
Informed consent
18.2
X
X
Premature 
discontinuation of trial 
products
6.4
8.1.9
X
X
X
X
X
X
X
X
X
X
X
Withdrawal from trial
6.5
8.1.10
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
8.2.5
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication (Diabetes)
8.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EFFICACY 
ASSESMENTS
Self-measured plasma 
glucose Once daily 
(pre-breakfast)
8.3.1
X
X
X
X
X
X
X
X
X
X
Fasting plasma glucose 8.5.1
X
X
X
X
HbA1c
8.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAFETY 


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
20 of 108
Trial NN1250-4252
Protocol section
Maintenance 2
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V57
V61
V65
V69
V73
V77
V81
V85
V89
V93
V94
V95
V57A V69A V81A V93A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P58
P59
P60
P62
P63
P64
P66
P67
P68
P70
P71
P72
P74
P75
P76
P78
P79
P80
P82
P83
P84
P86
P87
P88
P90
P91
P92
Timing of visit 
(maintenance weeks)
0
4
8
12
16
20
24
28
32
36
37
40
0
12
24
36
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
ASSESMENTS
Adverse events
8.4.1
12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic 
episodes 
8.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
8.4.3
X
X
X
Vital signs
8.4.4
X
Physical examination
8.4.5
X
Eye examination 
(Fundoscopy or fundus 
photography)
8.4.6
X
ECG
8.4.7
X
Anti-insulin antibodies 8.5.2
X
X
Biochemistry
8.5.2
X
Haematology
8.5.2
X
Pregnancy test
8.5.2
X
Technical complaints
12.1.6
X
X
X
X
X
X
X
X
X
X
X
OTHER 
ASSESSMENTS
SF-36v2® Standard
8.6
X
TRIM-D
8.6
X


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
21 of 108
Trial NN1250-4252
Protocol section
Maintenance 2
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V57
V61
V65
V69
V73
V77
V81
V85
V89
V93
V94
V95
V57A V69A V81A V93A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P58
P59
P60
P62
P63
P64
P66
P67
P68
P70
P71
P72
P74
P75
P76
P78
P79
P80
P82
P83
P84
P86
P87
P88
P90
P91
P92
Timing of visit 
(maintenance weeks)
0
4
8
12
16
20
24
28
32
36
37
40
0
12
24
36
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
TRIM-D device
8.6
X
Insulin Pen 
Questionnaire
8.6
X
Hypoglycaemia 
resource use 
questionnaire
8.6
X
X
X
X
X
X
X
X
X
X
TRIAL MATERIAL
NPH dosing (Date and 
Dose)
8.1.6
X
Dosing (Date, Dose 
and time of trial 
insulin), every day
8.3.2
X
X
X
X
X
X
X
X
X
X
New prescribed dose 
of trial insulin
8.3.2
X
X
X
X
X
X
X
X
X
Dispensing visit
9.4
X
X
X
X
X
X
X
X
X
X
Drug accountability
9.4
X
X
X
X
X
X
X
X
X
X
X
IWRS session
10
X
X
X
X
X
X
X
X
X
X
REMINDERS
Attend visit fasting
8.1.4
X
X
X
X
X
Confirmation of 
unchanged OAD
8.2.6
X
X
X
X
X
X
X
X
X
X
X
Hand-out and instruct 
8.1.2
X


Protocol
UTN: U1111-1184-8175
Date:
23 February 2018
Status:
Final
Novo Nordisk
Trial ID: NN1250-4252
EudraCT no.: 2016-002801-20
Version:
3.0
Page:
22 of 108
Trial NN1250-4252
Protocol section
Maintenance 2
36 weeks
End Of 
Treatment
Follow-up
Premature discontinuation
Visit number
V57
V61
V65
V69
V73
V77
V81
V85
V89
V93
V94
V95
V57A V69A V81A V93A
Weekly Phone 
Contact number (P) 
(For details see 
separate flow chart 
below)
P58
P59
P60
P62
P63
P64
P66
P67
P68
P70
P71
P72
P74
P75
P76
P78
P79
P80
P82
P83
P84
P86
P87
P88
P90
P91
P92
Timing of visit 
(maintenance weeks)
0
4
8
12
16
20
24
28
32
36
37
40
0
12
24
36
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
in Abbott BG meter
Hand-out diary
X
X
X
X
X
X
X
X
X
X
X
Collect diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Make appointment for 
eye examination
8.4.6
X
End Of Treatment
8.1.6
X
X
End of trial
7
X
X
Sign off Casebook
X
X


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
23 of 108
Table 2–3
Flow chart – phone contacts during titration and maintenance 1
ONLY applicable until the new glycaemic data collection system (an Abbott BG-meter and 
paper diary) is available. As soon as the new glycaemic data collection system is available the 
subject should come for a visit 57 and enter maintenance 2 (Table 2–2) irrespectively of their 
current visit.
NN1250-4252
Phone contacts during titration and maintenance 1 (P)
Time shown in site visit flow chart
Protocol 
section
P3-P53
PX
Contact window (days)
± 3
± 5
Criteria for premature discontinuation of trial products
6.4
X
Concomitant medication
8.2.5
X
Concomitant medication (Diabetes)
8.2.6
X
X
Self-measured plasma glucose, Once daily (pre-breakfast)
8.3.1
X
First date on trial product
8.3.2
P3
Dosing
8.3.2
X
New prescribed dose of trial insulin
8.3.2
X
Adverse events 
8.4.1 12
X
X
Hypoglycaemic episodes
8.4.2
X
X
Technical complaints
12.4
X
End of Trial
7
Table 2–4
Flow chart – phone contacts during maintenance 2
NN1250-4252
Phone contacts during maintenance period 2 (P)
Time shown in site visit flow chart
Protocol 
section
P58-P92
PX
Contact window (days)
± 3
± 5
Criteria for premature discontinuation of trial products
6.4
X
Concomitant medication
8.2.5
X
Concomitant medication (Diabetes)
8.2.6
X
X
Self-measured plasma glucose, Once daily (pre-breakfast)
8.3.1
X
Dosing
8.3.2
X
New prescribed dose of trial insulin
8.3.2
X
Adverse events 
8.4.1 12
X
Hypoglycaemic episodes
8.4.2
X
X
Technical complaints
12.4
X
X
End of Trial
7
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
24 of 108
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
Therapeutic area
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance, impaired insulin secretion
and increased hepatic glucose output due to glucagon dysregulation resulting in chronic 
hyperglycaemia3. A number of landmark studies have demonstrated the importance of maintaining 
tight glycaemic control to reduce the risk of long-term complications associated with diabetes4. The 
current treatment cascade follows a stepwise approach comprising lifestyle changes in combination 
with pharmacological intervention. Metformin is recommended as initial pharmacological therapy, 
followed by combination therapy with other oral anti-diabetic drugs (OADs), glucagon-like peptide 
1 receptor agonists (GLP-1) and insulin as the disease progresses5.
Insulin treatment is associated with hypoglycaemia, and fear of hypoglycaemia, especially severe 
hypoglycaemia, is widely acknowledged as the main limiting factor for achieving tight glycaemic 
control. Given the impact on quality of life, the potentially life-threatening consequences of severe 
and nocturnal hypoglycaemia, reducing the risk of hypoglycaemia is critical to the lives of patients.
Information on the hypoglycaemia profile of insulin products is considered an important part of the 
information foundation for health care professionals in considering individualised treatment. Thus it 
is important to compare different insulin analogues in terms of efficacy and safety to be able to 
offer subjects with T2DM in need of insulin treatment the best possible option.
Insulin degludec
Insulin degludec (IDeg) is an insulin analogue with unique pharmacological properties and a long 
duration of action8. IDeg provides similar glycaemic control to comparators with a 14–18% lower 
risk of confirmed hypoglycaemia and a 23–38% lower risk of nocturnal confirmed hypoglycaemia
compared to insulin glargine 100 U/mL (IGlar 100 U/mL) in T2DM (phase 3a trials)6, 7. Moreover, 
in the SWITCH 2 trial (T2DM, phase 3b trial) IDeg was associated with a 23% lower risk of 
overall confirmed symptomatic hypoglycaemia, a 25% lower risk of nocturnal confirmed 
symptomatic hypoglycaemia and a 51% lower risk of severe hypoglycaemia compared to IGlar 
100 U/mL8. The hypoglycaemic risk reduction for IDeg compared to IGlar 100 U/mL was more 
pronounced in the maintenance period in all trials6-8.
IDeg is developed in two strengths (100 U/mL and 200 U/mL) that are bio-equivalent in clinical 
pharmacology trials. IDeg has been approved in more than 70 countries globally and is indicated for 
treatment of diabetes mellitus as monotherapy, in combination with oral anti-diabetic agents and 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
25 of 108
GLP-1, and as part of a basal-bolus insulin regimen in adults and children from the age of 1 year 
(GLP-1 co-usage and paediatric indication <18 years is not an approved indication in all countries
with market authorisation). For further details please refer to the current version of the IDeg 
Investigator’s Brochure (IB)9, of the Tresiba® summary of product characteristics(SmPC)10, U.S. 
Label Information (LI)11 and any updates thereof.
Insulin glargine 300 U/mL
Insulin glargine 300 U/mL (IGlar 300 U/mL), a new long-acting insulin analogue approved in USA,
Canada, EU and Japan, is indicated for treatment of diabetes mellitus as monotherapy, in 
combination with oral anti-diabetic agents and as part of a basal-bolus insulin regimen. The 
development programme established comparable efficacy and safety versus IGlar 100 U/mL12, 13. 
Furthermore, a tendency towards a reduction in the incidence of hypoglycaemia with IGlar 300 
U/mL was found in subjects with T2DM. For further details, please refer to the current version of 
the Toujeo® SmPC14 or local labelling15, 16.
For an assessment of benefits and risks of the trial, see Section 18.1.
3.2
Rationale for the trial
The overall purpose of the trial is to compare the hypoglycaemia profile and the insulin dose 
requirements of IDeg versus IGlar 300 U/mL in subjects with T2DM inadequately controlled on 
basal insulin with or without OADs.
Both IDeg and IGlar 300 U/mL used IGlar 100 U/mL as comparator during the phase 3 
development programme achieving non-inferiority with respect to the glycaemic endpoint measured 
by the reduction in HbA1c from baseline to end of trial. In T2DM patients treatment with IDeg 
showed a consistent hypoglycaemia benefit compared to IGlar 100 U/mL whereas a lower number 
of hypoglycaemic episodes for IGlar 300 U/mL compared to IGlar 100 U/mL was primarily 
observed during the first weeks of treatment13, 17.
IGlar 300 U/mL has a lower bioavailability compared to IGlar 100 U/mL leading to higher mean 
pre-breakfast SMPG values and FPG levels for patients treated with IGlar 300 U/mL compared to 
IGlar 100 U/mL. This is most evident during the first weeks of treatment and makes assessment of a 
possible hypoglycaemic benefit difficult during this time period.
Across the trial programme for IGlar 300 U/mL a 12-17% higher dose usage was needed with IGlar 
300 U/mL to reach the same level of glycaemic control at end of trial compared to IGlar 
100 U/mL12, 18. In the IDeg phase 3a program an overall higher dose of approximately 10% was 
seen for IGlar 100 U/mL compared to IDeg19 and in the SWITCH 2 trial a post hoc analysis 
demonstrated  significantly lower insulin dose with IDeg compared with IGlar 100 U/mL after 32 
weeks of treatment.
The present trial seeks to confirm the safety of IDeg particularly in the assessment of overall, 
nocturnal and severe hypoglycaemic episodes when similar glycaemic control levels have been 
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obtained. Moreover, the trial will provide guidance on insulin dose requirements for achieving 
glycaemic control.
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4
Objective(s) and endpoint(s)
4.1
Objective(s)
Primary objective
To compare the effects of IDeg OD and IGlar 300 U/mL OD on hypoglycaemia in subjects with 
T2DM, inadequately treated with basal insulin with or without OADs.
Secondary objectives
To compare IDeg and IGlar 300 U/mL in terms of basal insulin requirement.
To compare IDeg and IGlar 300 U/mL in terms of safety and parameters of glycaemic control.
4.2
Endpoint(s)
4.2.1
Primary endpoint
!
Number of severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes 
during maintenance 2 (36 weeks)
4.2.2
Secondary endpoints
4.2.2.1
Confirmatory secondary endpoints
!
Basal insulin dose (U) at end of treatment (up to 88 weeks)
!
Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes during 
maintenance 2 (36 weeks
!
Number of severe hypoglycaemic episodes during maintenance 2 (36 weeks )
4.2.3
Other endpoints
Other efficacy endpoints
!
Change in HbA1c from baseline to end of treatment (up to 88 weeks)
!
Change in fasting plasma glucose (FPG) from baseline to end of treatment (up to 88 weeks)
!
FPG ≤ 7.2 mmol/L (130 mg/dL) at end of treatment (up to 88 weeks) (yes/no)
!
FPG ≤ 5 mmol/L (90 mg/dL) at end of treatment (up to 88 weeks) (yes/no)
!
HbA1c < 7% (53 mmol/mol) at end of treatment (up to 88 weeks) and no severe or BG
confirmed symptomatic hypoglycaemic episodes during maintenance 2 (36 weeks ) (yes/no)
!
HbA1c < 7% (53 mmol/mol) at end of treatment (up to 88 weeks) and no nocturnal, severe or 
BG confirmed symptomatic hypoglycaemic episodes during maintenance 2 (36 weeks ) 
(yes/no)
!
Change in mean pre-breakfast self-measured plasma glucose used for titration from baseline 
to end of treatment (up to 88 weeks)
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Other safety endpoints
!
Hypoglycaemia
o
Number of severe or BG confirmed symptomatic hypoglycaemic episodes during 
treatment (up to 88 weeks)
o
Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes 
during treatment (up to 88 weeks)
o
Number of severe hypoglycaemic episodes during treatment (up to 88 weeks)
!
Number of adverse events during treatment (up to 88 weeks)
!
Change in clinical evaluations from baseline to end of treatment (up to 88 weeks) in terms 
of:
o
Vital signs (including blood pressure and pulse)
o
Dilated fundoscopy or fundus photography
o
Electrocardiogram (ECG)
!
Change in body weight from baseline to end of treatment (up to 88 weeks)
!
Change in central laboratory assessments from baseline to end of treatment (up to 88 weeks)
in terms of
o
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes)
o
Biochemistry (creatinine, alanine aminotransferase , aspartate aminotransferase , 
alkaline phosphatase , sodium, potassium, albumin, total bilirubin)
!
Special laboratory assessment during treatment (up to 88 weeks)in terms of
o
Anti-insulin antibodies
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5
Trial design
5.1
Type of trial
This is a up to 88-week, randomised (1:1), open-label, parallel, multi-centre, multi-national, treat-
to- target, active controlled trial comparing efficacy and safety of IDeg 200 U/mL with IGlar 300
U/mL both administered OD ± OADs in subjects with T2DM previously treated with basal insulin 
OD or twice daily (BID) ± OADs excluding sulfonylureas/glinides. Type and dose of any pre-trial 
OAD treatment should remain unchanged throughout the trial.
The trial design is summarised schematically in Figure 5–1. The total trial duration will be up to 94
weeks divided into the following periods:
!
Screening up to two weeks
o
Screening (V1)
o
Randomisation (V2)
!
Treatment period consisting of
o
A 16-week titration period
o
An up to 36-week maintenance 1 period
o
A 36-week maintenance 2 period
!
30 days post treatment follow-up period including two follow-up (FU) contacts
o
FU1  7-12 days after end of treatment
o
FU2 30-35 days after end of treatment
Total treatment period up to 88 weeks
-2                         0                                                                                                  
                         Up to 94 weeks
IDeg 200 U/mL OD ± OADsa
IGlar 300 U/mL OD ± OADsa
Randomisation 1:1 
(morning or evening)
Wash out 1 week for 
antibody measurements
V1                       V2                          V18                  Maintenance 1                       V54  V55 (FU1)     V56 (FU2)
                                                           V57                  Maintenance 2                       V93  V94 (FU1)     V95 (FU2)
Screening
(≤ 2 weeks)
Up to 36 weeks maintenance 1 
+ 36 weeks maintenance 2
Follow-up
(minimum 30 days to FU 2)
16 weeks 
titration
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aOral Anti-diabetic Drugs (OADs): Metformin, Dipeptidyl peptidase-4 inhibitor, Sodium-glucose co-transporter 2 
inhibitor, Alpha-glucosidase-inhibitors (acarbose), Thiazolidinediones, marketed oral combination products only 
including the products listed in inclusion criteria 5a-5e.
IDeg: insulin degludec, IGlar: insulin glargine, OD: once daily, FU: follow-up, EOT: End of Treatment
Figure 5–1
Trial design
5.2
Rationale for trial design
In this trial an open-labelled trial design is chosen to minimize inconvenience for the subjects since 
a blinded trial due to different pen injector systems would require a double dummy approach.
Subjects with recent severe and non-severe hypoglycaemia, hypoglycaemia symptom unawareness, 
moderate chronic renal failure, or long-term insulin treatment are eligible to participate in this trial. 
Thus, this trial includes a broader population of subjects, compared to previous phase 3a trials with 
IDeg.
For subjects randomised to IDeg OD, the daily basal insulin dose should be reduced by 20% from 
pre-trial dose.
Subjects randomised to IGlar 300 U/mL should switch unit-to-unit, if they prior to randomisation 
received basal insulin once daily. For subjects that prior to randomisation received a BID basal 
insulin regimen, the following applies:
!
US subjects that prior to randomisation received a BID basal regimen with Neutral 
Protamine Hagedorn (NPH) insulin should have their total daily NPH dose reduced by 20% 
and given once daily.
!
US subjects that prior to randomisation received a BID basal regimen with other basal 
insulin types should have their total daily basal insulin dose added up and injected once 
daily.
!
EU subjects that prior to randomisation received a BID basal regimen with any basal insulin 
type should have their total daily basal insulin dose reduced by 20% and given once daily.
The basal insulin IDeg and IGlar 300 U/mL will be administered in the morning (from waking up to 
breakfast) or in the evening (from main evening meal to bedtime), as per randomisation and should 
be taken at the same time of day throughout the trial.
The 1:1 randomisation to morning or evening dosing of the basal insulin is applied to avoid any 
confounding from injection time on a particular time interval (such as nocturnal) during which 
subjects would be at highest risk of hypoglycaemic episodes.
The trial is conducted with a treat-to-target principle: the insulin dose is adjusted for each individual 
subject with the aim of achieving identical glycaemic targets for IDeg and IGlar 300 U/mL. This 
allows for a valid comparison of safety endpoints such as hypoglycaemia.
Due to an unusual data reporting pattern of hypoglycaemia and glycaemic values being linked to the 
glycaemic data collection system (the combined use of MyGlucoHealth with the electronic diary) it 
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was decided on 13 February 2018 to apply a new data collecting system consisting of an Abbott 
BG-meter and a paper diary.
To accommodate changes in the data collection system and to ensure sufficient data collection with 
respect to the confirmatory endpoints a new maintenance period (maintenance 2) of 36 weeks 
duration was included in the trial.
5.3
Treatment of subjects
Insulin treated subjects with T2DM can enter the trial if they present with an HbA1c equal to or 
below 9.5% (80 mmol/mol) and have been treated with basal insulin for ≥ 90 days prior to the day 
of screening (V1) with or without OADs (metformin, DPP-4i, SGLT2i, thiazolidinedione, alpha-
glucosidase-inhibitors or marketed oral combination products only including the products listed in 
inclusion criteria 5a-5e), at stable doses for ≥ 90 days prior to V1.
Pre-trial treatment with IDeg or IGlar 300 U/mL is not allowed within 90 days prior to the 
screening visit. Any previous use of bolus insulin, insulin pump or pre-mix insulin excludes 
subjects from the trial, as well as use of any GLP-1 receptor agonist (e.g., exenatide or liraglutide) 
or SU/glinides, all within the 90 days prior to the screening visit.
At randomisation (V2) subjects who met all inclusion criteria and no exclusion criteria will be 
randomly allocated 1:1 into one of two treatment arms:
!
IDeg -200 U/mL OD ± OADs
!
IGlar -300 U/mL OD ± OADs
Within each treatment arm, subjects will be randomised 1:1 to morning (from waking up to 
breakfast) or evening dosing (from main evening meal to bedtime). The dosing time will be kept 
throughout the entire treatment period.
Following randomisation pre-trial insulin treatment must be discontinued and the subject switched 
to randomised treatment.
Type and dose of any pre-trial OAD treatment should remain unchanged throughout the trial and 
subjects should continue pre-trial OAD treatment from screening (V1) to end of treatment (V54 or 
V93), unless for safety reasons.
The maximum duration of treatment will be 88 weeks. No maximum trial insulin dose is specified. 
Doses are adjusted according to plasma glucose values (see titration guideline; Appendix A).
Surveillance of insulin titration will be performed by Novo Nordisk.
At end of treatment (V54 or V93) all subjects will be switched to insulin NPH for at least one week 
to ensure that all IDeg/IGlar is washed out when measuring anti-insulin antibodies.
After End of treatment each subject will have a 30-day safety follow-up period including two 
follow-up contacts (FU1 and FU2).
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FU1 (V55 or V94) will be at least 7 days after end of treatment (V54 or V93). The purpose is to 
collect all treatment emergent adverse events (AEs) including hypoglycaemia and antibody 
samples.
FU2 (V56 or V95) will be at least 30 days after end of treatment (V54 or V93). The purpose is to 
collect information on anti-diabetic medication and AEs including hypoglycaemia occurring in the 
period between the two follow-up contacts.
All trial products and insulin NPH are administered subcutaneously and should be injected in the 
thigh, upper arm or abdomen. The injection areas should be consistent throughout the trial, however 
rotation of injection sites within the area is recommended.
For both treatment arms diet and exercise counselling is continued as per the standard of care at the 
investigational site.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end of treatment visit or if trial product is 
discontinued prematurely, the subject will be instructed to switch insulin treatment to the 
intermediate acting insulin NPH until the first follow-up visit FU1. At FU1 the subject should be 
switched to a suitable marketed product at the discretion of the investigator. Doses of subsequent 
anti-diabetic treatment should be carefully titrated based on blood glucose measurements, 
considering the long half-life of IMPs.
5.5
Rationale for treatment
The treat-to-target design and consequent visit schedule is used in order to ensure optimal insulin 
titration based on self-measured plasma glucose (SMPG) values and to ensure improvement in 
glycaemic control. The 16 week titration period is applied to ensure optimal time to achieve 
improved and stable HbA1c for both treatments before entering maintenance period 1. The second 
maintenance period is applied to obtain sufficient data for efficacy and safety evaluation after 
including the new data collecting system.
The switch from trial insulin treatment to the ‘washout’ insulin (NPH) between the end of treatment 
visit (V54 or V93) and the 7-day follow-up visit (FU1), is done in order to provide basal insulin 
coverage while reducing the level of IDeg/IGlar present at antibody sampling and consequently to 
reduce the possibility for interference with antibody measurements.
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6
Trial population
6.1
Number of subjects
Number of subjects planned to be screened: 2,271
Number of subjects planned to be randomised: 1,590
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”.
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial.
2. Male or female, age above or equal to 18 years at the time of signing informed consent.
3. Subjects fulfilling at least one of the below criteriaa:
a.
Experienced at least one severe hypoglycaemic episode within the last year 
(according to the ADA definition, April 2013b)
b. Moderate chronic renal failure, defined as glomerular filtration rate 30 - 59 
mL/min/1.73 m2 per CKD-EPI20, 21 by central laboratory analysis
c.
Hypoglycaemic symptom unawarenessc
d. Treated with insulin for more than 5 years
e.
Episode of hypoglycaemia (defined by symptoms of hypoglycaemia and/or episode 
with low glucose measurement (≤ 70 mg/dL [≤ 3.9 mmol/L])) within the last 12 
weeks prior to Visit 1(screening)
4. Subjects diagnosed with type 2 diabetes mellitus.
5. Treated with basal only insulin (once daily or twice-daily insulin (insulin detemir; insulin 
glargine 100 U/mL, biosimilar of insulin glargine 100 U/mL or NPH)) ≥ 90 days prior to the 
day of screening with or without any of the following anti-diabetic drugs/regimens with 
stable doses for ≥ 90 days prior to screening:
a.
Metformin
b. Dipeptidyl peptidase-4 inhibitor
c.
Sodium-glucose co-transporter 2 inhibitor
d. Alpha-glucosidase-inhibitors (acarbose)
e.
Thiazolidinediones
f.
Marketed oral combination products only including the products listed in criteria 5a-
5e
6. HbA1c ≤ 9.5% (80 mmol/mol) at screening by central laboratory analysis.
7. BMI ≤ 45 kg/m2.
8. Ability and willingness to adhere to the protocol including self-measurement of plasma 
glucose according to the protocol.
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aFor inclusion criterion 3 the aim is to include minimum 80% of individuals with a previous episode
of hypoglycaemia (3e). The remaining subjects will have to fulfil at least one of criteria a-d.
bAn 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.
cHistory of impaired autonomic responses (tremulousness, sweating, palpitations, and hunger) 
during hypoglycaemia.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”.
1. Acute impairment of glycaemic control requiring immediate intensification of treatment to 
prevent severe metabolic dysregulation (e.g. diabetes ketoacidosis) ≤90 days prior to the 
day of the screening.
2. Known or suspected hypersensitivity to trial product(s) or related products.
3. Previous participation in this trial. Participation is defined as signed informed consent.
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measure 
as required by local regulation or practice).
For Denmark: Contraceptive measures considered adequate include:
a.
intrauterine devices or hormonal contraception (oral contraceptive pills, implants, 
transdermal patches, vaginal rings or long-acting injections)
For Estonia: Contraceptive measures considered adequate include:
a.
double barrier method (a combination of male condom with either cap, diaphragm or 
sponge with spermicide)
For Germany: The following contraceptive measures are considered adequate: 
a.
combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, transdermal or intravaginal)
b. progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable or implantable)
c.
intrauterine device
d. intrauterine hormone-releasing system
e.
sexual abstinence
f.
vasectomised partner
g. double barrier method (a combination of male condom with either cap, diaphragm or 
sponge with spermicide)
5. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product (IMP) within 30 days prior to screening.
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6. Any of the following: myocardial infarction, stroke or hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and between 
screening and randomisation.
7. Subjects presently classified as being in New York Heart Association (NYHA) Class IV.
8. Planned coronary, carotid or peripheral artery revascularization known on the day of 
screening.
9. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
<30 mL/min/1.73 m2 as defined by KDIGO 2012 classification22 using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening.
10. Impaired liver function, defined as ALT or AST ≥2.5 times upper limit of normal at 
screening.
11. Inadequately treated blood pressure as defined as Grade 3 hypertension or higher (Systolic 
≥180 mmHg or diastolic ≥110 mmHg) at screening.
12. Treatment with any medication for the indication of diabetes or obesity ot her than stated in 
the inclusion criteria within the past 90 days prior to the day of screening.
13. Anticipated initiation or change in concomitant medications (for more than 14 consecutive 
days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid 
hormones, or corticosteroids).
14. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation.
15. Presence or history of malignant neoplasms within the last 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinomas in-situ are allowed.
16. Any condition, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
6.4
Criteria for premature discontinuation of trial product
Efforts should be made so that subjects attend and complete all scheduled visit procedures. Subjects 
should stay in the trial irrespective of lack of adherence to randomised treatment, lack of adherence 
to visit schedule or missing assessments. Only subjects who decline any further contact with the site 
in relation to the trial will be considered as withdrawn from the trial (see Section 6.5).
The subject may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
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The subject must be prematurely discontinued from trial product if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria.
2. Pregnancy.
3. Intention of becoming pregnant.
4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
5. Initiation of concomitant medication(s) for more than 14 calendar days, which in the 
investigator’s opinion could affect weight or glucose metabolism.
6. Lack of efficacy; if all of the fasting SMPG values taken on three consecutive days or if any 
of the FPG samples analysed by the central laboratory exceeds the limit of:
a.
13.3 mmol/L (240 mg/dL) from visit 18 to visit 26 (both inclusive)
b. 11.1 mmol/L (200 mg/dL) from visit 26 (not included) to visit 54 or visit 93
(included)
and if no treatable intercurrent cause for the hyperglycaemia has been identified, the subject 
must be called for a confirmatory FPG measurement at a scheduled or unscheduled visit as 
soon as possible. A confirmatory FPG must be obtained and analysed by the central 
laboratory. If this FPG exceeds the limits described above, the trial product must be 
discontinued.
See Section 8.1.9 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.5
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected.
If the subject considers withdrawing consent the investigator must underline to the subject the 
importance of continuing in the trial despite trial product discontinuation. If the subject agrees to 
discontinue trial products but to stay in the trial, procedures described in section 8.1.9 must be 
followed.
Only subjects who decline any further contact with the site in relation to the trial, and hence do not 
agree to provide information concerning morbidities, which are relevant for the assessment of AEs 
and/or other trial endpoints at the planned end of trial, should be withdrawn from trial.
See Section 8.1.10 for procedures to be performed for subjects withdrawing consent.
A subject will be considered lost to follow-up if he/she repeatedly fails to attend the scheduled visits 
and the Investigator is unable to establish contact with the subject.
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The following actions must be taken in relation to a subject who fails to attend the site for a 
required visit:
!
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible.
!
The site must re-train the subject in the importance of maintaining the scheduled visits.
!
In cases in which the subject is deemed lost to follow-up the investigator must make every 
effort to regain contact with the subject (e.g. telephone calls to friends or family members, e-
mails or certified letter to the subject as applicable). These contact attempts must be 
documented in the subject’s medical records. Should the subject continue to be unreachable, 
only then will he/she be considered to have withdrawn from the trial with the primary reason 
being “lost to follow-up”.
6.6
Subject replacement
Subjects who discontinue trial product prematurely will not be replaced.
6.7
Rationale for trial population
A population of insulin-treated subjects with T2DM presenting with an HbA1c equal to or below 
9.5% while treated continuously with basal insulin with or without OADs for at least 90 days and 
who recently have experienced hypoglycaemia or have increased risk of severe hypoglycaemia has 
been chosen for this trial. This population reflects a general T2DM population qualifying for 
optimisation of basal insulin treatment. The trial is not excluding individuals at high risk of 
developing hypoglycaemia making the population generalizable for the T2DM population. Subjects 
requiring treatment with basal bolus are not included to avoid the confounding element of bolus 
insulin. Treatment with SUs/glinides and insulin in combination creates an increased risk of 
hypoglycaemia, and therefore, SU/glinides are not allowed as pre-trial, and subsequently trial 
treatment.
A BMI ≤ 45.0 kg/m2 was chosen to include as broad a population as possible, while excluding 
severely insulin resistant subjects in order to secure a rather homogenous population with regard to 
insulin needs.
The inclusion and exclusion criteria applied in this trial should ensure relevance of trial results for a 
broad population of subjects with T2DM.
The 20% reduction of IDeg when transferring from pre-trial insulin regimen, is to reduce the risk of 
subjects experiencing hypoglycaemia in the initial treatment phase and to secure equal and 
comparable levels of glycaemic control initially, given that IGlar 300 U/mL has a known lower 
potency compared to IGlar 100 U/mL and hence also IDeg.
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7
Milestones
Planned duration of recruitment period, which is from first patient first visit ( FPFV) – last patient 
first visit (LPFV): 24 weeks.
End of trial is defined as last patient last visit (LPLV).
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects screened during the recruitment period 
and found eligible for randomisation can be randomised within the timelines specified in the flow 
chart, see Section 2.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure23 it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)24, the Food and Drug Administration Amendment Act25, European 
Commission Requirements26, 27 and other relevant recommendations or regulations. If a subject 
requests to be included in the trial via the Novo Nordisk e-mail contact at these web sites, Novo 
Nordisk may disclose the investigator’s contact details to the subject. As a result of increasing 
requirements for transparency, some countries require public disclosure of investigator names and 
their affiliations.
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8
Methods and assessments
8.1
Visit procedures
Timing of assessments and procedures are specified in the flow chart (see Section 2). This section 
includes a description.
Informed consent must be obtained before any trial related activity, see Section 18.2.
8.1.1
Screening visit (Visit 1)
The subjects will attend a screening visit in order to assess eligibility.
Before any trial-related activity, the investigator must give the subject oral and written information 
about the trial in a form that the subject can read and understand. The informed consent process 
must be completed before any trial-related activity.
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 will be obtained 
from the subject before any trial-related activity. The responsibility for seeking informed consent 
must remain with the investigator, but the task may be delegated by the investigator to a medically 
qualified person, in accordance with local requirements. The informed consent form must be signed 
and personally dated by the person who seeks the informed consent.
The investigator should inform the subject's primary physician about the subject's participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. The informed consent will include permission for the investigator to obtain 
information from the subject and/or from his/her primary physician or other healthcare professional 
/next of kin on vital status. The consent will include that this information can be obtained until trial 
completion even if the subject stops the investigational products and/or trial procedures 
prematurely.
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirements and adhere to ICH GCP1 and the Declaration of Helsinki2.
The date of informed consent must be transcribed to the eCRF.
If information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial, the investigator must inform the subject in a timely manner, and a revised 
written informed consent must be obtained.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy it after the last visit.
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Date:
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Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial. The first 3 digits indicate the site number and the last 3 digits are unique for the 
subject.
A screening session must be performed in the IWRS, see Section 10.
All assessments related to the inclusion and exclusion criteria must be performed. If any inclusion 
criterion is answered “no” or any exclusion criterion answered “yes”, the subject is a screening
failure and no further assessments should be done. Please refer to the flow chart in section 2 for the 
full list of assessments and procedures to be performed at this visit.
In- or exclusion criteria cannot not be ticked “Yes” or “No” in the electronic case report form 
(eCRF) before source data is available. In this case “Result pending” must be chosen. This is 
particularly relevant for lab samples and in some cases the ECG and eye examination result. 
Subjects cannot be randomized until all results are available.
The subject has to complete the Baseline Hypo Questionnaire at the screening visit.
8.1.1.1
Screening failures
For screening failures the screening failure form in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events from screening failures must be transcribed by the 
investigator into the eCRF. Follow-up on serious adverse events (SAEs) must be carried out 
according to Section 12.
A screening failure session must be made in the IWRS. When data has been monitored and queries 
have been resolved the case book must be signed.
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria, this 
includes re-sampling if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters. Re-sampling is allowed in case the sample is haemolysed, leaked during 
transit etc.
8.1.2
Randomisation visit (V2)
All screening including laboratory results must be available and reviewed and the subject confirmed 
eligible before randomisation can take place. Randomisation should take place as soon as trial 
products are available on site and no later than 14 days after screening visit. A randomisation 
session must be performed in IWRS; see Section 10 and trial product must be dispensed.
The Investigator should record the following in the eCRF:
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Date:
23 February 2018
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Trial ID: NN1250-4252
Version:
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Status:
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!
Last date on pre-trial insulin
!
Total dose of pre-trial insulin administered within the last 24 hours
!
Frequency of pre-trial insulin injections
!
First date on trial product (registered at P3)
!
First dose of trial product (registered at P3)
!
Time point of trial product administered (morning or evening as specified by IWRS)
The subject must attend randomisation visit fasting. For definition of fasting, please see Section 
8.1.4.
At randomisation baseline laboratory values of HbA1c and anti-insulin antibodies will be taken. 
Please refer to the flow chart in section 2 for the full list of assessments and procedures to be 
performed at this visit.
A BG meter and an electronic diary (eDiary) must be provided to the subjects at V2. Subjects must 
be trained in the use of the BG meter. A practice eDiary must be completed before the eDiary can 
be used. Subject must be instructed that entries must be made according to the protocol, see Section 
8.3.1, 8.3.2 and 8.4.2 and instructions provided.
8.1.3
Phone contacts
Before any phone contact, both the Investigator and subject should agree on the timing and 
direction of the call. The Investigator remains responsible for ensuring that the phone contacts occur 
even if it is agreed that the subject should call the site.
A phone contact may be converted to a site visit if needed. For scheduled phone contacts and their 
time points; see Section 2.
8.1.4
Fasting visits
The subjects must attend the visits specified in section 2 in a fasting condition. Fasting is defined as 
at least eight hours without drink or food intake prior to the visit except for water.
No diabetes treatment (neither trial insulin, nor any OADs) is allowed up to eight hours prior to the
blood sampling. Non-anti-diabetic medication is still allowed to be taken.
If a subject attends the visit non-fasting, then the subject’s blood samples should be re-scheduled 
preferable within the next two working days. If blood sampling has already been done before 
realising the subject was not fasting, only the FPG needs to be re-drawn.
8.1.5
Maintenance 2 initiation visit (V57)
As soon as the new glycaemic data collection system (an Abbott BG-meter and paper diary) is 
available all subjects should come for a maintenance 2 initiation visit (V57) to enter maintenance 2
(Table 2–2) irrespectively of their current visit in maintenance 1. Subjects should not complete all 
the maintenance 1 visits.
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Date:
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Trial ID: NN1250-4252
Version:
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Status:
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Subjects who discontinued trial drug treatment prematurely during titration or maintenance 1 can 
enter maintenance 2 off treatment and continue to follow the abbreviated visit schedule as specified 
in section 8.1.9. These subjects should come for a maintenance 2 initiation visit (V57A) to enter 
maintenance 2 (Table 2–2) irrespectively of their current visit maintenance 1. Subjects should not 
complete all the maintenance 1 abbreviated visits.
At V57 the subject should stop using their own BG meter.
An Abbott BG meter and a diary must be provided to the subject. The subject must be trained in the 
use of the BG meter and instructed that entries must be made in the diary according to Section 8.3.1
and the instructions provided
8.1.6
End of Treatment visit (V54 or V93)
Subjects entering maintenance 2 should attend the V93 End of Treatment visit.
Subjects who do not re-consent to enter the maintenance period should attend the V54 End of 
Treatment visit as soon as possible.
At the end of treatment visit (V54 or V93) the treatment with trial product must be stopped and the 
subjects will be instructed to switch insulin treatment to the intermediate acting insulin NPH until 
the first follow-up visit (FU1). A completion session must be performed in IWRS, see Section 10.
NPH will be dispensed as part of the completion session.
Last date on the randomised trial product (basal insulin) must be recorded in the eCRF.
Since NPH insulin is an intermediate acting insulin, it should be administered twice daily. To 
determine the dose of insulin NPH to be taken during the follow-up period, the total daily basal 
dose at end of the treatment period should be reduced by 20% and divided into two doses; one to be 
administered in the morning and one in the evening.
Date and dose of first injection of insulin NPH must be recorded in the eCRF.
Please refer to the flow chart in section 2 for the full list of assessments and procedures to be 
performed at this visit.
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CONFIDENTIAL
Date:
23 February 2018
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Trial ID: NN1250-4252
Version:
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Status:
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8.1.7
Follow up visits
Subjects entering maintenance 2 should attend:
!
FU1 (V94) a site visit which must take place 7-12 days after the end of treatment visit (V93)
!
FU2 (V95) a site visit which must take place 30-35 days after the end of treatment visit 
(V93)
Subjects who do not re-consent to enter maintenance 2 should attend:
FU1 (V55) a site visit which must take place 7-12 days after the end of treatment visit (V54)
FU2 (V56) a site visit which must take place 30-35 days after end of treatment (V54)
Follow-up visit FU1 (V55 or V94)
At the first follow up visit (V55 or V94) treatment with insulin NPH must be stopped.
The following data will be collected:
!
Date and dose of last injection of insulin NPH
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Technical complaints
!
Antibody sample
Please refer to the flow chart in section 2 for the full list of assessments and procedures to be 
performed at this visit.
Follow-up visit FU2 (V56 or V95)
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
8.1.8
Unscheduled site visits
If the subject attends the clinic outside the visit schedule, an unscheduled visit form in the eCRF 
should be completed. An unscheduled visit form should not be completed if the subject attends the 
clinic only to obtain additional trial supplies or for re-scheduled visits.
If more trial product is needed an additional dispensing session in the IWRS must be performed.
If blood resampling is needed the laboratory requisition form must be completed with the visit 
number to which the sample belongs.
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Date:
23 February 2018
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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8.1.9
Premature discontinuation of trial product
If a subject prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for the end of treatment visit (V54 or V93) as soon as possible including fasting 
blood sampling and dispensing of wash-out insulin NPH, see Section 8.1.6.
Treatment discontinuation must be performed in IWRS.
Furthermore two follow up visits similar to FU1 and FU2 must be performed 7-12 and 30-35 days
after discontinuation of trial product, respectively.
Subjects who discontinued trial drug treatment prematurely during titration or maintenance 1 should 
come for an abbreviated maintenance 2 initiation visit (V57A) to enter maintenance 2 (Table 2–2) 
irrespectively of their current visit. Subjects should not complete all the maintenance 1 abbreviated.
Follow-up visit FU1 (V55 or V94)
At the first follow up visit (V55 or V94) the subject should be switched to treatment with a suitable 
marketed product at the discretion of the investigator.
The following data will be collected:
!
Date and dose of last injection of insulin NPH prior to V55
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Technical complaints
!
Antibody sample
Follow-up visit FU2 (V56 or V95)
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
In addition, subjects prematurely discontinued from trial product should come in for abbreviated 
site visits:
!
V69A
!
V81A
The abbreviated site visits can be converted to phone contacts if needed.
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CONFIDENTIAL
Date:
23 February 2018
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Trial ID: NN1250-4252
Version:
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UTN: U1111-1184-8175
Status:
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The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Blood sample to measure HbA1c (only if site visit)
In between the abbreviated site visits listed above monthly phone contacts (PX visits) should be 
performed until the originally planned end of treatment.
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
The earliest of the abbreviated site visits or monthly phone contacts (whichever comes first) should 
be scheduled at least 30 days after FU2. If the timing of a monthly phone contact (PX visit) is less 
than two weeks from a planned abbreviated site visit, the phone contact can be omitted.
Subjects prematurely discontinued from trial products should come in for a final visit (V93A) at the 
originally planned end of treatment date to collect:
!
Date and dose of basal insulin
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Blood sample to measure HbA1c
The primary reason for premature discontinuation of trial product must be specified in the End-of-
Treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
8.1.10
Withdrawal from trial
If a subject withdraws consent, the investigator should aim to undertake procedures similar to those 
for the end of treatment visit (V54 or V93) as soon as possible.
If the subject agrees, the follow up visits (FU1 and FU2) must be performed 7-12 and 30-35 days 
after discontinuation of trial product.
The End-of-Treatment and End of Trial forms must be completed, and final drug accountability 
must be performed even if the subject is not able to come to the trial site. A treatment 
discontinuation session must be made in IWRS. The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
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Date:
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Trial ID: NN1250-4252
Version:
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Status:
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Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the End-of-Trial form in the eCRF.
Subjects withdrawing consent during the follow up period will be considered as completers.
8.1.11
Review of results
Review of ECG results, eye examination report, laboratory reports, data entered in the diaries, etc. 
must be documented either on the documents, printouts  or in the subject’s medical record.
If clarification of entries or discrepancies in the diary is needed, the subject must be questioned and 
a conclusion made in the subject’s medical record. Care must be taken not to bias the subject.
8.2
Subject related information/assessments
8.2.1
Demography
Demography will be recorded at screening, unless not permitted by local regulations, and consists 
of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Diabetes history
Diabetes history will be recorded at screening and consists of:
!
Date of diagnosis of type 2 diabetes
8.2.3
Hypoglycaemia unawareness
Information on hypoglycaemia unawareness will be recorded at screening according to Clarke’s 
questionnaire, question 828.
The investigator must ask the subject in the following way: “To what extent can you tell by your 
symptoms that your blood glucose is low?” The subject can answer never, rarely, sometimes, often 
or always.
Subjects answering ‘never, rarely or sometimes’ are considered as having impaired awareness of 
hypoglycaemia.
8.2.4
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit (V1)) 
or found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product.
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CONFIDENTIAL
Date:
23 February 2018
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Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
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Date of diagnosis of type 2 diabetes should be reported separately in the Diabetes History Form in 
the eCRF.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history as judged by the investigator should be reported.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.5
Concomitant medication
A concomitant medication is any medication, other than the pre-trial insulin, trial products and 
OADs, which is taken during the trial, from the screening visit (V1) until end of treatment (V54 or 
V93).
Details of any concomitant medication must be recorded at V1. Changes in concomitant medication 
must be recorded at each visit as they occur.
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.6
Concomitant medication (Diabetes)
Any diabetes medication other than the trial product(s) which is taken during the trial, from the 
screening visit (V1) until FU2 (V56 or V95) must be recorded in a separate concomitant medication 
(diabetes) form in the eCRF.
At V1 the pre-trial insulin and pre-trial OADs must be recorded including:
!
Trade name or generic name
!
Total daily dose
!
Start date
!
Stop date or continuation
For subjects treated with OADs it is the start date and dose of latest stable OAD dose which should 
be reported.
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Date:
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Trial ID: NN1250-4252
Version:
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Status:
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At the randomisation visit (V2) pre-trial insulin must be discontinued and a stop date recorded in 
the eCRF. For subjects treated with OADs, the investigator should at each weekly contact (V2 until 
V55 or V94), confirm with the subject that dose and frequency of OADs has been unchanged. This 
should be documented in the medical records.
8.2.7
Childbearing potential
It must be recorded in the eCRF whether female subjects are of childbearing potential. Reason for 
not being of childbearing potential must be documented in the medical records.
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.2. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 1 week after end of treatment.
Female of non-childbearing potential is defined as:
!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation
!
Postmenopausal defined as no menses for 12 months without an alternative medical cause
!
Other medical reasons preventing childbearing potential
8.2.8
Tobacco use
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily.
Smoking status:
!
Never smoked
!
Previous smoker
!
Current smoker
8.3
Efficacy assessments
8.3.1
Self-measured plasma glucose
At V2, subjects will be provided with a BG meter including auxiliaries as well as instructions for 
use. The subjects will be instructed in how to use the device.
As soon as the new glycaemic data collection system (an Abbott BG-meter and paper diary) is 
available the subject should come for a V57 or V57A to enter maintenance 2 (Table 2–2).
At V57 or V57A subjects will be provided with a new glycaemic data collection system.
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display.
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CONFIDENTIAL
Date:
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Trial ID: NN1250-4252
Version:
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Status:
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Only the BG meter provided by Novo Nordisk should be used for the measurements required in the 
protocol.
Subjects must be instructed to measure their pre-breakfast SMPG daily from V57 to End of 
Treatment (V93).
Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time point and value. All 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 must be corrected.
Occasional review by the investigator of the values stored in the memory of the blood glucose meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the trial database.
8.3.2
Insulin dose
After applying the new glycaemic data collection system at V57 the subjects should be instructed to 
report date, dose and time point of basal insulin in the diary on a daily basis.
The recommended insulin doses will be calculated in the eCRFon recommendations from the 
Insulin Titration Guideline (see Appendix A). At each visit/phone contact the Investigator will 
titrate the subjects by making prescribed dose adjustments based on the recommendation from the 
eCRF if applicable.
The subject should report the following in the diary:
!
Date, dose and time of trial basal insulin daily
The Investigator should record the following in the eCRF:
!
Prescribed doses of trial products
!
Reason for deviating in dose adjustments from the titration guideline
!
Actual daily dose of trial product including injection time
!
Last date on trial product
!
Last dose of trial product
8.4
Safety assessments
All safety assessments are outlined in the flow chart in section 2.
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the concomitant illness form if it is present at screening. Any new abnormal, clinically significant 
finding during the trial and any clinically significant worsening from baseline must be reported as 
an AE.
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Date:
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Version:
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8.4.1
Adverse events
During each contact (site visits and phone contacts) the subject must be asked about AEs and 
technical complaints, for example by asking: "Have you experienced any problems since the last 
contact?" This must be documented in the subject’s medical record. AEs must be reported at each 
visit in accordance with the procedures outlined in Section 12.
8.4.1.1
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form:
!
Trial product(s) involved
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error
!
Suspected primary reason for the medication error
For definition of medication errors, see Section 12.1.4.
8.4.1.2
Adverse events requiring additional data collection
For some AEs additional data collection is required and specific event forms must be completed in 
the eCRF in addition to the AE form.
In case any of these events fulfil the criteria for a serious adverse event, please report accordingly, 
see Section 12.
Acute coronary syndrome
If an event of Acute Coronary Syndrome (ranging from unstable angina pectoris to myocardial 
infarction) is observed during the trial the following additional information must be reported if 
available on the acute coronary syndrome form:
!
Duration of symptoms
!
Changes in ECG
!
Collection of cardiac biomarkers
!
Cardiac imaging
!
Cardiac stress testing
!
Angiography
!
Use of thrombolytic drugs
!
Revascularisation procedures
Cerebrovascular events
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Date:
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Version:
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If a cerebrovascular event (e.g. transient ischaemic attack (TIA), stroke, and haemorrhage) is 
observed during the trial the following additional information must be reported if available on the 
cerebrovascular event form:
!
Type of event (e.g. TIA, Stroke)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the event
!
Treatment given for the event
Neoplasm
All events of benign, pre-malignant/carcinoma in-situ and malignant neoplasm must be reported 
during the trial and the following additional information should be obtained if available as part of 
standard of care on the neoplasm form:
!
Type of neoplasm
!
Symptoms and laboratory results leading to identification of event
!
Diagnostic imaging
!
Pathological examination (outcome and staging)
!
Treatment given for the event
!
Participation in screening programs
!
Relevant risk factors associated to the event
Events for adjudication
Severe hypoglycaemia or hypoglycaemic episodes reported as an SAE and all fatal events will be 
subject to external independent adjudication. For these AEs a (hypoglycaemia) Adjudication Form 
must be completed in the eCRF. For detailed information on event adjudication, please refer to 
Section 12.7.2.
8.4.2
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below throughout the trial from visit 2
to the End of Trial visit (V56 or V95).
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Date:
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Trial ID: NN1250-4252
Version:
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Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance to current guidelines29.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 min after onset on a hypoglycaemic episode, will by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is >3.9 
mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form. SMPG measurements ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic 
symptoms after the 60 min period shall trigger the reporting of a new hypoglycaemia episode and 
prompt the subject to fill out a new hypoglycaemic episode form until a succeeding measurement is 
>3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.
In case of several low SMPG values within the 60 minutes interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
!
Start date and time of the hypoglycaemic episode
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No)
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if 
the subject experiences symptoms later during the episode. 
!
Whether the subject was able to treat him/herself
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode 
should be reported reflecting the most severe degree of hypoglycaemia. 
!
Date, time and dose of last trial product administration prior to the episode
!
Date and time of last main meal (not including snacks) prior to the episode
!
Whether the episode occurred in relation to physical activity
!
Whether the episode related  to a change in a pre-existing disease
!
Any sign of fever and/or other acute disease
!
Whether the subject was asleep when the episode occurred
o
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
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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 concentration29.
Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-
medical person)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose 
or other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, 
medication error (i.e. overdose, mix-up between products, incorrect use of device), 
miscalculation of dose of anti-diabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms30 (layman term used in the diary 
is specified in brackets if different from the protocol term)?
o
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
o
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate 
movement)
o
General malaise: headache or malaise (feeling discomfort/unease)
!
Other symptoms.
The investigator must review the diary data for low SMPG values not reported as hypoglycaemic 
episodes. The subject must be questioned whether any of the low values were severe, i.e. whether
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported 
as a severe hypoglycaemic episode.
All hypoglycaemic episodes 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 must be corrected.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value, if any symptoms were present and 
whether the subject was able to self-treat due to decreased validity of such data31, 32.
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The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form, a safety information 
form and an adjudication form must also be filled in, see Section 12.
8.4.3
Body measurements
Body weight should be measured in kilogram (kg) or pounds (lb) without coat and shoes wearing 
only light clothing. Body weight will be recorded to one decimal. The body weight should be 
assessed on the same weighing scale equipment throughout the trial, if possible.
Height should be assessed without shoes. Height is measured in inches or meters at visit 1 
(screening) and recorded to one decimal place (inches) or two decimal places (meters) respectively.
From the body weight and height the BMI will be calculated in the eCRF.
8.4.4
Vital signs
Diastolic blood pressure, systolic blood pressure and pulse will be assessed following standard 
clinical practice. Abnormal and clinically significant findings must be recorded as described in 
Section 8.4.
8.4.5
Physical examination
Physical examination will include:
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
The evaluation must follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
Abnormal and clinically significant findings must be recorded as described in Section 8.4.
8.4.6
Eye examination
Fundus photography or dilated fundoscopy must be performed by the investigator or local 
opthalmologist, or an optometrist according to local practice. The result of the fundus 
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photography/dilated fundoscopy will be interpreted by the investigator. To document this, the 
Investigator must sign and date the interpretation in the subject’s medical records.
The evaluation must follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
Abnormal and clinically significant findings must be recorded as described in Section 8.4.
If a fundus photography/dilated fundoscopy have been performed within 90 days prior to V2, and if 
the results are available at V2, then the procedure do not need to be repeated. If performed before 
the subject consents to participate in the trial, it must also be stated in the subject’s medical records 
that this procedure was not performed in relation to the trial.
A subject cannot be randomised without results confirming there is no acute treatment-requiring 
retinopathy.
Eye examination performed within a period of three weeks before end of treatment visit (V54 or 
V93) is acceptable, if results are available at the end of treatment visit.
8.4.7
Electrocardiogram
A 12-lead ECG must be performed at the trial site. The ECG must be interpreted by the 
investigator, and documented by Investigator signature and date on the ECG print-out. .
The evaluation must follow the categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
The baseline ECG must be performed at screening (V1) or in the period between screening (V1) 
and randomisation (V2). The result must be available prior to randomisation.
ECGs at the end of treatment visit (V54 or V93) should be performed at the day of the visit.
Abnormal and clinically significant findings must be recorded as described in Section 8.4.
8.5
Laboratory assessments
Laboratory analyses will be performed at laboratories contracted by Novo Nordisk. A central 
laboratory will provide all laboratory supplies for the sampling and transportation of all blood 
samples taken during the trial.
A detailed description of the procedures for obtaining the samples, handling, storage, and shipment 
of the samples are specified in a trial-specific laboratory manual provided to the sites by the central 
laboratory. Information regarding laboratory materials such as tubes and labels are also described.
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If laboratory samples need to be retaken due to missing result(s) (e.g. haemolysed, sample leaked 
during transit, sample not being conclusive, lost in transit, etc.), the subject should be called in for 
resampling. Please see the laboratory manual for further guidance.
Samples will be coded in order to keep subject’s identity anonymous.
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 AEs and report these according to Section 8.2.4 and Section 12. Review 
of laboratory reports must be documented either on the documents and/or in the subject's medical 
record.
Antibody results will not be provided to the investigator on an ongoing basis, as these results will 
not be used for any clinical evaluation during the trial.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory.
Laboratory samples will be destroyed no later than at end of trial or no later than at finalisation of 
the clinical trial report.
Antibody samples will be stored as described in Section 24.2.
8.5.1
Laboratory assessments for efficacy
Glucose metabolism
FPG is measured in order to evaluate metabolic control. The subject must attend these visits fasting. 
For definition of fasting, see Section 8.1.4.
A FPG result ≤3.9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as a 
clinical laboratory adverse event (CLAE) at the discretion of the investigator (see Section 12.1.1).
Low plasma or blood glucose values (e.g. FPG) reported by a laboratory in connection to trial 
related visits should NOT be reported as hypoglycaemic episodes; these should be reported as AEs 
related to the procedure at the discretion of the investigator.
Blood samples will be drawn to determine the HbA1c level in order to evaluate metabolic control.
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8.5.2
Laboratory assessments for safety
Haematology
Blood samples for haematology will be analysed to determine:
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Erythrocytes
!
Thrombocytes
Biochemistry
Blood samples for biochemistry will be analysed to determine:
!
ALT
!
Albumin
!
AST
!
Alkaline phosphatase
!
Bilirubins, total
!
Creatinine
!
Potassium
!
Sodium
eGFR will be calculated (at screening) by the central laboratory based on the creatinine value using 
the CKD-EPI equation20, 21 in order to assess inclusion criteria 3b.
Pregnancy testing
For females of childbearing potential (see Section 8.2.7) a blood human Chorion Gonadotropin 
(hCG) test will be performed at screening (V1) and End of Treatment (V54 or V93). In addition, 
urine pregnancy tests will be performed locally during the trial if pregnancy is suspected or if 
required by local law. A positive urine test should be followed by a confirmatory serum -hCG 
(central laboratory).
The central laboratory will provide the pregnancy kits for urine testing performed locally at the site.
Anti-insulin antibodies
Antibody samples may be retained and used for further characterisation of antibody responses 
towards drug if required by health authorities, for safety reasons or in relation to exploratory 
analysis, see Section 24.2.
Serum samples will be analysed at a special lab for anti-insulin degludec or anti-insulin glargine 
antibodies. Anti-degludec antibodies and anti-glargine antibodies will be tested for cross-reactivity 
to human insulin.
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!
Blood samples will be drawn for determination of antibodies to insulin degludec or insulin 
glargine (including cross-reacting antibodies to human insulin).
The subjects must attend the antibody sampling visits specified in section 2 in a fasting condition. 
Fasting is defined as at least eight hours without drink or food intake prior to the visit except for 
water.
No diabetes treatment (neither trial insulin, nor any OADs) is allowed up to eight hours prior to the 
blood sampling. Non-anti-diabetic medication is still allowed to be taken.
8.6
Other assessments
Patient reported outcome questionnaires
The patient reported outcome (PRO) questionnaires are to be completed by the subject without 
assistance of the site personnel, and should preferably be completed after all fasting-related 
activities are completed, but before any other visit related procedures are conducted. Instructions on 
how to complete the questionnaires will be provided to the subject. The questionnaires will be used 
to investigate the health related quality of life, hypoglycaemic episode experience as well as 
treatment and device satisfaction. The completed questionnaires must be transcribed into the eCRF 
and filed at site as source documents.
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The following PRO questionnaires will be supplied in a linguistically validated version in all 
languages relevant for this trial:
!
SF-36v2® The ‘Short-Form 36 Health Survey version 2 is a questionnaire concerning 
various health-related quality-of-life questions. It is a sensitive, validated and widely used 
instrument which will allow direct comparison with other trials including subjects with 
T2DM. SF-36v2 consists of 36 items grouped into 8 domains
!
TRIM-D measures treatment related impact on subjects of diabetes medication across the 
spectrum of pharmacological treatment over the past two weeks. The TRIM-D consists of 28 
items grouped into five domains. The domains are treatment burden, daily life, diabetes 
management, compliance and psychological health
!
TRIM-DD measures the impact of the treatment delivery system as an eight-item 
instrument. The instrument consists of eight items grouped into two domains: Device 
Function and Device Bother
!
Insulin Pen questionnaire measures how easy or difficult it is to reach the dose button 
when injecting insulin, how easy or difficult it is to use the pen and whether or not the 
subject will recommend the pen to others
!
Baseline Hypo Questionnaire measures the subjects experience with hypoglycaemic 
episodes
Besides the five subject completed questionnaires an investigator interview questionnaire is to be 
completed if the subject has reported any hypoglycaemic episode(s) since the last visit:
!
Hypoglycaemia resource use is collected as an interview administered questionnaire 
regarding resource use of the latest hypoglycaemic episode within the last four weeks. The 
questionnaire includes questions regarding the length of the hypoglycaemic episode, the 
number of extra blood monitoring, contact to health care professionals, and time missed at 
work
The questionnaires should be completed as specified in the flow chart, see Section 2.
8.6.1
Training in the pen injector
The subjects must be trained in how to handle the pen injector when handed out the first time. 
Training must be repeated at V6 in order to ensure correct use of the device. The following should 
be emphasised:
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!
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
!
Priming the pen to ensure product flow
!
Injection technique as per DFU
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance.
To ensure treatment compliance, the investigator will at each visit assess the subject’s compliance 
by evaluating the glycaemic control, adherence to the visit schedule and completion of the subject’s 
diary including the SMPG measurements, hypoglycaemia reporting and PRO questionnaire 
completion. In addition, subject compliance will be assessed by monitoring of drug accountability 
at specified visits, please refer to the flow chart, see Section 2. The unused amount IMP will be 
assessed against the dispensed amount and, in case of discrepancies, the subject must be asked.
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: It is important to ensure subjects adhere to treatment. Therefore, during 
the treatment period the investigator must at each weekly contact (visit or phone contact), evaluate 
if the subject has adhered to trial treatment since last contact.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM).
Trial products must not be dispensed to any person not included in the trial.
Trial insulin products (Investigational medicinal product (IMPs)) must not be used, if they do not 
appear clear and colourless.
Insulin NPH product (Non-Investigational Medicinal Product (NIMP)) must not be used if it does 
not appear uniformly white and cloudy after re-suspension.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
Insulin degludec (Tresiba®)
(IMP)
200 U/mL
Solution for 
injection
Subcutaneous
3 mL PDS290
pre-filled pen 
injector
(FlexTouch®)
Insulin glargine (Toujeo®)
(IMP)
300 U/mL
Solution for 
injection
Subcutaneous
1.5 mL
pre-filled pen 
injector(SoloStar®)
Human isophane insulin (NPH)
(Insulatard®/Prothaphane®/Novolin® N)
(NIMP)
100 IU/mL
Suspension for 
injection
Subcutaneous
3 mL
pre-filled pen
injector
(FlexPen®)
The following Non-Investigational Medicinal Products (NIMPs) will not be provided by Novo 
Nordisk:
!
Metformin, tablets for oral use
!
DPP-4i, tablets for oral use
!
SGLT2i, tablets for oral use
!
Thiazolidinedione, tablets for oral use
!
Alpha-glucosidase-inhibitor, tablets for oral use
!
Marketed oral combination products only including the products listed above, tablets for 
oral use
However, metformin, DPP-IVi, SGLTi, Thiazolidinedione, Alpha-glucosidase-inhibitor or 
marketed combination products only including the products listed in inclusion criteria 5a-5e will be 
reimbursed if required by the country’s regulatory authority or IRB/IEC.
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9.2
Labelling
The trial products will be labelled in accordance with Annex 13 33, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation.
The investigator must document that direction for use is given to the subject orally and in writing at 
the first dispensing visit (V2). Direction for use can be provided as needed at the following 
dispensing visits.
9.3
Storage
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
Insulin degludec (Tresiba®)
(IMP)
!
Store in refrigerator 
(2°C - 8°C)
!
Protect from light
!
Do not freeze
!
Do not store above 
30°C
!
Protect from light
!
Can be stored in 
refrigerator (2°C - 8°C)
!
Do not freeze
Use within 8 weeks
Insulin glargine (Toujeo®)b
(IMP)
!
Store in refrigerator 
(2°C - 8°C)
!
Protect from light
!
Do not freeze
!
Store below 30°C
!
Protect from light
!
Do not refrigerate
!
Do not freeze
For CA: Store at room 
temperature (15°C – 30°C)
Use within 26 days
Insulin NPH
(Insulatard®/Prothaphane®/
Novolin® N)
(NIMP)
!
Store in refrigerator 
(2°C - 8°C)
!
Protect from light
!
Do not freeze
!
Store below 30°C
!
Protect from light
!
Do not refrigerate
!
Do not freeze 
For US: Use within 14 days
For CA: Use within 4 weeks
For EU: Use within 6 weeks
aIn-use time starts when first dose is taken.
bBefore first use, the Toujeo® pre-filled pen injector must be stored at room temperature at least 1 hour.
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
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9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
Subjects are instructed to return all used, partly used and unused trial product at each dispensing 
visit after V2. Please refer to the flowchart, see Section 2 for timing of the dispensing visits.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk:
!
Direction for use for the pen injectors
!
Novo Nordisk needles for prefilled systems
!
BG Meter and strips, lancets and control solution for BG meters
Only needles provided by Novo Nordisk must be used for administration of trial product.
Please refer to the TMM for further auxiliary supplies’ details.
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10
Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons.
IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing and Additional Dispensing between scheduled visits
!
Dispensing Verification (when barcode scanner is used)
!
Treatment discontinuation
!
Completion
!
Drug accountability
!
Data change
Notifications generated as a result of sessions performed in the IWRS should be archived in the 
investigator trial file or together with other source documents for the subject.
At any time during the trial only dispensing unit numbers (DUN) allocated by the IWRS are 
allowed to be dispensed to a subject. By doing this it will be ensured that:
!
correct trial product is dispensed to subject
!
stock is available at sites as needed for the subjects
!
no trial product that will expire before the next dispensing visit will be allocated
!
drug accountability can be made in the IWRS
IWRS user manuals will be provided to each trial site.
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11 Randomisation procedure
The IWRS is used for randomisation. Subjects complying with the inclusion- and exclusion criteria 
will be randomised 1:1 into one of the two treatment arms. Within each treatment arm, subjects will 
be randomised 1:1 to morning or evening dosing.
In IWRS this means that there will be four different treatment regimens:
!
IDeg 200 U/mL OD morning dosing ± OADs
!
IDeg 200 U/mL OD evening dosing ± OADs
!
IGlar 300 U/mL OD morning dosing ± OADs
!
IGlar 300 U/mL OD evening dosing ± OADs
Recruitment will be closed as soon as the total number of planned subjects to be randomised is 
achievable, taking the number of screened subjects and the screening failure rate into account. All 
investigators will be notified immediately when the recruitment period ends (estimated to be 24 
weeks), after which no further subjects may be screened and the IWRS will be closed for further 
screening. All subjects included in the screening period and eligible for randomisation can be 
randomised.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. Active management includes active treatment 
or further investigations, for example change of medicine dose or more frequent follow-up 
due to the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial 
procedures performed before exposure to trial product (pre-existing conditions should be 
reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from the first trial related activity after the subject has signed the informed 
consent.
!
Non-serious hypoglycaemia is an AE, but is from V2 until FU1 reported on a 
hypoglycaemic episode form instead of on an AE form, see Section 8.4.2. However, FPG 
results ≤ 3.9 mmol/L (70 mg/dL) should not be reported as hypoglycaemic episodes but as a 
CLAE at the discretion of the investigator.
The following three definitions are used when assessing an AE:
!
Severity
o
Mild – no or transient symptoms, no interference with the subject’s daily activities.
o
Moderate – marked symptoms, moderate interference with the subject’s daily 
activities.
o
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality
Relationship between an AE and the relevant trial product(s):
o
Probable - Good reason and sufficient documentation to assume a causal 
relationship.
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o
Possible - A causal relationship is conceivable and cannot be dismissed.
o
Unlikely - The event is most likely related to aetiology other than the trial product.
•
Final outcome
o
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.
o
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.
o
Recovered/resolved with sequelae - The subject has recovered from the condition, 
but with lasting effect due to a disease, injury, treatment or procedure. If a sequela 
meets an SAE criterion, the AE must be reported as an SAE.
o
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
o
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.
o
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement 
- they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition of SAEd.
a
The term “life threatening” in the definition of SAE refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it was more severe.
b
The term “hospitalisation” is used when a subject:
o
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or
o
Stays at the hospital for treatment or observation for more than 24 hours
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Medical judgement must always be exercised, and when in doubt, the hospital contact 
should be regarded as a hospitalisation. Hospitalisations for administrative, trial related and 
social purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. 
Hospital admissions for surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs.
c
A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following 
the event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity 
and/or quality of life).
d
For example intensive treatment in an emergency room or at home of allergic 
bronchospasm, blood dyscrasia or convulsions that do not result in hospitalisation or 
development of drug dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product
!
risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x upper normal limit (UNL) and total bilirubin >2 x UNL, where no alternative 
aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug or use of wrong device.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 
misuse or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. That is a dose lower or 
higher than 20% of the prescribed/intended dose; 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.
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.1.1.
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12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety.
Some events in this trial will be adjudicated by an independent external committee as described in 
Section 12.7.2.
Table 12–1 lists AEs that require completion of specific event forms in the eCRFs and/or are 
subject to event adjudication.
Table 12–1
Adverse events requiring completion of specific event forms and/or are subject 
to event adjudication
Event
Specific event 
form
Event 
adjudication
Fatal event
No
Yesa
Acute coronary syndrome (myocardial infarction or 
hospitalisation for unstable angina)
Yes
No
Cerebrovascular event (stroke or transient ischaemic 
attack)
Yes
No
Neoplasm
Yes
No
Severe hypoglycaemia or hypoglycaemic episodes reported 
as an SAE
Nob
Yes
Medication error
Yes
No
aFatal events will be adjudicated as potential hypoglycaemic episodes (Hypoglycaemia Adjudication form to be 
completed).
bHypoglycaemia will be captured in the diary by the subject.
For details about specific event forms, see Section 8.4.1.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
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Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (V56). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12–1.
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”.
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. All AEs must be recorded by the investigator on an AE form. The investigator should 
report the diagnosis, if available. If no diagnosis is available, the investigator should record each 
sign and symptom as individual AEs using separate AE forms.
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs.
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar
days of the investigator’s first knowledge of the SAE. Both forms must be signed within 7 
calendar days from the date the information was entered in the eCRF.
For SAEs requiring reporting on a specific event form: In addition to the above the 
specific event form within 14 calendar days from the investigator’s first knowledge of the 
AE.
!
Events for Adjudication: The adjudication form should be completed within 14 calendar 
days of the investigator’s first knowledge of the AE, see Section 12.7.2. The investigator 
should provide copies of the source documentation preferably within 4 weeks of event 
identification.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
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eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF. Contact details (fax, telephone, e-mail and address) are provided in the investigator trial 
master file.
AE identified
AE identified
Does the AE require 
a specific event 
form?
Is the AE subject to 
adjudication and/or 
is the outcome fatal?
AE form < 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs: 
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
Adjudication form
< 14 calendar days
Source data < 4 
weeks
Queries and follow-up 
requests to be resolved 
< 14 calendar days
Timelines are for the completion of forms from the time of investigator’s awareness
AEs requiring specific event forms are descibed in Section 12.1.4 and 12.1.5
AEs for adjudication are described in Section 12.7.2
No additional action
No additional action
AE: Adverse event   SIF: Safety information form
Serious
Yes
Yes
Non-serious
No
No
Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness:
Novo Nordisk assessment of expectedness is performed according to the current versions and any 
updates of the following reference documents:
!
IDeg IB9
!
IGlar 300 U/mL SmPC14 or local labelling15, 16
Reporting of trial product-related SUSARs by Novo Nordisk:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and ICH GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and ICH GCP 1, 
unless locally this is an obligation of the investigator.
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Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as
non-investigational medicinal product (Insulatard®/Prothaphane®/Novolin N™) or concomitant 
medication in the trial, it is important that the suspected relationship is reported to Novo Nordisk, 
e.g. in the alternative aetiology section on the safety information form. Novo Nordisk may need to 
report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The investigator must record follow-up information by updating the forms in the eCRF.
Follow-up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. 
Cases of chronic conditions, cancer or AEs ongoing at time of death (where death is due to 
another AE) may be closed with the outcome “recovering/resolving” or “not recovered/not 
resolved”. Cases can be closed with the outcome of “recovering/resolving” when the subject 
has completed the follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of 
the information. This is also the case for previously non-serious AEs which subsequently 
become SAEs.
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until 
the end of the follow-up period stated in the protocol, whichever comes first, and until all 
queries related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs 
ongoing at time of death (where death is due to another AE) may be closed with the 
outcome “recovering/resolving” or “not recovered/not resolved”. Cases can be closed with 
the outcome of “recovering/resolving” when the subject has completed the follow -up period 
and is expected by the investigator to recover.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after t he subject has 
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ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the fo llowing products:
!
Insulin degludec 3ml PDS290 pen injector (FlexTouch®)
!
Insulin glargine (Toujeo®)1.5ml prefilled pen (SoloStar®)
!
Insulin NPH (Insulatard®/Prothaphane®/Novolin N™) 3ml prefilled pen (FlexPen®)
!
Novo Nordisk needles for pre-filled pen systems
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs and/or SAEs.
Technical complaints must be reported on a separate technical complaint form:
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each 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:
!
Technical complaint assessed as related to an SAE within 24 hours
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
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The investigator must ensure that the technical complaint sample contains the batch or lot number 
and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.
12.5
Pregnancies 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 new-born infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the new-born infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
new-born infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the new-born infant(s) 
has to be reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, 
further information has to be reported for the female subject on Maternal Form 2. In 
addition, information from the male partner has to be reported on the Paternal Form, after an 
informed consent has been obtained from the male partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus 
and new-born infant(s). The SAEs that must be reported include abnormal outcome, such as 
foetal 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.
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Forms and timelines for reporting AEs:
Non-serious AEs:
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or 
follow-up information to the non-serious AE.
SAEs:
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
Safety information form within 5 calendar days of the investigator’s first knowledge of the 
SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information.
a
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or new-born infant. If the AE occurred in the foetus or new-born infant, 
the AE can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
During treatment with insulin, there is a risk of hypoglycaemia (see Section 8.4.2). Symptoms 
usually occur suddenly and may include cold sweat, nervousness or tremor, anxious feelings, 
unusual tiredness, confusion, difficulty in concentration, excessive hunger, temporary vision 
changes, headache, nausea and palpitation. Prolonged or severe hypoglycaemia can lead to a loss of 
self-control, spasms, and/or unconsciousness and, in extreme cases, death.
Hypoglycaemic episodes should be treated following best practice at the discretion of the 
investigator. As with all long-acting insulin preparations, their prolonged effect may delay recovery 
from a hypoglycaemic episode.
Asymptomatic hypoglycaemia and symptoms of hypoglycaemia should be treated with 
carbohydrates. Mild to moderate symptoms can be treated by ingestion of carbohydrate (for 
example juice). Severe hypoglycaemia resulting in loss of consciousness should be treated with 
parenteral glucose, glucagon or dextrose.
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For further details, please refer to current versions and any updates of the following:
!
IDeg IB9
!
IGlar 300 U/mL SmPC14 or local labelling15, 16
!
NPH SmPC34 or local labelling35, 36
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal IDeg safety committee to perform ongoing safety 
surveillance.
The IDeg safety committee may recommend un-blinding of any data for further analysis, and in this 
case an independent ad hoc group will be established in order to maintain the blinding of the trial 
personnel.
12.7.2
Event adjudication committee
An independent external event adjudication committee is established to perform validation of 
selected AEs according to pre-defined diagnostic criteria. The validation is based on review of pre-
defined clinical data related to the specific AE.
The events are reviewed by the event adjudication committee in a blinded manner. The EAC will 
have no authorisations to impact on trial conduct, trial protocol or amendments. The EAC is 
composed of permanent members covering required medical specialities. The EAC members must 
disclose any potential conflicts of interest and must be independent of Novo Nordisk.
The AEs for adjudication are listed in Table 12–2.
Table 12–2
Events for adjudication
Event
Description of events in scope for 
adjudication
Adjudication Outcome
Fatal event
All cause death
Severe hypoglycaemia
Severe hypoglycaemia or 
hypoglycaemic episodes reported as 
an SAE
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 episode, but neurological 
recovery following the return of 
plasma glucose to normal is 
considered sufficient evidence that the 
event episode was induced by a low 
plasma glucose concentration
Severe hypoglycaemia
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.
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The following describes the ways events are captured for adjudication:
Direct reporting by investigator:
AEs for adjudication must be reported according to Section 12.2 and Table 12–1. In addition the 
specific adjudication form should be completed within 14 calendar days of the investigator’s first 
knowledge of the AE, and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual.
Hypoglycaemic episodes will be reported by the subject in the diary. For severe hypoglycaemic 
episodes the adjudication form must be completed by the investigator in the eCRF. If a 
hypoglycaemic episode fulfils the criteria as an SAE as well as for all fatal events the AE, SIF and 
adjudication forms must be completed.
Screening of SAEs:
All SAEs will be screened to detect potential missed events for adjudication. If needed, the 
investigator will be requested to provide additional information such as an alternative aetiology, 
underlying cause(s) and/or clinical details.
Based on the information provided, the Event Adjudication supplier or Event Adjudication 
Committee can decide to have an SAE adjudicated even if not initially reported as an event for 
adjudication by the investigator. If so, the investigator must complete the Adjudication form and 
upload source data, when they receive the request from Novo Nordisk or the Event Adjudication 
supplier.
EAC identified events:
During the review of source data, the EAC may identify additional events relevant for adjudication, 
not reported as for such by the investigator. In case an additional event is identified, the site will be 
informed and asked to consider reporting the event. If the site does not report the event, it may still 
be adjudicated.
For all events for adjudication, the source documentation should be anonymised by investigator 
according to the Event Adjudication Site Manual. Prior to submitting the source documentation to 
the EAC, the Event Adjudication supplier will ensure translation into English.
For each source document the investigator should specify/indicate on the adjudication form when/if 
the required documents will be available. If a document is unobtainable this needs to be specified. If 
no source data are available, a clinical narrative should be provided.
For further details regarding event adjudication, please refer to the Event Adjudication Site Manual.
The assessment made by the event adjudication committee will be included in the clinical trial 
report as well as the assessments made by the investigator. However, the adjudication made by the 
event adjudication committee, given its independent analysis of each event, will be attributed with 
greater importance of the two.
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
The investigator must ensure that all relevant questions are answered, and that no empty data field 
exists. If a test or an assessment has not been done and will not be available, or if the question is 
irrelevant (e.g. is not applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms
!
Safety information forms
!
Technical complaint forms (also to be used to report complaints that are not subject related 
(e.g. discovered at trial site before allocation)
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
Corrections to the data in the paper CRFs should be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that were crossed out. Each 
correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff.
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13.2
Case report form flow
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes. Queries will be generated on an ongoing basis and 
investigator must ensure that queries are resolved as soon as possible, preferable within 5 calendar 
days.
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 FPFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the eCRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, but will not exceed 12 weeks until LPLV at the trial site.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF, except for:
!
Age and BMI which are calculated by the EDC system
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 monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
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The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
!
Screen Failure Form/Reason
!
SAEs
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken.
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15 Data management
Data management is the responsibility of Novo Nordisk.
Appropriate measures, including encryption of data files containing 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.
The eDiary software and hardware implementation are compliant with the requirements of FDA 21 
CFR Part 11 and ICH E6 (EU directive for personal data protection). After trial finalisation, Novo 
Nordisk and each site will be supplied with long-life DVDs. These DVDs will contain site-specific 
subject records including the subject’s eDiary data and audit trail as well as any data additions and 
corrections made on each form. The eDiary vendor will furthermore retain and securely store copies 
of all archived documents and data for 50 years or as required by local data retention laws for trial 
data.
17 Statistical considerations
17.1
General considerations
For subjects withdrawing from the trial as well as for subjects not discontinuing randomised 
treatment prematurely, the trial period completion is at visit 54 (subject not entering maintenance 2) 
or visit 93 (subjects entering maintenance 2). For subjects who prematurely discontinue randomised 
treatment during the titration period or maintenance 1 but do not withdraw, the trial period 
completion is at visit 93A. Treatment period completion is defined as the date when randomised 
treatment is discontinued.
All efficacy, PRO and hypoglycaemic endpoints will be summarised using the full analysis set 
(FAS) and safety endpoints excluding hypoglycaemic endpoints will be summarised using the 
safety analysis set (SAS).
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All statistical analysis of efficacy and safety endpoints will be based on the FAS unless otherwise 
specified. Confirmatory analysis addressing the primary estimand will include on-treatment data 
and not available retrieved (V93A) data.
The primary objective is to compare the effects of IDeg OD and IGlar 300 U/mL OD on the rate of 
hypoglycaemia in subjects with type 2 diabetes mellitus, inadequately treated with basal insulin 
with or without oral anti-diabetic drugs. The primary estimand is the treatment difference between 
IDeg and IGlar 300 U/mL assuming that all randomised subjects adhered to the randomised 
treatment, that is a de jure estimand. The primary estimand addresses the treatment difference for 
subject that can be long-term treated with either of the two insulins. Data collected after premature 
treatment discontinuation will not be used when addressing the primary estimand. With the aim of 
comparing a safety endpoint this estimand is considered the most relevant as it compares the 
occurrence of a safety endpoint that is caused by the drug during exposure to the drug. The 
confirmatory endpoints will additionally be investigated with a de-facto estimand, other endpoints 
will be analysed only with a de jure estimand to support the primary analysis of the primary 
endpoint.
The secondary estimand is the treatment difference between IDeg and IGlar 300 U/mL regardless of 
whether subjects adhered to the randomised treatment throughout the trial, that is a treatment policy 
estimand. For this de-facto estimand, data collected after premature discontinuation will be used.
In accordance with guidance37 endpoints will be assessed at frequent visits and also for subjects 
who prematurely discontinue treatment. The baseline value is defined as the value from the 
randomisation visit. If this value is missing the last recorded value before randomisation visit will 
be used.
The severe hypoglycaemia episodes included in the statistical analysis are all events adjudicated 
with the outcome severe hypoglycaemia.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
The primary and secondary endpoints will be tested in a hierarchical order to control the family 
wise Type I error in the strong sense. Inferences will be based on the primary estimand.
Presentation of results from a statistical analysis will include the estimated treatment means as well 
as estimated mean treatment difference (or ratio) together with the two-sided 95% confidence 
interval and corresponding two-sided p-value.
In the statistical models explanatory factors will be categorized as follows:
1. Treatment: IDeg, IGlar 300 U/mL
2. Pre-trial 0 OADs, 1OAD, ≥2 OADs
3. Region: Europe , North America
4. Sex: male, female
5. Dosing time: morning, evening
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17.2
Power calculation
The power is based on the primary objective and the primary endpoint, number of hypoglycaemic 
episodes during maintenance treatment.
For the power calculations it is assumed that the true treatment rate ratio (RR) is 0.75 corresponding 
to a 25% reduction in rate of hypoglycaemia in maintenance period with IDeg OD compared to 
IGlar 300 U/mL OD. Sample size is determined based on a negative binomial model with log-offset 
equal to exposure time in maintenance. The observed rate of severe or BG confirmed symptomatic 
hypoglycaemia for IDeg is assumed to be 1.8 per patient years of exposure (PYE) and the 
dispersion parameter in the negative binomial distribution is assumed to be 3.1. Furthermore it is 
assumed that 4% of subjects will withdraw before starting the maintenance period and therefore 
have no on-treatment data for the maintenance period. For these 4% the treatment ratio is set to 1. 
Rate assumptions are based on experience from SWITCH 2 (NN1250-3998), which has similar 
inclusion criteria. Dispersion parameter assumptions are based on experience from the Degludec 
phase 3a and 3b program. Assumptions concerning withdrawal are similarly based on actual 
withdrawal rate of the trial during titration and maintenance 1.
The power equals 79% with the number of randomised subjects and the assumptions above.
Table 17–1
Power for the primary estimand for combinations of RR and event rates
Yearly event rate
1.5
1.8
2.0
RR
Adjusted RR
Primary
Primary
Primary
0.80
0.812
55%
57%
58%
0.75
0.765
77%
79%
79%
0.70
0.718
92%
93%
93%
The marginal power for detecting a difference between IDeg OD and IGlar 300 U/mL OD with 805 
subjects per treatment arm assuming a one-sided t-test at the 2.5% significance level for the 
confirmatory secondary dose endpoints is shown below. The assumptions are based on data from 
NN1250-3998 with respect to hypoglycaemic episodes and the phase 3a+b program for the dose-
difference.
Table 17–2
Marginal power for confirmatory secondary endpoints
Assumptions
Endpoint
True ratio
Adjusted RR
CV/
Over dispersion
Rate in IDeg 
treatment arm
Power
Number of nocturnal, severe or 
BG confirmed symptomatic 
hypoglycaemic episodes during 
maintenance 2
0.7
0.718
3.1
0.55
82%
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Insulin dose (U)
0.90
0.906
0.65
-
92%
Number of severe 
hypoglycaemic episodes during 
maintenance 2
0.6
0.624
3.1
0.03
31%
17.3
Definition of analysis sets
Full analysis set (FAS): includes all randomised subjects. In exceptional cases, subjects may be 
eliminated from the full analysis set. In such cases the elimination will be justified and documented. 
In the statistical evaluation of the full analysis set subjects contribute "as treated" when addressing 
the primary estimand and "as randomised" when addressing the secondary estimand".
Safety analysis set (SAS): includes all subjects receiving at least one dose of the investigational 
product or comparator. Subjects in the safety set will contribute to the evaluation “as treated”.
Randomised subjects who are lost to follow up and where no exposure information of the 
investigational product or comparators is available after randomisation will be handled as 
unexposed.
Before data are released for statistical analysis, a review of all data will take place to identify 
protocol deviations that could potentially affect the results. In exceptional cases a decision to 
exclude any subject or observation from the statistical analysis can be made. This is the joint 
responsibility of the members of the study group. The subjects or observations to be excluded, and 
the reasons for their exclusion must be documented before database lock. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report.
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17.4
Primary endpoint
17.4.1
Primary statistical analysis for the primary estimand
The primary estimand will be estimated based on information from maintenance 2 collected when 
subjects use randomised treatment (on-treatment data). Subjects that discontinue randomised 
treatment during maintenance 2 will contribute with the available on treatment data from 
maintenance 2. For subjects that discontinue randomised treatment during the titration period or 
maintenance 1, the number of events in maintenance 2 will be imputed based on data from the same 
arm from maintenance 2 for subjects that discontinued randomised treatment during maintenance 2. 
Missing data within each group will be imputed as follows:
!
First 1000 samples from the posterior distribution of model parameters will be extracted. 
The model will be fitted to the on-treatment maintenance 2 data for subjects that 
discontinued randomised treatment during maintenance 2. This will be done using a Bayes 
negative binomial log-link model with the factors descried in section 17.1 (except 
treatment), age as covariate, and log of exposure time as offset.
!
For each sample of model parameters, the total number of hypoglycaemia events for 
subjects that discontinued randomised treatment in the titration period or maintenance 1 will 
be imputed as a random number of events from a negative binomial distribution using the 
sampled parameters.
Having 1000 complete data sets that have maintenance 2 data for all randomised subjects, the mean 
treatment ratio will be estimated using a negative binomial model with all the factors described in 
section 17.1, age as covariate and log exposure time as offset. The estimates and standard deviations 
will be pooled to one estimate and associated standard deviation using Rubin’s formula. From these 
the 95% confidence intervals for the treatment ratio and the associated p-value will be calculated.
If the model in step one above cannot fit due to sparse data, factors will be left out one by-one in the 
model using data from all subjects discontinuing rando mised treatment in the following order, until 
a model fits: 
!
sex
!
region
!
previous OAD treatment
If the above model cannot fit either the model is fitted to the on-treatment data for subjects that 
discontinued randomised treatment during either titration or maintenance periods.
17.4.2
Sensitivity analyses for the primary estimand
To investigate missing not at random scenarios, a tipping point analysis of the hypothesis that IDeg 
is superior to IGlar 300 U/mL will be performed for the primary estimand. In this analysis the event 
rates for subjects that discontinued randomised treatment in the IDeg OD arm during either titration 
or maintenance periods is gradually increased until the difference between the two treatments is no 
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longer statistically significantly different. If the penalty found by this method is evaluated to be 
clinically plausible the sensitivity analysis does not support the primary analysis. If the penalty is 
not considered plausible the sensitivity analysis supports the primary analysis.
To investigate the potential influence of subjects with high number of events, the analysis of the 
primary estimand will be repeated on data where the maximal number of events in maintenance 2 is 
truncated at three. The value three is based on data from SWITCH 2 (NN1250-3998) where three 
hypos correspond to the 95% percentile in the IDeg arm.
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses.
17.4.3
Statistical analysis for the secondary estimand
The secondary estimand will be estimated based on information from maintenance 2 collected 
regardless of whether subjects used randomised treatment or not, i.e. including data after premature 
discontinuation.
Missing data for withdrawn subjects will be imputed based on off-treatment data from the same arm 
from maintenance 2 for subjects that discontinued randomised treatment during maintenance 2. The 
imputations and the analysis will be made using the same method as for the primary estimand.
17.4.4
Sensitivity analysis for the secondary estimand
The same sensitivity analysis as the sensitivity analysis for the primary estimand will be performed.
17.5
Secondary endpoints
17.5.1
Confirmatory secondary endpoints
Provided that IDeg OD is superior to IGlar 300 U/mL OD for the primary endpoint using the 
primary estimand, the confirmatory secondary endpoints will be tested for superiority of IDeg OD 
over IGlar 300 U/mL OD using the primary estimand.
The confirmatory secondary endpoints are given below; the order of the endpoints defines the 
testing sequence. The hierarchical testing strategy will control the family wise type 1 error in the 
strong sense at 5% (two sided).
1. Basal insulin dose (U) at end of maintenance 2 (up to 88 weeks)
2. Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes during 
maintenance 2 (36 weeks)
3. Number of severe hypoglycaemic episodes during maintenance 2 (36 weeks)
The hypoglycaemic endpoints will be analysed with the same analysis method as the primary 
endpoint and with similar sensitivity analysis.
Basal insulin dose at end of maintenance 2 will be analysed as follows: A basal insulin dose at 
every titration, maintenance and end of treatment visit mentioned in the flow chart will be 
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calculated as a mean of the insulin doses in the 7 day period before the visits. These doses will be 
analysed on log-scale with an MMRM with the factors described in section 17.1 and age at baseline 
and pre-trial insulin dose as covariate. If this model does not converge visits and/or factors will be 
excluded from the analysis.
Insulin dose will also be analysed with a de-facto estimand, i.e. including using insulin dose 
collected after premature discontinuation. This is done using a pattern mixture model using multiple 
imputation to handle missing data. Imputation of missing data at end of trial will be done within the 
4 groups of subjects defined by randomised treatment and whether subjects discontinued 
randomised treatment or not. Missing data within each group will be imputed as follows:
!
An analysis of covariance model for insulin dose at week 52 with the factors listen in 17.1
(except treatment) and pre-trial insulin dose and age at baseline as covariates will be fitted to 
the observed data.
!
The estimated parameters will be used to impute 1000 values for insulin dose at week 52, 
creating 1000 complete datasets.
Having 1000 complete datasets, each of these will be analysed using an analysis of covariance 
model with all the factors listed in 17.1, pre-trial insulin dose and age at baseline as covariates. The 
estimates and standard deviations will be pooled to one estimate and associated standard deviation 
using Rubin’s formula. From these the 95% confidence intervals for the treatment ratio and the 
associated p-value will be calculated.
17.6
Other endpoints
17.6.1
Efficacy endpoints
Continuous supportive secondary efficacy endpoints will be summarised descriptively by visits and 
by mean plots of observed values and observed change from baseline.
17.6.2
Safety endpoints
Adverse events during the total treatment period (titration and maintenance periods)
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities.
A treatment-emergent AE (TEAE) is defined as an event that has onset date on or after the first day 
of exposure to randomised treatment and no later than 7 days after the last day of randomised 
treatment, or has onset date before the first day of exposure on randomised treatment and increases 
in severity during the treatment period and until 7 days after the last drug date. Major adverse 
cardiovascular events (MACEs, defined as all cardiovascular deaths, non-fatal myocardial 
infarctions and non-fatal strokes) are considered treatment-emergent until 30 calendar days after the 
last day of randomised treatment.
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TEAEs are summarised descriptively, whereas non-TEAEs are presented in listings. TEAE data 
will be displayed in terms of the number of subjects with at least one event (N), the percentage of 
subjects with at least one event (%), the number of events (E) and the event rate per 100 years of 
exposure (R).
Summaries of TEAEs and of serious TEAEs will be presented as an overview including all AEs, 
serious AEs, number of deaths, AEs by severity, AEs by relation to treatment and AEs leading to 
treatment discontinuation or withdrawal.
Furthermore summary tables based on system organ class and preferred terms are made for:
!
All TEAEs
!
Serious TEAEs
!
TEAEs possibly or probably related to trial product
!
Severe, moderate and mild TEAEs
!
TEAEs with preferred term that are experienced by at least 5% (1%) of the subjects in any 
treatment arm or by at least 5% (1%) of all subjects
Summary tables of SAEs including SAEs reported for subject that discontinue trial product 
prematurely will be presented including summary tables based on system organ class and preferred 
terms.
Hypoglycaemic episodes
For the definition and classification of hypoglycaemic episodes refer to section 17.7.
Data on treatment-emergent hypoglycaemic episodes are presented in terms of the number of 
subjects with at least one event (N), the percentage of subjects with at least one event (%), the 
number of events (E) and the event rate per 100 years of exposure (R).
Separate summaries are made by severity considering severe or BG confirmed symptomatic 
hypoglycaemic episodes, severe hypoglycaemic episodes, and the ADA classification of 
hypoglycaemia. The summaries are made for all and nocturnal (between 00:01 and 05.59 both 
inclusive) episodes respectively and for the total treatment period (titration and maintenance 
periods) and maintenance 2 only (36 weeks).
Body weight
Body weight (absolute value and change from baseline) will be summarised descriptively by visit.
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Clinical evaluation (ECG, vital signs, eye examination and physical examination) change from 
baseline after 52 weeks
Vital signs, physical examination, eye examination and 12-lead ECG findings will be summarised,
including:
!
Summaries for each visit
!
Shift tables from baseline to end of treatment
Laboratory assessments
Biochemistry and Haematology laboratory parameters will be summarised including:
!
Summaries by visit
!
Shift tables from baseline to end of treatment
!
Proportion of subjects with measurements outside reference range by treatment and visit
!
Box plots by visit
!
Listings of individual values outside reference ranges (abnormal values)
All laboratory values will be included in listings.
Anti-insulin antibodies will be summarised by visit.
17.7
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 IMP administration, and no later than the 7 days from 
last day on IMP.
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the ADA classification of hypoglycaemia (see Figure 17–2).
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) 38. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
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Novo Nordisk uses the following classification (see Figure 17–1) in addition to the ADA 
classification:
!
Severe hypoglycaemia according to the ADA classification29.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification29or BG confirmed by a plasma glucose value <3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia.
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1
Novo Nordisk classification of hypoglycaemia
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ADA classification29 of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
!
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured plasma glucose concentration > 3.9 
mmol/L (70 mg/dL) but approaching that level.
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent gl ucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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17.8
Health economics and/or patient reported outcomes
Health economics and/or patient reported outcomes will be analysed after the CTR.
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18 Ethics
18.1
Benefit-risk assessment of the trial
The trial population will consist of insulin-treated subjects with T2DM presenting with an HbA1c
equal to or below 9.5% while treated continuously with basal insulin with or without OADs for at 
least 90 days and who recently have experienced hypoglycaemia or have increased risk of severe 
hypoglycaemia. For all subjects participating in this trial, the anticipated benefits include improved 
glycaemic control. Titration algorithms, specifying recommended adjustments of the basal insulin 
dose at different plasma glucose levels, are used in order to ensure that subjects receive an optimal 
treatment. Subjects will receive intense medical care by means of close contact to the clinical sites 
with at least weekly contacts.
Trial products will be provided by Novo Nordisk free of charge. Subjects will receive IDeg or IGlar 
300 U/mL in prefilled pens and NPH during 7 days follow-up. For a description of risks and 
benefits please refer to current versions and any updates of the following:
!
IDeg IB9
!
IGlar 300 U/mL SmPC14 or local labelling15, 16
!
NPH SmPC34 or local labelling35, 36
The subjects will be provided with a glucose meter including lancets, plasma-calibrated test strips 
and control solutions as well as instructions for use.
The trial products may be associated with side effects, 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. These precautions include thorough information 
regarding the correct administration of the trial product and in handling of low BG measurement. 
Furthermore, subjects will be fully informed about possible AEs and inconveniences.
Clinical benefits and risk considerations for the trial
For the individual subjects, the personal health-related benefits are related to the medical 
examination and the benefit from a treatment regimen anticipated being equal to or better than the 
treatment they receive at the time they enter the trial. However, subjects will have to spend some 
extra time monitoring and recording data and on additional visits to the clinic and phone contacts.
The maximum trial duration for each subject is up to 94 weeks and the treatment duration for a 
subject is planned to be up to 88 weeks. Subjects will be asked to perform SMPG recording every 
day.
The very high frequency of contacts between the subject and the investigator and the thorough 
evaluation of SMPG values will provide the opportunity for optimising the titration of basal insulin 
based on SMPG values and thereby may contribute to obtaining improved HbA1c results.
For the individual subjects, the anticipated side effects associated with the trial products are not 
different from what is seen with other insulins and include hypoglycaemia, hypersensitivity 
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reactions, injection site reactions, lipodystrophy and antibody development (for more detailed 
description, please refer to the local labelling for each product). The side effects will be mitigated 
by the close supervision of the subjects and the frequent measurements of BG levels.
All treatments are contraindicated in case of hypersensitivity to the active substances or any of the 
excipients. The risk of hypersensitivity is partly mitigated by excluding subject with known 
hypersensitivity towards any trials products or related products.
Injection site reactions can occur. The nature of the injection site reactions is expected to be mild, 
transient, and more of a visual character and is not expected to be of concern to the subject’s safety. 
Lipodystrophy (including lipohypertrophy, lipoatrophy) at the injection site can occur. Continuous 
rotation of the injection site within the particular injection area may help to reduce the risk of 
developing these reactions.
Conclusion
Subjects in this trial will benefit from a basal insulin treatment in a treat-to-target setting under 
close supervision.
The safety profiles of the trial products are well established.
It is concluded that the clinical benefits from the trial outweigh the potential risks of participating in 
this trial.
18.2
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand.
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.
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If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow up 
visits will be retained by Novo Nordisk, entered into the database and used for the clinical 
trial report.
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain the letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject at the discretion of the investigator. The subject may 
receive a “welcome to the trial letter” and a “thank you for your participation letter” after 
completion of the trial. Further the subject may receive letters during the trial.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation.
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database.
Documentation on protocol deviations must be kept in the investigator trial master file and sponso r 
trial master file.
19.2
Prevention of missing data
A significant proportion of missing data is a potential source of bias when analysing data in clinical 
trials leading to a risk of misinterpretation of the trial results. Missing data may affect both 
estimation of treatment effect and the confidence interval that surrounds it as well as the 
representativeness of the sample size in relation to the target population.
Only absolutely necessary criteria to discontinue trial drug have been stated, see Section 6.4, and a 
process has been set up to follow-up on subjects discontinuing trial drug prematurely, see section 
8.1.9.
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites.
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. In addition, only absolutely necessary 
criteria for premature discontinuation of trial products primarily focusing on subjects safety are 
included and thereby reducing the number of discontinuations and limiting the amount of missing 
data.
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites.
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure, SmPC or similar labelling
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For US trial sites: FDA form 1572 must be completed and signed by the investigator at each 
site
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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 if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1
applicable regulatory requirements and the Declaration of Helsinki2.
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data.
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
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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 publications39.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure23.
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Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.
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 Editors39 (sometimes referred to as the Vancouver 
Criteria).
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.
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23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database.
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human bio samples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs, and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be reta ined for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human bio samples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities, for safety reasons or in relation to 
exploratory analysis.
Remaining anti-insulin antibody samples may be used for exploratory investigation of anti bodies. 
The analyses will be performed by Immunogenicity Assessment, Novo Nordisk A/S or a laboratory 
assigned by Novo Nordisk A/S. Results will be reported under a separate study and the data 
documented independently from the clinical trial report.
The samples will be stored at a central bio-repository after end of trial and until marketing 
authorisation approval or until the research project terminates, but no longer than 15 years from end 
of trial after which they will be destroyed.
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The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples.
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples.
Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
For Poland only: Novo Nordisk carries liability for the trial exclusively in the scope defined by the 
applicable laws and in particular by the Civil Code and the Pharmaceutical Law dated 6 September 
2001 (uniform version Journal of Laws of 2008 No. 45 item 271 with amendments). In order to 
support potential claims for liability attributable to the trial, Novo Nordisk and the investigators are 
covered by the insurance policy issued according to applicable Polish law.
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27 References
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World Medical Association. Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
3.
Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res. 2005;36(3):197-209.
4.
Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal TP, Hemmingsen C, et al. Targeting 
intensive glycaemic control versus targeting conventional glycaemic control for type 2 
diabetes mellitus. Cochrane Database Syst Rev. 2013(11):CD008143.
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Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
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Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, et al. Insulin 
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Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, et al. 
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Wysham H. Carol, Bhargava A, Chaykin BL, Rosa RDL, Handelsman Y, Troelsen NL, et 
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Novo Nordisk A/S. Investigator's Brochure, insulin degludec (11th edition). December 
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Novo Nordisk A/S. Tresiba® (insulin degludec) EU Summary of Product Characteristics 
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Novo Nordisk A/S. Tresiba® U.S. Label information. 2015.
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Ritzel R, Roussel R, Bolli GB, Vinet L, Brulle-Wohlhueter C, Glezer S, et al. Patient-level 
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Diabetes Obes Metab. 2015;17(9):859-67.
13.
Yki-Järvinen H, Bergenstal R, Ziemen M, Wardecki M, Muehlen-Bartmer I, Boelle E, et al. 
New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 
diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month 
randomized controlled trial (EDITION 2). Diabetes Care. 2014;37(12):3235-43.
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European Medicines Agency. Toujeo® - Summary of Product Characteristics. 4/24/ 2015.
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Food and Drug Administration. Toujeo® - U.S. Label information. 2015.
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Health Canada. ToujeoTM SoloSTAR®, CA Prescribing Information (PI). 15-July-2015 
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17.
Yki-Järvinen H, Bergenstal RM, Bolli GB, Ziemen M, Wardecki M, Muehlen-Bartmer I, et 
al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin 
glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral 
antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month 
extension. Diabetes Obes Metab. 2015;17(12):1142-9.
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Home PD, Bergenstal RM, Bolli GB, Ziemen M, Rojeski M, Espinasse M, et al. New 
Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 
Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4). Diabetes Care. 
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19.
Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1 
and type 2 diabetes mellitus: a meta-analysis of endpoints in phase 3a trials. Diabetes Ther. 
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Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.
21.
Stevens LA, Schmid CH, Zhang YL, Coresh J, Manzi J, Landis R, et al. Development and 
validation of GFR-estimating equations using diabetes, transplant and weight. Nephrol Dial 
Transplant. 2010;25(2):449-57.
22.
Lamb EJ, Levey AS, Stevens PE. The Kidney Disease Improving Global Outcomes 
(KDIGO) guideline update for chronic kidney disease: evolution not revolution. Clin Chem. 
2013;59(3):462-5.
23.
Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx.
24.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
25.
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007. 27 September 2007.
26.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Councill of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 1 May 
2001.
27.
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 
Official Journal of the European Communities. 2004.
28.
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22.
29.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
108 of 108
30.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
31.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. December 2009.
32.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
33.
Rewers MJ, Pillay K, de Beaufort C, Craig ME, Hanas R, Acerini CL, et al. ISPAD Clinical 
Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in 
children and adolescents with diabetes. Pediatr Diabetes. 2014;15 Suppl 20:102 -14.
34.
Novo Nordisk A/S. Insulatard® (human isophan insulin), EU Summary of Product 
Charateristics. SEP 2015.
35.
Novo Nordisk A/S. NOVOLIN® N, US Prescribing Information (PI). 01-August-2016 2016.
36.
Novo Nordisk A/S. Novolin®ge, CA prescribing Information (PI). 11-March-2016 2016.
37.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 
Rev. 1). 2 Jul 2010.
38.
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81.
39.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
1 of 9
Appendix A: Insulin Titration Guideline
Trial ID: NN1250-4252
A trial comparing the efficacy and safety of insulin degludec 
and insulin glargine 300 units/mL in subjects with type 2 
diabetes mellitus inadequately treated with basal insulin with 
or without oral anti-diabetic drugs
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
2 of 9
Table of Contents
Page
Table of Contents........................................................................................................................................2
Table of tables.............................................................................................................................................2
1
Introduction .........................................................................................................................................3
2
Treatment regimens.............................................................................................................................4
2.1
Injection area ............................................................................................................................4
2.2
Time of injection.......................................................................................................................4
3
Initiation and titration.........................................................................................................................5
3.1
Initiation ...................................................................................................................................5
3.2
Titration....................................................................................................................................5
3.3
Deviations from the algorithm...................................................................................................6
4
Data collection......................................................................................................................................7
5
Review procedure ................................................................................................................................8
6
References ............................................................................................................................................9
Table of tables
Page
Table 1
IDeg 200 U/mL or IGlar 300 U/mL dose increase......................................................................5
Table 2
IDeg 200 U/mL or IGlar 300 U/mL reduction............................................................................6
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
3 of 9
1
Introduction
The goal of insulin therapy is to achieve near normoglycaemia, i.e. to reach a pre-defined HbA1c
level with a low rate of hypoglycaemic episodes and as little weight gain as possible. Several trials 
have shown that this is difficult to achieve, unless plasma glucose (PG) values are intensively 
monitored and the insulindose(s) frequently adjusted1-6.
To ensure treatment uniformity between the sites, as well as to ensure that subjects receive an 
optimal treatment, titration algorithms have been developed specifying recommended dose 
adjustments at different PG levels.
It is recognised that treatments differ between different regions and countries. Likewise, specific 
titration guidelines may not be applicable in certain clinical situations. It is important that other 
information, such as symptoms of hypo/hyperglycaemia, previous response to dose adjustments, 
other glucose measurements and other indicators of the subject’s level of glycaemic control, is 
taken into consideration when decisions on dosing are made. The investigator should always use his 
clinical judgement to avoid safety hazards. The investigator is responsible for the treatment of the 
subjects and can therefore overrule the guideline.
To optimise and maintain glycaemic control, the investigator should,throughout the trial be at least 
in weekly contact with the subjects to assist the subjects in adjusting insulin doses and to ensure the 
subject’s welfare.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
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2
Treatment regimens
At Visit 2 (randomisation), pre-trial insulin treatment must be discontinued. Eligible subjects are 
randomised 1:1 into one of the two treatment arms:
!
Insulin degludec (IDeg 200 U/mL) either morning or evening OD ± OAD
!
Insulin glargine (IGlar 300 U/mL) either morning or evening OD ± OAD
The treat-to-target approach is applied in both treatment arms in order to optimise titration and 
glycaemic control throughout the trial.
There are no maximum or minimum doses.
2.1
Injection area
Both products should be injected subcutaneously into the thigh, upper arm (deltoid area) or the 
abdomen. The chosen region should be the same throughout the trial. Rotation of injection sites 
within a given region is recommended.
2.2
Time of injection
According to the randomisation the daily dose of basal insulin should be taken either in the morning 
between waking up and breakfast or in the evening from main evening meal to bedtime.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
5 of 9
3
Initiation and titration
3.1
Initiation
For patients randomised to IDeg 200 U/mL OD, the daily basal insulin dose should be reduced by 
20% from pre-trial dose.
Patients randomised to IGlar 300 U/mL should switch unit-to-unit, if they prior to randomisation 
received basal insulin once daily. For patients that prior to randomisation received a BID basal 
insulin regimen, the following applies:
!
US patients that prior to randomisation received a BID basal regimen with NPH insulin should
have their total daily insulin dose reduced by 20% and injected once daily
!
US patients that prior to randomisation received a BID basal regimen with other basal insulin
types than NPH should have a unit to unit conversion of their total daily basal insulin dose and
injected once daily
!
EU patients that prior to randomisation received a BID basal regimen with any basal insulin
type should have their total daily basal insulin dose reduced by 20% and injected once daily
3.2
Titration
After randomisation the insulin dose will be adjusted once weekly by the investigator in connection 
with the scheduled visits/phone contacts.
The dose adjustment will be based on the mean of three fasting SMPG values measured on two 
days prior to titration and on the day of the visit. Adjustments will be in accordance with Table 1
and Table 2.
If one or more SMPG values are missing, the dose adjustment should be performed on the 
remaining SMPG value(s). The insulin dose adjustment should aim to reach a SMPG of 4.0–5.0 
mmol/L (71–90 mg/dL).
Table 1
IDeg 200 U/mL or IGlar 300 U/mL dose increase
Mean pre-breakfast SMPG
Dose adjustment
mmol/L
mg/dL
U
4.0 – 5.0
71 – 90
No adjustment
5.1 – 7.0
91 – 126
+ 2
7.1 – 8.0
127 – 144
+ 4
8.1 – 9.0
145 – 162
+ 6
> 9.0
> 162
+ 8
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
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Table 2
IDeg 200 U/mL or IGlar 300 U/mL reduction
Lowest pre-breakfast SMPG
Dose adjustment
mmol/L
mg/dL
U
3.1 – 3.9
56 – 70
- 2
<3.1
< 56
- 4
3.3
Deviations from the algorithm
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust theIDeg200 U/mLor IGlar 300 U/mLdoses are based on all relevant information as 
described in Section1. A reason for deviating from thealgorithmshould be entered into the 
eCRF .
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
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4
Data collection
The following data should be entered into the eCRF within 24 hours (on weekdays) after a site 
visit/phone contact:
!
Per protocol pre-breakfast SMPG values measured since last visit/telephone contact as
described in section 3.2
!
IDeg 200 U/mL/IGlar 300 U/mL doses taken day -2 and day -1 prior to the visit/phone contact
!
New IDeg 200 U/mL/IGlar 300 U/mL dose prescribed at this contact.
!
Reasons for deviation from the titration algorithms, if applicable
!
Hypoglycaemic episodes
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
8 of 9
5
Review procedure
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased manner. It 
is important that data regarding dose titration is entered into the eCRF within 24 hours (on 
weekdays). If delays occur, action cannot be taken in due time before the subject’s next site 
visit/phone contact. The aim is to reduce the time periods in which a subject may receive 
suboptimal treatment.
The data listed in section 4 will be reviewed by Novo Nordisk within 24 hours (on weekdays). The 
reviewer may contact the investigator to get clarification regarding the reason for deviation or to 
request entry of missing data.
When the investigator receives an inquiry, a response should be received at Novo Nordisk within 24 
hours (on weekdays).
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the 
glycaemic control. Novo Nordisk may be in contact with sites (visit or phone contact) to discuss 
progress in glycaemic control and titration of individual subjects based on SMPGs and HbA1c. This 
will be done in an unbiased and whenever possible in a blinded manner.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
9 of 9
6
References
1.
Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised,
52-week, treat-to-target trial comparing insulin detemir with insulin glargine when
administered as add-on to glucose-lowering drugs in insulin-naive people with type 2
diabetes. Diabetologia. 2008;51(3):408-16.
2.
Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, Home P, et al. A 26-week,
randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as
add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes.
Diabetes Care. 2006;29(6):1269-74.
3.
Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B.
Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral
antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28(10):1569-81.
4.
Riddle MC, Rosenstock J, Gerich J, Insulin Glargine Study I. The treat-to-target trial:
randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic
patients. Diabetes Care. 2003;26(11):3080-6.
5.
Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, et al. Insulin
degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment
with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3,
randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1498-
507.
6.
Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. Insulin degludec, an ultra-
longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime
insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-
label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-97.
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:
insulin degludec
Trial ID: NN1250-4252
Clinical Trial Report
Appendix 16.1.1
29 May 2019
1.0
Final
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
1 of 9
Protocol Amendment
no 1
to Protocol, final version 2.0
dated 11 November 2016
Trial ID: NN1250-4252
A trial comparing the efficacy and safety of insulin degludec and insulin glargine 300 
units/mL in subjects with type 2 diabetes mellitus inadequately treated with basal insulin with 
or without oral anti-diabetic drugs
Trial phase: 3b
Applicable to Serbia
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
2 of 9
Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Introduction including rationale for the protocol amendment...........................................................3
1.1
Rationale for amendment ..........................................................................................................3
2
Changes ................................................................................................................................................3
2.1
Section 8.1.6. Follow up visits...................................................................................................3
2.2
Section 8.1.8 Premature discontinuation of trial product ............................................................4
2.3
Section 8.1.9 Withdrawal from trial...........................................................................................6
2.4
Section 9.5 Auxiliary supplies ...................................................................................................6
2.5
Section 12.4.1 Reporting of technical complaints.......................................................................7
2.6
Section 13.3 eDiary...................................................................................................................7
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
3 of 9
1
Introduction including rationale for the protocol amendment
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
1.1
Rationale for amendment
As stated in the protocol the MyGlucoHealth BG-meter used in NN1250-4252 is not marketed in 
Serbia and therefore regarded as an investigational device.
This protocol amendment has been created to reflect:
!
The process for Technical Complaint handling on the MyGlucoHealth BG-meter, strips, lancets 
and control solution, including technical complaints related to adverse events and serious 
adverse events in Serbia
!
The requirements to collect the MyGlucoHealth BG-meter at End of Trial for each subject in 
Serbia
2
Changes
2.1
Section 8.1.6.
Follow up visits
The first follow up visit (V55) is a site visit and must take place 7-12 days after the end of treatment 
visit. Follow-up visit 2 (V56) is a site visit and must take place 30-35 days after end of treatment.
Follow-up visit 1 (V55)
At the first follow up visit (V55) treatment with insulin NPH must be stopped.
The following data will be collected:
!
Date and dose of last injection of insulin NPH
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Technical complaints
!
Antibody sample
The eDiary must be returned by the subject at this visit. Subjects who prematurely discontinue trial 
product should keep the eDiary and not return it until at V54A.
Please refer to the flow chart in section 2 for the full list of assessments and procedures to be 
performed at this visit.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
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Follow-up visit 2 (V56)
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
The eDiary must be returned by the subject at this visit. Subjects who prematurely discontinue trial 
product should keep the eDiary and not return it until at V54A.
For Serbia: The BG meter must also be collected by the investigator. Subjects who prematurely 
discontinue trial product should keep the BG meter and not return it until at V54A.
2.2
Section 8.1.8
Premature discontinuation of trial product
If a subject prematurely discontinues trial product, the investigator must undertake procedures 
similar to those for the end of treatment visit (V54) as soon as possible including fasting blood 
sampling and dispensing of wash-out insulin NPH, see Section 8.1.5.
Treatment discontinuation must be performed in the eDiary web portal and in the IWRS.
Furthermore two follow up visits similar to V55 and V56 must be performed 7-12 and 30-35 days 
after discontinuation of trial product, respectively.
Follow-up visit 1 (V55)
At the first follow up visit (V55) the subject should be switched to treatment with a suitable 
marketed product at the discretion of the investigator.
The following data will be collected:
!
Date and dose of last injection of insulin NPH prior to V55
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Technical complaints
!
Antibody sample
Follow-up visit 2 (V56)
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
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!
Concomitant medication (diabetes)
In addition, subjects prematurely discontinued from trial product should come in for abbreviated 
site visits at week 16 (V18A), week 28 (V30A) and at week 40 (V42A) after randomisation 
depending on when the subject discontinues trial product. The abbreviated site visits can be 
converted to phone contacts if needed.
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Blood sample to measure HbA1c (only if site visit)
In between the abbreviated site visits listed above monthly phone contacts (PX visits) should be 
performed until the originally planned end of treatment.
The following data will be collected:
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
The earliest of the abbreviated site visits or monthly phone contacts (whichever comes first) should 
be scheduled at least 30 days after FU2. If the timing of a monthly phone contact (PX visit) is less 
than two weeks from a planned abbreviated site visit, the phone contact can be omitted.
Subjects prematurely discontinued from trial products should come in for a final visit (V54A) at the 
originally planned end of treatment date to collect:
!
Date and dose of basal insulin
!
AEs
!
Hypoglycaemic episodes
!
Concomitant medication (diabetes)
!
Blood sample to measure HbA1c
The eDiary must be returned by the subject at this visit.
For Serbia: The BG meter must also be collected by the investigator.
The primary reason for premature discontinuation of trial product must be specified in the End-of-
Treatment form in the eCRF, and final drug accountability must be performed. A treatment 
discontinuation session must be made in the IWRS.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
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2.3
Section 8.1.9
Withdrawal from trial
If a subject withdraws consent, the investigator should aim to undertake procedures similar to those 
for the end of treatment visit (V54) as soon as possible. The eDiary must be returned by the subject 
at this visit.
For Serbia: The BG-meter must also be collected by the investigator.
If the subject agrees, the follow up visits (V55 and V56) must be performed 7-12 and 30-35 days 
after discontinuation of trial product.
The End-of-Treatment and End of Trial forms must be completed, and final drug accountability 
must be performed even if the subject is not able to come to the trial site. A treatment 
discontinuation session must be made in the eDiary web portal and in the IWRS. The case book 
must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the End-of-Trial form in the eCRF.
Subjects withdrawing consent during the follow up period will be considered as completers.
2.4
Section 9.5
Auxiliary supplies
The following will be provided by Novo Nordisk:
!
Direction for use for the pen injectors
!
Novo Nordisk needles for prefilled systems
!
MyGlucoHealth Wireless Meter (CE approved) and strips, lancets and control solution for BG 
meters
!
eDiary
Only needles provided by Novo Nordisk must be used for administration of trial product.
For Serbia: The BG-meter is regarded as an investigational device. Technical complaints regarding 
the BG-meter including technical complaints related to AEs and SAEs should be reported to the 
manufacturer of the device (Entra Health Systems). Refer to Section 12.4.1 for details. This device 
has been selected in order to have automatic transfer of SMPG data to the eDiary and thereby 
increase the accuracy of SMPG values. It is expected that the better accuracy in SMPG data will 
facilitate an improvement in the insulin titration efforts during the trial.
Please refer to the TMM for further auxiliary supplies’ details.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
7 of 9
2.5
Section 12.4.1
Reporting of technical complaints
All technical complaints on any of the following products:
!
Insulin degludec 3ml PDS290 pen injector (FlexTouch®)
!
Insulin glargine (Toujeo®)1.5ml prefilled pen (SoloStar®)
!
Insulin NPH (Insulatard®/Prothaphane®/Novolin N™) 3ml prefilled pen (FlexPen®)
!
Novo Nordisk needles for pre-filled pen systems
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs and/or SAEs.
Technical complaints must be reported on a separate technical complaint form:
!
One technical complaint form must be completed for each affected DUN
!
If DUN is not available, a technical complaint form for each 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:
!
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.
For Serbia: Technical complaints on the BG meter, strips, lancets and control solutions must be 
reported to ENTRA on a separate technical complaint paper form within the same timelines as for 
technical complaints specified above. AEs and SAEs related to the technical complaints on the BG 
meter must also be reported to Novo Nordisk, see Section 12.2 for details. Contact details (fax, e-
mail and address) are provided in Attachment I to the protocol.
2.6
Section 13.3
eDiary
An eDiary will be used to capture patient reported data, see Sections 8.3.1, 8.3.2 and 8.4.2. The 
Investigator must carefully instruct the subject in how to use the eDiary. All data entered in the 
eDiary is considered source data. All data from the eDiary will be transferred electronically to the 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
8 of 9
electronic patient reported outcomes (ePRO) database. Data in the ePRO database will be viewable 
to investigator and Novo Nordisk personnel on a secure, password protected eDiary web portal.
The investigator must review all the data for the subjects belonging to the site through the eDiary 
web portal. The review of hypoglycaemic episode confirmation must be documented in the web 
portal, while review of remaining data must be documented in the subject’s medical record. The 
review of data must be performed before or during each visit/phone contact.
In case of corrections to transferred data are needed, a query flow must be initiated by the 
investigator. Upon review by Novo Nordisk, data will be corrected accordingly by the vendor. An 
audit trail will be maintained.
The Investigator should record the following administrative information in the eDiary/web portal:
!
Subject ID
!
Visit confirmation
!
Hypoglycaemic episode confirmation
!
Prescribed doses of trial products or confirm recommended dose
!
Reason for deviation from the recommended dose, if needed
!
Evaluate if a hypoglycaemic episode qualifies as an SAE
Data will be transferred to the Novo Nordisk trial database at defined intervals. For details on 
eDiary data flow, see Figure 13-1.
Figure 13-1 eDiary data flow
Oracle Clinical
ePRO Vendor
Investigator site
Subject
Novo Nordisk
ePRO database
eDiary device
Web Portal
Trial Team
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
25 July 2017
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
9 of 9
Selected titration data (e.g. certain SMPGs and dose data) will only be used during the trial for 
central titration surveillance, to ensure compliance with the titration guideline (Appendix A), and 
will not be reported in the clinical trial report (CTR). All data will be stored by Novo Nordisk (see 
Section 24).
The eDiary should be collected by the Investigator at FU2 (V56).
For Serbia: The BG-meter mustalso be collected by the investigatorat FU2 (V56).
Subjects who prematurely discontinue trial product should keep the eDiary and not return it until at 
V54A.
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
1 of 4
Protocol Amendment
no 2
to Protocol, version 2.0
dated 11 Nov 2016
Trial ID: NN1250-4252
A trial comparing the efficacy and safety of insulin degludec and insulin glargine 300 
units/mL in subjects with type 2 diabetes mellitus inadequately treated with basal insulin with 
or without oral anti-diabetic drugs
Trial phase: 3b
Applicable to all countries
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 2
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
2 of 4
Table of Contents
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
Due to an unusual data reporting pattern of hypoglycaemia and glycaemic values in two ongoing 
randomised clinical trials (NN1250-4252 and NN1218-4113), Novo Nordisk has decided to 
discontinue the glycaemic data collection system (i.e. the combined use of a BG-meter and eDiary) 
in trials using this system to protect the safety of the trial participants. This affects the 
NN1250-4252, NN1218-4113 and NN1250-4300 trials.
This protocol amendment has been created in alignment with the above decision to replace the 
electronic glycaemic data collection system with a paper diary solution.
2
Changes
The discontinuation of the glycaemic data collection system necessitates update of many sections. 
of the Protocol, Titration guideline and Protocol Metadata Document (PMD).
The changes are affecting the following sections of the protocol:
-
1 Summary
-
2 Flowchart
-
4 Objective(s) and endpoint(s)
-
5 Trial design
-
6.4 Criteria for premature discontinuation of trial product
-
8.1.5 Maintenance2initiationvisit (57)New section
-
8.1.6 End of TreatmentVisit
-
8.1.7 Follow up visits
-
8.1.9 Premature discontinuation of trial product
-
8.1.10 Withdrawal from trial
-
8.1.11 Review of results
-
8.2.5 Concomitant medication
-
8.2.6Concomitant medication(Diabetes)
-
8.3.1Self-measured plasma glucose
-
8.3.2 Insulin dose
-
8.4.2 Hypoglycaemic episodes
-
8.4.6 Eye examination
-
8.4.7 Electrocardiogram
-
8.5.2 Laboratory assessments for safety
-
8.6 Other assessments
-
8.7 Subject compliance
-
9.5 Auxiliary supplies
-
12.1.5 Adverse events requiring additional data collection
-
12.7.2 Event adjudication committee
CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
23 February 2018
Novo Nordisk
Trial ID: NN1250-4252
Version:
1.0
UTN: U1111-1184-8175
Status:
Final
EudraCT no.: 2016-002801-20
Page:
4 of 4
-
13.3 eDiary – complete section deleted
-
14 Monitoring procedures
-
17 Statistical considerations
-
18 Ethics
-
19.2 Prevention of missing data
The changes are affecting the following sections of the Titration guideline:
-
3.3 Deviations from the algorithm
-
4 Data collection
-
5 Review procedure
The Protocol Metadata Document (PMD) will be updated after PRC approval of the updated 
flowchart.
CONFIDENTIAL


From:
To:
TMF
Memo
Copy:
Ref.: PLLP
11 January 2019
Novo Nordisk A/S
Trial Operations 3, Insulin & Devices
Telephone:
+45 4444 8888
E-mail:
Internet:
www.novonordisk.com
CVR Number:
Vandtårnsvej 114
DK-2860 Søborg
Denmark
NN1250-4252 Handling of Anti-insulin antibodies
On 16 January 2018 it was decided by the Corporate Vice President not to analyse 
Anti-insulin antibodies collected in NN1250-4252 as the data are not required at 
present.
All collected antibody samples are being sent to the Central Laboratory and then 
transferred to the Novo Nordisk Laboratory in Måløv for storage until further notice.
The protocol states in section 17.6.2: “Anti-insulin antibodies will be summarised by 
visit”. 
This has been deleted from the Statistical Analysis Plan (SAP).
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03078478 
Sponsor trial ID: 
NN1250-4252 
Official title of study: 
A trial comparing the efficacy and safety of insulin degludec 
and insulin glargine 300 units/mL in subjects with type 2 
diabetes mellitus inadequately treated with basal insulin with or 
without oral antidiabetic drugs 
Document date: 
21 May 2019 
 


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
insulin degludec
Trial ID: NN1250-4252
Clinical Trial Report
Appendix 16.1.9
21 May 2019
1.0
Final
16.1.9 Documentation of statistical methods
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
1 of 31
Statistical Analysis Plan
Trial ID: NN1250-4252
A trial comparing the efficacy and safety of insulin degludec 
and insulin glargine 300 units/mL in subjects with type 2 
diabetes mellitus inadequately treated with basal insulin with 
or without oral antidiabetic drugs
Trial phase: 3b
Author:
 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
2 of 31
Table of contents                                                                                   Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................4
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.1.1
Other endpoints and assessments..............................................................................6
1.2
Scope of the statistical analysis plan..........................................................................................8
2
Statistical considerations .....................................................................................................................9
2.1
General considerations ..............................................................................................................9
2.2
Power calculation....................................................................................................................10
2.3
Definition of analysis sets........................................................................................................12
2.4
Primary endpoint.....................................................................................................................12
2.4.1
Primary statistical analysis for the on-treatment estimand.......................................12
2.4.2
Sensitivity analyses for the on-treatment estimand..................................................13
2.4.3
Statistical analysis for the ITT estimand.................................................................14
2.4.4
Sensitivity analysis for the ITT estimand................................................................14
2.5
Secondary endpoints ...............................................................................................................14
2.5.1
Confirmatory secondary endpoints.........................................................................14
2.6
Other endpoints and assessments.............................................................................................15
2.6.1
Efficacy endpoints .................................................................................................15
2.6.2
Safety endpoints ....................................................................................................15
2.6.3
Safety assessments.................................................................................................18
2.7
Classification of hypoglycaemia..............................................................................................18
2.8
Health economics and/or patient reported outcomes.................................................................19
3
Changes to the statistical analyses planned in the protocol..............................................................20
3.1
Update of specifying safety assessments..................................................................................20
3.2
Update and clarification of definition of in trial and on treatment period, maintenance 
period 1 and 2, and completer definition:.................................................................................21
3.3
Update of baseline value .........................................................................................................22
3.4
Specifying tables on treatment discontinued/withdrawn subjects prior to maintenance 2 ..........22
3.5
Handling of ULOQ values.......................................................................................................22
3.6
Contribution in FAS................................................................................................................23
3.7
Changing imputation model in primary analysis from negative binomial to Poisson, fewer 
covariates and different backup strategy. .................................................................................23
p. 85 l. 2051-2080 is replaced by:............................................................................................23
“Primary statistical analysis for the on-treatment estimand ......................................................23
3.8
Clarification of handling of treatment emergent hypoglycaemic episodes during follow-up 
period......................................................................................................................................24
3.9
Sensitivity analyses for primary analysis on-treatment estimand:.............................................25
3.10
Omitting backup strategy for ITT estimand .............................................................................25
3.11
Sensitivity analyses for primary analysis ITT estimand:...........................................................26
3.12
Clarification of primary analysis ITT estimand:.......................................................................26
3.13
Handling of zero doses............................................................................................................26
3.14
Tables on adverse events.........................................................................................................27
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
3 of 31
3.15
Analyse hypoglycaemic episodes during total treatment period................................................27
3.16
Presentation of lab data ...........................................................................................................28
3.17
Omit antibodies from statistical section ...................................................................................29
3.18
Updated ADA hypo classification ...........................................................................................29
4
References ..........................................................................................................................................31
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
4 of 31
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ANCOVA
analysis of covariance
BG
blood glucose
FAS
full analysis set
FPG
fasting plasma glucose
HbA1c
glycosylated haemoglobin
IDeg
insulin degludec
IGlar
insulin glargine
ITT
intention-to-treat 
MACE
major adverse cardiovascular events
MMRM
mixed model for Repeated Measurement
OAD
oral antidiabetic drug
SAP
statistical analysis plan
SAS
safety analysis set
SD
standard deviation
TEAE
treatment-emergent adverse event
TID
three times daily
T2DM
type 2 diabetes mellitus
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
5 of 31
1
Introduction
1.1
Trial information
Objectives and endpoints
The primary objective
!
To compare the effects of IDeg OD and IGlar 300 U/mL OD on hypoglycaemia in subjects 
with T2DM, inadequately treated with basal insulin with or without OADs.
The secondary objectives
To compare IDeg and IGlar 300 U/mL in terms of basal insulin requirement.
To compare IDeg and IGlar 300 U/mL in terms of safety and parameters of glycaemic control.
Primary endpoint
!
Number of severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes 
during maintenance 2 (36 weeks)
Confirmatory secondary endpoints
!
Basal insulin dose (U) at end of maintenance 2 (up to 88 weeks)
!
Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes during 
maintenance 2 (36 weeks)
!
Number of severe hypoglycaemic episodes during maintenance 2 (36 weeks )
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
6 of 31
1.1.1
Other endpoints and assessments
Other efficacy endpoints
!
Change in HbA1c from baseline to end of maintenance 2 (up to 88 weeks)
!
Change in fasting plasma glucose (FPG) from baseline to end of treatment (up to 88 weeks)
!
FPG ≤ 7.2 mmol/L (130 mg/dL) at end of treatment (up to 88 weeks) (yes/no)
!
FPG ≤ 5 mmol/L (90 mg/dL) at end of treatment (up to 88 weeks) (yes/no)
!
HbA1c < 7% (53 mmol/mol) at end of maintenance 2 (up to 88 weeks) and no severe or BG 
confirmed symptomatic hypoglycaemic episodes during maintenance 2 (36 weeks ) (yes/no)
!
HbA1c < 7% (53 mmol/mol) at end of maintenance 2 (up to 88 weeks) and no nocturnal, 
severe or BG confirmed symptomatic hypoglycaemic episodes during maintenance 2 (36 
weeks ) (yes/no)
!
Change in mean pre-breakfast self-measured plasma glucose used for titration from baseline 
to end of treatment (up to 88 weeks)
Other safety endpoints
!
Hypoglycaemia
!
Number of severe or BG confirmed symptomatic hypoglycaemic episodes from 
randomisation until end of maintenance 2 (up to 88 weeks)
!
Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes 
from randomisation until end of maintenance 2 (up to 88 weeks)
!
Number of severe hypoglycaemic episodes from randomisation until end of 
maintenance 2 (up to 88 weeks)
!
Number of adverse events from randomisation until end of maintenance 2 (up to 88 weeks)
!
Change in body weight from baseline to end of treatment (up to 88 weeks)
Safety assessments
!
Change in clinical evaluations from baseline to end of treatment (up to 88 weeks) in terms 
of:
o
Vital signs (including blood pressure and pulse)
o
Dilated fundoscopy or fundus photography
o
Electrocardiogram (ECG)
!
Change in central laboratory assessments from baseline to end of treatment (up to 88 weeks) 
in terms of
o
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes)
o
Biochemistry (creatinine, alanine aminotransferase , aspartate aminotransferase , 
alkaline phosphatase , sodium, potassium, albumin, total bilirubin)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
7 of 31
Trial design:
This is a up to 88-week, randomised (1:1), open-label, parallel, multi-centre, multi-national, treat-
to- target, active controlled trial comparing the efficacy and safety of insulin degludec 200 units/mL 
with insulin glargine 300 units/mL both administered once daily ± oral anti-diabetic drugs in 
subjects with type 2 diabetes mellitus previously treated with basal insulin once or twice daily ± 
oral anti-diabetic drugs excluding sulfonylureas/glinides. Type and dose of any pre-trial oral anti-
diabetic treatment should remain unchanged throughout the trial.
Within each treatment arm, subjects will be randomised 1:1 to morning (from waking up to 
breakfast) or evening dosing (from main evening meal to bedtime). The dosing time will be kept 
throughout the entire treatment period.
The trial is conducted with a treat-to-target principle: the insulin dose is adjusted for each individual 
subject with the aim of achieving identical glycaemic targets for IDeg and IGlar 300 U/mL. This 
allows for a valid comparison of hypoglycaemia.
Due to an unusual data reporting pattern of hypoglycaemia and glycaemic values being linked to the 
glycaemic data collection system (the combined use of MyGlucoHealth with the electronic diary) it 
was decided on 14 February 2018 to apply a new data collecting system consisting of an Abbott 
BG-meter and a paper diary.
To accommodate changes in the data collection system and to ensure sufficient data collection with 
respect to the confirmatory endpoints a new maintenance period (maintenance 2) of 36 weeks 
duration was included in the trial. Following the protocol amendment, the total trial duration will be 
up to 94 weeks divided into the following periods:
!
Screening up to two weeks
!
Screening (V1)
!
Randomisation (V2)
!
Treatment period consisting of
!
A 16-week titration period
!
An up to 36-week maintenance 1 period
!
A 36-week maintenance 2 period
!
30 days post treatment follow-up period including two follow-up (FU) contacts
!
FU1  7-12 days after end of treatment
!
FU2 30-35 days after end of treatment
In case of premature treatment discontinuation, subjects will be encourage to remain in trial and 
come in for abbreviated visits according to the visit schedule until the planned time of V54/V93.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
8 of 31
Further details
For further details on trial design and endpoints please see the NN1250-4252 protocol version 3.0.
1.2
Scope of the statistical analysis plan
This SAP is based on the NN1250-4252  protocol version 3.0.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
9 of 31
2
Statistical considerations
2.1
General considerations
The in-trial period will include information collected at or after the date of randomisation and until
the date of:
!
The last scheduled subject-site contact
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
Death for subjects who die before any of the above
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product. The period starts on day of the first dose of trial product and ends 7 days after last dose of 
trial product is taken, but no later than the end of the in-trial period.
Maintenance period 1 starts on the day of V18/V18A. For subjects not attending neither V18 nor 
V18A, but still in trial for more than 16 weeks, maintenance 1 instead starts 16 weeks (112 days) 
after randomisation. 
Maintenance period 2 starts at the date of V57/V57A. Subjects not attending neither V57 nor V57A 
will not have a maintenance 2 period, regardless of duration in trial.
A subject is completing the trial if he/she attends V93 or V93A at the end of maintenance 2 period. 
It is considered completing trial on treatment if the subject attends V93 without premature 
discontinuation of trial product.
All efficacy endpoints will be summarised using the full analysis set (FAS) and safety endpoints 
excluding hypoglycaemic endpoints will be summarised using the safety analysis set (SAS). For 
hypoglycaemia, the SAS will be used when on-treatment data is used, and FAS is used for in-trial 
data.
All statistical analysis of efficacy and safety endpoints will be based on the FAS unless otherwise 
specified. Confirmatory analysis addressing the primary estimand will include on-treatment data 
and not available retrieved (V93A) data.
The primary objective is to compare the effects of IDeg OD and IGlar 300 U/mL OD on the rate of 
hypoglycaemia in subjects with type 2 diabetes mellitus, inadequately treated with basal insulin 
with or without oral anti-diabetic drugs. The primary estimand is the treatment difference between 
IDeg and IGlar 300 U/mL assuming that all randomised subjects adhered to the randomised 
treatment, and is thus referred as the on-treatment estimand. The on-treatment estimand addresses 
the treatment difference for subjects who can be long-term treated with either of the two insulins. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
10 of 31
Data collected after premature treatment discontinuation will not be used when addressing the on-
treatment estimand. With the aim of comparing a safety endpoint this estimand is considered the 
most relevant as it compares the occurrence of a safety endpoint that is caused by the drug during 
exposure to the drug. The confirmatory endpoints will additionally be investigated with a ITT 
estimand.
The secondary estimand is the treatment difference between IDeg and IGlar 300 U/mL regardless of 
whether subjects adhered to the randomised treatment throughout the trial, that is an ITT estimand. 
For this ITT estimand, data collected after premature discontinuation will be used.
In accordance with guidance9 endpoints will be assessed at frequent visits and also for subjects who 
prematurely discontinue treatment. When an assessment is planned at randomisation visit, this value 
will be used as baseline value. If this value is missing the last recorded value before randomisation 
visit will be used. For assessments planned only at screening, the screening values will be used as 
baseline. If this value is missing, the first recorded visit after screening, but no later than the day of 
randomisation, will be used.
For patients not initiating maintenance period 2 on treatment a summary table of reasons for 
treatment discontinuation will be reported.
The severe hypoglycaemia episodes included in the statistical analysis are all events adjudicated 
with the outcome severe hypoglycaemia.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
Laboratory values above the upper limit of quantification (ULOQ) will be set to ULOQ+1.
The primary and secondary endpoints will be tested in a hierarchical order using the on-treatment
estimand to control the family wise Type I error in the strong sense. Presentation of results from a 
statistical analysis will include the estimated treatment means as well as estimated mean treatment 
difference (or ratio) together with the two-sided 95% confidence interval and corresponding two-
sided p-value.
In the statistical models explanatory factors will be categorized as follows:
1. Treatment: IDeg, IGlar 300 U/mL
2. Pre-trial 0 OADs, 1OAD, ≥2 OADs
3. Region: Europe , North America
4. Sex: male, female
5. Dosing time: morning, evening
2.2
Power calculation
The power is based on the primary objective and the primary endpoint, number of hypoglycaemic 
episodes during maintenance treatment.
For the power calculations it is assumed that the true treatment rate ratio (RR) is 0.75 corresponding 
to a 25% reduction in rate of hypoglycaemia in maintenance period with IDeg OD compared to 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
11 of 31
IGlar 300 U/mL OD. Sample size is determined based on a negative binomial model with log-offset 
equal to exposure time in maintenance. The observed rate of severe or BG confirmed symptomatic 
hypoglycaemia for IDeg is assumed to be 1.8 per patient years of exposure (PYE) and the 
dispersion parameter in the negative binomial distribution is assumed to be 3.1. Furthermore it is 
assumed that 4% of subjects will withdraw before starting the maintenance period and therefore 
have no on-treatment data for the maintenance period. For these 4% the treatment ratio is set to 1. 
Rate assumptions are based on experience from SWITCH 2 (NN1250-3998), which has similar 
inclusion criteria. Dispersion parameter assumptions are based on experience from the Degludec 
phase 3a and 3b program. Assumptions concerning withdrawal are similarly based on actual 
withdrawal rate of the trial during titration and maintenance 1.
The power equals 79% with the number of randomised subjects and the assumptions above.
Table 2–1
Power for the on-treatment estimand for combinations of RR and event rates
Yearly event rate
1.5
1.8
2.0
RR
Adjusted RR
Primary
Primary
Primary
0.80
0.812
55%
57%
58%
0.75
0.765
77%
79%
79%
0.70
0.718
92%
93%
93%
The marginal power for detecting a difference between IDeg OD and IGlar 300 U/mL OD with 805 
subjects per treatment arm assuming a one-sided t-test at the 2.5% significance level for the 
confirmatory secondary dose endpoints is shown below. The assumptions are based on data from 
NN1250-3998 with respect to hypoglycaemic episodes and the phase 3a+b program for the dose-
difference.
Table 2–2
Marginal power for confirmatory secondary endpoints
Assumptions
Endpoint
True ratio
Adjusted RR
CV/
Over dispersion
Rate in IDeg
treatment arm
Power
Insulin dose (U)
0.90
0.906
0.65
-
92%
Number of nocturnal, severe or 
BG confirmed symptomatic 
hypoglycaemic episodes during 
maintenance 2
0.7
0.718
3.1
0.55
82%
Number of severe 
hypoglycaemic episodes during 
maintenance 2
0.6
0.624
3.1
0.03
31%
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2.3
Definition of analysis sets
Full analysis set (FAS): includes all randomised subjects. In exceptional cases, subjects may be 
eliminated from the full analysis set. In such cases the elimination will be justified and documented. 
In the statistical evaluation of the full analysis set subjects contribute "as randomised".
Safety analysis set (SAS): includes all subjects receiving at least one dose of the investigational 
product or comparator. Subjects in the safety set will contribute to the evaluation “as treated”.
Randomised subjects who are lost to follow up and where no exposure information of the 
investigational product or comparators is available after randomisation will be handled as 
unexposed.
Before data are released for statistical analysis, a review of all data will take place to identify 
protocol deviations that could potentially affect the results. In exceptional cases a decision to 
exclude any subject or observation from the statistical analysis can be made. This is the joint 
responsibility of the members of the study group. The subjects or observations to be excluded, and 
the reasons for their exclusion must be documented before database lock. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report.
2.4
Primary endpoint
2.4.1
Primary statistical analysis for the on-treatment estimand
The on-treatment estimand will be estimated based on information from maintenance 2 collected 
when subjects use randomised treatment including a 7-day follow-up period (on-treatment data). 
Subjects that discontinue randomised treatment during maintenance 2 will contribute with the 
available on treatment data from maintenance 2. For subjects that discontinue randomised treatment 
during the titration period or maintenance 1, the number of events in maintenance 2 will be imputed 
based on data from the same arm from maintenance 2 for subjects that discontinued randomised 
treatment during maintenance 2. Missing data within each group will be imputed as follows:
!
First 1000 samples from the posterior distribution of model parameters will be extracted. 
The model will be fitted to the on-treatment maintenance 2 data for subjects that 
discontinued randomised treatment during maintenance 2. This will be done using a Bayes 
Poisson log-link model dosing time as a factor, age as covariate, and log of exposure time as 
offset.
!
For each sample of model parameters, the total number of hypoglycaemia events for 
subjects that discontinued randomised treatment in the titration period or maintenance 1 will 
be imputed as a random number of events from a Poisson distribution using the sampled 
parameters.
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Having 1000 complete data sets that have maintenance 2 data for all randomised subjects, the mean 
treatment ratio will be estimated using a negative binomial model with all the factors described in 
section 2.1, age as covariate and log exposure time as offset. The estimates and standard deviations 
will be pooled to one estimate and associated standard deviation using Rubin’s formula. From these 
the 95% confidence intervals for the treatment ratio and the associated p-value will be calculated.
If the above imputation model cannot fit or leads to inflate the standard error of the treatment ratio 
on logscale by more than 15% compared to a negative binomial model fitted to the available on-
treatment data during maintenance 2 without any imputation, an alternative model is used for the 
analysis: The imputation model will be a negative binomial model fitted to all available on-
treatment data during maintenance 2 and including all factors described in section2.1, age as 
covariate and log exposure time as offset.If this model cannot fit either, the imputation model is fit 
as a Poisson model to all available on-treatment maintenance 2 data, and if needed factors are left 
out from the imputation model in the following order:
!
sex
!
region
!
previous OAD treatment
2.4.2
Sensitivity analyses for the on-treatment estimand
To investigate missing not at random scenarios, a tipping point analysis of the hypothesis that IDeg 
is superior to IGlar 300 U/mL will be performed for the on-treatment estimand. In this analysis the 
event rates for subjects that discontinued randomised treatment in the IDeg OD arm during either 
titration or maintenance 1 periods is gradually increased until the difference between the two 
treatments is no longer statistically significantly different. If the penalty found by this method is 
evaluated to be clinically plausible the sensitivity analysis does not support the primary analysis. If 
the penalty is not considered plausible the sensitivity analysis supports the primary analysis.
To investigate the potential influence of subjects with high number of events, the analysis of the on-
treatment estimand will be repeated on data where the maximal number of events in maintenance 2 
is truncated at three. The value three is based on data from SWITCH 2 (NN1250-3998) where three 
hypos correspond to the 95% percentile in the IDeg arm. Furthermore, a statistical sensitivity 
analysis is performed with a truncation at seven, to accommodate for the longer analysis period in 
the current trial (36 weeks instead of 16 weeks).
The primary analysis will be performed using only available on-treatment data during maintenance 
2. Subjects without on-treatment data for maintenance 2 period will be excluded from this analysis,
and thus no imputation is needed.
The primary analysis will be repeated, but considering the full maintenance period (maintenance 1 
and maintenance 2). Missing data will be imputed for subjects that discontinued randomised 
treatment during titration period only, using on-treatment data for maintenance 1 and 2. This 
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analysis evaluates if including the data from the discontinued BG-meter challenge the overall 
conclusion of the trial.
The primary analysis will be repeated, with the exemption of imputation of hypoglycaemic episodes 
for subjects in IDeg arm actively refusing to reconsent to the extended trial period following the 
protocol amendment, defined as subjects discontinuing treatment after 15FEB2018 and either not 
reconsenting or not taking any doses of trial product later than the date of reconsenting. For these 
subjects, the imputation will be based on the usual statistical model fitted to all maintenance 2 data 
in the IGlar arm. This analysis evaluates if the conclusion of the primary analysis is different if non-
consenters on IDeg arm are worse off than consenters.
The impact of protocol deviations and outliers may be investigated further in sensitivity analyses.
2.4.3
Statistical analysis for the ITT estimand
The ITT estimand will be estimated based on information from maintenance 2 collected regardless 
of whether subjects used randomised treatment or not, i.e. including data after premature 
discontinuation.
Missing data for withdrawn subjects prior to maintenance 2 will be imputed based on off-treatment 
data from the same arm from maintenance 2 . The imputations and the analysis will be made using 
the same method as for the on-treatment estimand. If the imputation model cannot fit or leads to 
inflate the standard error of the treatment ratio on logscale by more than 15% compared to a 
negative binomial model fitted to the available on- and off-treatment data during maintenance 2 
without any imputation the analysis will not be performed.
2.4.4
Sensitivity analysis for the ITT estimand
A tipping point sensitivity analysis similar to the one for the on-treatment estimand will be 
performed. The penalty will only be added to withdrawn subjects in IDeg arm. Further sensitivity 
analyses may be performed.
2.5
Secondary endpoints
2.5.1
Confirmatory secondary endpoints
Provided that IDeg OD is superior to IGlar 300 U/mL OD for the primary endpoint using the on-
treatment estimand, the confirmatory secondary endpoints will be tested for superiority of IDeg OD 
over IGlar 300 U/mL OD using the on-treatment estimand.
The confirmatory secondary endpoints are given below; the order of the endpoints defines the 
testing sequence. The hierarchical testing strategy will control the family wise type 1 error in the 
strong sense at 5% (two sided).
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1. Basal insulin dose (U) at end of maintenance 2 (up to 88 weeks)
2. Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes during 
maintenance 2 (36 weeks)
3. Number of severe hypoglycaemic episodes during maintenance 2 (36 weeks)
The hypoglycaemic endpoints will be analysed with the same analysis method as the primary 
endpoint including backup strategy and with similar sensitivity analysis.
Basal insulin dose at end of maintenance 2 will be analysed as follows: A basal insulin dose at 
every titration, maintenance and end of treatment visit mentioned in the flow chart will be 
calculated as a mean of the insulin doses in the 7 day period before the visits. For the on-treatment
estimand these doses will be analysed on log-scale with an MMRM with the factors described in 
section 2.1 and age at baseline and logarithm of pre-trial insulin dose as covariate, all nested within 
visit. If this model does not converge visits and/or factors will be excluded from the analysis.
Before transforming to log-scale, dose values of 0 will be assigned the value 0.5.
Insulin dose will also be analysed with the ITT estimand, i.e. including insulin dose collected after 
premature discontinuation. This is done using a pattern mixture model using multiple imputation to 
handle missing data. Imputation of missing data at end of trial will be done within the 4 groups of 
subjects defined by randomised treatment and whether subjects discontinued randomised treatment 
or not. Missing data within each group will be imputed as follows:
!
An analysis of covariance model for insulin dose at visit 93 and 93A with the factors listen 
in 2.1 (except treatment) and pre-trial insulin dose and age at baseline as covariates will be 
fitted to the observed data.
!
The estimated parameters will be used to impute 1000 values for insulin dose at visit 
93/93A, creating 1000 complete datasets.
Having 1000 complete datasets, each of these will be analysed using an analysis of covariance 
model with all the factors listed in 2.1, pre-trial insulin dose and age at baseline as covariates. The 
estimates and standard deviations will be pooled to one estimate and associated standard deviation 
using Rubin’s formula. From these the 95% confidence intervals for the treatment ratio and the 
associated p-value will be calculated.
2.6
Other endpoints and assessments
2.6.1
Efficacy endpoints
Supportive secondary efficacy endpoints will be summarised descriptively by visits and and 
supplemented by mean plots of observed values for the continuous endpoints.
2.6.2
Safety endpoints
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Adverse events during the total treatment period (titration and maintenance periods)
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities.
A treatment-emergent AE (TEAE) is defined as an event that has onset date on or after the first day 
of exposure to randomised treatment and no later than 7 days after the last day of randomised 
treatment, or has onset date before the first day of exposure on randomised treatment and increases 
in severity during the treatment period and until 7 days after the last drug date. Major adverse 
cardiovascular events (MACEs, defined as all cardiovascular deaths, non-fatal myocardial 
infarctions and non-fatal strokes) are considered treatment-emergent until 30 calendar days after the 
last day of randomised treatment.
AEs are summarised descriptively. AE data will be displayed in terms of the number of subjects 
with at least one event (N), the percentage of subjects with at least one event (%), the number of 
events (E) and the event rate per 100 years of exposure (R).
Summaries are presented as an overview including all AEs, serious AEs, number of deaths, AEs by 
severity, AEs by relation to treatment and AEs leading to treatment discontinuation as summary 
tables based on system organ class and preferred terms for the following AEs:
!
All TEAEs
!
All AEs
!
All TEAEs during maintenance 2
!
Serious TEAEs
!
TEAEs possibly or probably related to trial product
!
Severe TEAEs
!
TEAEs with preferred term that are experienced by at least 5%  of the subjects in any 
treatment arm or by at least 5% of all subjects
.
Hypoglycaemic episodes
For the definition and classification of hypoglycaemic episodes refer to section 2.7.
Data on treatment-emergent hypoglycaemic episodes are presented in terms of the number of 
subjects with at least one event (N), the percentage of subjects with at least one event (%), the 
number of events (E) and the event rate per 100 years of exposure (R).
Separate summaries are made by severity considering severe or BG confirmed symptomatic 
hypoglycaemic episodes, severe hypoglycaemic episodes, and the Novo Nordisk interpretation of
ADA classification of hypoglycaemia from 2018. The summaries are made for all and nocturnal 
(between 00:01 and 05.59 both inclusive) episodes respectively and for the total treatment period 
(titration and maintenance periods) and maintenance 2 only (36 weeks).
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For both periods, hypoglycaemic episodes during the 7 days treatment-emergent period after last 
drug day will be included.
The number of severe or BG confirmed symptomatic hypoglycaemic events during total treatment 
period (up to 88 weeks) will be analysedstatistically, addressing both theon-treatmentand ITT
estimand.Also nocturnal severe or BG confirmed symptomatic hypoglycaemic events as well as 
severe hypoglycaemic events during total treatment period will be analysed following these 
procedures.
The on-treatmentestimand is estimated based on on-treatment data and a negative binomial model 
including the factors in section 2.1, age as covariate and the logarithm of the time period in which a 
hypoglycaemic episode was considered treatment emergent as offset. The model will use log as link 
function. 
The ITTestimand is based on in-trial data. For withdrawn subjects, data after withdrawal will be 
imputed for a period lasting from the day after withdrawal up until 36 weeks after entering 
maintenance 2 period, and until 36 weeksafter first reconsent of any subject in trial (i.e.until 
09NOV2018)for subjects not entering maintenance 2. The imputation will follow the procedure 
described in section 2.4.1, using all off-treatment data to build the imputationmodel. Observed and 
imputed data are summarised by subject, and analysed through a negative binomial model including 
the factors in section 2.1, age as covariateand the logarithm of the total time period where 
hypoglycaemic episodes are either observed or imputed as offset. The model will use log as link 
function.If the imputation model cannot fit or leads to inflate the standard error of the treatment 
ratio on logscale by more than 15% compared to a negative binomial model fitted to the available 
on-and off-treatment data during total treatment period without any imputation the analysis will not 
be performed.
Body weight
Body weight (absolute value and change from baseline) will be summarised descriptively by visit.
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2.6.3
Safety assessments
Clinical evaluation (ECG, vital signs, eye examination and physical examination) change from 
baseline 
Vital signs, physical examination, eye examination and 12-lead ECG findings will be summarised, 
including:
!
Summaries for each visit
!
Shift tables from baseline to end of treatment
Laboratory assessments
Biochemistry and Haematology laboratory parameters will be summarised including:
!
Summaries by visit
!
Shift tables from baseline to end of treatment
2.7
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 IMP administration, and no later than the 7 days from 
last day on IMP.
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia, the ADA 2013 classification of hypoglycaemia and the Novo Nordisk 
interpretation of ADA 2018 interpretation 
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)1. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
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Novo Nordisk uses the following classification in addition to the ADA classification:
!
Severe hypoglycaemia according to the ADA 2013 classification2: 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.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ADA classification2 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 
mg/dL) with symptoms consistent with hypoglycaemia.
Novo Nordisk interpretation of ADA 2018 definition of hypoglycaemia
Classification of hypoglycaemia
Level
Glycaemic criteria
Description
Hypoglycaemia alert 
value (level 1)
< 3.9 mmol/L (70 mg/dL) 
and 
≥ 3.0 mmol/L (54 mg/dL)  
Sufficiently low for treatment with fast-acting 
carbohydrate and dose
adjustment of glucose-lowering therapy
Clinically significant 
hypoglycaemia (level 2)
< 3.0 mmol/L (54 mg/dL)
Sufficiently low to indicate serious, clinically 
important hypoglycaemia
Severe hypoglycaemia 
(level 3)
No specific glucose threshold
Hypoglycaemia associated with severe 
cognitive impairment requiring
external assistance for recovery
Notes: Novo Nordisk terms adapted from IHSG 3, ADA-20184, ISPAD5, Type 1 diabetes outcomes 
program6, ATTD7. Severe hypoglycaemia as defined by Seaquist8.
2.8
Health economics and/or patient reported outcomes
Health economics and/or patient reported outcomes will be analysed after the CTR.
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3
Changes to the statistical analyses planned in the protocol
Below substantial updates to section 17 in protocol version 3.0 is described. Linguistic updates for 
clarity are not described.
3.1
Update of specifying safety assessments
p.28 l.,89-409 is replaced by:
“Other safety endpoints
!
Hypoglycaemia
o
Number of severe or BG confirmed symptomatic hypoglycaemic episodes from 
randomisation until end of maintenance 2 (up to 88 weeks)
o
Number of nocturnal, severe or BG confirmed symptomatic hypoglycaemic episodes  
from randomisation until end of maintenance 2 (up to 88 weeks)
o
Number of severe hypoglycaemic episodes from randomisation until end of 
maintenance 2 (up to 88 weeks)
!
Number of adverse events from randomisation until end of maintenance 2 (up to 88 weeks)
!
Change in body weight from baseline to end of treatment (up to 88 weeks)
Safety assessments
!
Change in clinical evaluations from baseline to end of treatment (up to 88 weeks) in terms 
of:
o
Vital signs (including blood pressure and pulse)
o
Dilated fundoscopy or fundus photography
o
Electrocardiogram (ECG)
!
Change in central laboratory assessments from baseline to end of treatment (up to 88 weeks) 
in terms of
o
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes)
o
Biochemistry (creatinine, alanine aminotransferase , aspartate aminotransferase , 
alkaline phosphatase , sodium, potassium, albumin, total bilirubin)”
Update leads to new subsection on reporting of safety assessments.
Rationale:
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Vital signs, fundoscopy, ECG, haematology and biochemistry are standard safety assessments, 
which are not actual endpoints for this trial.
3.2
Update and clarification of definition of in trial and on treatment period, maintenance 
period 1 and 2, and completer definition:
p.81 l.1965-1970 is replaced by:
“The in-trial period will include information collected at or after the date of randomisation and 
until the date of:
!
The last scheduled subject-site contact
!
Withdrawal for subjects who withdraw their informed consent
!
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up
!
Death for subjects who die before any of the above
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product. The period starts on day of the first dose of trial product and ends 7 days after last dose of 
trial product is taken, but no later than the end of the in-trial period.
Maintenance period 1 starts on the day of V18/V18A. For subjects not attending neither V18 nor 
V18A, but is still in trial for more than 16 weeks, maintenance 1 instead starts 16 weeks (112 days) 
after randomisation. 
Maintenance period 2 starts at the date of V57/V57A. Subjects not attending neither V57 nor V57A 
will not have a maintenance 2 period, regardless of duration in trial.
A subject is completing the trial if he/she attend V93 or V93A at the end of maintenance 2 period. It 
is considered completing trial on treatment if the subject attends V93 without premature 
discontinuation of trial product.”
Rationale:
Update to in-trial and on-treatment definition is aligned to project derivation rules. Specification of
the maintenance periods.
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3.3
Update of baseline value
p.82 l. 1993-1995:
“The baseline value is defined as the value from the randomisation visit. If this value is missing the 
last recorded value before randomisation visit will be used.” 
is updated to:
“When an assessment is planned at randomisation visit, this value will be used as baseline value. If 
this value is missing the last recorded value before randomisation visit will be used. For 
assessments planned only at screening, the screening values will be used as baseline. If this value is 
missing, the first recorded visit after screening, but no later than the day of randomisation, will be 
used.”
Rationale:
Some assessments are planned only at screening visits and should be used as baseline under such 
circumstances.
3.4
Specifying tables on treatment discontinued/withdrawn subjects prior to maintenance 
2
Before p. 81 l. 1996, the following paragraph is added:
“For patients not initiating maintenance period 2 on treatment a summary table of reasons for 
treatment discontinuation will be reported.”
Rationale:
Prespecifying output to check for potential bias in early treatment discontinuations/withdrawals 
compared to all treatment discontinuations/withdrawals.
3.5
Handling of ULOQ values
In p. 82 l. 1998 the following is added:
“Laboratory values above the upper limit of quantification (ULOQ) will be set to ULOQ+1.”
Rationale:
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Statistical Analysis Plan
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Include project derivation rule of handling of ULOQ values
3.6
Contribution in FAS
p. 84 l. 2036-2037 is replaced by:
“In the statistical evaluation of the full analysis set subjects contribute "as randomised".”
Rationale:
To align with project standard and ensure unambiguous definition of dosing time point.
3.7
Changing imputation model in primary analysis from negative binomial to Poisson, 
fewer covariates and different backup strategy.
p. 85 l. 2051-2080 is replaced by:
“Primary statistical analysis for the on-treatment estimand
The on-treatment estimand will be estimated based on information from maintenance 2 collected 
when subjects use randomised treatment including a 7-day follow-up period (on-treatment data). 
Subjects that discontinue randomised treatment during maintenance 2 will contribute with the 
available on treatment data from maintenance 2. For subjects that discontinue randomised 
treatment during the titration period or maintenance 1, the number of events in maintenance 2 will 
be imputed based on data from the same arm from maintenance 2 for subjects that discontinued 
randomised treatment during maintenance 2. Missing data within each group will be imputed as 
follows:
!
First 1000 samples from the posterior distribution of model parameters will be extracted. 
The model will be fitted to the on-treatment maintenance 2 data for subjects that 
discontinued randomised treatment during maintenance 2. This will be done using a Bayes 
Poisson log-link model dosing time as a factor, age as covariate, and log of exposure time 
as offset.
!
For each sample of model parameters, the total number of hypoglycaemia events for 
subjects that discontinued randomised treatment in the titration period or maintenance 1 
will be imputed as a random number of events from a Poisson distribution using the 
sampled parameters.
Having 1000 complete data sets that have maintenance 2 data for all randomised subjects, the 
mean treatment ratio will be estimated using a negative binomial model with all the factors 
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Statistical Analysis Plan
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described in section 2.1, age as covariate and log exposure time as offset. The estimates and 
standarddeviations will be pooled to one estimate and associated standard deviation using Rubin’s 
formula. From these the 95% confidence intervals for the treatment ratio and the associated p-
value will be calculated.
If the above imputation model cannot fit or leads to inflate the standard error of the treatment ratio 
on logscale by more than 15% compared to a negative binomial model fitted to the available on-
treatment data during maintenance 2 without any imputation, an alternative model is used for the 
analysis: The imputation model will be a negative binomial model fitted to all available on-
treatment data during maintenance 2 and including all factors described in section 2.1, age as 
covariate and log exposure time as offset. If this model cannot fit either, the imputation model is fit 
as a Poisson model to all available on-treatment maintenance 2 data, and if needed factors are left 
out from the imputation model in the following order:
!
sex
!
region
!
previous OAD treatment
”
Rationale:
Due to a low number of subjects discontinuing treatment during maintenance 2, the imputation 
model specified in the protocol is unstable and leads to an extreme number of imputed hypos in 
several instances (subjects having in the magnitude of millions or billions of hypos in a 36 week 
period). The instability of the model persists when the simplest imputation model, containing only
dosing time and age as factors/covariates, is applied. To ensure the scientific integrity in the reality 
of sparse data the imputation model is simplified.
In case the subjects discontinuing treatment during maintenance 2 is far from equally distributed 
across the trial arms, there is a risk that also the simplified Poisson imputation leads to unstable 
results. As the backup model in the original protocol has proven not always to be able to fit, an 
alternative is introduced for the on-treatment estimands with imputations.
3.8
Clarification of handling of treatment emergent hypoglycaemic episodes during 
follow-up period
After p. 88 l. 2179 is added:
“For both periods, hypoglycaemic episodes during the 7 days treatment-emergent period after last 
drug day will be included.”
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Statistical Analysis Plan
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Date:
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Rationale:
Clarification to align with project derivation rules.
3.9
Sensitivity analyses for primary analysis on-treatment estimand:
p.85 after l. 2092 is added:
!
“Furthermore, a statistical sensitivity analysis is performed with a truncation at seven, the 
current observed 95% percentile in the blinded uncleaned data.
!
The primary analysis will be performed using only available on-treatment data during 
maintenance 2. Subjects without on-treatment data for maintenance 2 period will be 
excluded from this analysis, and thus no imputation is needed.
!
The primary analysis will be repeated, but considering the full maintenance period 
(maintenance 1 and maintenance 2). Missing data will be imputed for subjects that 
discontinued randomised treatment during titration period only, using on-treatment data for 
maintenance 1 and 2. This analysis evaluates if including the data from the discontinued 
BG-meter challenge the overall conclusion of the trial.
!
The primary analysis will be repeated, with the exemption of imputation of hypoglycaemic 
episodes for subjects in IDeg arm actively refusing to reconsent to the extended trial period 
following the protocol amendment defined as subjects discontinuing treatment after 
15FEB2018 and either not reconsenting or not taking any doses of trial product later than 
the date of reconsenting. For these subjects, the imputation will be based on the usual 
statistical model fitted to all maintenance 2 data in the IGlar arm. This analysis evaluates if 
the conclusion of the primary analysis is different if non-consenters on IDeg arm are worse 
off than consenters.”
Rationale:
Additional sensitivity analyses are needed to evaluate the impact of the protocol amendment for the 
on-treatment estimand of the primary analysis. As the truncation value in the sensitivity analysis is 
selected based on a 16 weeks maintenance period, an extra truncation analysis is added.
3.10
Omitting backup strategy for ITT estimand
After p 86 l. 2100 the following is added:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
26 of 31
“If the imputation model cannot fit or leads to inflate the standard error of the treatment ratio on 
logscale by more than 15% compared to a negative binomial model fitted to the available on- and 
off-treatment data during maintenance 2 without any imputation the analysis will not be 
performed.”
Rationale:
For ITT estimand it is not appropriate to include on-treatment data in the imputation model, and the 
statistical analysis is thus omitted if the imputations model is deemed unstable.
3.11
Sensitivity analyses for primary analysis ITT estimand:
p. 85 l 2101: 
“The same sensitivity analysis as the sensitivity analyses for the on-treatment estimand will be 
performed.”
is replaced by 
“A tipping point sensitivity analysis similar to the one for the on-treatment estimand will be 
performed. The penalty will only be added to withdrawn subjects in IDeg arm. Further sensitivity 
analyses may be performed.”
Rationale: The sensitivity analysis addressing missing data patterns is considered the primary 
sensitivity analysis, other sensitivity analysis will be performed if necessary.
3.12
Clarification of primary analysis ITT estimand:
p 86 l. 2116: the following is deleted:
“for subjects that discontinued randomised treatment during maintenance 2”
Rationale:
Not intended statement in original protocol, as we want to impute base on all available off-treatment 
data.
3.13
Handling of zero doses
p.87, after l. 2122 to be added:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
27 of 31
“Before transforming to log-scale, dose values of 0 will be assigned the value 0.5”
Rationale:
To ensure that zero doses does not count as missing in analysis.
3.14
Tables on adverse events
p.88, after l. 2157-2169  is replaced by:
“Summaries are presented as an overview including all AEs, serious AEs, number of deaths, AEs by 
severity, AEs by relation to treatment and AEs leading to treatment discontinuation and as
summary tables based on system organ class and preferred terms for the following AEs:
!
All TEAEs
!
All AEs
!
All TEAEs during maintenance 2
!
Serious TEAEs
!
TEAEs possibly or probably related to trial product
!
Severe TEAEs
!
TEAEs with preferred term that are experienced by at least 5%  of the subjects in any
treatment arm or by at least 5% of all subjects”
Rationale:
Streamlining which outputs are actually needed.
3.15
Analyse hypoglycaemic episodes during total treatment period
Afterpage88 l. 2179, the following is added:
“The number of severe or BG confirmed symptomatic hypoglycaemic events during total treatment 
period (up to 88 weeks) will be analysed statistically, addressing both theon-treatment and ITT 
estimand,Also nocturnal severe or BG confirmed symptomatic hypoglycaemic events as well as 
severe hypoglycaemic events during total treatment period will be analysed following these 
procedures.
The on-treatmentestimand is estimated based on on-treatment data and a negative binomial model 
including the factors in section 2.1, age as covariate and the logarithm of the time period in which a 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
28 of 31
hypoglycaemic episode was considered treatment emergent as offset. The model will use log as link
function.
The ITTestimand is based on in-trial data. For withdrawn subjects, data after withdrawal will be 
imputed for a period lasting from the day after withdrawal up until 36 weeks after entering 
maintenance 2 period, and until the 36 weeks after first of reconsent of any subject in trial (i.e. until 
09NOV2018)  for subjects not entering maintenance 2. The imputation will follow the procedure 
described in section 2.4.1, using all off-treatment data to build the imputation model. Observed and 
imputed data are summarised by subject, and analysed through a negative binomial model 
including the factors in section 2.1, age as covariate and the logarithm of the total time period 
where hypoglycaemic episodes are either observed or imputed as offset. The model will use log as 
link function.If the imputation model cannot fit or leads to inflate the standard error of the 
treatment ratio on logscale by more than 15% compared to a negative binomial model fitted to the 
available on-and off-treatment data during total treatment period without any imputation the 
analysis will not be performed.”
Rationale:
Hypoglycaemic episodes are always clinical relevant, and though the data on hypoglycaemic 
episodes during titration and maintenance 1 periods is less reliable than during maintenance 2, for 
completeness the treatment difference during the full period should still be analysedstatistically.
3.16
Presentation of lab data
p. 89 l. 2193:
Delete:
!
“Proportion of subjects with measurements outside reference range by treatment and visit
!
Box plots by visit
!
Listings of individual values outside reference ranges (abnormal values)”
Rationale:
Limit number of outputs on lab data, as both insulins are approved with known safety profiles also 
regarding lab.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
29 of 31
3.17
Omit antibodies from statistical section
p. 89. l. 2196:
Delete “Anti-insulin antibodies will be summarised by visit.”
Rationale:
Antibodies will not be available to Biostat at time point of CTR.
3.18
Updated ADA hypo classification
in p.88 l. 2176-2177:
“and the ADA classification of hypoglycaemia.”
is replaced by
“and the Novo Nordisk interpretation of ADA classification of hypoglycaemia from 2018.”
Instead of p.9l l 2217-2236 the following is added:
”Novo Nordisk interpretation of ADA 2018 definition of hypoglycaemia
Classification of hypoglycaemia
Level
Glycaemic criteria
Description
Hypoglycaemia alert 
value (level 1)
< 3.9 mmol/L (70 mg/dL) and 
≥ 3.0 mmol/L (54 mg/dL)  
Sufficiently low for treatment with fast-acting 
carbohydrate and dose
adjustment of glucose-lowering therapy
Clinically significant 
hypoglycaemia (level 2)
< 3.0 mmol/L (54 mg/dL)
Sufficiently low to indicate serious, clinically 
important hypoglycaemia
Severe hypoglycaemia 
(level 3)
No specific glucose threshold
Hypoglycaemia associated with severe 
cognitive impairment requiring
external assistance for recovery
Notes: Novo Nordisk terms adapted from IHSG 21, ADA-201822, ISPAD23, Type 1 diabetes outcomes 
program24, ATTD25. Severe hypoglycaemia as defined by Seaquist26.
”
Furthermore, figures describing the classification process are omitted, as incorrect due to the 
adjudication of severe hypoglycaemic events.
Rationale:
Include the more updated ADA 2018 hypoglycaemia definition in descriptive tables. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
30 of 31
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
12 March 2019
Novo Nordisk
Trial ID: NN1250-4252
Version:
3.0
UTN: U1111-1184-8175
Status:
Final
EudraCT No.: 2016-002801-20
Page:
31 of 31
4
References
1.
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81.
2.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95.
3.
International Hypoglycaemia Study Group. Glucose Concentrations of Less Than 3.0 
mmol/L (54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the 
American Diabetes Association and the European Association for the Study of Diabetes. 
Diabetes Care. 2017;40(1):155-7.
4.
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64.
5.
Jones TW, Group IHGW. Defining relevant hypoglycemia measures in children and 
adolescents with type 1 diabetes. Pediatr Diabetes. 2017.
6.
Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. Standardizing 
Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes: A Consensus 
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Society, and the T1D Exchange. Diabetes Care. 2017;40(12):1622-30.
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Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International 
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40.
8.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95.
9.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 Rev. 
1). 2 Jul 2010.
CONFIDENTIAL