Conditions: Diabetes Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 532
Healthy volunteers: no

Brief summary:
Trial comparing effect and safety of insulin degludec/insulin aspart vs. insulin glargine plus insulin aspart in subjects with type 2 diabetes treated with basal insulin with or without oral antidiabetic treatment in need of treatment intensification.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Insulin degludec/insulin aspart intervention 2: Insulin glargine intervention 3: Insulin aspart
Intervention descriptions: intervention 1: Administered subcutaneously (s.c. under the skin) once daily. intervention 2: Administered subcutaneously (s.c. under the skin) once daily. intervention 3: Administered subcutaneously (s.c. under the skin) once daily.

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02906917 
Sponsor trial ID: 
NN5401-4266 
Official title of study: 
A 38 week trial comparing effect and safety of insulin 
degludec/insulin aspart vs. insulin glargine plus insulin aspart 
in subjects with type 2 diabetes treated with basal insulin with 
or without oral antidiabetic treatment in need of treatment 
intensification 
Document date: 
22 June 2018 
 


Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol amendment 1 global............................................................................................................
Attachment I and II............................................................................................................................
Appendix A - (Titration guideline) ...................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
IDegAsp
Trial ID: NN5401-4266
Clinical Trial Report
Appendix 16.1.1
22 June 2018
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
1 of 119
Protocol
Trial ID: NN5401-4266
A 38 week trial comparing effect and safety of insulin degludec/insulin aspart 
vs. insulin glargine plus insulin aspart in subjects with type 2 diabetes treated 
with basal insulin with or without oral antidiabetic treatment in need of 
treatment intensification.
Trial phase: 3b
Protocol originator
Clinical Operations 2, Insulin and Diabetes Outcomes
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
2 of 119
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................6
Table of Tables..................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................11
2
Flow Chart...............................................................................................................................................16
3
Background information and rationale for the trial............................................................................21
3.1
Background information..............................................................................................................21
3.1.1
Therapeutic area – type 2 diabetes mellitus...............................................................21
3.1.2
Insulin aspart..............................................................................................................21
3.1.3
Insulin degludec/insulin aspart ..................................................................................22
3.1.4
Insulin glargine ..........................................................................................................22
3.1.5
Insulin antibodies.......................................................................................................22
3.2
Rationale for the trial...................................................................................................................23
4
Objectives and endpoints........................................................................................................................24
4.1
Objectives ....................................................................................................................................24
4.2
Endpoints .....................................................................................................................................24
4.2.1
Primary endpoint........................................................................................................24
4.2.2
Supportive secondary endpoints ................................................................................24
4.2.2.1
Supportive secondary efficacy endpoints............................................24
4.2.2.2
Supportive secondary safety endpoints:..............................................25
5
Trial design ..............................................................................................................................................28
5.1
Type of trial .................................................................................................................................28
5.2
Rationale for trial design..............................................................................................................29
5.3
Treatment of subjects...................................................................................................................30
5.3.1
Treatment regimens arms...........................................................................................30
5.3.2
Trial insulin products.................................................................................................30
5.3.3
Trial insulin treatment................................................................................................31
5.4
Oral antidiabetic treatment...........................................................................................................31
5.4.1.1
Allowed OADs....................................................................................32
5.4.1.2
OADs prohibited during trial treatment: .............................................32
5.5
Treatment after discontinuation of trial product ..........................................................................32
5.6
Rationale for treatment ................................................................................................................33
6
Trial population.......................................................................................................................................34
6.1
Number of subjects......................................................................................................................34
6.2
Inclusion criteria ..........................................................................................................................34
6.3
Exclusion criteria.........................................................................................................................35
6.4
Randomisation criteria.................................................................................................................36
6.5
Rescue criteria..............................................................................................................................36
6.6
Criteria for premature discontinuation of trial product................................................................36
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Protocol
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Date:
04 May 2016
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Trial ID: NN5401-4266
Version:
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Status:
Final
EudraCT no.: 2015-004768-12
Page:
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6.7
Withdrawal from trial ..................................................................................................................37
6.8
Subject replacement.....................................................................................................................38
6.9
Rationale for trial population.......................................................................................................38
7
Milestones.................................................................................................................................................39
8
Methods and assessments .......................................................................................................................40
8.1
Visit procedures...........................................................................................................................40
8.1.1
Investigator assessments............................................................................................40
8.1.2
Visit Schedule............................................................................................................40
8.1.3
Phone contacts ...........................................................................................................40
8.1.4
Fasting requirements..................................................................................................41
8.1.5
Diaries........................................................................................................................41
8.1.6
Screening ...................................................................................................................42
8.1.6.1
Screening failures................................................................................42
8.1.7
Randomisation visit (V2)...........................................................................................43
8.1.8
Treatment period (V3-V40).......................................................................................43
8.1.9
Follow-up visits .........................................................................................................44
8.1.10
Unscheduled visits.....................................................................................................44
8.1.11
Premature discontinuation of trial product ................................................................45
8.1.12
Withdrawal from trial ................................................................................................45
8.2
Subject related information/assessments .....................................................................................46
8.2.1
Demography...............................................................................................................46
8.2.2
Diabetes history and diabetes complications .............................................................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
Childbearing potential................................................................................................47
8.2.7
Tobacco use ...............................................................................................................48
8.3
Efficacy assessments....................................................................................................................48
8.3.1
Self-measured plasma glucose...................................................................................48
8.3.1.1
Self-measured plasma glucose used for insulin dose adjustment........49
8.3.1.2
9-point self-measured plasma glucose profiles ...................................49
8.4
Safety assessments.......................................................................................................................49
8.4.1
Body measurements...................................................................................................49
8.4.2
Vital signs ..................................................................................................................50
8.4.3
Physical examination.................................................................................................50
8.4.4
Eye examination ........................................................................................................50
8.4.5
Electrocardiogram - 12 lead.......................................................................................51
8.4.6
Adverse events...........................................................................................................51
8.4.6.1
Medication error..................................................................................51
8.4.6.2
Adverse events requiring additional data collection ...........................52
8.4.7
Technical complaints.................................................................................................53
8.4.8
Hypoglycaemic episodes ...........................................................................................53
8.5
Laboratory assessments ...............................................................................................................55
8.5.1
Laboratory samples....................................................................................................55
8.5.1.1
Sample collection and handling ..........................................................56
8.5.1.2
Fasting samples ...................................................................................56
8.5.1.3
Re-sampling ........................................................................................56
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Protocol
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
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8.5.1.4
Reporting of results to investigator .....................................................56
8.5.1.5
Sample destruction..............................................................................57
8.5.2
Laboratory assessments for efficacy..........................................................................57
8.5.2.1
HbA1c...................................................................................................57
8.5.2.2
Fasting plasma glucose........................................................................57
8.5.3
Laboratory assessments for safety .............................................................................57
8.5.3.1
Haematology and Biochemistry assessments......................................57
8.5.3.2
Pregnancy testing ................................................................................58
8.5.3.3
Antibody measurements......................................................................58
8.6
Other Assessments.......................................................................................................................58
8.6.1
Patient reported outcomes..........................................................................................58
8.6.2
Hypoglycaemia resource use .....................................................................................59
8.6.3
Training in use of the trial product/pre-filled pen device ..........................................60
8.7
Subject compliance......................................................................................................................60
9
Trial supplies ...........................................................................................................................................62
9.1
Trial insulin products...................................................................................................................62
9.2
Non-IMPs.....................................................................................................................................62
9.3
Labelling......................................................................................................................................63
9.4
Storage .........................................................................................................................................64
9.5
Drug accountability and destruction............................................................................................65
9.6
Auxiliary supplies........................................................................................................................65
10 Interactive voice/web response system ..................................................................................................66
11 Randomisation procedure and breaking of blinded codes..................................................................67
11.1
Breaking of blinded codes ...........................................................................................................67
12 Adverse events, and technical complaints and pregnancies................................................................68
12.1
Definitions ...................................................................................................................................68
12.1.1
Adverse event ............................................................................................................68
12.1.2
Serious adverse event.................................................................................................69
12.1.3
Non-serious adverse event.........................................................................................70
12.1.4
Medication errors.......................................................................................................70
12.1.5
Adverse events requiring additional data collection..................................................70
12.1.6
Technical complaints.................................................................................................71
12.2
Reporting of adverse events.........................................................................................................71
12.3
Follow-up of adverse events........................................................................................................74
12.4
Technical complaints and technical complaint samples ..............................................................75
12.4.1
Reporting of technical complaints .............................................................................75
12.4.2
Collection, storage and shipment of technical complaint samples ............................76
12.5
Pregnancies in female subjects ....................................................................................................76
12.6
Precautions and/or overdose ........................................................................................................78
12.7
Committees related to safety........................................................................................................78
12.7.1
Novo Nordisk safety committee ................................................................................78
13 Case report forms....................................................................................................................................79
13.1
Corrections to case report forms..................................................................................................79
13.2
Case report form flow..................................................................................................................80
14 Monitoring procedures ...........................................................................................................................81
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
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15 Data management....................................................................................................................................83
16 Computerised systems.............................................................................................................................84
17 Statistical considerations ........................................................................................................................85
17.1
Primary and secondary estimands................................................................................................85
17.2
Sample size calculation................................................................................................................86
17.3
Definition of analysis sets............................................................................................................88
17.4
Primary endpoint..........................................................................................................................90
17.5
Supportive secondary endpoints ..................................................................................................92
17.5.1
Efficacy endpoints .....................................................................................................92
17.5.2
Safety endpoints.........................................................................................................94
17.6
Health economics and/or patient reported outcomes.................................................................101
18 Ethics......................................................................................................................................................102
18.1
Benefit-risk assessment of the trial............................................................................................102
18.2
Informed consent .......................................................................................................................103
18.3
Data handling.............................................................................................................................103
18.4
Information to subject during trial.............................................................................................104
18.5
Premature termination of the trial and/or trial site.....................................................................104
19 Protocol compliance..............................................................................................................................105
19.1
Protocol deviations ....................................................................................................................105
19.2
Prevention of missing data.........................................................................................................105
20 Audits and inspections ..........................................................................................................................106
21 Critical documents ................................................................................................................................107
22 Responsibilities......................................................................................................................................109
23 Reports and publications......................................................................................................................110
23.1
Communication of results..........................................................................................................110
23.1.1
Authorship ...............................................................................................................111
23.1.2
Site-specific publication(s) by investigator(s) .........................................................111
23.2
Investigator access to data and review of results.......................................................................111
24 Retention of clinical trial documentation and human biosamples....................................................112
24.1
Retention of clinical trial documentation...................................................................................112
24.2
Retention of human biosamples.................................................................................................112
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............114
26 Indemnity statement .............................................................................................................................115
27 References..............................................................................................................................................116
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
6 of 119
Appendices:
Appendix A–Titration Guideline
Attachments:
Attachment I – Global list of key staff and relevant departments and suppliers
Attachment II – Country list of key staff and relevant departments
Table of Figures 
Page
Figure 5–1
Trial Design ...........................................................................................................................28
Figure 12–1
Reporting of AEs...................................................................................................................73
Figure 17–1
Novo Nordisk classification of hypoglycaemia.....................................................................98
Figure 17–2
ADA classification of hypoglycaemia...................................................................................99
Table of Tables
Page
Table 2–1 
Flow chart...............................................................................................................................16
Table 2–2
Phone Contacts ......................................................................................................................20
Table 9–1
Trial insulin products (IMPs)..................................................................................................62
Table 9–2
Washout insulin products ......................................................................................................63
Table 9–3
Storage Conditions and In-use time for IMPs and washout insulin........................................64
Table 12–1
Adverse events requiring completion of specific event forms...............................................71
Table 17–1
Assumptions for sample size calculation................................................................................87
Table 17–2
Sensitivity of sample size to variations in SD and power......................................................88
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
7 of 119
List of abbreviations
AB
antibody
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BG-meter
blood glucose meter
BiAsp
biphasic insulin aspart
BHQ
baseline hypo questionnaire
BID
two times a day
CAS
Completer analysis set
CCDS
Company Core Data Sheet 
CLAE
clinical laboratory adverse event
CPMP
Committee for Proprietary Medicinal Products 
CRF
case report form
CRO
contract research organisation
CS
clinically significant
DFU
directions for use
DPP-4
di-peptidyl-peptidase IV
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
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DUN
dispensing unit number
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capturing system
EMA
European Medicines Agency
EOT
end of treatment
FAS
full analysis set
FDA
U.S. Food and Drug Administration
FPFV
first patient first visit
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
glycosylated haemoglobin
IAsp
insulin aspart
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDeg
insulin degludec
IDegAsp
insulin degludec/insulin aspart
IEC
independent ethics committee
IGlar
insulin glargine
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Protocol
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Date:
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Trial ID: NN5401-4266
Version:
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Status:
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IMP
investigational medicinal product
ITT
intention-to-treat 
IRB
institutional review board
IWRS
interactive voice/web response system
LLOQ
lower limit of quantification
LPFV
last patient first visit
LPLV
last patient last visit
MMRM
mixed model for Repeated Measurement
NA
not applicable
NCS
non clinically significant
ND
not done
NI
non-inferiority
NPH
neutral protamine Hagedorn
OAD
oral antidiabetic drug
OD
once daily
PG
plasma glucose
PP
per protocol
PRO
patient reported outcomes
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous(ly)
SD
standard deviation
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Protocol
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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SDV
source data verification
SGLT-2
sodium/glucose co-transporter 2
SF-36v2®
Short-Form Health Survey 36 version 2
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SU
sulfonylurea
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TID
three times daily
TMM
Trial Materials Manual
TE
treatment effect
TRIM-D
Treatment Related Impact Measure-Diabetes
T2DM
type 2 diabetes mellitus
U.S. LI
U.S. Label Information
UTN
Universal Trial Number
UNL
upper normal limit
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Protocol
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Date:
04 May 2016
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Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
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1
Summary
Objectives and endpoints:
Primary objective
!
To confirm the effect of insulin degludec/insulin aspart once daily versus insulin glargine
once daily in combination with insulin aspart once daily in controlling glycaemia after 26 
weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
Primary endpoint
Change from baseline in glycosylated haemoglobin (HbA1c) (%) after 26 weeks.
Secondary objectives
!
To compare other effect parameters  and safety of insulin degludec/insulin aspart once daily 
versus insulin glargine once daily in combination with insulin aspart once daily after 26 
weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
!
To compare the effect and safety of insulin degludec/insulin aspart once daily or twice daily 
versus insulin glargine once daily in combination with insulin aspart (1-3 times daily) after 
38 weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
Key supportive secondary efficacy endpoints
At 26 weeks
!
Responder (Yes/No) for HbA1c after 26 weeks
o
HbA1c < 7%
At 38 weeks
!
Change from baseline in HbA1c (%) after 38 weeks
!
Responder (Yes/No) for HbA1c after 38 weeks:
o
HbA1c < 7%
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Protocol
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Date:
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Trial ID: NN5401-4266
Version:
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EudraCT no.: 2015-004768-12
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Key supportive secondary safety endpoints
During 26 weeks
!
Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during 26 weeks
During 38 weeks
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 38 weeks
!
Incidence of treatment-emergent adverse events (TEAEs) during 38 weeks
Trial design:
This is a 38-week, multinational, open-label, two-arm, randomised (1:1), controlled, parallel-group, 
treat-to-target trial in subjects with type 2 diabetes mellitus treated with basal insulin with or 
without oral antidiabetic drug(s) in need of treatment intensification.
In need of treatment intensification is defined as an HbA1c level of 7-10% (53-85 mmol/mol), both 
inclusive.
Subjects will be randomised in a 1:1 manner to receive either insulin degludec/insulin aspart
(IDegAsp) OD or insulin glargine (IGlar) OD in combination with insulin aspart (IAsp) OD for the 
first 26 weeks followed by a 12-weeks intensification period.
Pre-trial basal insulin, sulfonylurea (SU) and glinides must be discontinued at randomisation.
Treatment with other oral antidiabetic drug(s) should continue unchanged during the trial.
The randomisation will be stratified based on the pre-trial basal insulin treatment regimen: OD or 
BID/TID (two/three times daily) dosing. Subjects on a BID/TID regimen will be shifted to OD
dosing in accordance with a titration guideline, Appendix A.
Subjects will remain in the same treatment arm throughout the trial, with the possibility of
intensification of their treatment as described below.
At week 26 (V28), subjects not achieving sufficient glycaemic control (V27 HbA1c L 7%) will be 
further intensified from either IDegAsp OD to IDegAsp BID or IGlar OD + IAsp OD to IGlar OD + 
IAsp BID, whereas subjects in good glycaemic control (V27 HbA1c < 7%) will continue their 
insulin treatment regimen.
At week 32 (V34), glycaemic control will be evaluated again, and subjects in good glycaemic 
control (V33 HbA1c < 7%) will continue their insulin treatment regimen. Subjects on IDegAsp OD 
not reaching the glycaemic target (V33 HbA1c L 7%) will be intensified to IDegAsp BID, whereas 
subjects in the IGlar arm not reaching glycaemic control will be intensified with one additional 
IAsp dose to IGlar OD + IAsp BID or TID daily for the remaining six weeks of the intensification 
period.
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Version:
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Status:
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The duration of the trial will be approximately 44 weeks including screening, randomisation, a 38-
week treatment period and a 30-day follow-up period.
Trial population:
Number of trial subjects
Planned number of subjects to be randomised/started on trial products: 528.
Key Inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial
!
Male or female, age L 18 years at the time of signing informed consent
Algeria: Male or female, age L 19 years at the time of signing informed consent
!
Diagnosed with type 2 diabetes mellitus
!
Treated with any basal insulin L 90 days prior to the day of screening
!
Subject not on any OAD(s) prior to trial participation OR subjects on stable daily dose(s) of
OAD(s) for at least 90 days prior to screening visit (V1). The OAD(s) include any of the 
following anti-diabetic drug(s)/regimen:
a.
Biguanides (metformin L 1500 mg or maximum tolerated dose documented in the 
subject medical record)
b. Other OADs (L half of the maximum  approved dose according to local label or 
maximum tolerated dose as documented in subject medical record):
i.
Insulin secretagogues (SU and glinides)
ii.
Di-peptidyl-peptidase IV (DPP-4) inhibitors
iii.
N-glucosidase inhibitors
iv.
Sodium/glucose co-transporter 2 (SGLT-2) inhibitors
v.
Oral combination products (of the allowed individual OADs above)
!
HbA1c 7.0-10.0% (53-86 mmol/mol) (both inclusive) by central laboratory analysis
!
Body mass index (BMI) O 45.0 kg/m2
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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Key exclusion criteria:
!
Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within four weeks prior to the day of screening (V1)
!
Any chronic disorder or severe disease which, in the opinion of the investigator, might 
jeopardise subject’s safety or compliance with the protocol
!
Acute decompensation of glycaemic control requiring immediate intensification of treatment 
to prevent severe metabolic dysregulation (e.g. diabetes ketoacidosis) O 90 days prior to the 
day of the screening and between screening and randomisation
!
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
!
Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of 
< 60 ml/min/1.73 m2 as defined by KDIGO 2012 classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening
!
Impaired liver function, defined as alanine aminotransferase (ALT) L 2.5 times upper 
normal limit (UNL) at screening.
!
Subjects presently classified as being in New York Heart Association (NYHA) Class IV
!
Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening
!
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.
!
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)
Key assessments
Efficacy
!
HbA1c
!
FPG
!
SMPG
Safety
!
Body measurements (height and body weight)
!
Adverse events
!
Hypoglycaemic episodes
!
Dilated fundoscopy or fundus photography
!
Physical examination (including electrocardiogram)
!
Biochemistry and haematology (blood samples)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
15 of 119
!
Insulin antibodies (blood samples)
Other
General health status/health-related quality of life and diabetes treatment related impact measured 
by PRO questionnaires:
!
Short-Form Health Survey 36 version 2 (SF-36v2®)
!
Treatment Related Impact Measure-Diabetes (TRIM-D)
Trial products:
The below trial insulin products will be provided by Novo Nordisk A/S:
!
Insulin degludec/insulin aspart (Ryzodeg®) 100 units/mL, 3 mL pre-filled pen (FlexTouch®), 
solution for subcutaneous injection, Novo Nordisk A/S
!
Insulin glargine (Lantus®) 100 units/mL, 3 mL pre-filled pen (SoloStar®), solution for 
subcutaneous injection, Sanofi-Aventis
!
Insulin aspart (NovoRapid®/NovoLog®), 100 units/mL, 3 mL prefilled pen (FlexPen®),
solution for subcutaneous injection, Novo Nordisk A/S
CONFIDENTIAL


Protocol
UTN: U1111-1175-7895
Date:
04 May 2016
Status:
Final
Novo Nordisk
Trial ID: NN5401-4266
EudraCT no.: 2015-004768-12
Version:
3.0
Page:
16 of 119
2
Flow Chart
Table 2–1
Flow chart
Trial NN5401-4266
Screening
Randomisation
Treatment initiation
(week 0 - 26)
Treatment
Intensification
(week 27 - 38)
End of treatment
Follow-up
(30 days)
Pre-term 
discontinuation
of trial insulin
Visit Number (V)
V1
V2 V3
V6
V10 V14 V18 V22 V25 V27 V28
V32
V33
V34
V36
V40
V41n
V28ao V40ao
Weekly Phone Contact number 
(P)(For details see Table 2-2below)
        P4   P7    P11 P15   P19  P23   P26          P29    
P35       P37
P5    P8   P12  P16   P20  P24                      P30
P38
P9    P13   P17   P21
          P31
P39
P42n
Pxo
Time of visit (weeks)
-2
0a
1
4
8
12
16
20
23
25
26
30
31
32
34
38
39
42
X
26
38
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
±3
±5
±5
±3
Subject related info/assessment
Informed consent
X
Inclusion/Exclusion criteria
X
X
Demography
X
Date of diagnosis of diabetes/Diabetes 
complications
X
Diabetes treatment history
Current diabetes treatment
X
Dose of current diabetes treatment
X
Stop date of current diabetes treatment b
X
Hypoglycaemia unawareness
X
Concomitant illness/medical history
X
Concomitant medication/(OAD dosing)b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
Xo
Xo
Child bearing potential/Pregnancyc
X
X
X
Tobacco use
X
Body measurement
  Height
X
  Body weight
X
X
X
X
X
Randomisation
X


Protocol
UTN: U1111-1175-7895
Date:
04 May 2016
Status:
Final
Novo Nordisk
Trial ID: NN5401-4266
EudraCT no.: 2015-004768-12
Version:
3.0
Page:
17 of 119
Trial NN5401-4266
Screening
Randomisation
Treatment initiation
(week 0 - 26)
Treatment
Intensification
(week 27 - 38)
End of treatment
Follow-up
(30 days)
Pre-term 
discontinuation
of trial insulin
Visit Number (V)
V1
V2 V3
V6
V10 V14 V18 V22 V25 V27 V28
V32
V33
V34
V36
V40
V41n
V28ao V40ao
Weekly Phone Contact number (P)
(For details see Table 2-2 below)
            P4   P7    P11 P15   P19  P23   P26          P29                             P35       P37
            P5    P8   P12  P16   P20  P24                      P30                                          P38
                     P9    P13   P17   P21                               P31                                          P39
P42n
Pxo
Time of visit (weeks)
-2
0a
1
4
8
12
16
20
23
25
26
30
31
32
34
38
39
42
X
26
38
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
±3
±5
±5
±3
Premature discontinuation/withdrawal
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue Criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy
Self-measured plasma glucose
  SMPGs for titrationd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  9-point profilee
X
X
X
X
X
Glucose metabolism
  Fasting plasma glucose
X
X
X
X
X
X
  HbA1c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
Xo
Technical complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic episodes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Eye examination
Xf
Xg
Xg
Vital signs
X
X
X
Physical examination
X
X
X
ECG
Xh
Xi
Xi
Antibody sampling
X
X
X
X
X
X
X
Biochemistry
X
X
X
Haematology
X
X
X
Other assessments
PRO questionnaires
  Baseline Hypo Questionnaire
X
  SF-36v2®
X
X
X
  TRIM-D
X
X
X


Protocol
UTN: U1111-1175-7895
Date:
04 May 2016
Status:
Final
Novo Nordisk
Trial ID: NN5401-4266
EudraCT no.: 2015-004768-12
Version:
3.0
Page:
18 of 119
Trial NN5401-4266
Screening
Randomisation
Treatment initiation
(week 0 - 26)
Treatment
Intensification
(week 27 - 38)
End of treatment
Follow-up
(30 days)
Pre-term 
discontinuation
of trial insulin
Visit Number (V)
V1
V2 V3
V6
V10 V14 V18 V22 V25 V27 V28
V32
V33
V34
V36
V40
V41n
V28ao V40ao
Weekly Phone Contact number (P)
(For details see Table 2-2 below)
            P4   P7    P11 P15   P19  P23   P26          P29                             P35       P37
            P5    P8   P12  P16   P20  P24                      P30                                          P38
                     P9    P13   P17   P21                               P31                                          P39
P42n
Pxo
Time of visit (weeks)
-2
0a
1
4
8
12
16
20
23
25
26
30
31
32
34
38
39
42
X
26
38
Visit window (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
±3
±5
±5
±3
Hypoglycaemia resource use see section 8.6.2
X
X
X
X
X
X
X
X
X
Trial material
Administration of trial product
  Dispensing visit 
X
X
X
X
X
X
X
X
X
X
Xj
  Doses of trial insulin on three consecutive 
daysd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  New dose of trial insulin
X
X
X
X
X
X
X
X
X
X
X
X
X
  Last date and dose on trial product
X
IWRS session
X
X
X
X
X
X
X
X
X
X
X
Xj
X
Drug accountability 
X
X
X
X
X
X
X
X
X
Xj
X
Trial conduct
  Hand out ID card
X
  Handout and instruct in BG-meter
X
  Handout and instruct in diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  Attend visit fastingk
X
X
X
X
X
X
X
X
  Training in trial product and pen handling
Xl
Xl
Xm
  Diary collect & review + enter visit data in
EDC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  Make appointment for eye examination
X
X
  End of trial/ Sign off case book
X
X


Protocol
UTN: U1111-1175-7895
Date:
04 May 2016
Status:
Final
Novo Nordisk
Trial ID: NN5401-4266
EudraCT no.: 2015-004768-12
Version:
3.0
Page:
19 of 119
Flow chart footnotes
___________________________________________
a Randomisation (V2) should take place within 14 days after the screening visit (V1). Screening results must be available and evaluated prior to randomisation.
b Subjects must discontinue pre-trial basal insulin, SU and glinides at randomisation. Treatment with other OADs should continue unchanged during the trial.
c A serum pregnancy test is required for females of childbearing potential at screening (V1), before intensification (V28) and the end of treatment (EOT) visit (V40). If a menstrual period is 
missed or pregnancy suspected, a urine pregnancy test must be performed as soon as possible.
d Recordings of SMPG values and insulin doses on three consecutive days just prior to dose adjustment as described in the Titration Guideline, Appendix A.
e 9-point SMPG profile should be measured starting in the morning two days prior to the scheduled visit – for timing of measurements - Section 8.3.1.2.
f Dilated fundoscopy/fundus photography performed for any reason unrelated to this trial within 90 days prior to Visit 2 is acceptable provided no clinical symptoms suggestive of eye 
disease have occurred in the meantime. It is allowed to perform the screening visit (V1) dilated fundoscopy/fundus photography between the screening visit (V1) and randomisation (V2).
g Dilated fundoscopy/fundus photography within a period of three weeks prior to V28 & V40 is acceptable provided no clinical symptoms suggestive of eye disease have occurred in the 
meantime.
h 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.
i ECGs before intensification (V28) and at the EOT visit (V40) should be performed at the day of the visit.
j Dispense of ‘washout’ insulin products (BiAsp 30 or NPH + IAsp) to be used in the period between the EOT visit (V40) and the 7-day follow-up visit (V41) – Section 8.1.8. 
k The subjects must attend these visits fasting to collect FPG samples (Visits 2, 10, 14, 28, 34 and 40) and antibody samples (Visits 2, 6, 10, 14, 28, 40 & 41). Fasting is defined as at least 
eight hours without food and liquids, except for water. No diabetes treatment (neither trial insulin nor any oral antidiabetic treatment) is allowed up to eight hours prior to these 
measurements. Intake of other prescribed medicine is however allowed. If non-fasting, blood sampling should be re-scheduled, preferably within the next two working days. 
l Investigator or delegate staff will ensure proper training in trial product and pen handling. For subjects in the IGlar arm, the training must include pen differentiation. Directions for use 
(DFU) will be provided to the subjects. Hand-out of the DFU(s) to the subject must be documented in the subject’s medical file. Re-training must be performed again at V3 and should be 
repeated during the trial based on the individual subject’s needs.
m At the EOT visit (V40) the subjects should be properly trained in how to handle ‘washout’ insulin products to be used in the period until the 7-day follow-up visit (V41). Handout of 
DFUs must be documented in the subject’s medical file.
n Two follow-up visits are to be conducted. The first (V41) must take place no earlier than seven days and no later than 12 days after the EOT visit (V40). The last follow-up visit (P42) will 
take place approximately 30 days after the EOT visit (V40) and will be conducted as a phone contact (P42).
o For subjects prematurely discontinued from trial insulin products, monthly phone contacts (Px), as applicable, should be conducted after the 30-day follow-up (P42) and until the date 
where the EOT visit (V40) was originally planned to take place (38 weeks after Visit 2). Here an additional abbreviated visit 40 (V40a) should be performed. If the timing of a monthly 
phone contact is less than two weeks from a planned abbreviated visit, the phone contact can be omitted. If subject discontinues from trial product prior to Visit 28, an additional 
abbreviated visit 28 (V28a) should be scheduled at the date of the originally planned V28. At the abbreviated visits (V28a and V40a) HbA1c samples and information on adverse events 
(AEs) will be collected. At these visits, only information about antidiabetic treatment will be collected.


Protocol
UTN: U1111-1175-7895
Date:
04 May 2016
Status:
Final
Novo Nordisk
Trial ID: NN5401-4266
EudraCT no.: 2015-004768-12
Version:
3.0
Page:
20 of 119
Table 2–2
Phone Contacts
NN5401-4266
Phone contacts (P)a
Timing of visits are shown in Flow Chart Table 2-1 above
P4-P39
P42
Pxd
Visit window (days)
± 3
±3
±5
SMPG for titrationb
X
Doses of trial insulin(s) on three consecutive daysb
X
New dose(s) of trial insulin(s)
X
Concomitant medication
X
Xc
Xc
Adverse events and technical complaints
X
X
X
Hypoglycaemic episodes
X
Rescue criteria/Premature discontinuation/Withdrawal criteria
X
X
Enter titration data in EDC – preferably within 24 hours
X
Footnotes:
________________________________________________
a A phone contact may be converted to a site visit, if needed.
b Recordings of self-measured plasma glucose values and insulin doses on three consecutive days just prior to dose adjustment – refer to the Titration Guideline, Appendix A.
c Only information about antidiabetic treatment will be collected.
d For subjects prematurely discontinued from trial insulin products, monthly phone contacts (Px), as applicable, should be conducted after the 30-day follow-up (P42) and until the date 
where the EOT visit (V40) was originally planned to take place (38 weeks after Visit 2). Here an additional abbreviated visit 40 (V40a) should be performed. If the timing of a monthly 
phone contact is less than two weeks from a planned abbreviated visit, the phone contact can be omitted.


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
21 of 119
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation, Guideline for Good Clinical Practice (ICH GCP)1 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
3.1.1
Therapeutic area – type 2 diabetes mellitus
Type 2 diabetes mellitus (T2DM) is a progressive disorder characterized by insulin resistance, 
impaired insulin secretion and increased hepatic glucose output and thus chronic hyperglycaemia. A 
number of landmark studies have demonstrated the importance of maintaining tight glycaemic 
control to reduce the risk of long-term complications associated with diabetes3-7. The current 
treatment guideline by the American Diabetes Association (ADA) and the European Association for 
the Study of Diabetes (EASD) follows a stepwise approach comprising lifestyle changes and
pharmacological intervention. Metformin is recommended as initial pharmacological therapy, 
followed by combination therapy with other oral antidiabetic drug(s) (OADs), glucagon-like peptide 
1 receptor agonists (GLP-1 RA) or insulin as the disease progresses8.
As T2DM progresses, intensification of treatment is needed. Basal insulin in combination with 
either mealtime insulin or GLP-1 RA is recommended, however the combination of basal insulin 
and mealtime insulin is the most commonly used9. Accordingly, products containing both basal and 
mealtime insulin are a convenient and widely used intensification option.
3.1.2
Insulin aspart
Insulin aspart (IAsp) is a rapid-acting analogue indicated for the treatment of diabetes mellitus, and 
is the drug substance of the currently marketed products NovoRapid®, NovoMix® and NovoLog®.
IAsp is homologous to human insulin, with the exception of the substitution of proline with aspartic 
acid at position B28. The rapid action of IAsp is related to a weakened tendency of the insulin 
molecules to self-associate due to this modification and is thereby related to faster absorption as 
compared with human insulin.
Compared with human insulin, IAsp has a faster onset and a shorter duration of action, resulting in 
superior postprandial glycaemic control by means of lowering total glucose excursion following a 
meal, both in subjects with Type 1 diabetes mellitus and in subjects with T2DM10-12. IAsp should 
generally be given immediately (within 5V10 minutes) prior to the start of a meal. 
For further details, refer to the EU Summary of Product Characteristics (EU SmPC)13 and/or the 
U.S. Label Information (U.S. LI)14 and/or the local package insert for IAsp, and any updates 
thereof.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
22 of 119
3.1.3
Insulin degludec/insulin aspart
Insulin degludec/insulin aspart (IDegAsp) is the approved international non-proprietary name for 
the soluble co-formulation of insulin degludec (IDeg) and insulin aspart (IAsp). The co-formulation 
consists of 70% IDeg and 30% IAsp and is currently marketed as Ryzodeg® and Ryzodeg® 70/30.
Insulin degludec is the approved international non-proprietary name for the insulin analogue 
formerly named insulin 454, and is the drug substance of the currently marketed product Tresiba®. 
IDeg differs from human insulin in that the threonine in position B30 has been omitted, and a side-
chain consisting of glutamic acid and a fatty acid has been attached. The protracted action of insulin 
degludec is related to its ability to self-assemble into soluble multi-hexamers at the injection site 
and, to a lesser degree, through the ability to bind to albumin via the fatty-acid side-chain. This way
IDeg mimics the endogenous basal insulin secretion with an ultra-long duration of action with a low 
risk of hypoglycaemia. When co-formulating IAsp with IDeg, the benefits of the flat and stable 
ultra-long-acting basal IDeg and the rapid-acting IAsp are combined in one injection with each 
component acting independently. Accordingly, IDegAsp provides both a basal insulin affecting 
fasting plasma glucose (FPG) and a mealtime insulin affecting post prandial glucose with the 
convenience of a single injection. For further details refer to current version of the EU SmPC15
and/or U.S. LI16 and the Investigator’s Brochure (IB) of IDegAsp17 and any updates thereof.
3.1.4
Insulin glargine
Insulin glargine, (IGlar, Lantus®) is a long-acting insulin analogue, indicated for treatment of 
diabetes mellitus in combination with oral antidiabetic agents and as part of a basal-bolus insulin 
regimen.
An amino-acid substitution at position A21 (compared with human insulin) causes precipitation of 
insulin glargine upon injection, forming a depot from which it is slowly released18.Compared with 
neutral protamine Hagedorn (NPH) insulin, this results in a prolonged action, lower mean FPG 
levels and a lower incidence of nocturnal hypoglycaemia, whereas within-subject variation in 
absorption is comparable to that observed with NPH insulin19-26.
For further details, refer to the current versions of the EU SmPC27 and U.S. LI18 or local package 
insert for IGlar, and any updates thereof.
3.1.5
Insulin antibodies
Exposure to a new insulin product can trigger antibody development. As part of the assessment of 
the long-term safety of IDeg or IDegAsp, antibodies specific to IDeg as well as antibodies cross
reacting to human insulin were measured in some phase 3 trials. From these trials there was no 
evidence of neutralising antibodies following treatment with IDeg or IDegAsp. There was no 
correlation of antibodies to HbA1c, nor to the dose in the IDeg or IDegAsp trials17, 28.
For an assessment of benefits and risks of the trial, see Section 18.1
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
23 of 119
3.2
Rationale for the trial
IDegAsp (Ryzodeg®) is approved for treatment of diabetes mellitus in adults in more than 60
countries worldwide including U.S., India and Europe. However, so far no clinical trials have been 
conducted investigating stepwise intensification of IDegAsp OD to twice daily (BID).
Further, additional efficacy and safety data for IDegAsp OD, including comparison against a fair 
comparator as a basal and a single daily bolus regimen (IGlar OD+ IAsp OD) is needed to further 
support the IDegAsp OD use.
This trial will also provide information on the efficacy and safety of a stepwise intensification with 
IDegAsp OD to BID compared to IGlar OD + IAsp (1-3 times daily) in subjects with T2DM 
inadequately controlled on basal insulin with and without OAD(s).
The immunological response to the trial insulin products will be monitored following the European 
Medicines Agency (EMA) guideline on this subject29.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
24 of 119
4
Objectives and endpoints
4.1
Objectives
The primary objective
To confirm the effect of insulin degludec/insulin aspart once daily versus insulin glargine 
once daily in combination with insulin aspart once daily in controlling glycaemia after 26 
weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
The secondary objectives
!
To compare other effect parameters  and safety of insulin degludec/insulin aspart once daily 
versus insulin glargine once daily in combination with insulin aspart once daily after 26
weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
!
To compare the effect and safety of insulin degludec/insulin aspart once daily or twice daily 
versus insulin glargine once daily in combination with insulin aspart (1-3 times daily) after 
38 weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
4.2
Endpoints
4.2.1
Primary endpoint
Change from baseline in glycosylated haemoglobin (HbA1c) (%) after 26 weeks
4.2.2
Supportive secondary endpoints
4.2.2.1
Supportive secondary efficacy endpoints
At 26 weeks:
!
Responder (Yes/No) for HbA1c after 26 weeks
o
HbA1c < 7%*
o
HbA1c < 7% without nocturnal (00:01-05:59) blood glucose (BG) confirmed 
symptomatic hypoglycaemia
!
Change from baseline in fasting plasma glucose (FPG) after 26 weeks
                                                
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and EudraCT)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
25 of 119
!
Self-measured plasma glucose measurements (SMPG) after 26 weeks
o
Mean pre-breakfast measurements used for titration
o
9-point profile

Post-prandial increments
At 38 weeks:
!
Change from baseline in HbA1c (%) after 38 weeks*
!
Responder (Yes/No) for HbA1c after 38 weeks:
o
HbA1c < 7%*
o
HbA1c < 7% without nocturnal (00:01-05:59) BG confirmed symptomatic 
hypoglycaemia
!
Change from baseline in fasting plasma glucose (FPG) after 38 weeks
!
Self-measured plasma glucose measurements (SMPG) after 38 weeks
o
Mean pre-breakfast measurements used for titration
o
9-point profile

Post-prandial increments
4.2.2.2
Supportive secondary safety endpoints:
During 26 weeks:
!
Number of nocturnal, treatment-emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 26 weeks
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 26 weeks
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 26 weeks*
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 26 
weeks
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during maintenance (week 16-26)
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during maintenance (week 16-26)
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during maintenance (week 16-26)
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 
maintenance (week 16-26)
!
Total insulin dose at week 26
!
Change in weight from baseline to week 26
!
Incidence of treatment-emergent adverse events (TEAEs) from baseline to week 26
                                                
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and EudraCT)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
26 of 119
!
Change from baseline to week 26 in:
o
Physical examination
o
Vital signs (blood pressure and pulse)
o
Dilated fundoscopy or fundus photography
o
12-lead electrocardiogram
o
Laboratory assessments
o
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes)
o
Biochemistry (creatinine, alanine aminotransferase, aspartate aminotransferase , 
alkaline phosphatase, sodium, potassium, albumin, total bilirubin)
o
Insulin antibodies
During 38 weeks:
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 38 weeks
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 38 weeks
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 38 weeks*
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 38 
weeks
!
Total insulin dose at week 38
!
Change in weight from baseline to week 38
!
Incidence of treatment-emergent adverse events (TEAEs) during 38 weeks*
!
Change from baseline to week 38 in:
o
Physical examination
o
Vital signs (blood pressure and pulse)
o
Dilated fundoscopy or fundus photography
o
12-lead electrocardiogram
o
Laboratory assessments:

Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, 
leucocytes)

Biochemistry (creatinine, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, sodium, potassium, albumin, total 
bilirubin)

Insulin antibodies
                                                
* Key supportive secondary endpoint prospectively selected for disclosure (e.g. clinicaltrials.gov and EudraCT)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
27 of 119
Supportive secondary patient reported health economics endpoints
!
Change from baseline to week 26 for:
o
Health-related quality of life as evaluated by the SF-36v2®
o
Treatment related impact as evaluated by TRIM D
!
Change from baseline to week 38 for:
o
Health-related quality of life as evaluated by the SF-36v2®
o
Treatment related impact as evaluated by TRIM-D
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
Page:
28 of 119
5
Trial design
5.1
Type of trial
This is a 38-week, multinational, open-label, randomised (1:1), controlled, parallel, treat-to-target 
trial in subjects with T2DM treated with basal insulin with or without OAD(s) in need of treatment 
intensification. The aim of the trial is to compare IDegAsp OD vs IGlar OD + IAsp OD with or 
without OAD(s) after 26 weeks of treatment. In addition, a comparison of a stepwise treatment 
intensification of 12 weeks with IDegAsp OD to BID vs. IGlar OD + IAsp 1 to 3 times daily will be
performed.
Subjects will be randomised in a 1:1 manner into one of the stepwise treatment intensification arms 
below and treated as described in Section 5.3.3.
IDegAsp arm:
!
Initial 26 weeks: IDegAsp OD administered at the largest meal each day ± OAD(s)
!
Intensification period – Week 26-38: IDegAsp OD/BID administered at the largest meal(s) each 
day based on individual needs ± OAD(s)
IGlar + IAsp arm:
!
Initial 26 weeks: IGlar OD administered in accordance with local labelling and IAsp OD 
administered at the largest meal ± OAD(s)
!
Intensification period – Week 26-38: IGlar OD administered in accordance with local labelling 
and IAsp 1-3 times daily administered at main meals based on individual needs ± OAD(s)
The trial design is summarised schematically in Figure 5–1
Figure 5–1
Trial Design
Randomisation will be stratified based on the pre-trial basal insulin treatment regimen: OD or 
BID/TID dosing. Subjects on a BID/TID regimen will be shifted to OD dosing in accordance with 
the Titration Guideline, Appendix A.
CONFIDENTIAL


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CONFIDENTIAL
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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A population of subjects with HbA1c between 7.0-10.0% (both inclusive) treated with any basal 
insulin with or without OAD(s), and thus not achieving the recommended treatment target, and 
therefore in need of treatment intensification has been chosen. 
The duration of the trial will be approximately 44 weeks and includes: 
!
Screening Visit (V1)
!
Randomisation Visit (V2)
!
Weekly contacts (phone or clinic visits (V3-V40)) throughout the 38 weeks’ treatment 
period, refer to flow chart (Section 2)
!
Two Follow-up visits at 7-12 days (V41) and 30 days (P42) after the end of treatment (EOT)
visit (V40)
5.2
Rationale for trial design
An open label trial design has been chosen as blinding is not feasible due to the different regimens 
in the two treatment arms.
The reason for stratifying according to pre-trial basal insulin dosing OD or BID/TID is to ensure 
that these sub-populations are equally represented in both arms. The treat to target design will be 
implemented using a very tight visit schedule in order to ensure optimal insulin titration based on 
SMPG values and to ensure improvement in glycaemic control in the treatment initiation period. 
The initial 26-week treatment period is expected to be sufficient to initiate and up-titrate the trial 
treatment to obtain data for evaluation of efficacy, safety and PROs.
Similarly the 12-week intensification period is expected to be sufficient to intensify and up-titrate 
the trial treatment to obtain data for evaluation of efficacy, safety and PROs.
The multinational approach is to ensure that the results are applicable for subjects with different 
demographic characteristics.
The primary endpoint HbA1c is a laboratory parameter and consequently the probability of 
assessment bias is limited.
The two follow-up visits are included to ensure proper follow-up on subject safety after end of trial 
drug-treatment.
A 1-week interval between the EOT visit (V40) and the 7-day follow-up visit (V41) is necessary to 
allow for trial insulin ‘washout’ prior to measurement of insulin antibodies. Due to the much shorter 
duration of the type of basal insulins (NPH or biphasic insulin aspart 30 (BiAsp 30)) used in the 
‘washout’ period, the levels of insulin will be lower at the sampling time point at the 7-day follow-
up (V41). For insulin treatment in the ‘washout’ period, see Section 5.5.
A 30-day follow-up (P42) after last trial insulin treatment (V40) will be performed in order to 
collect information about antidiabetic treatment and adverse events (AEs) occurring between V41 
and P42.
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Version:
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5.3
Treatment of subjects
Subjects with T2DM treated with any basal insulin with or without OAD(s) can enter the trial if 
they have an HbA1c between 7.0-10.0% (both inclusive).
Subjects will attend a screening visit (V1) where inclusion and exclusion criteria will be assessed.
If eligible, subjects will be randomised to their trial insulin treatment at the randomisation visit 
(V2), refer to Sections 5.3.1 and 5.3.2.
At randomisation subjects must discontinue pre-trial insulin, SU and glinides. Treatment with other 
OADs should continue during the trial as described in Section 5.4.
For subjects in both treatment arms diet and exercise counselling should be continued as per the 
standard of care at the investigational site.
At the EOT visit (V40) subjects should be switched to ‘washout’ insulin as described in Section 5.5
5.3.1
Treatment regimens arms
Subjects will be randomised into a 1: 1 manner as described in Section 5.1 into the two stepwise 
treatment intensification arms below and treated as described in Section 5.3.3:
IDegAsp arm:
!
Initial 26 weeks: IDegAsp OD administered at the largest meal each day ± OAD(s)
!
Intensification period – Week 26-38: IDegAsp OD/BID administered at the largest meal(s) each 
day based on individual needs ± OAD(s)
IGlar + IAsp arm:
!
Initial 26 weeks: IGlar OD administered in accordance with local labelling and IAsp OD 
administered at the largest meal ± OAD(s)
!
Intensification period – Week 26-38: IGlar OD administered in accordance with local labelling 
and IAsp 1-3 times daily administered at main meals based on individual needs ± OAD(s)
5.3.2
Trial insulin products
The below trial insulin products will be provided by Novo Nordisk A/S:
!
Insulin degludec/insulin aspart (Ryzodeg®) 100 units/mL, 3 mL pre-filled pen (FlexTouch®), 
solution for subcutaneous injection, Novo Nordisk A/S
!
Insulin glargine (Lantus®) 100 units/mL, 3 mL pre-filled pen (SoloStar®), solution for 
subcutaneous injection, Sanofi-Aventis
!
Insulin aspart (NovoRapid®/NovoLog®), 100 units/mL, 3 mL pre-filled pen (FlexPen®),
solution for subcutaneous injection, Novo Nordisk A/S
CONFIDENTIAL


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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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The subjects must be trained in how to handle the above pre-filled pen-devices when handed out the 
first time (refer to section 8.6.3). For further information on trial insulin products, see Section 9.
5.3.3
Trial insulin treatment
Subjects will receive either IDegAsp OD or IGlar OD + IAsp OD during the first 26 weeks and 
continue into a 12-week intensification period.
Subjects on a pre-trial BID/TID basal insulin regimen will be shifted to OD dosing in accordance 
with the Titration Guideline, Appendix A.
For information about initial doses, area of injection, dosing time and the weekly dose adjustments 
during the initial treatment period (week 2-26), refer to the Titration Guideline, Appendix A.
At week 26 (V28) , subjects not achieving sufficient glycaemic control (V27 HbA1c L 7%) will be 
further intensified from either IDegAsp OD to IDegAsp BID or IGlar OD + IAsp OD to IGlar OD + 
IAsp BID. Subjects in good glycaemic control (V27 HbA1c < 7%) will continue their insulin 
treatment regimen.
At week 32 (V34), glycaemic control will be evaluated again, and subjects in good glycaemic 
control (V33 HbA1c < 7%) will continue their insulin treatment regimen. Subjects on IDegAsp OD 
not reaching the glycaemic target (V 33 HbA1c L 7%) will be intensified to IDegAsp BID, whereas 
subjects in the IGlar arm not reaching glycaemic control will be intensified with one additional 
IAsp dose to IGlar OD + IAsp BID or TID daily for the remaining six weeks of the intensification 
period.
Information about doses, dosing time and dose adjustments during the treatment intensification
period (week 27-38) can be found in the Titration Guideline, Appendix A. 
Information about insulin treatment in the ‘washout’ period between the EOT visit (V40) and the 7-
day follow-up visit (V41) can be found in Section 5.5.
5.4
Oral antidiabetic treatment
Upon trial entry, subjects treated with any of the below allowed OADs should continue their 
treatment unchanged, meaning subjects should not:
!
start treatment with any other antidiabetic treatment
!
change the pre-randomisation OAD(s) dose or dosing frequencya)
!
start treatment with any medication known to interfere significantly with glucose 
metabolism
a) However, for safety reasons, a decrease in the OAD(s) dose is allowed if deemed necessary by the 
investigator.
OADs are not considered trial products and will not be supplied by Novo Nordisk A/S, refer to 
Section 9.1.
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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5.4.1.1
Allowed OADs
As prior to randomisation:
!
Metformin
!
N-glucosidase-inhibitors
!
DPP-4 inhibitors
!
SGLT2 inhibitors
!
Oral combination products (of the allowed individual OADs above)
5.4.1.2
OADs prohibited during trial treatment:
Below OADs must be discontinued upon randomisation visit (V2) and must not be initiated during 
the trial:
!
Insulin secretagogues (SU and glinides)
5.5
Treatment after discontinuation of trial product
When discontinuing trial product(s), either at the scheduled EOT visit (V40) or if trial product is 
discontinued prematurely, the subject should be asked to attend the trial site for completion of the 
following visits:
!
EOT visit (V40)
At this visit the subjects randomised to the two treatment arms should be switched to the following 
‘washout’ insulin treatment and continue other oral antidiabetic treatment until the 7-day follow-up
visit (V41):
o
IDegAsp arm: Switch IDegAsp dose to BiAsp 30 BID. The total daily IDegAsp dose at end 
of the treatment period should be reduced by 20% and divided into two BiAsp 30 doses and 
administered with breakfast/lunch and evening meal.
o
IGlar + IAsp arm: Switch IGlar dose to NPH insulin BID. The IGlar dose at the end of the 
treatment period should be reduced by 20% and divided into two NPH doses and 
administered in the morning and in the evening. IAsp doses should be continued as in the 
treatment period.
!
7-days follow-up visit (V41):
At this visit subjects should be switched to suitable marketed insulin product(s) at the discretion of 
the investigator.
!
A 30-day follow-up visit (P42) – refer to section 8.1.9
In addition, for subjects pre-term discontinued, monthly phone contacts (Px) as applicable, an 
abbreviated V28 (V28a), if applicable, and an additional abbreviated EOT visit (V40a) will be 
conducted as described in Sections 8.1.9 and 8.1.11 also refer to the flow chart (Section 2).
CONFIDENTIAL


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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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5.6
Rationale for treatment
In patients not achieving treatment target on basal insulin, addition of either mealtime insulin or 
GLP-1 RA is recommended by the ADA/European Association for the Study of Diabetes (EASD)
guidelines. The combination of basal insulin and mealtime insulin is the most commonly used; 
either as basal/bolus regimens or as combination products. Accordingly, this trial will provide 
information on the efficacy and safety of the combination product IDegAsp OD compared to IGlar
OD + IAsp OD and of the stepwise intensification of mealtime insulin with two different treatment 
intensification regimens.
Subjects treated with SU and glinides should discontinue the use of these at randomisation because 
the combination with trial insulin products could lead to an increased risk of hypoglycaemia.
Dosing is individual and the treat to target approach is used to optimise glycaemic control 
throughout the trial.
The subcutaneous administration form of all trial products is in accordance with approved 
documents as follows:
!
IDegAsp: IB and/or EU SmPC and/or U.S. LI
!
IGlar: U.S. LI/ EU SmPC
!
IAsp: EU SmPC and/or U.S. LI
IGlar has been chosen as the comparator as it is approved for OD use only, is commonly used for 
insulin initiation in T2DM subjects and is currently the most widely used basal insulin in many 
countries.
Based on data from the clinical development programme for IDegAsp, and the fact that there is no 
maximum dose of IDegAsp treatment, the chosen duration of the trial is considered appropriate for 
the purpose of obtaining meaningful information on efficacy and safety of IDegAsp when 
intensifying treatment from OD to BID.
The switch from trial insulin treatment to the ‘washout’ insulin (BiAsp 30 or NPH + IAsp) between 
the EOT visit (V40) and the 7-day follow-up visit (V41), is done in order to provide basal insulin 
coverage while reducing the level of exogenous insulin present at antibody sampling and 
consequently to reduce the possibility for interference with antibody measurements.
CONFIDENTIAL


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CONFIDENTIAL
Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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6
Trial population
6.1
Number of subjects 
Planned number of subjects to be screened meaning the number of subjects providing informed 
consent: 754.
Planned number of subjects to be randomised/started on trial products: 528.
Expected number of subjects to complete the trial: 449.
A screening failure rate of 30% and a premature discontinuation of trial drug/withdrawal rate of 
randomised subjects of 15% are expected.
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 L 18 years at the time of signing informed consent
Algeria: Male or female, age L 19 years at the time of signing informed consent
3. Diagnosed with type 2 diabetes mellitus
4. Treated with any basal insulin L 90 days prior to the day of screening
5. Subject not on any OAD(s) prior to trial participation OR subjects on stable daily dose(s) of
OAD(s) for at least 90 days prior to screening visit (V1). The OAD(s) include any of the 
following anti-diabetic drug(s)/regimen:
a.
Biguanides (metformin L 1500 mg or maximum tolerated dose documented in the 
subject medical record)
b. Other OADs (L half of the maximum  approved dose according to local label or 
maximum tolerated dose as documented in subject medical record):
i.
Insulin secretagogues (SU and glinides)
ii.
DPP-4 inhibitors
iii.
N-glucosidase inhibitors
iv.
SGLT-2 inhibitors
v.
Oral combination products (of the allowed individual OADs)
6. HbA1c 7.0-10.0% (53-86 mmol/mol) (both inclusive) by central laboratory analysis
7. Body mass index (BMI) O 45.0 kg/m2
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8. Ability and willingness to adhere to the protocol including self-measurement of plasma 
glucose according to the protocol
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”
1. Known or suspected hypersensitivity to trial product(s) or related products
2. Previous participation in this trial. Participation is defined as signed informed consent
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using adequate contraceptive methods (adequate contraceptive measures as 
required by local regulation or practice)
4. Participation in any clinical trial of an approved or non-approved investigationalmedicinal 
product within four weeks prior to the day of screening (V1)
5. Any chronic disorder or severe disease which, in the opinion of the investigator, might 
jeopardise subject’s safety or compliance with the protocol
6. Acute decompensation of glycaemic control requiring immediate intensification of treatment 
to prevent severe metabolic dysregulation (e.g. diabetes ketoacidosis)  O 90 days prior to the 
day of the screening
7. 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
8. Subjects presently classified as being in New York Heart Association (NYHA) Class IV
9. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening
10. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of < 60 
ml/min/1.73 m2 as defined by KDIGO 2012 classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening
11. Impaired liver function, defined as ALT L 2.5 times upper normal limit (UNL) at screening
12. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic 
L180 mmHg or diastolic L110 mmHg) at screening
13. 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
14. 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)
15. Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to randomisation
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16. Presence or history of malignant neoplasms within the past five years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed
6.4
Randomisation criteria
Not applicable for this trial.
6.5
Rescue criteria
If any of the fasting SMPG values taken on three consecutive days or if any of the FPG samples 
analysed by the central laboratory exceed the limit of: 
!
15.0 mmol/L (270 mg/dL) from baseline to end of week 12
!
13.3 mmol/L (240 mg/dL) from week 13 to end of week 38
and if no treatable inter current 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.
The subject should be prescribed alternative therapy at investigator´s discretion, and be retained in 
the trial.
If prematurely withdrawn from trial drug, effort should be made to follow the procedures described 
in Section 8.1.11. Also refer to Section 5.5.
6.6
Criteria for premature discontinuation of trial product 
Efforts must be made so that subjects attend and complete all scheduled visit procedures. Subjects 
should stay in the trial 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 6.7).
The subject may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern or if judged non-compliant with trial procedures.
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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 any of the inclusion and/or exclusion criteria
2. Pregnancy
3. Intention of becoming pregnant
4. Initiation or significant change in concomitant medications for more than 14 calendar days
which in the investigator’s opinion could affect weight or glucose metabolism
5. Simultaneous participation in another clinical trial of an approved or non-approved
investigational medicinal product
6. The fasting SMPGs values taken on three consecutive days or any FPG samples analysed by
the central laboratory exceeding the limit of(refer to section ):
!
15.0 mmol/L (270 mg/dL) from baseline to end of week 12
!
13.3 mmol/L (240 mg/dL) from week 13 to end of week 38
Subjects discontinued from trial product should be prescribed alternative therapy at investigator´s 
discretion, and be retained in the trial.
For procedures to be performed for subjects discontinuing trial product prematurely, see Sections
8.1.11 and 5.5.
6.7
Withdrawal from trial 
The subject may withdraw consent at will at any time.
Subjects who consider withdrawing informed consent should be encouraged to have procedures 
performed according to end of trial visit and the follow-up contacts (V41 and P42) as described in 
Section 8.1.9.
A subject who agrees to provide information on HbA1c, AEs and other assessments relevant for the 
evaluation of trial endpoints at the planned end of the trial are not to be considered withdrawn from 
the trial.
Only subjects who decline any further contact with the site in relation to the trial, and hence do not 
agree to report information should be considered as withdrawn.
Subjects who are withdrawn will not be replaced. For procedures to be performed for subjects 
withdrawing consent, see Section 8.1.12.
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Protocol
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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6.8
Subject replacement
Subjects who discontinue trial product prematurely will not be replaced.
6.9
Rationale for trial population 
A population of subjects with T2DM treated with basal insulin with or without OAD(s) with an 
HbA1c between 7.0-10% (both inclusive) has been chosen for this trial to confirm the efficacy of 
IDegAsp OD vs IGlar OD + IAsp OD with or without OAD(s) in controlling glycaemia and also to 
demonstrate that treatment intensification with IDegAsp OD to BID is efficacious and safe in 
subjects not achieving recommended treatment target on OD treatment.
The inclusion and exclusion criteria applied in this trial were selected to allow for inclusion of a 
trial population as broad as possible to ensure generalizability of trial results to the broad population 
of subjects with T2DM treated with basal insulin with or without OAD(s) in need of treatment 
intensification.
A BMI limit of O 45.0 kg/m2 was chosen to include as broad a population as possible only limiting 
extremely obese subjects with high insulin resistance.
Stable glucose lowering therapy prior to trial enrolment ensures stable levels of glycaemia which 
could otherwise influence the trial endpoints.
Only serious concomitant conditions (NYHA class IV, history of recent serious cardiac events, 
neoplastic disease, renal or hepatic impairment, and pre-planned major surgery etc.) which could 
interfere with subject safety and trial procedures preclude subjects from entering into the trial.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
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7
Milestones
Planned duration of recruitment period (i.e. first patient first visit (FPFV) – last patient first visit 
(LPFV)): 
16 weeks
Planned date for FPFV: 
20 Sep 2016
Planned date for last patient last visit (LPLV): 
16 Nov 2017
End of trial is defined as LPLV.
Recruitment:
The screening and randomisation rate will be followed closely via the interactive voice/web 
response system (IWRS) in order to estimate when to stop screening. All investigators will be 
notified immediately when the recruitment period ends, after which no further subjects may be 
screened and the IWRS will be closed for further screening. All subjects screened during the 
recruitment period and found eligible for randomisation can be randomised within the timelines 
specified in the flow chart (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 Disclosure30, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)31, the Food and Drug Administration Amendment Act (FDAAA)32, 
European Commission Requirements33, 34 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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Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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8
Methods and assessments
8.1
Visit procedures
The following Sections describe the assessments and procedures as well as how to record the 
results. Timing of the site visits, telephone contacts, visit windows and the assessments to be 
performed are specified in the flow chart (Section 2).
8.1.1
Investigator assessments
Review of the electrocardiogram (ECG) results and the eye examination reports must be 
documented by the dated signature on the documents and/or in the subject’s medical record.
Investigator must evaluate laboratory results and document this by dated signature on the laboratory 
report printouts. In case any laboratory result is outside the reference range, the investigator must 
evaluate and document if clinically significant (CS) or not clinically significant (NCS) at the 
printouts.
Screening results must be evaluated, dated and signed prior to randomisation. For the subsequent 
visits, evaluation and sign-off should take place as soon as possible upon the receipt of the 
documents. The signed documents must be retained at the trial site as source documentation.
In case of abnormal CS findings (ECGs, dilated fundoscopy or fundus photography, physical 
examination and laboratory parameters) the investigator must state a comment in the subject’s 
medical record. If present at screening V1, this should be documented in the concomitant illness
form in the electronic case report form (eCRF). At subsequent visits, any clinically significant 
changes or new clinically significant findings must be reported as an AE according to Section 12.
8.1.2
Visit Schedule
It is the responsibility of the investigator to ensure that all site visits and phone contacts occur 
according to the flow chart (Section 2).
After the randomisation visit (V2), the visit scheduling should always be based on the actual V2 
date, except for the follow-up visits V41 and P42, which should be scheduled based on the EOT
visit (V40) date, refer to Section 8.1.9
8.1.3
Phone contacts
A phone contact may be converted to a site visit if preferred. Before any phone contacts, the 
delegated site staff and the subject should agree on the timing and direction of the call. The 
investigator remains responsible for ensuring the contacts occur, even if agreed that the subject 
should be calling the site.
If for some reason a planned phone contact was not completed, the investigator should ensure to 
perform the phone contact within the allowed visit window.
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8.1.4
Fasting requirements
The subject should attend some clinic visits in fasting condition - refer to flow chart (Section 2).
Fasting is defined as at least eight hours without food and liquids, except for water. No diabetes 
treatment (neither trial insulin, nor any OADs) is allowed up to eight hours prior to these 
measurements. Any other prescribed medication should be taken as usual.
If non-fasting, blood sampling should be re-scheduled preferably within the next two working days, 
refer to Section 8.5.1.2.
8.1.5
Diaries
At each clinic visit, the subjects must receive diaries related to the following visit and/or phone 
contact(s). The diaries dispensed to subjects should be collected at the following clinic visit. 
However, for the screening visit (V1), the 30-days follow-up visit (P42) and the monthly phone 
contacts (in case of pre-term discontinuation of trial insulin products) no diaries will be provided.
The investigator should instruct subjects how to complete the diaries and ensure completion of these 
in accordance with the instruction provided.
Investigator or delegated staff must review data entered in the subject diaries, including PROs. 
Review of the diary and PROs must be documented either on the document and/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.
It is the responsibility of the investigator to review the diary for subject’s notes regarding possible 
AEs, hypoglycaemic episodes and concomitant medication, see Sections 12, 8.4.7 and 8.2.5.
Safety data from the diaries must be handled according to timelines described in Section 12.2.
The investigator or delegated staff should transcribe diary data into the eCRF as soon as possible 
after each site visit/phone contact. If necessary, the investigator should convert the format of data 
used by the subject into the format used in the eCRF.
Titration data should preferably be entered within 24 hours (refer to Appendix A). If data is 
obtained via phone and a discrepancy is later detected, the values in the eCRF should be corrected 
to the diary.
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The investigator is only allowed to record the following data in the diary:
!
Subject ID
!
Site contact details
!
Time and date of next visit or phone contact
!
Prescribed dose(s) of trial insulin(s)
!
Review signature
The subject must record the following information in the diary:
!
Dates and doses of trial product injection, including first and last dose of trial product (V2-V40)
!
Date, time and value of SMPG measurements used for weekly titration purposes (V2-V40)
!
9-point SMPG profile measurements including: date and actual clock time (V2, V18, V28, V34
and V40)
!
Medical condition(s) including: hypoglycaemic episodes, other AEs, and potential change(s) in 
concomitant medication during the trial (V2-P41)
8.1.6
Screening
Informed consent must be obtained before any trial related activity, refer to Section 18.2.
Details about retention long-term storage of antibody (AB) samples will be included in the informed 
consent, and subjects will be asked to consent to this. For further information, refer to Section 24.2
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log.
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
At this visit, information about the subjects’ pre-trial basal insulin and OAD treatment (start date 
and current dose) should be captured in the subjects’ medical notes and transcribed into the eCRF.
Subjects will receive a blood glucose meter (BG-meter) and a diary. Investigator or delegated staff 
will instruct the subject in how to use both, see Sections 8.1.5 and 8.3.1.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial.
A screening session in IWRS must be made, refer to Section 10.
8.1.6.1
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 and non-serious AEs from screening failures must be transcribed 
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by the investigator into the eCRF. Follow-up on serious adverse events (SAEs) must be carried out 
according to Section 12.
A screening failure session must be made in the IWRS. The case book must be signed. 
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.
8.1.7
Randomisation visit (V2)
Randomisation (V2) should take place within 14 days after the screening visit (V1). All results from 
screening assessments, including laboratory results, ECG and eye examination must be available, 
reviewed, dated and signed by the investigator and the in/exclusion criteria carefully reviewed to 
ensure subject eligibility prior to randomisation.
Randomisation of subjects will be done using IWRS, see Sections 10 and 11.
At V2 trial insulin products will be supplied to the subject after having completed the IWRS 
dispense call, see Section 10. Investigator or delegate staff will ensure proper training in trial 
product and pen handling. For subjects in the IGlar arm, the training must include pen 
differentiation. Directions for use (DFUs) will be provided to the subjects, refer to Section 8.6.3.
Hand-out of the DFU(s) to the subject must be documented in the subject’s medical file.
At randomisation subjects must discontinue their pre-trial insulin, SU and glinides and the stop-
date(s) must be recorded in the subjects’ medical notes and transcribed into the eCRF. Treatment 
with other OADs should continue unchanged during the trial, see Section 5.4.
PRO questionnaires including baseline hypoglycaemia questionnaire (BHQ) must be completed by 
the subjects - please refer to Section 8.6.1.
For further details on trial procedures and assessments, refer to the Flow chart (Section 2).
8.1.8
Treatment period (V3-V40)
The treatment period includes the following:
!
The treatment initiation period weeks 2-26 (V3-V28)
!
The intensification period weeks 27-38 (V29-V40)
!
The EOT visit (V40)
After randomisation and until the EOT visit (V40), trial products to subjects will be allocated and
dispensed to subjects and accounted for at pre-specified visits utilising IWRS, refer to Flow chart
(Section 2) and Section 10.
For details on trial drug treatment, refer to Sections 5.3 and 9.
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Subjects are instructed to return all used, partly used and unused trial product at each dispensing 
visit during the treatment period ending at V40 with the EOT visit. At this visit subjects must 
discontinue trial insulin treatment.
At the EOT visit (V40) ‘washout’ insulin (BiAsp 30 or NPH + IAsp) to be used in the ‘washout’
period between V40 and the 7-day follow-up visit (V41) will be dispensed to all subjects. A DFU
must be handed out at V40 and this must be documented in the subject’s medical file. For dosing of 
‘washout’ insulin, see Section 5.5.
For other procedures and assessments performed during the treatment period, refer to the flow chart
(Section 2).
8.1.9
Follow-up visits
In order to properly follow-up on subject safety after subjects have stopped their trial insulin 
treatment the subjects should attend two follow-up visits after the EOT visit (V40):
!
Clinic Visit (V41); which will be conducted 7-12 days after V40
!
Phone Contact (P42); 30-35 days after V40 (according to visit window)
Subjects should attend V41 fasting for AB sampling (refer to Section 8.1) and subjects should 
return ‘washout’ insulin products at trial site for final drug accountability. Information about
concomitant medication and AEs including hypoglycaemia will be collected. Subjects will be 
switched to a marketed insulin product at the discretion of the investigator.
For the last follow-up visit (P42) and potential monthly phone contacts (Px), no paper diary will be 
provided. Consequently, source data for these phone contacts will be the notes written in the 
subject’s medical record. At these contacts only information about antidiabetic treatment and AEs 
will be collected.
8.1.10
Unscheduled visits
Unscheduled visits can be performed at any time at the discretion of the investigator. An 
unscheduled visit should be performed if, e.g. an AE occurs that needs further attention.
An unscheduled visit form in the eCRF must be completed, stating the reason for the visit.
However, completion of the unscheduled visit form should not be carried out if the subject attends 
the clinic:
!
For a visit rescheduled within the allowed visit window
!
Only to obtain additional trial insulin products or auxiliary supplies
If a subject requires additional trial insulin products, an additional IWRS dispensing session must 
be performed.
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If blood samples for a subject are re-taken, a laboratory requisition form should always be 
completed, and the visit number to which the sample belongs clearly indicated (please refer to the 
Laboratory Manual).
8.1.11
Premature discontinuation of trial product
In case of premature discontinuation of trial product the investigator should make all effort to call 
the subject in for an unscheduled visit as soon as possible and must aim to undertake procedures 
similar to those for the EOT visit (V40), including fasting blood sampling and hand-out of 
‘washout’ insulin products (refer to Section 5.3.3) to be used in the period between the EOT visit 
(V40) and the 7-day follow-up visit (V41), where the last AB sampling will be performed.
Furthermore, the follow-up visits (V41 and P42) must be performed as described in Section 8.1.9. 
For subjects prematurely discontinued from trial insulin products, monthly phone contacts (Px), as 
applicable, should be conducted after the 30-day follow-up (P42) and until the date where the EOT
visit (V40) was originally planned to take place (38 weeks after Visit 2). Here an additional 
abbreviated visit 40 (V40a) should be performed. If the timing of a monthly phone contact is less 
than two weeks from a planned abbreviated visit, the phone contact can be omitted. If subject
discontinues from trial product prior to Visit 28, an additional abbreviated visit 28 (V28a) should be 
scheduled at the date of the originally planned V28. At V28a and V40a HbA1c samples and 
information of AEs and antidiabetic treatment will be collected, refer to the flow chart (Section 2).
The primary reason for premature discontinuation of trial product must be specified in the ‘End of 
trial form’ in the eCRF, and final drug accountability must be performed. Furthermore, a treatment 
discontinuation session must be made in the IWRS.
8.1.12
Withdrawal from trial
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those 
for the EOT visit (V40) as soon as possible. If the subject agrees, the follow-up visits (V41 and 
P42) must be performed 7-12 days and approximately 30 days after discontinuation of trial product 
(refer to Section 8.1.9 above).
The end of trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS, and 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 should be encouraged to attend the EOT visit (V40) and the 7-day’ follow-up visit (V41) 
and to make an appointment for the 30-day follow-up phone contact (P42). If accepted, the subject 
should be encouraged to switch to ‘washout’ insulin products (BiAsp 30 or NPH + IAsp), 
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depending on their treatment arm, at their EOT visit (V40) which should be continued until the day 
prior to V41, where the last AB sample should be taken.
8.2
Subject related information/assessments
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Diabetes history and diabetes complications 
Diabetes history and diabetes complications will be recorded at screening and consists of:
!
Date of diagnosis of T2DM
!
Information regarding diabetes complications including date of onset
o
Diabetic retinopathy
o
Diabetic neuropathy
o
Diabetic nephropathy
o
Macro angiopathy (including peripheral vascular disease)
8.2.3
Hypoglycaemia unawareness 
Information on hypoglycaemia unawareness will be recorded at screening according to Clarke’s 
questionnaire, question 835. 
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 screening 
visit (V1) or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product. A concomitant illness is any illness other than the diabetes history and 
diabetic complications (refer to Section 8.2.2 above). All concomitant illness must be recorded.
Medical history is a medical event that the subject has experienced in the past.
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The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Any change to a concomitant illness should be recorded during the trial. 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 trial product(s), which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the screening visit (V1), including OAD 
treatment and pre-trial basal insulin, which subjects continue using between the screening visit (V1) 
and the randomisation visit (V2). For details on OAD treatment, refer to Section 5.4.
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, total daily dose and route of administration, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to Section 12. 
In case the concomitant medication is a systemic treatment which in the investigator’s opinion 
could interfere with the glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or
corticosteroids – refer to exclusion criterion 14 (Section 6.3)), this information needs to be captured 
in the eCRF.
If the change influences the subject’s eligibility to continue in the trial or trial product treatment, the 
monitor must be informed.
8.2.6
Childbearing potential 
It must be recorded in the eCRF whether female subjects are of childbearing potential.
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.3.2.
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:
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!
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation
!
Postmenopausal defined as no menses for 12 months without an alternative medical cause
!
Other medical reasons preventing childbearing potential
8.2.7
Tobacco use
Details of tobacco use (smoking status) must be recorded at the screening visit (V1). Smoking is 
defined as smoking at least one cigarette or equivalent daily. The collected information should 
include whether or not the subject smokes or has smoked as follows:
Smoking status:
!
Never smoked
!
Previous smoker
!
Current smoker
8.3
Efficacy assessments
Assessments related to subjects’ glycaemic control are listed below:
!
Laboratory assessments - refer to Section 8.5.2:
o
HbA1c
o
Fasting plasma glucose
!
SMPG recordings - refer to Section 8.3.1
8.3.1
Self-measured plasma glucose 
At screening (V1), subjects will be provided with a blood glucose meter including auxiliaries as 
well as instructions for use. The subjects will be instructed in how to use the device and the 
instruction will be repeated if applicable based on the need of each individual subject.
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.
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 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 BG-meter and 
correct reporting of these in the diary is advised in order to ensure adequacy of the data reported in 
the trial database.
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8.3.1.1
Self-measured plasma glucose used for insulin dose adjustment
Subjects should be asked to perform SMPG recordings on three consecutive days prior to the 
weekly dose adjustment. The number and timing of the SMPG measurements varying from 1 
SMPG to 4 SMPGs per day, depending on the treatment arm, to which the subject is randomised 
and the subject’s individual need for treatment intensification and thus the number of insulin dose 
administrations as specified below:
!
IDegAsp OD:
1 SMPG/day
!
IDegAsp BID:
2 SMPGs/day
!
IGlar OD + IAsp OD
1-2 SMPGs/day (depending on timing of IAsp dose)
!
IGlar OD + IAsp BID 
2-3 SMPGs/day (depending on timing of IAsp doses)
!
IGlar OD + IAsp TID 
3-4 SMPGs/day (depending on the timing of IAsp doses)
These SMPG recordings are required for the individual and optimal dose adjustment and 
maintenance as described in the Titration Guideline, Appendix A.
8.3.1.2
9-point self-measured plasma glucose profiles
9-point SMPG profiles will be used to evaluate blood sugar fluctuations and will be performed five
times during the trials, refer to the flow chart (Section 2).
9-point SMPG profiles should be measured starting in the morning two days prior to the scheduled 
visit at the time points described below – for details to be recorded in the diary see Section 8.1.5:
1. Before breakfast (two days prior to visit)
2. 90 minutes after start of the breakfast
3. Before lunch
4. 90 minutes after start of the lunch
5. Before dinner/main evening meal
6. 90 minutes after start of the dinner/main evening meal
7. At bedtime (two days or one day prior to visit depending on actual clock time)
8. At 4 a.m. (one day prior to visit)
9. Before breakfast at the following day (one day prior to the visit)
8.4
Safety assessments
8.4.1
Body measurements
Body measurements will be performed at time points specified in the flow chart, Section 2.
Body measurements consist of the following parameters:
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!
Body weight: should be measured without shoes and only wearing light clothing. It should be
recorded with one decimal (kg or lb) and preferably using the same set of scales throughout the 
trial
!
Height: should be assessed without shoes and measured in inches or meters and recorded to one 
or two decimal places respectively
!
Body mass index (BMI): will be calculated by the eCRF system based on the height and weight
8.4.2
Vital signs
Blood pressure and pulse will be measured at time points specified in the flow chart, Section 2.
The method for measuring systolic and diastolic blood pressure needs to follow the standard clinical 
practice at the trial site.
8.4.3
Physical examination
A physical examination must be performed at the visits specified in the flow chart, Section 2 and 
must include:
!
General appearance
!
Head, ears, eyes, nose, throat, neck
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Central and peripheral nervous system
!
Skin
Any abnormalities found at the screening visit (V1) should be recorded as concomitant illness.
Any new abnormal, clinically significant findings during the trial and any clinically significant 
worsening from baseline must be reported as an AE.
8.4.4
Eye examination
A dilated fundoscopy or fundus photography must be performed and interpreted locally by the 
investigator.
The evaluation of the dilated fundoscopy or fundus photography must follow the categories:
!
Normal
!
Abnormal
o
Was result clinically significant (Yes/No)
Dilated fundoscopy/fundus photography performed for any reason unrelated to this trial within 90 
days prior to the randomisation visit (V2) is acceptable provided no clinical symptoms suggestive of 
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eye disease have occurred in the meantime. It is allowed to perform the screening visit dilated 
fundoscopy/fundus photography between the screening visit (V1) and the randomisation visit (V2).
A subject cannot be randomised without results confirming there is no treatment-requiring 
retinopathy or maculopathy.
Dilated fundoscopy/fundus photography within a period of three weeks prior to Visit 28 and the 
EOT visit (V40) is acceptable, provided no clinical symptoms suggestive of eye disease have 
occurred in the meantime.
In case of “abnormal, clinically significant”, 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.
8.4.5
Electrocardiogram - 12 lead
A 12-lead ECG must be performed and interpreted locally by the investigator.
The evaluation of ECGs 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 Visit 28 and the EOT visit (V40) should be performed at the day of the visit.
In case of “abnormal, clinically significant”, 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.
8.4.6
Adverse events
Adverse events must be reported at each visit in accordance with the procedures outlined in Section
12. AEs including those related to technical complaints will be reported in the CTR as described in 
section 17.5.2.
8.4.6.1
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: 
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!
Trial product(s) involved
!
Classification of medication error
!
Whether the subject experienced any hypoglycaemic episode and/or AEs as a result of the 
medication error
!
Suspected primary reason for the medication error
For definition of medication errors, see Section 12.1.4.
8.4.6.2
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 SAE, please report accordingly, see Section 12.
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:
!
Acute coronary syndrome
!
Cerebrovascular event
!
Neoplasm
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: 
!
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, stroke, haemorrhage) is observed during 
the trial the following additional information must be reported if available: 
!
Type of event (e.g. transient ischaemic attack, stroke, haemorrhage)
!
Contributing condition
!
Neurologic signs and symptoms
!
History of neurologic disease
!
Imaging supporting the event
!
Treatment given for the event
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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EudraCT no.: 2015-004768-12
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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:
!
Type of neoplasm
!
Symptoms leading to identification of event
!
Diagnostic imaging
!
Pathological examination results
!
Treatment given for the event
!
Participation in screening programs
!
Relevant risk factors associated to the event
!
Relevant laboratory tests
!
New diagnosis or recurrence/relapse of the neoplasm
8.4.7
Technical complaints
“Only technical complains related to AEs will be reported in the clinical trial report”
For further details on technical complaints reporting please refer to sections 12.1.6 and 12.4.1.
8.4.8
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All plasma glucose values:
!
O 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 
randomisation (Visit 2) to the follow-up (Visit 41).
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 guidelines36.
A SMPG value O3.9 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 of 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 O3.9 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.
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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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.
If a new low SMPG value is measured or the subject still has symptoms more than 60 minutes after 
the first reported low SMPG value and/or symptoms, it will be considered as a new hypoglycaemic 
episode and a new hypoglycaemic episode form is to be filled in.
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 insulin administration prior to the episode
!
Date and time of last main meal (not including snacks) prior to the episode
!
Whether the episode occurred in relation to physical activity
!
Change in any concomitant illness
!
Any sign of fever and/or other acute disease 
!
Whether the subject was asleep when the episode occurred
o
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration36.
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)?
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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Page:
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!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose or 
other)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. overdose, mix-up between products, incorrect use of device), miscalculation of dose 
of antidiabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?
!
Did the subject experience any of the following symptoms37 (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 for low SMPG values not reported as hypoglycaemic 
episodes. The subject must be questioned whether any of the low values were severe, i.e. whether 
the subject was able to self-treat or not. If the subject was not able to self-treat, it has to be reported 
as a severe hypoglycaemic episode.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within seven days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data38, 39.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes.
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in, see Section 12.
8.5
Laboratory assessments
8.5.1
Laboratory samples
Laboratory samples should be taken at specific visits according to the flow chart (Section 2) and 
includes both efficacy parameters and safety parameters, refer to Sections 8.1.5 and 8.5.2.
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CONFIDENTIAL
Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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Only laboratory samples specified in Sections 8.5.1 and 8.5.2 of the protocol should be sent to the 
central laboratory. If additional laboratory sampling is needed, e.g. to follow-up on AEs, this should 
be done at a local laboratory.
All laboratory parameters, except from antibodies will be analysed at the central laboratory. 
Antibody samples will be analysed at a special laboratory. For contact information related to central 
and special laboratories, please refer to Attachment I.
8.5.1.1
Sample collection and handling
Sampling and shipping material including requisition forms and airway bills will be provided by the 
central laboratory. Description of the procedures for obtaining samples, handling and storage 
conditions, packaging and shipment will be included in the laboratory manual or laboratory 
flowchart, provided by the central laboratory vendor.
8.5.1.2
Fasting samples
For some laboratory parameters sample collection in fasting condition is required, refer to Section
8.1.4. Subjects should therefore attend the clinic fasting at selected visits where the below
parameters will be assessed, refer to the flow chart (Section 2):
!
FPG - refer to Section 8.5.2.2
!
AB samples - refer to Section 8.5.3.3
If non-fasting, blood sampling should be re-scheduled preferably within the next two working days. 
If blood sampling has already been done before realising that the subject was not fasting, only the 
FPG/ AB sampling needs to be re-scheduled.
8.5.1.3
Re-sampling
If blood samples are clotted or missed, re-sampling should be performed as an unscheduled visit, 
refer to Section 8.1.10.
8.5.1.4
Reporting of results to investigator
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.
During the trial the investigator will not be able to review the results of antibody measurements in 
relation to AEs as these are often analysed after LPLV.
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Date:
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Trial ID: NN5401-4266
Version:
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Status:
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8.5.1.5
Sample destruction
Samples collected, except for AB samples, will be destroyed on an ongoing basis, and no later than 
at finalisation of the clinical trial report. Antibody samples will be stored and destructed as 
described in Section 24.2.
8.5.2
Laboratory assessments for efficacy
8.5.2.1
HbA1c
The HbA1c result taken at the screening visit (V1) must be available prior to the 
randomisation visit (V2).
HbA1c is measured regularly during the trial in order to assess glycaemic control and sites will 
receive individual HbA1c reports for each subject to be used for evaluation and subject 
training purposes in relation to insulin dose adjustment.
For subjects prematurely discontinuing trial product abbreviated visits (V28a and V40a) 
should be scheduled at the dates of the originally planned visit 28, if applicable and visit 40 in 
order to collect samples for HbA1c analysis – refer to flow chart (Section 2).
8.5.2.2
Fasting plasma glucose 
FPG is analysed six times during the trial, and is measured in order to evaluate metabolic 
control. The subject must attend these visits fasting. For definition of fasting, see Section
8.1.4 above.
A FPG results O3.9 mmol/L (70 mg/dL) should not be reported as hypoglycaemic episode but 
as a clinical laboratory adverse event (CLAE) at the discretion of the investigator, see Section
12.1.1.
8.5.3
Laboratory assessments for safety
8.5.3.1
Haematology and Biochemistry assessments
The below haematology and biochemistry parameters will be analysed at the randomisation 
visit (V2), prior to the intensification period (V28) and at the end-of-trial visit (V40), please 
refer to the flow chart (Section 2).
!
Haematology 
–
Haematocrit
–
Haemoglobin
–
Leucocytes
–
Erythrocytes
–
Thrombocytes
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Trial ID: NN5401-4266
Version:
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!
Biochemistry
–
ALT
–
Albumin
–
AST
–
Alkaline phosphatase
–
Bilirubin, total
–
Creatinine
–
Potassium
–
Sodium
–
GFR, estimated (eGFR) (only measured at screening visit)
8.5.3.2
Pregnancy testing
A serum pregnancy test (beta-human chorionic gonadotropin (b-hCG)) is only required for 
females of childbearing potential. If a menstrual period is missed or pregnancy suspected, a 
urine pregnancy test must be performed as soon as possible.
8.5.3.3
Antibody measurements
Blood samples for detection of IDeg and IGlar ABs will be collected at baseline (V2), and 
every four weeks in the initial three months (V6, V10, V14), at the start of the intensification 
period (V28), at the end-of-treatment (V40) and at the 7-day follow-up visit (V41). The 
immunological response to IDeg will be monitored following the EMA guideline on this 
subject10.
The following ABs will be analysed:
!
For IDegAsp arm: Anti-insulin degludec AB
!
For IGlar + IAsp arm: Anti-insulin glargine AB
!
For both arms: Cross-reacting AB to human insulin
Subjects must attend visits fasting to collect AB samples, refer to Section 8.1.4.
8.6
Other Assessments
8.6.1
Patient reported outcomes
The PRO questionnaires must be completed by the subject without assistance of the site personnel. 
Instructions on how to complete the questionnaires will be provided to the subject.
The PRO questionnaires will be used to investigate the health related quality of life and diabetes 
treatment related impact.
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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The following PRO questionnaires will be supplied in addition to the diaries in a linguistically 
validated version in all languages relevant for this trial:
!
BHQ is a questionnaire regarding the frequency of hypoglycaemic episodes and will be 
completed at baseline (randomisation visit (V2)) only.
!
SF-36v2® Health Survey is a survey which assesses the subject's general health status and 
health-related quality of life utilising 36 questions covering eight concepts. The concepts cover:
physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-
emotional, and mental health over the prior four weeks. Scores for the eight concepts and two
overall scores for the physical and the mental components are calculated.
!
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 (six items), daily life (five
items), diabetes management (five items), compliance (four items) and psychological health 
(eight items). A total score and scores for the five domains are calculated.
The SF-36v2® and TRIM-D will be completed at the baseline (randomisation visit (V2)), prior to 
the intensification period (V28) and at the EOT visit (V40). These PRO questionnaires should be 
completed at the day of visit, preferably before any trial related procedures, except from fasting 
blood sampling, which may be done before.
Site staff is only allowed to write in the headers and on the front page of the questionnaires.
It is the responsibility of the investigator to review the questionnaires for completeness and possible 
AEs. To confirm that this has been done, the review must be documented by dated signature on the 
PRO questionnaires and/or in the subject’s medical record. Care must be taken not to bias the 
subject.
If clarification of entries is needed, the subject should be questioned and a conclusion made in the 
subject’s medical record. Care should be taken not to bias the subject.
The above PRO questionnaires will be supplied as ‘no carbon required’ (NCR) paper CRFs. The 
original (first page of the NCR sample) of the completed paper CRFs will be shipped for data-entry
(refer to section 15). The copy (2nd page of NCR sample) will be retained at clinical trial site.
8.6.2
Hypoglycaemia resource use
Hypoglycaemic resource use is collected as an interview administered questionnaire regarding 
resource use of the latest hypoglycaemic episode within the last four weeks. This interview will take 
place at the majority of the clinic visits during the trial - refer to flow chart (Section 2).
The questionnaire includes questions regarding the number of extra blood glucose monitoring, 
contact to health care professionals, and time missed at work.
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Trial ID: NN5401-4266
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The interview questionnaire will be provided to the sites and will include instructions to the 
interviewer and instructions to the subject to be read aloud by the investigator prior to conducting 
the interview. The answers given by subjects should be recorded at the paper questionnaires and 
kept as source data at the sites. Data collected should be transcribed by the investigator or delegated
staff into the eCRF.
8.6.3
Training in use of the trial product/pre-filled pen device
The subjects must be trained in how to handle the pre-filled pen-devices: IDegAsp (FlexTouch®) or 
IGlar (SoloStar®) and IAsp (FlexPen®) when handed out the first time. For subjects in the IGlar 
arm, the training must include pen differentiation which is of outmost importance to avoid 
medication errors. Re-training must be performed again at V3 and should be repeated during the 
trial based on the individual subject’s needs in order to ensure correct use of the device. The 
following should be emphasised:
!
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
!
Priming the pen to ensure the insulin flow
!
The needle should be kept in the skin after the dose counter has returned to zero after 
injection as follows:
o
IDegAsp and IAsp:
While counting slowly to six
o
IGlar: 
10 seconds or as described in the DFU
If the needle is removed too early then the full dose may not have been delivered.
At the EOT visit (V40) subjects should be properly instructed in how to handle ‘washout’ insulins 
to be used in the period until the 7-day follow-up visit (V41).
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant, the 
investigator will remind the subject of the importance of following the instructions given including 
taking the trial products as prescribed.
Treatment compliance:
The investigator must assess the compliance of the subject based on adherence to visit schedule, 
subject diary completion and glycaemic control.
Occasional review by the investigator or delegated staff of the values stored in the memory of the 
BG-meter and correct reporting of these in the diary is advised in order to ensure adequacy of the 
SMPG data reported in the trial database.
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Date:
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Trial ID: NN5401-4266
Version:
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Status:
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In addition, subject compliance will be assessed by monitoring of drug accountability at specified 
visits, refer to the flow chart (Section 2). The unused amount of trial insulin products 
(investigational medicinal products (IMPs)) and washout insulin products (Non-IMPs) will be 
assessed against the dispensed amount and, in case of discrepancies, the subject must be asked.
Medical judgements by investigator and delegated staff should be used when assessing treatment 
compliance. An overall assessment of relevant information recorded in the subject diary (e.g.
completeness, available insulin doses and SMPG values) compared to the glycaemic control (HbA1c
and FPG) and the amount of trial insulin used will form basis of such medical judgements.
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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9
Trial supplies
Trial supplies comprise trial insulin products and auxiliary supplies. Additional details regarding 
trial supplies can be found in the Trial Materials Manual (TMM).
Trial insulin products must not be dispensed to any person not included in the trial.
9.1
Trial insulin products
The following trial insulin products will be provided by Novo Nordisk A/S:
Table 9–1
Trial insulin products (IMPs)
Trial insulin product 
(IMP)
Strength
Dosage form
Route of 
administration
Container/
delivery device 
Insulin degludec/ insulin 
aspart (Ryzodeg®); 
Novo Nordisk A/S
100 units/mL
Solution for 
injection
Subcutaneous 
injection
3 mL pre-filled pen 
(FlexTouch®)
Insulin glargine (Lantus®);
Sanofi-Aventis
100 units/mL
Solution for 
injection
Subcutaneous 
injection
3 mL pre-filled pen 
(SoloStar®)
Insulin aspart (NovoRapid®/
NovoLog®); 
Novo Nordisk A/S
100 units/mL
Solution for 
injection
Subcutaneous 
injection
3 mL pre-filled pen 
(FlexPen®)
Trial insulin products (IMPs) must not be used if they do not appear clear and colourless.
9.2
Non-IMPs
The following products are regarded as Non-IMPs:
!
Washout insulin
!
OADs
The ‘washout’ insulin products to be used in the follow-up period from the EOT visit (V40) to the 
7-day follow-up visit (V41) are listed in Table 9–2.
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7DEOH±
:DVKRXWLQVXOLQSURGXFWV
Washout  insulin product 
(Non-IMP)
Strength
Dosage form
Route of 
administration
Container/
delivery device 
Human isophane insulin 
(NPH) (Insulatard®, 
Protaphane®, 
Novolin® N)
Novo Nordisk A/S
100 IU/mL
Suspension for 
injection
Subcutaneous 
injection
3 mL pre-filled pen 
(FlexPen®)
Biphasic insulin aspart 30 
(BiAsp 30) (NovoMix® 30, 
NovoLog® Mix 70/30)
Novo Nordisk A/S
100 units/mL
Suspension for 
injection
Subcutaneous 
injection
3 mL pre-filled pen 
(FlexPen®)
Insulin aspart 
(NovoRapid®/
NovoLog®); 
Novo Nordisk A/S
100 units/mL
Solution for 
injection
Subcutaneous 
injection
3 mL pre-filled pen 
(FlexPen®)
Washout insulins BiAsp 30 and NPH product must not be used if they do not appear uniformly 
white and cloudy after re-suspension.
Furthermore, the below OADs are regarded as non-IMPs:
a.
Metformin
b. (DPP-IV) inhibitor
c.
N-glucosidase-inhibitors
d. SGLT-2 inhibitor
e.
oral combination products (of the allowed OADs above)
‘Washout’ insulin products will be supplied by Novo Nordisk A/S, whereas none of the OADs will 
be supplied by Novo Nordisk A/S. However, OADs will be reimbursed if required by the country’s 
regulatory authority or institutional review board (IRB)/independent ethics committee (IEC).
9.3
Labelling
The trial products will be labelled in accordance with Annex 1340, local regulations and trial 
requirements. Labelling will include the product related requirements and precautions.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and randomisation. 
The investigator must document that the DFU is given to the subject orally and in writing at the first 
dispensing visit (randomisation visit (V2)) and at V40.
If applicable, DFUs can be handed out to subjects at subsequent visits.
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9.4
Storage 
The trial products must be stored in accordance with the storage conditions listed in Table 9–3
below:
Table 9–3
Storage Conditions and In-use time for IMPs and washout insulin
Trial products
Storage conditions
(not-in-use)
In-use conditions
In-use time*
Insulin degludec/ insulin 
aspart 
(Ryzodeg®)
IMP
!
Protect from light
!
Do not freeze
!
Store in refrigerator (2°C –
8°C/36°F-46°F)
!
Protect from light
!
Do not freeze
!
Can be stored in 
refrigerator (2°C – 8°C
!
Do not store above 30°C
For U.S. only:
!
Protect from light
!
Do not freeze
!
Do not refrigerate
!
Store below 30°C/ 86°F
Use within 4 weeks
Insulin glargine (Lantus®)
IMP
!
Protect from light
!
Do not freeze
!
Store in refrigerator (2°C –
8°C/36°F-46°F)
!
Protect from light
!
Do not freeze
!
Do not refrigerate
!
Do not store above 
30°C/86°F 
Use within 4 weeks
Insulin aspart
(NovoRapid® / 
NovoLog®)
IMP & Non-IMP
!
Protect from light
!
Do not freeze
!
Store in refrigerator (2°C –
8°C/36°F-46°F)
!
Protect from light
!
Do not freeze
!
Do not refrigerate
!
Store below 30°C/86°F
Use within 4 weeks
Human isophane insulin 
(NPH) (Insulatard®, 
Protaphane®, 
Novolin® N)
Non-IMP
!
Store in refrigerator (2°C –
8°C/36° - 46°F) 
!
Do not freeze
!
Protect from light
!
Store below 30°C/86°F 
!
Do not refrigerate
!
Do not freeze
!
Protect from light
Use within 6 weeks
For U.S. only:
Use within 14 days
Biphasic insulin aspart 30
(BiAsp 30) (NovoMix®
30, NovoLog® Mix 
70/30)
Non-IMP
!
Store in refrigerator (2°C –
8°C/36° - 46°F) 
!
Do not freeze
!
Protect from light
!
Store below 30°C/86°F
!
Do not refrigerate 
!
Do not freeze
!
Protect from light
Use within 4 weeks
For U.S. only:
Use within 14 days
* In-use time starts when first dose is taken or when used as spare.
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.
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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.
9.5
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Subjects are instructed to return all used, partly used and unused trial insulin products at each 
dispensing visit after the randomisation visit (V2) and until the EOT visit (V40). Refer to the flow 
chart (Section 2) for the timing of drug accountability and dispensing visits.
Subjects are instructed to return all used, partly used and unused ‘washout’ insulin products at their 
7-day follow-up visit (V41).
The monitor will reconcile the drug accountability using the IWRS Drug Accountability module.
Drug accountability will be done at pen level.
Returned trial insulin and ‘washout’ insulin products (used/partly used and/or unused), expired or 
damaged trial products can be stored at room temperature and must be stored separately from non-
allocated trial products.
Non-allocated trial insulin and ‘washout’ insulin products including expired or damaged products 
must be accounted as unused at the latest at closure of the trial site.
Destruction of trial insulin and ‘washout’ insulin 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.
9.6
Auxiliary supplies
The following auxiliary supplies will be provided by Novo Nordisk, refer to the TMM:
!
DFU for all trial products (IMPs and ‘washout’ insulin)
!
BG-meters and supplies
!
Needles for pre-filled pens
Only needles provided by Novo Nordisk (no longer than 8 mm long) must be used for
administration of trial insulin products.
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons.
IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing of trial products
!
Treatment discontinuation
!
Completion
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site.
At any time during the trial only dispensing unit number(s) (DUNs) allocated by the IWRS are 
allowed to be dispensed to a subject. By doing this it will be ensured that:
!
Stock is available at a site when needed for the subjects
!
No allocation of trial product that will expire before the next dispensing visit
!
Drug accountability can be made in the IWRS
If a subject needs trial product between dispensing visits, the investigator must make an additional 
dispensing.
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11 Randomisation procedure and breaking of blinded codes
At Visit 2 a randomisation session will be carried out for all eligible subjects by using the IWRS.
Subjects will be randomised 1:1 manner into the two stepwise treatment intensification arms below. 
The randomisation will be stratified based on pre-trial basal insulin treatment regimen: OD or 
BID/TID dosing:
IDegAsp arm:
!
Initial 26 weeks: IDegAsp OD administered at the largest meal each day ± OAD(s)
!
Intensification period – Week 26-38: IDegAsp OD/BID administered at the largest meal(s) each 
day based on individual needs ± OAD(s)
IGlar+IAsp arm:
!
Initial 26 weeks: IGlar OD administered in accordance with local labelling and IAsp OD 
administered at the largest meal ± OAD(s)
!
Intensification period – Week 26-38: IGlar OD administered in accordance with local labelling 
and IAsp 1-3 times daily administered at main meals based on individual needs ± OAD(s)
11.1
Breaking of blinded codes 
Not applicable for this trial.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An AE is any untoward medical occurrence in a subject administered a medicinal product, and 
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.
An AE includes:
!
A clinically significant worsening of a concomitant illness
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to 
the abnormality
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness)
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see Section 8.4.7
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
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
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!
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 sequelae 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
An SAE is an experience that at any dose results in any of the following:
!
Death
!
A life-threateninga experience
!
In-patient hospitalisationb or prolongation of existing hospitalisation
!
A persistent or significant disability or incapacityc
!
A congenital anomaly or birth defect
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd
a
The term “life threatening” in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe
b
The term “hospitalisation” is used when a subject: 
! Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
! Stays at the hospital for treatment or observation for more than 24 hours
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 
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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 AEs must always be reported as an SAE using the important medical event criteria 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 or use of wrong device
Note: Use of wrong DUN is not considered a medication error unless it results in administration 
of wrong drug
!
Wrong route of administration, such as intramuscular instead of subcutaneous
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), 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 %; 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 8.4.6.1.
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 safety of the trial product.
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In this trial the following AEs require the completion of specific event forms in the eCRF:
!
Acute coronary syndrome (myocardial infarction or hospitalisation for unstable angina)
!
Cerebrovascular event (stroke, transient ischaemic attack or haemorrhage)
!
Neoplasm
For details, see Section 8.4.6.2.
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety.
Table 12–1 lists AEs that require completion of specific event forms in the eCRFs.
Table 12–1
Adverse events requiring completion of specific event forms 
Event
Specific event 
form
Acute coronary syndrome (myocardial infarction or 
hospitalisation for unstable angina)
Yes
Cerebrovascular event (stroke, transient ischaemic attack or 
haemorrhage)
Yes
Neoplasm
Yes
Fatal event
No
Medication errors
Yes
For details about specific event forms, see Sections 8.4.6.1 and 8.4.6.2.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push
button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (P42). The events must be recorded in the applicable eCRF 
forms in a timely manner, see timelines below and Figure 12-1.
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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 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 additional data collection: In addition to the above, the specific event form 
within 14 calendar days from the investigator’s first knowledge of the AE.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
The paper forms or safety information form must be forwarded to Novo Nordisk either by fax, e-
mail or courier.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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AE identified
Does the AE require
a specific event
form?
AE form< 24 hours
SIF < 5 calendar days
Specific event form 
For SAEs: 
< 14 calendar days
Is the AE serious or 
non-serious?
AE form
Non-serious
Serious
No
Yes
Queries and follow-up 
requests to be resolved 
< 14 calendar days
AE: Adverse Event
SIF:Safety Information form 
AEs requiring a specific event form:Medication errors, Acute 
coronary syndrome, Cerebrovascular events, neoplasms
AE categories descibed in the protocol chapter 8.4
All timelines are from investigators awareness
No additional action
Figure 12–1
Reporting of AEs
Novo Nordisk assessment of AE expectedness: 
Novo Nordisk assessment of expectedness is performed according to the following reference 
documents, current versions or any updates thereto:
!
Insulin degludec/insulin aspart (Ryzodeg®), 100 units/mL, 3 mL prefilled pen (FlexTouch®):
IB17, and/or Company Core Data Sheet (CCDS)41
!
Insulin aspart (NovoRapid®/NovoLog®), 100 U/mL, 3 mL prefilled pen (FlexPen®):
CCDS42 EU SmPC13
!
Insulin glargine (Lantus®), 100 units/mL, 3 mL pre-filled pen (SoloStar®): EU SmPC27
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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 (e.g. Insulin NPH, 100 IU/mL, 3 mL pre-
filled pen (FlexPen®) 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 AE 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.
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The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow-up
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints
All technical complaints on any of the following trial products:
!
Insulin degludec/insulin aspart (Ryzodeg®) 100 units/ml, 3 mL pre-filled pen, FlexTouch®
!
Insulin aspart (NovoRapid®/NovoLog®), 100 units/mL, 3 mL, pre-filled pen, FlexPen®
!
Insulin glargine (Lantus®) 100 units/mL, 3 mL, pre-filled pen, SoloStar®
!
Novo Nordisk needles for prefilled pens
and ‘washout’ insulin products: 
!
Human isophane insulin ((NPH) (Insulatard®, Protaphane®, Novolin® N), 100 IU/mL,
3 mL pre-filled pen, FlexPen®
!
Biphasic insulin aspart 30 (BiAsp 30), (NovoMix® 30, NovoLog® Mix 70/30), 100 U/mL,
3 mL pre-filled pen, FlexPen®
!
Insulin aspart (NovoRapid®/NovoLog®), 100 U/mL, 3 mL pre-filled pen, FlexPen®
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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
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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
! Technical complaint on an investigational medical device that could have led 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 the trial site. The monitormust coordinate the shipment to 
Customer Complaint Center, Novo Nordisk(the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the 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 newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
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The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner.
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
Paper AE forma within 14 calendar days of the investigator’s first knowledge of the 
initial or follow-up information to the non-serious AE
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE
!
Safety information form within 5 calendar days of the investigator’s first knowledge 
of the SAE
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the investigator’s first knowledge of the follow-up information
a It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE and safety information form
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Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
During treatment with insulin, there is a risk of hypoglycaemia. 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. Severe hypoglycaemia may lead to unconsciousness and even 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 by ingestion of 
carbohydrate (e.g. juice). Severe hypoglycaemia resulting in loss of consciousness should be treated 
with parenteral glucose, glucagon or dextrose at the investigator’s discretion.
Please refer to current edition and any updates to the documents related to trial products listed 
below:
IMPs:
!
Insulin degludec/insulin aspart (Ryzodeg®) 100 units/ml, 3 mL pre-filled pen, FlexTouch®: 
IB17, and/or CCDS41, the EU SmPC15 and the U.S. LI16.
!
Insulin aspart (NovoRapid®/NovoLog®), 100 U/mL, 3 mL, pre-filled pen, FlexPen®: the 
CCDS42, the EU SmPC13 and the U.S. LI14.
!
Insulin glargine (Lantus®) 100 units/mL, 3 mL pre-filled pen, SoloStar®: the EU SmPC27
and U.S. LI18.
Non-IMPs:
!
Human isophane insulin (NPH), (Insulatard®, Protaphane®, Novolin® N), 100 IU/mL, 3 mL 
pre-filled pen, FlexPen®: the CCDS43 and the EU SmPC44
!
Biphasic insulin aspart (BiAsp 30), (NovoMix® 30, NovoLog® Mix 70/30, 100 U/mL, 3mL 
pre-filled pen, FlexPen®: the CCDS45, the EU SmPC46, and US LI47.
!
Insulin aspart (NovoRapid®/NovoLog®), 100 U/mL, 3 mL pre-filled pen, FlexPen®: the 
CCDS42, the EU SmPC13 and the U.S. LI14.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal IDegAsp safety committee to perform ongoing safety 
surveillance.
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13
Case report forms 
For this trial a combination of eCRF and paper CRF will be used.
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs only:
!
Pregnancy forms
!
PRO questionnaire - refer to Section 8.6.1
o
BHQ
o
SF-36v2®
o
TRIM-D
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 CRFs 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.
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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 paper Pregnancy forms, AE forms, Safety information forms and 
Technical complaint forms may only be made by drawing a straight line through the incorrect data 
and then writing the correct entry next to the data that was crossed out. Each correction must be 
initialled, dated and explained (if necessary). If corrections are made by the investigator’s delegated 
staff after the date of the investigator’s signature on the affirmation statement, the affirmation 
statement must be signed and dated again by the investigator.
Corrections necessary after the CRFs have been removed from the trial site must be documented on 
a data clarification form (DCF) or a monitor-initiated discrepancy form (MIDF). If the affirmation 
statement for the subject has not yet been signed, any corrections must be approved by the 
investigator or her/his delegated staff. If the affirmation statement for the subject has already been 
signed, the investigator must approve any correction.
13.2
Case report form flow
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within five days after the visit. During the trial, SMPG measurements and corresponding insulin 
doses for titration purposes should be recorded as soon as possible, preferably within 24 hours after 
the visit/phone contact. At the end of the trial the investigator must ensure that all remaining data 
have been recorded in the eCRF no later than 24 hours after last subject’s last visit at the site. Once 
data have been entered, they will be available to Novo Nordisk for data verification and validation 
purposes.
Site specific eCRF data (in an electronic readable format) will be provided to the site before access 
to the eCRF is revoked. These data must be retained at the site.
The original (first copy of the NCR sample) of the paper CRFs completed by site staff and PRO 
questionnaires completed by the subjects (refer to Section 13.1 above) will be shipped from sites for 
data management. NN will be responsible for data management (refer to Section 15). Originals will 
be archived by NN upon final data entry. A copy (2nd page of the NCR) will be retained at clinical 
trial site.
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14 Monitoring procedures 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FPFV at 
the trial site and no later than four 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).
Data recorded in the diary by the subject will be considered source data.
Considering the electronic source data environment, it is accepted that the earliest practically 
retainable record should be considered as the location of the source data and therefore the source 
document.
All other 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 original of the completed diaries and/or PROs must not be removed from the trial site, unless 
they form part of the CRF/eCRF and a copy is kept at the site.
The monitor will ensure that the eCRFs are completed on an ongoing basis, and that paper CRFs are 
collected.
The following data will be source data verified for screening failures:
!
Date for obtaining informed consent
!
Reason for screening failure
!
SAEs
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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. For U.S.: the follow-up letter must be signed by 
the investigator.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a CRO.
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.
Entry of information captured at the PRO questionnaires BHQ, SF36v2® and TRIM-D will be done 
by double data entry.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
Novo Nordisk will analyse and report data from all sites together. 
Unless otherwise specified, all continuous measurements will be summarised descriptively at each 
visit by treatment using in-trial data. Endpoints that are analysed untransformed and endpoints that 
are not formally analysed are summarised by the arithmetic mean, standard deviation (SD), median, 
and minimum and maximum value. Endpoints that are analysed log-transformed are supplemented 
with the geometric mean and coefficient of variation. For measurements over time, mean values 
will be plotted to explore the trajectory over time. The geometric mean values will be plotted for 
endpoints that are analysed log-transformed. All descriptive summaries and plots will be based on 
in-trial data unless otherwise specified.
If an assessment has been made both at screening and randomisation, and if not otherwise specified, 
the value from the randomisation visit will be used as the baseline value. If the value measured at 
the randomisation visit is missing and the assessment has also been made at screening, then the 
screening value will be used as the baseline value. For summaries and statistical analysis of all 
endpoints the first non-missing values is used. The value should be taken according to the 
specification in the protocol, e.g. non-fasting FPG-values are not used. Re-tests of non-missing 
values are only included in subject specific listings.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
for absolute values and change from baseline. The estimated means are either obtained by Rubin’s 
rule48 weighing together estimated means from multiple imputation  or directly from estimation in a 
parameterized statistical model. In addition estimated mean treatment differences (or ratios) will be 
presented together with two-sided 95% confidence intervals and corresponding two-sided p-values.
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
17.1
Primary and secondary estimands
The primary estimand will be the difference in change from baseline at week 26 or week 38 
depending on the endpoint considered between IDegAsp OD and IGlar OD + IAsp OD, for all 
randomised subjects regardless of whether the subjects remained on initially assigned treatment 
until week 26 or week 38. This estimand is a de facto estimand addressing effectiveness.
The secondary estimand will be the difference in change from baseline at week 26  or week 38 
depending on the endpoint considered between IDegAsp OD and IGlar OD + IAsp OD if all 
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randomised subjects had adhered to treatment until week 26 or week 38. This estimand is a de jure 
estimand addressing efficacy.
For hypoglycaemic episode endpoints, only the de jure estimand will be used. The reason for this is 
that data for hypoglycaemic episodes will not be systematically collected after treatment 
discontinuation.
17.2
Sample size calculation
The sample size is based on confirming non-inferiority of the primary estimand for the primary 
endpoint assessed at week 26 using the full analysis set (FAS). Sample sizes are also given for 
confirming non-inferiority for the primary estimand of the primary endpoint on the per-protocol set.
The primary objective is to confirm the effect of IDegAsp OD versus IGlar OD + IAsp OD in 
controlling glycaemia in basal insulin-treated subjects with T2DM.
This will be done by comparing the difference between IDegAsp OD and IGlar OD + IAsp OD in 
change from baseline in HbA1c after 26 weeks to a non-inferiority limit of 0.4%. The non-inferiority 
limit of 0.4% is aligned with the phase 3a programme and is considered appropriate to ensure a 
relevant effect of IDegAsp compared to placebo since a superior treatment effect of V0.85% [V1.04; 
V0.66] of IGlar versus placebo was reported in a placebo controlled clinical trial in T2DM 
subjects49. Supplementing IGlar with IAsp OD would further increase the treatment effect 
compared to placebo.
Formally, let D be the mean treatment difference (IDegAsp OD minus IGlar OD + IAsp OD) in 
change from baseline in HbA1c. The null-hypothesis of IDegAsp OD inferior by 0.4% or more will 
be tested against the alternative hypothesis of non-inferiority as given by
H0: D L0.40% against HA: D <0.40%
Non-inferiority will be considered confirmed if the upper bound of the two-sided 95% confidence 
interval for D is strictly below 0.4%. This is equivalent to using a one-sided test of size 2.5%, which 
means that the Type 1 error rate is controlled at 2.5% level.
Accordingly, the sample size is calculated using a t-statistic under the assumptions of a one-sided 
test of size 2.5%, a mean treatment difference of 0.0%, a standard deviation of SD=1.3%, and a 
non-inferiority limit of 0.40%. It is assumed that 15% of the randomised subjects will discontinue 
randomised treatment before week 26 or have missing data at week 26, and that 10% of the 
randomised subjects will be excluded from the per protocol (PP) analysis set. The assumptions are 
based on the results from a phase 3a trial (NN5401-3593). 
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When estimating the primary estimand for the evaluation of the non-inferiority hypothesis, missing 
data will be imputed based on in-trial data. A penalty will be added to the change in HbA1c at week 
26 for all subjects in the IDegAsp OD arm who discontinued trial product prior to week 26 or who 
have missing data at week 26. The penalty corresponds to the non-inferiority limit of 0.4%.
In total an expected 15% will have missing on-treatment data at week 26, 10% will not be part of 
the PP analysis set. This means that 5/90*100%= 5.56% of the PP analysis set is expected to be 
non-completers, hence the expected treatment differences (adjusted treatment effect (TE) resulting 
from the applied penalty) for the non-inferiority hypothesis of the primary estimand is:
1) FAS: 0.15*0.4=0.06
2) PP: 0.0556*0.4=0.0222
The sample size assumptions for TE and the common SD are given in Table 17–1.
From these assumptions, and based on a 1:1 randomisation, the sample size is set to 264 subjects 
per treatment arm, in total 528 subjects. This will ensure a nominal power of at least 85% for 
confirming the primary objective based on the FAS as well as on the PP analysis set.
Table 17–1
Assumptions for sample size calculation
Primary 
Estimand
Analysis set 
Non-
inferiority 
margin 
SD
TE
Adjusted TE
Randomisation 
Scheme
Required 
Power
FAS 
0.4%
1.3%
0.0%
0.06%
1:1
85%
PP
0.4%
1.3%
0.0%
0.0222%
1:1
85%
Abbreviations: SD = standard deviation; TE = Treatment effect
The sample size calculation was done using SAS 9.4.
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Table 17–2
Sensitivity of sample size to variations in SD and power
#subjects in total
SD=1.1%
SD=1.2%
SD=1.3%
SD=1.4%
Power 80%
FAS
332
394
462
536
PP
300
356
416
482
Power 85%
FAS
378
450
528
612
PP
342
406
476
552
Power 90%
FAS
442
526
618
716
PP
400
474
556
644
Power 95%
FAS
546
650
762
884
PP
494
586
686
796
17.3
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E950. 
!
Full Analysis Set (FAS): includes all randomised subjects. In exceptional cases, subjects 
may be excluded. In such cases the elimination will be justified and documented. The 
statistical evaluation of the FAS will follow the intention-to-treat (ITT) principle and 
subjects will contribute to the evaluation “as randomised”.
!
Per-Protocol (PP) analysis set: includes all subjects in the Full Analysis Set who fulfils the 
following criteria:
o
Have not violated any inclusion criteria
o
Have not fulfilled any exclusion criteria
o
Have a non-missing HbA1c at screening or randomisation
o
Have at least one non-missing HbA1c after 12 weeks of exposure
o
Have at least 12 weeks of exposure
Subjects in the PP will contribute to the evaluation “as treated”.
!
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”.
!
Completer analysis set (CAS): includes all randomised subjects who have completed the 
trial without discontinuation from randomised treatment. Subjects in the completer analysis 
set will contribute to the evaluation “as randomised”.
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Before data are released for statistical analysis, a review of all data will take place to ensure a 
sufficient data quality and to ensure the planned statistical analysis are applicable. Any data 
decisions not foreseen in the protocol will be documented before database lock.
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. 
The decision to exclude any subject or observation from the statistical analysis is the joint 
responsibility of the study group. The subjects or observations to be excluded, and the reasons for 
their exclusion will be documented before database lock. The subjects and observations excluded 
from the analysis sets, and the reasons for this, will be described in the clinical trial report.
Definition of the observation periods:
In-trial: This observation period will include information collected at or after date of randomisation 
and up to the last subject-site contact which is scheduled as a follow-up visit. For subjects who 
withdraw their informed consent, the in-trial observation period ends at their date of withdrawal. If 
a subject is lost to follow-up, the end of the in-trial period is defined as the date of the last subject-
investigator contact (site or phone visit). In case a subject dies during the trial the date of death will 
be the end-date of the in-trial observation period regardless of the above defined end-dates. This 
observation period will be used for estimating the effectiveness estimand.
On-treatment: This observation period is a subset of the in-trial observation period and represents 
the time period in which a subject is considered exposed to trial product. For adverse events an 
ascertainment window of 30 days after last date on trial product will be used. The first follow-up 
visit is scheduled to take place seven days after the EOT visit (V40) to collect all AEs including 
hypoglycaemia. The second follow-up visit is scheduled to take place 30 days after EOT visit (V40) 
only to report AEs. This observation period will be used for estimating the efficacy estimand and 
for evaluating safety.
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17.4
Primary endpoint
Primary statistical analysis for primary estimand
The primary estimand will be estimated based on the FAS using all post baseline HbA1c
measurements obtained on planned visits up until week 26, including week 26 measurements from 
subjects withdrawing from randomised treatment (in-trial observation period), mimicking an ITT 
scenario. To estimate this estimand for evaluation of non-inferiority of HbA1c, multiple imputation 
of missing values with separate imputation from each treatment arm will be applied. The use of data 
from prematurely treatment discontinued subjects in analyses will equalise treatment effects and the 
inclusion of a penalty equal to the non-inferiority margin will remedy this. Imputation will be done 
as follows:
!
In the first step, intermittent missing values are imputed using a Markov Chain Monte Carlo 
(MCMC) method, in order to obtain a monotone missing data pattern. This imputation is 
done for each treatment arm separately and 1000 copies of the dataset will be generated.
!
In the second step, for each of the 1000 copies of the dataset, an analysis of covariance 
(ANCOVA) for each treatment arm with region, sex, previous insulin regimen and previous 
OAD treatment as categorical fixed effects and baseline HbA1c measurement and age as a 
covariate will be fitted to the change in HbA1c from baseline to week 8 (visit 10). The 
estimated parameters and their variance from this model are used to impute missing values 
at week 8 for subjects in the respective treatment arms based on region, sex, previous insulin 
regimen, previous OAD treatment, age and HbA1c at baseline.
!
In the third step, for each of the 1000 copies of the dataset, an analysis of covariance model 
with region, sex, previous insulin regimen and previous OAD treatment as categorical fixed 
effects, and age, baseline HbA1c and HbA1c at week 8 (Visit 10) as covariates is fitted to the 
change in HbA1c from baseline to week 12 (Visit 14) for each treatment arm. The estimated 
parameters and their variances from this model are used to impute missing values at week 
12 for subjects in the respective treatment arms, based on region, sex, previous insulin 
regimen, previous OAD treatment, age and HbA1c at baseline and week 8.
!
Step three is repeated over the available planned visits, adding one visit at a time until week 
26. In each step the model is expanded to include a covariate from the previous visit.
!
Finally, a penalty equal to the non-inferiority margin 0.4% is added to the week 26 (visit 28) 
HbA1c value for any prematurely treatment discontinued subject in the IDegAsp OD arm, 
irrespective if the value was retrieved (V28A) data or an imputed value from the sequential 
imputation. 
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For each of the 1000 (now complete) imputed data sets the change from baseline to week 26 will be 
analysed using an ANCOVA with treatment, region, sex, previous insulin treatment regimen and 
previous OAD treatment as categorical fixed effects and baseline HbA1c and age as covariate. The 
estimates and standard deviations for the 1000 data sets are pooled to one estimate and associated 
standard deviation using Rubin’s rule. From these pooled estimates the confidence interval for the 
treatment differences and the associated p-value are calculated.
Non-inferiority of IDegAsp OD vs. IGlar OD + IAsp OD will be considered confirmed if the 95% 
confidence interval for the mean treatment difference lies entirely below 0.40%. A conclusion on 
non-inferiority will be based on the FAS and the primary estimand. The addition of the 0.4% 
penalty in the last imputation step corresponds to the non-inferiority null method, as described by
Koch51.
Sensitivity analyses for the primary estimand
The following sensitivity analyses will be performed:
!
The primary analysis will be repeated based on the PP analysis set in line with the 
Committee for Proprietary Medicinal Products (CPMP) Points to Consider 
(CPMP/EWP/482/99).
!
The primary analysis will be repeated on the FAS but without adding the penalty for 
subjects in the IDegAsp OD arm. The result of this analysis is regarded to give the most fair 
and unbiased estimate of the difference between the two treatments, in contrast to the 
primary analysis that due to the penalty is biased in favour of the IGlar treatment.
!
A tipping point analysis based on the FAS and the primary analysis for the primary estimand 
will be performed. In this analysis subjects who withdraw from the IDegAsp OD arm or 
have missing values at visit 26 are assumed to have an effect that is inferior to the de facto 
effect of IDegAsp OD . The extent of the inferiority (also termed a ‘penalty’) will be 
gradually increased to evaluate at which value IDegAsp OD is no longer non-inferior to 
IGlar OD + IAsp OD. This penalty value, also known as the tipping point, corresponds to 
the hypothetical degree of efficacy deterioration in withdrawn subjects that would change 
the conclusion of non-inferiority.
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Primary analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using post-baseline measurements up 
to and including week 26 from the on-treatment observation period. To estimate this estimand, the 
change from baseline in HbA1c after 26 weeks of treatment will be analysed using the mixed model 
for Repeated Measurement (MMRM) method with a restricted maximum likelihood (REML). The 
model will include treatment, sex, previous insulin treatment regimen, previous OAD treatment and 
region as factors and baseline HbA1c and age as covariates, all nested within visit. An unstructured 
covariance matrix for HbA1c measurements within the same subject will be employed, assuming 
measurements from different subjects are independent.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is missing at random (MAR). Under 
this assumption the statistical behaviour of the missing data (given the observed responses and 
model fixed effects and covariates) is assumed to be the same as the observed data. 
In a non-inferiority trial the efficacy estimand may be more appropriate than the effectiveness 
estimand, since it is not confounded by the effects of changing treatment from the randomised 
treatment to other treatments. 
Sensitivity analyses for the secondary estimand
The following sensitivity analyses will be performed:
!
The above MMRM analysis will be repeated on the PP and CAS using the on-treatment 
period. These analyses will be done to align with the reporting of the phase 3a trials.
!
Using the FAS, the change in HbA1c from baseline after 26 weeks of treatment will be 
analysed using an analysis of variance (ANOVA) method with treatment, sex, previous 
insulin treatment regimen, previous OAD treatment and region as fixed factors, and age and 
baseline HbA1c as covariates, and where missing values will be imputed using the Last 
Observation Carried Forward (LOCF) method. This is done to align with the reporting of the 
phase 3a trials.
17.5
Supportive secondary endpoints
17.5.1
Efficacy endpoints
For the following continuous supportive efficacy endpoints, analyses similar to those for the 
primary and secondary estimands of the primary endpoint will be done, with the adjustment that the 
non-inferiority-penalty (NI-penalty) in step five of multiple imputation is not applied (this is only 
considered relevant for non-inferiority testing). Continuous safety endpoints that are analysed 
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statistically will also follow this procedure. A further change to the above specified model is that 
the model will include the baseline measurement of the endpoint as a covariate instead of the 
baseline HbA1c measurement.
HbA1c
Change from baseline in HbA1c (%) after 38 weeks.
Fasting plasma glucose
!
Change from baseline in FPG after 26 weeks
!
Change from baseline in FPG after 38 weeks
Self-measured plasma glucose measurements (SMPG)
!
SMPG after 26 weeks
o
Change from baseline in mean pre-breakfast measurements after 26 weeks
o
Change from baseline in post-prandial increments after 26 weeks
!
SMPG after 38 weeks
o
Change from baseline in mean pre-breakfast measurements after 38 weeks
o
Change from baseline in post-prandial increments after 38 weeks
Furthermore, the mean PG before breakfast used for dose-titration and the 9-point profile will be 
calculated at each visit using the available data. 
Responder for HbA1c
!
Responder (Yes/No) for HbA1c after 26 weeks:
o
HbA1c < 7%
o
HbA1c < 7% without nocturnal (00:01-05:59) (BG) confirmed symptomatic 
hypoglycaemia 
!
Responder (Yes/No) for HbA1c after 38 weeks:
o
HbA1c < 7%
o
HbA1c < 7% without nocturnal (00:01-05:59) BG confirmed symptomatic 
hypoglycaemia
Subjects with less than 16 weeks of treatment will be set as non-responders. Nocturnal 
hypoglycaemic episodes will be based on the available data. 
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
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Analysis of each of the responder endpoints will be based on a logistic regression model which will 
include treatment, sex, previous insulin treatment regimen, previous OAD treatment and region as 
fixed factors, and age and baseline HbA1c as covariates. 
The primary estimand for the responder endpoints will be derived using the HbA1c values from the 
1000 datasets originating from multiple imputation analysis of HbA1c, without applying the NI-
penalty. Each of these datasets will be analysed using the above logistic regression model and the 
results will then be pooled using Rubin’s rule.
The secondary estimand for the responder endpoints will be derived using the MMRM imputed 
HbA1c values.
17.5.2
Safety endpoints
Adverse events
The AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities coding.
A treatment-emergent adverse event (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 seven days after the last day of 
randomised treatment. If the event has onset date before the first day of exposure on randomised 
treatment and increases in severity during the treatment period and until seven days after the last 
drug date, then this event should also be considered as a TEAE.
TEAEs are summarised descriptively, whereas non-treatment-emergent AE’s 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 serious TEAEs will be presented as an overview including all AEs, 
serious AEs, number of deaths, AEs by severity, AEs by relation to treatment as assessed by the 
investigator and AEs of special interest including AEs leading to withdrawal and AEs leading to 
drug withdrawn. The EAC confirmed adverse events will be listed and summarised descriptively.
Furthermore summary tables based on system organ class and preferred terms are made for:
!
All TEAEs
!
Serious TEAEs
!
Possibly and probably related TEAEs 
!
Severe, moderate and mild TEAEs
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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!
TEAEs reported by safety area of interest
!
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
!
TEAEs leading to withdrawal of subject or drug withdrawn
A listing of non-treatment-emergent events with onset date before the first day of exposure to 
randomised treatment will be presented. A listing will also be presented for non-treatment-emergent 
adverse events collected after the treatment-emergent period according to the definition of the 
TEAE.
Hypoglycaemic episodes 
The definition and classification of hypoglycaemic episodes is given after the description of the 
statistical analysis.
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 (R). Separate summaries are made by severity 
considering all confirmed hypoglycaemic episodes, nocturnal confirmed hypoglycaemic episodes 
and the ADA classification of hypoglycaemia.
In addition, to the extent where data allows, the following endpoints are analysed statistically.
During 26 weeks:
!
Number of nocturnal, treatment-emergent severe or blood glucose (BG) confirmed 
symptomatic hypoglycaemic episodes during 26 weeks
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 26 weeks
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 26 weeks
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 26 
weeks
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during maintenance (week 16-26)
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during maintenance (week 16-26)
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during maintenance (week 16-26)
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 
maintenance (week 16-26)
During 38 weeks:
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 38 weeks
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 38 weeks
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 38 weeks
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 38
weeks
For endpoints addressing the hypoglycaemic rate in the 26 weeks or the 38 weeks period, a negative 
binomial model will be used, including treatment, previous insulin treatment regimen, previous
OAD treatment, sex, and region as factors and age as covariate. The model will use a log-link 
function and the logarithm of the time period in which a hypoglycaemic episode was considered 
treatment emergent as offset. 
The rationale for investigating the hypoglycaemic rate during the maintenance is to reflect long 
term use, as prior to this period (the titration period) the glycaemic control might be unstable. For 
endpoints addressing hypoglycaemic rate in the maintenance period, a negative binomial regression 
model using data from both the titration and maintenance periods will be used. This is done to 
comply with the randomisation principle, i.e. to include all randomised subjects in the analyses, also 
those who withdrew during the titration period. The model will use a log-link function and the 
logarithm of the time period in which a hypoglycaemic episode was considered treatment emergent 
as offset. Subject will be included as a random effect. The model includes treatment, previous 
insulin treatment regimen, previous OAD treatment, sex, region and period (titration or 
maintenance) as factors and age as covariate. The interaction between each factor and covariate 
with period will also be included. 
From the above negative binomial models the treatment rate ratios will be estimated and 95% 
confidence intervals will be calculated.
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CONFIDENTIAL
Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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The analyses and data presentations of hypoglycaemic events will be based on the hypoglycaemic 
episode form.
Classification of Hypoglycaemia:
Hypoglycaemic episodes are recorded by the subjects in their trial diaries throughout the trial. The 
information collected includes PG before treating the episode and whether the subject was able treat 
him/herself. This information is used by Novo Nordisk to classify episodes according to the 
confirmed hypoglycaemia definition and the ADA definition (severe, documented symptomatic, 
asymptomatic, probably symptomatic and pseudo).
!
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset 
of the episode occurs on or after the first day of trial product administration, and no later than 7 
calendar days after the last day on trial product 
!
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)52. Therefore, Novo Nordisk has included hypoglycaemia with plasma 
glucose levels below this cut-off point in the definition of BG confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–1) in addition to the ADA 
classification: 
!
Severe hypoglycaemia according to the ADA classification36
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification36or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
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Version:
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!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value <3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification36 or  BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or 
without symptoms consistent with hypoglycaemia
Hypoglycaemic
episode
PG  3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–1
Novo Nordisk classification of hypoglycaemia
ADA classification36 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 O 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 O 3.9 mmol/L 
(70 mg/dL).
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Trial ID: NN5401-4266
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!
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 O 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG  3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2 ADA classification of hypoglycaemia
Insulin dose
!
Total insulin dose at week 26
!
Total insulin dose at week 38
Observed values of total insulin dose at week 26 and week 38 will be summarised by the arithmetic 
mean, SD, median, and minimum and maximum value and supplemented with the geometric mean 
and coefficient of variation. Separate summaries will also be made for the basal insulin dose and the 
bolus insulin dose.
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Version:
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Weight
!
Change in weight from baseline to week 26
!
Change in weight from baseline to week 38
are summarised descriptively and analysed statistically using the primary statistical analysis for 
both the primary and secondary estimand.
Clinical evaluations at week 26 and week 38
!
Physical examination
!
Vital signs (blood pressure and pulse)
!
Dilated fundoscopy or fundus photography
!
12-lead electrocardiogram
will be summarised descriptively including:
!
Change from baseline to week 26
!
Change from baseline to week 38
Any findings in the physical examination evaluation at screening will be presented as listings. Any 
clinically significant deterioration of a pre-existing condition after the screening visit, as well as any 
new clinically findings will be recorded as adverse events.
Laboratory assessments
!
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes)
!
Biochemistry (creatinine, ALT, AST, AP, sodium, potassium, albumin, total bilirubin)
!
Insulin antibodies
All laboratory parameters will be summarised descriptively.
The following tables will be presented based on observed data:
!
Shift tables from baseline to week 26
!
Shift tables from baseline to week 38
!
Change from baseline to week 26
!
Change from baseline to week 38
!
Proportion of subjects with measurements outside reference range by treatment and week.
Laboratory values will be presented graphically as box plots by treatment and week.
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For each laboratory parameter, individual values outside the reference range (abnormal values) will 
be listed. 
17.6
Health economics and/or patient reported outcomes
The following PRO endpoints are included in the trial:
Change from baseline to week 26 for:
o
Health-related quality of life as evaluated by SF-36v2® Health Survey
o
Treatment related impact as evaluated by the Treatment Related Impact Measure-
Diabetes (TRIM-D)
Change from baseline to week 38 for:
o
Health-related quality of life as evaluated by the SF-36v2® Health Survey
o
Treatment related impact as evaluated by the TRIM-D
The domain and overall scores for both SF-36 and TRIM-D will be summarised descriptively based 
on observed data and explorative statistical analysis may be performed.
The data collected in the BHQ will not be included in the clinical trial report, nor will the data 
collected in the hypoglycaemic resource use interview questionnaire. Data from the latter will be 
used to assess costs associated with hypoglycaemia and provide information to be used in health 
economic analyses.
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Trial ID: NN5401-4266
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18 Ethics
18.1
Benefit-risk assessment of the trial
The trial population will consist of subjects with T2DM. For all subjects participating in this trial 
the anticipated benefits include improved glycaemic control. Titration algorithms, specifying 
recommended adjustments of trial insulin dose for:
!
IDegAsp: co-formulation of basal insulin degludec and bolus insulin aspart
!
IGlar: basal insulin
!
IAsp: bolus insulin
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.
The maximum trial duration for each subject is 44 weeks and the treatment duration for a subject is 
planned to be 38 weeks. Subjects will be asked to perform SMPG recordings and measure 9-point 
profiles at scheduled visits during the trial.
Trial products, including the ‘washout’ insulin will be provided by Novo Nordisk free of charge. 
Subjects will receive IDegAsp, IGlar and IAsp in prefilled pens that are all distinguishable in order 
to minimise the risk of medication errors. Both IAsp and IGlar are marketed products. Please refer 
to the local labelling of these products for a description of risks and benefits.
IDegAsp is currently approved worldwide in many countries within U.S., EU and Japan, although 
not available at the market in all countries in these regions yet.
The subjects will be provided with a BG-meter including lancets, plasma-calibrated test strips and 
control solutions as well as instructions for use.
Subjects randomised to the trial will be transferred to a treatment regimen anticipated to be better 
than or equal to the treatment they receive at the time they enter the trial.
It is expected that all subjects participating in the trial will benefit from participation through close 
contact to trial site, frequent follow-up visits and thereby an intensified evaluation of their diabetes.
Treatment discontinuation criteria (rescue criteria – refer to protocol 6.5) are defined in order ensure 
subject safety and adjust treatment if deemed necessary. Subjects may be prematurely discontinued 
from trial product at the discretion of the investigator due to a safety concern or if judged non-
compliant with trial procedures. When prematurely discontinued from trial product, the subject will 
be prescribed alternative therapy at the investigator's discretion. Subjects who prematurely 
discontinue trial product will be offered to remain in the trial and attend and complete end of trial 
assessments and monthly phone contacts. An effort will be made to try to accomplish this for all 
prematurely discontinued subjects.
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 
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inconveniences of participating in the trial. These precautions include thorough information 
regarding the correct administration of the trial products. Furthermore, subjects will be fully 
informed about possible AEs and inconveniences. The side effects associated with trial products are 
not different from what is seen with other insulins and include hypoglycaemia, hypersensitivity 
reactions, injection site reactions, lipodystrophy and peripheral oedema. For more detailed 
description, refer to the IB17  the CCDS41 and/or EU SmPC15 for IDegAsp, the CCDS42 and 
EU SmPC13 for IAsp, and the EU SmPC27 for IGlar or similar local labelling.
18.2
Informed consent
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. This includes the use of an impartial witness where required according to local 
requirements.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
18.3
Data handling
If the subject 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
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! Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subject during trial
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 by 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. Furthermore, 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 sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial.
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites.
The investigator will make every effort to ensure that all assessments are performed and data are 
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.
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21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, 
any other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of the IB or EU SmPC or similar labelling as appropriate
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s 
site and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
Only applicable for U.S. trial sites:
!
For U.S. trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest
!
For U.S. trial sites: FDA form 1572 must be completed and signed by the investigator at 
each site
FDA form 1572:
For U.S. sites:
!
Intended for U.S. sites
!
Conducted under the IND
!
All U.S. investigators, as described above, will sign FDA Form 1572
For sites outside the U.S.:
!
Intended for participating sites outside of the U.S.
!
Not conducted under the IND
!
All investigators outside of the U.S. 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.
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By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1, 
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data.
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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CONFIDENTIAL
Date:
04 May 2016
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted 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 ICMJE for research publications53. The 
signatory investigator will be appointed before LPLV.
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 Disclosure4.
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.
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04 May 2016
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Version:
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In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the ICMJE53
(sometimes referred to as the Vancouver Criteria).
The investigator(s) offered authorship will be asked to comment and approve the publication.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided after 
results are available.
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CONFIDENTIAL
Date:
04 May 2016
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Trial ID: NN5401-4266
Version:
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Status:
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24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems 
supplied by Novo Nordisk. These data must be retained by the trial site. If the provided data (e.g. 
the CD-ROM) is not readable during the entire storage period, the investigator can request a new 
copy. A Copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biosamples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities or for safety reasons.
The samples will be stored at a central bio-repository after end of trial and until marketing 
authorisation approval in all countries 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.
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Date:
04 May 2016
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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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:
04 May 2016
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, 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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
Final
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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.
If a country has specific laws, acts and/or guidelines, and the local regulatory authorities require 
specifically to identify such laws/acts/guidelines in the protocol, these should be referred to by 
stating: Novo Nordisk accepts liability in accordance with: Insert reference to local 
laws/acts/guidelines. Ensure these local additions are in agreement with the Head of CMR or Global 
Legal.
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CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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27 References
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World Medical Association. Declaration of Helsinki. Ethical Principles for Medical 
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3.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional 
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Effect of intensive blood-glucose control with metformin on complications in overweight 
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Gaede P, Vedel P, Larsen N, Jensen GVH, Parving H, Pedersen O. Multifactorial 
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6.
Patel A, Group AC, MacMahon S, Chalmers J, Neal B, Woodward M, et al. Effects of a 
fixed combination of perindopril and indapamide on macrovascular and microvascular 
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controlled trial. Lancet. 2007;370(9590):829-40.
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Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of 
glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 
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Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
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Balena R, Hensley IE, Miller S, Barnett AH. Combination therapy with GLP-1 receptor 
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Home PD, Lindholm A, Riis A, European Insulin Aspart Study Group. Insulin aspart vs. 
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Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin 
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Raskin P, Riis A, Guthrie RA, Jovanovic L, Leiter L. Use of insulin aspart, a fast-acting 
insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. 
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Novo Nordisk A/S. Insulin NovoRapid® EU Summary of Products Characteristics. JAN-
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Novo Nordisk A/S. Ryzodeg® EU Summary of Products Characteristics. 2015.
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CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
EudraCT no.: 2015-004768-12
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17.
Novo Nordisk A/S. Investigator's Brochure, Insulin degludec/insulin aspart (Ryzodeg®) 
(11th edition). December 2015.
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19.
Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action 
profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with 
those of NPH insulin and placebo. Diabetes Care. 2000;23(5):644-9.
20.
Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, et al. 
Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human 
insulin analog glargine, NPH insulin, and ultralente human insulin and continuous 
subcutaneous infusion of insulin lispro. Diabetes. 2000;49(12):2142-8.
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Porcellati F, Rossetti P, Fanelli G. Glargine vs NPH as basal insulin in intensive treatment of 
T1DM given lispro at meals: One year comparison. Diabetes. 1998;47(Suppl. 1: A 103).
22.
Raskin P, Klaff L, Bergenstal R, Halle JP, Donley D, Mecca T. A 16-week comparison of 
the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with 
insulin lispro in patients with type 1 diabetes. Diabetes Care. 2000;23(11):1666-71.
23.
Raskin P, Park G, Zimmerman J. For the U.S. Study Group of HOE 901 in Type 2 Diabetes 
Mellitus. The effect of HOE 901 in glycemic control in type 2 diabetes. Diabetes. 
1998;47(Suppl 1: A103).
24.
Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycemia 
with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of 
Insulin Glargine in Type 1 Diabetes. Diabetes Care. 2000;23(5):639-43.
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Rosenstock J, Schwartz SL, Clark CM, Jr., Park GD, Donley DW, Edwards MB. Basal 
insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and 
NPH insulin. Diabetes Care. 2001;24(4):631-6.
26.
Scholtz HE, Pretorius SG, Wessels DH, Becker RHA. Pharmacokinetic and glucodynamic 
variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy 
volunteers using a euglycaemic clamp technique. Diabetologia. 2005;48(10):1988-95.
27.
EU Summary of Product Characteristics for Lantus®, insulin glargine, current version 2015 
[updated 2015].
28.
Novo Nordisk A/S. Investigator´s Brochure, insulin degludec (11th edition). December 
2015.
29.
European Medicines Agency Committee for Proprietary Medicinal Products. 
EMEA/CHMP/BMWP/14327/2006 - Guideline on Immunogenicity Assessment of 
Biotechnology-Derived Therapeutic Proteins. 2006.
30.
Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx.
31.
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 
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U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
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33.
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 
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CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
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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.
34.
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.
35.
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.
36.
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.
37.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
38.
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.
39.
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-
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Volume 4, Annex 13, Investigational Medicinal Products. Brussels, February. 2010.
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Novo Nordisk A/S. Ryzodeg® Company Core Data Sheet version 6.0 (27-JAN). 2016.
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MAR). 2013.
43.
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44.
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Charateristics. SEP 2015.
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Novo Nordisk A/S. EU Summary of product characteristics, NovoMix® 30. 20 Jan 2016.
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Novo Nordisk A/S. US Prescribing Information, NovoLog® Mix 70/30. April 2015.
48.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
49.
Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs 
insulin glargine and placebo in combination with metformin and sulfonylurea therapy in 
type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 
2009;52(10):2046-55.
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International Conference of Harmonisation. ICH Harmonised Tripartite Guideline E9. 
Statistical Principles for Clinical Trials, Step 4 Version. 5 Feb 1998.
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Koch GG. Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med. 2008;27(3):333-42.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 May 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
3.0
UTN: U1111-1175-7895
Status:
Final
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52.
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.
53.
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 Amendment
CONFIDENTIAL
Date:
08 December 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
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Protocol Amendment
no 1
to Protocol, final version 3.0
dated 04 May 2016
Trial ID: NN5401-4266
A 38 week trial comparing effect and safety of insulin degludec/insulin aspart
vs. insulin glargine plus insulin aspart in subjects with type 2 diabetes treated
with basal insulin with or without oral antidiabetic treatment in need of
treatment intensification.
Trial phase: 3b
Applicable to all countries 
Amendment originator:
, 
Trial Operations 3, Insulin & Devices
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:
08 December 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
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Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................2
Table of Tables..................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Section 1, Summary.......................................................................................................................3
2.2
Section 2, Flow chart .....................................................................................................................3
2.3
Section 4.2.2.1, Supportive secondary efficacy endpoints ............................................................4
2.4
Section 5.2, Rationale for trial design............................................................................................4
2.5
Section 6.5, Rescue criteria............................................................................................................4
2.6
Section 7, Milestones.....................................................................................................................5
2.7
Section 8.1.5, Diaries.....................................................................................................................5
2.8
Section 8.1.9, Follow-up visits ......................................................................................................5
2.9
Section 8.1.11, Premature discontinuation of trial product............................................................5
2.10
Section 8.2.5, Concomitant medication.........................................................................................5
2.11
Section 8.4.8, Hypoglycaemic episodes ........................................................................................6
2.12
Section 8.5.3.1, Haematology and Biochemistry assessments ......................................................7
2.13
Section 12.1.1, Adverse event........................................................................................................7
2.14
Section 14, Monitoring procedures................................................................................................7
2.15
Section 17.5.1, Efficacy endpoints ................................................................................................7
2.16
Section 17.5.2, Safety endpoints....................................................................................................8
2.17
Appendix A, section 3.6.2..............................................................................................................9
Table of Figures   
Page
No table of figures entries found.
Table of Tables   
Page
No table of figures entries found.
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Protocol Amendment
CONFIDENTIAL
Date:
08 December 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
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1
Introduction including rationale for the protocol amendment
Main reason for global amendment no. 1 is that recruitment period is extended. New standard for 
statistical data handling has been implemented to meet new requirements from the FDA. At the 
same time identified important errors and  necessary clarifications are implemented. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 1, Summary
Correction of error:
In need of treatment intensification is defined as an HbA1c level of 7-10% (53-856 mmol/mol), both 
inclusive.
2.2
Section 2, Flow chart 
Specification of visit window at P42 : ±3+3
Addition of ‘x’ for hypoglycaemic episodes at P42, table 2-1, to highlight that hypoglycaemic 
episodes are collected in the follow up period : x
Addition of ‘x’ for hypoglycaemic episodes at P42, table 2-2,to highlight that hypoglycaemic 
episodes are collected in the follow up period: x
Clarification of text in foot note n: 
Two follow-up visits are to be conducted. The first (V41) must take place no earlier than seven days 
and no later than 12 days after the EOT visit (V40). The last follow-up visit (P42) will take place 
approximately no earlier than 30 days after the EOT visit (V40) and no later than 33 days after the 
EOT visit (V40) and will be conducted as a phone contact (P42).
Clarification of foot note o: 
At the abbreviated visits (V28a and V40a) HbA1c samples and information on adverse events (AEs) 
including hypoglycaemic episodes will be collected
Addition of new foot note ‘p’ for 9-point-profile at V40 : p
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
08 December 2016
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
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Addition of new foot note p, to clarify that 9-point-profile is not required at V40 for subjects 
prematurely discontinued : 
p For subjects prematurely discontinued from trial insulin products the 9-point-profile is omitted at 
visit corresponding to V40
2.3
Section 4.2.2.1, Supportive secondary efficacy endpoints
Update of supportive secondary efficacy endpoints to implement new guidelines from FDA: 
!
At 26 weeks:
o
Responder (Yes/No) for HbA1c after 26 weeks:
o
HbA1c <7%
o
HbA1c <7% without nocturnal (00:01-05:59) severe or blood glucose (BG) 
confirmed symptomatic hypoglycaemia
o
HbA1c < 7% without severe or BG confirmed symptomatic hypoglycaemia
!
At 38 weeks:
o
Responder (Yes/No) for HbA1c after 38 weeks:
o
HbA1c <7%
o
HbA1c <7% without nocturnal (00:01-05:59) severe or blood glucose (BG) 
confirmed symptomatic hypoglycaemia
o
HbA1c < 7% without severe or BG confirmed symptomatic hypoglycaemia
2.4
Section 5.2, Rationale for trial design
Clarification of the rationale for trial design to highlight that hypoglycaemic episodes are to be 
collected in the follow up period: 
A 30-day follow-up (P42) after last trial insulin treatment (V40) will be performed in order to 
collect information about antidiabetic treatment and adverse events (AEs) including hypoglycaemic 
episodes occurring between V41 and P42.
2.5
Section 6.5, Rescue criteria
Correction of rescue criteria text to clarify which SMPG values are to be used: 
If any of the fasting SMPG values taken on three consecutive days or if any of the FPG samples 
analysed by the central laboratory exceed the limit of: 
!
15.0 mmol/L (270 mg/dL) from baseline to end of week 12
!
13.3 mmol/L (240 mg/dL) from week 13 to end of week 38
and if no treatable inter current 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.
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2.6
Section 7, Milestones
Change of timelines to reflect that recruitment period has been extended: 
Planned duration of recruitment period (i.e. first patient first visit (FPFV) – last patient first visit
(LPFV)): 169 weeks and 3 days
Planned date for FPFV: 20 Sep 2016
Planned date for last patient last visit (LPLV): 16 Nov 12 Dec 2017
2.7
Section 8.1.5, Diaries 
Correction to specify when diaries are provided to subjects:
At each clinic visit, the subjects must receive diaries related to the following visit and/or phone
contact(s). The diaries dispensed to subjects should be collected at the following clinic visit.
However, for the screening visit (V1), the 30-days follow-up visit (P42) and the monthly phone
contacts (in case of pre-term discontinuation of trial insulin products) no diaries will be provided. 
2.8
Section 8.1.9, Follow-up visits
Clarification to highlight that hypoglycaemic episodes are to be collected at last follow up visit 
(P42) and at potential monthly phone contacts (Px):
For the last follow-up visit (P42) and potential monthly phone contacts (Px), no paper diary will be 
provided. Consequently, source data for these phone contacts will be the notes written in the 
subject’s medical record. At these contacts only information about antidiabetic treatment and AEs 
including hypoglycaemic episodes will be collected.
2.9
Section 8.1.11, Premature discontinuation of trial product
Clarification to highlight that 9-point-profile is not needed at the visit corresponding to V40 for 
subjects prematurely discontinued from trial product:
In case of premature discontinuation of trial product the investigator should make all effort to call
the subject in for an unscheduled visit as soon as possible and must aim to undertake procedures
similar to those for the EOT visit (V40), except 9-point-profile but including fasting blood sampling 
and hand-out of ‘washout’ insulin products (refer to Section 5.3.3) to be used in the period between 
the EOT visit (V40) and the 7-day follow-up visit (V41), where the last AB sampling will be 
performed.
2.10
Section 8.2.5, Concomitant medication
To clarify the definition and the reporting requirements for concomitant medications:
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A concomitant medication is any medication, other than the trial product(s), which is taken during 
the trial, including the screening and follow-up periods.
Details of any concomitant medication must be recorded at the screening visit (V1), including OAD 
treatment and pre-trial basal insulin, which subjects continue using between the screening visit (V1) 
and the randomisation visit (V2). For details on OAD treatment, refer to Section 5.4.
The information collected for each anti-diabetic concomitant medication includes trade name or 
generic name, indication, total daily dose and route of administration, start date and stop date or 
continuation. For concomitant medication other than anti-diabetic concomitant medication only 
trade name or generic name, indication, start date and stop date or continuation are to be 
collected.
In case the concomitant medication is a systemic treatment which in the investigator’s opinion 
could interfere with the glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or 
corticosteroids – refer to exclusion criterion 14 (Section 6.3)), this information needs to be captured 
in the eCRF.
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, total daily dose and route of administration, start date and stop date or continuation.
If a change is due to an AE, then this must be reported according to Section 12. 
In case the concomitant medication is a systemic treatment which in the investigator’s opinion 
could interfere with the glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or 
corticosteroids – refer to exclusion criterion 14 (Section 6.3)), this information needs to be captured 
in the eCRF.
If the change influences the subject’s eligibility to continue in the trial or trial product treatment
(refer to premature discontinuation criterion 4, section 6.6), the monitor must be informed.
2.11
Section 8.4.8, Hypoglycaemic episodes
Specification of process for recording of hypoglycaemic episodes during follow-up period:
All plasma glucose values:
• J 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
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randomisation (Visit 2) to the follow-up (Visit 41). Hypoglycaemic episodes occurring between 
Visit 41 and the last follow up visit (P42) should be recorded on a hypoglycaemic episode form in 
the eCRF.   
2.12
Section 8.5.3.1, Haematology and Biochemistry assessments
Clarification that lab parameters will be analysed at screening and not at randomisation as 
previously indicated:
The below haematology and biochemistry parameters will be analysed at the randomisation
screening visit (V2V1), prior to the intensification period (V28) and at the end-of-trial visit (V40), 
please refer to the flow chart (Section 2).
2.13
Section 12.1.1, Adverse event
Correction of cross-reference to a wrong section in the protocol:
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead of 
an AE form, see Section 8.4.7.  8.4.8
2.14
Section 14, Monitoring procedures
Deletion of US requirement as this is wrong:
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. For U.S.: the follow-up letter must be signed by 
the investigator.
2.15
Section 17.5.1, Efficacy endpoints
Update of supportive secondary efficacy endpoints to implement new guidelines from FDA: 
Responder for HbA1c
!
Responder (Yes/No) for HbA1c after 26 weeks:
o
HbA1c <7%
o
HbA1c <7% without nocturnal (00:01-05:59) (BG) severe or BG confirmed 
symptomatic hypoglycaemia
o
HbA1c < 7% without severe or BG confirmed symptomatic hypoglycaemia
!
Responder (Yes/No) for HbA1c after 38 weeks:
o
HbA1c <7%
o
HbA1c <7% without nocturnal (00:01-05:59) (BG) severe or BG confirmed 
symptomatic hypoglycaemia
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o
HbA1c < 7% without severe or BG confirmed symptomatic hypoglycaemia
Subjects with less than 16 weeks of treatment will be set as non-responders. Nocturnal 
Hhypoglycaemic episodes will be based on the available data.
2.16
Section 17.5.2, Safety endpoints
Update of supportive secondary efficacy endpoints to implement new guidelines from FDA: 
For endpoints addressing the hypoglycaemic rate in the 26 weeks or the 38 weeks period, a negative 
binomial model will be used, including treatment, previous insulin treatment regimen, previous 
OAD treatment, sex, and region as factors and age as covariate. The model will use a log-link 
function and the logarithm of the time period in which a hypoglycaemic episode was considered 
treatment emergent as offset. The treatment rate ratios will be estimated and 95% confidence 
intervals will be calculated.
The rationale for investigating the hypoglycaemic rate during the maintenance is to reflect long 
term use, as prior to this period (the titration period) the glycaemic control might be unstable. For 
endpoints addressing hypoglycaemic rate in the maintenance period, a negative binomial regression 
model using data from both the titration and maintenance periods will be used. This is done to 
comply with the randomisation principle, i.e. to include all randomised subjects in the analyses, also 
those who withdrew during the titration period. The model will use a log-link function and the 
logarithm of the time period in which a hypoglycaemic episode was considered treatment emergent 
as offset. Subject will be included as a random effect. The model includes treatment, previous 
insulin treatment regimen, previous OAD treatment, sex, region and period (titration or 
maintenance) as factors and age as covariate. The interaction between each factor and covariate 
with period will also be included. 
From the above negative binomial models the treatment rate ratios will be estimated and 95% 
confidence intervals will be calculated.
The rationale for investigating the hypoglycaemic rate during the maintenance is to reflect long 
term use, as prior to this period (the titration period) the glycaemic control might be unstable. For 
endpoints addressing hypoglycaemic rate in the maintenance period, subjects that discontinue 
randomised treatment during the maintenance period will contribute with the available 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 maintenance period for subjects that discontinued randomised treatment during the 
maintenance period. For these subjects, the number of events will be imputed corresponding to a 10 
weeks maintenance period as follows: 
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!
In the first step, 1000 samples from the posterior distribution of model parameters are 
extracted. The model is fitted to the on-treatment maintenance data for subjects that 
discontinued randomised treatment during the maintenance period for each treatment arm 
separately. This is done using a Bayes negative binomial log-link model with the same 
factors, covariates and offset as in the analyses of hypoglycaemic episodes described above. 
The 1000 samples are used as sampled parameter estimates in the next step. 
!
For each sample of model parameters, the total number of hypoglycaemic events in the 
maintenance period for subjects that discontinued randomised treatment in the titration 
period is imputed as a random number of events from a negative binomial distribution using 
the sampled parameters. 
!
For each of the 1000 imputed data sets, that now have maintenance period data for all 
randomised subjects, the mean treatment ratio is estimated using the same negative 
binomial model as in the analyses of hypoglycaemic episodes described above. 
!
The estimates and standard deviations for the 1000 imputed data sets are pooled to one 
estimate and associated standard deviation using Rubin’s formula. From these the 95% 
confidence interval for the treatment ratio and the associated p-value are calculated.
If the above model cannot fit due to sparse data, the model in step 1 is fitted to the on-treatment 
data for subjects that discontinued randomised treatment during either titration or maintenance, i.e. 
do not complete the scheduled 26 weeks of treatment. 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 
before week 26 in the following order, until a model fits:
!
sex
!
age
!
region
!
previous insulin treatment regimen
!
previous OAD treatment
2.17
Appendix A, section 3.6.2
Clarification of titration procedure:
If HbA1c aAt week 32 is @ 7.0% IAsp treatment should , subjects can be further intensified with an 
additional dose of IAsp initiated at 4U, if deemed necessary by the investigator.
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Content: Global key staff and Country key staff
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Clinical Trial Report
Appendix 16.1.1
16 April 2018
0.1
Review
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Appendix A: Insulin Titration Guideline
Trial ID: NN5401-4266
A 38 week trial comparing effect and safety of 
insulin degludec/insulin aspart vs. insulin glargine plus 
insulin aspart in subjects with type 2 diabetes treated with 
basal insulin with or without oral antidiabetic treatment in 
need of treatment intensification
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
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disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
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Table of Contents
Page
Table of Contents..............................................................................................................................................2
List of in-text 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 of IGlar...........................................................................................................................5
3.2
Initiation of IDegAsp.....................................................................................................................5
3.3
Initiation of IAsp............................................................................................................................5
3.4
Treatment of IGlar .........................................................................................................................5
3.5
Treatment during week 1-26 of IDegAsp and IAsp.......................................................................6
3.5.1
Titration of IDegAsp OD.............................................................................................6
3.5.2
Titration of IAsp ..........................................................................................................7
3.6
Treatment after week 26 of IDegAsp and IAsp.............................................................................7
3.6.1
Titration of IDegAsp BID............................................................................................7
3.6.2
Titration of IAsp ..........................................................................................................8
3.7
Deviations from the algorithm.......................................................................................................8
4
Data collection ...........................................................................................................................................9
5
Review procedure....................................................................................................................................10
6
References................................................................................................................................................11
List of in-text tables
Page
Table 1
Adjustment of IGlar.......................................................................................................................5
Table 2
Dose reduction of IGlar .................................................................................................................6
Table 3
Adjustment of IDegAsp OD ..........................................................................................................6
Table 4
Dose reduction of IDegAsp OD.....................................................................................................6
Table 5
Adjustment of IAsp........................................................................................................................7
Table 6
Adjustment of IDegAsp BID .........................................................................................................8
Table 7
Dose reduction of IDegAsp BID....................................................................................................8
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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 PG values are intensively monitored and the 
insulin dose(s) frequently adjusted 1-6.
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.
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2
Treatment regimens
At randomisation all subjects will be randomised in a 1:1 manner into two parallel treatment 
groups:
!
Insulin degludec/insulin aspart (IDegAsp) OD ± OADs
!
Insulin glargine (IGlar) OD +  insulin aspart (IAsp) OD ± OADs
First dosing should take place on day of randomisation or on the day following randomisation.
There are no minimum or maximum doses for IDegAsp, IGlar or IAsp.
2.1
Injection area
Both IDegAsp, IGlar and IAsp should be injected subcutaneously into the thigh, upper arm (deltoid 
region) or the abdomen. 
The injection site should remain the same throughout the trial. Rotation of injection sites within a 
given region is recommended.
2.2
Time of injection
IDegAsp OD will be administered with the largest meal. From week 26 subjects in need of 
intensification will be administered IDegAsp BID with the two largest meals; one being dinner.
During intensification the timing of IDegAsp (BID) dosing can be changed at the discretion of the 
investigator, but one of doses must be administered with the dinner.
IGlar will be administered OD according to local labelling.
IAsp OD should be administered with the largest meal. From week 26 subjects in need of 
intensification should be administered IAsp BID with the largest and second largest meal. From 
week 32 subjects in need of further intensification should be administered IAsp TID with largest 
and second largest meals and the third meal of the day. Extra bolus dosing should be avoided, 
except for short term safety reasons. Extra bolus doses and reasons should be documented in the 
diary.
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3
Initiation and titration
3.1
Initiation of IGlar
Subjects receiving OD basal insulin will transfer unit-to-unit to IGlar OD. Subjects receiving more 
than OD basal insulin should reduce the initial total daily dose by 20% or according to local 
labelling and transfer to IGlar OD.
3.2
Initiation of IDegAsp
Subjects receiving basal insulin OD or more will transfer unit-to-unit to IDegAsp OD. 
3.3
Initiation of IAsp 
IAsp will be initiated at 4U with the largest meal. 
3.4
Treatment of IGlar
During the entire treatment period IGlar doses will be titrated once weekly by the investigator based 
upon the subject’s SMPG levels and the insulin titration guideline in connection with the scheduled 
visits/phone contacts.
Dose adjustment will be based on the three pre-breakfast SMPG values measured on the day of the 
titration and the two days prior to the titration in accordance with Table 1 and Table 2.
Table 1
Increase of IGlar
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
If one or more SMPGs values are missing, the adjustment should be performed on the remaining 
SMPG value(s).
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Table 2
Dose reduction of IGlar
Lowest pre-breakfast SMPG
Dose adjustment
mmol/L
mg/dL
U
3.1 –  3.9
56 – 70
-2
< 3.1
< 56
-4
3.5
Treatment during week 1-26 of IDegAsp and IAsp
During the entire treatment period insulin doses will be titrated once weekly by the investigator 
based upon the subject’s SMPG levels and the insulin titration guideline in connection with the 
scheduled visits/phone contacts.
3.5.1
Titration of IDegAsp OD
Dose adjustment will be based on the three pre-breakfast SMPG values measured on the day of the 
titration and the two days prior to the titration in accordance with Table 3 and Table 4.
Table 3
Increase of IDegAsp OD
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
If one or more SMPGs values are missing, the adjustment should be performed on the remaining 
SMPG value(s).
Table 4
Dose reduction of IDegAsp OD
Lowest pre-breakfast or pre-dinner SMPG
Dose adjustment
mmol/L
mg/dL
U
3.1 –  3.9
56 – 70
-2
< 3.1
< 56
-4
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3.5.2
Titration of IAsp
IAsp will be dosed once daily with the largest meal. 
Dose adjustment will be based on the three pre-prandial or bedtime SMPG values measured on the 
three days prior to titration in accordance with Table 5.
!
Breakfast dose will be adjusted based on pre-lunch SMPG values
!
Lunch dose will be adjusted based on pre-dinner SMPG values
!
Dinner dose will be adjusted based on bedtime SMPG values
Table 5
Adjustment of IAsp
Pre-prandial or bedtime SMPG
Dose adjustment
U
Rules for dose 
adjustments
mmol/L
mg/dL
< 4.0
< 71
-1
J 1 SMPGs below target
4.0 – 6.0
71 K 108
0
0K1 SMPG above target
No SMPGs below target
> 6.0
> 108
+1
J 2 SMPGs above target
No SMPGs below target 
3.6
Treatment after week 26 of IDegAsp and IAsp
If HbA1c taken at week 25 is <7.0%, the subject should be titrated at week 26 according to Table 3
and Table 4. 
If HbA1c taken at week 25 is J 7.0% IDegAsp treatment should be intensified to BID at week 26 as 
described below. 
At week 32 subjects still on IDegAsp OD should be intensified to BID if HbA1c taken at week 31 is 
J 7.0%. 
Intensification from IDegAsp OD to BID should be done by splitting the total daily dose of 
IDegAsp OD into two doses of IDegAsp. The split can be even or uneven as based on the size of 
the meals. Subjects with HbA1c < 7.0% measured at week 25 or 31 can be switched to IDegAsp 
BID at weeks 26 or 32 at the discretion of the investigator based on the needs of the individual 
subject.
3.6.1
Titration of IDegAsp BID
The breakfast/lunch dose adjustment will be based on the three pre-dinner SMPG values measured
on three days prior to the titration in accordance with Table 6 and Table 7.
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The dinner dose adjustment will be based on the mean of three pre-breakfast SMPG values 
measured on the day of titration and the two days prior to the titration in accordance with Table 6
and Table 7.
Table 6
Increase of IDegAsp BID
Mean pre-breakfast or pre-dinner 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
If one or more SMPG values are missing, the dose adjustment should be performed on the 
remaining SMPG value(s). 
Table 7
Dose reduction of IDegAsp BID
Lowest pre-breakfast or pre-dinner SMPG
Dose adjustment
mmol/L
mg/dL
U
3.1 –  3.9
56 – 70
-2
< 3.1
< 56
-4
3.6.2
Titration of IAsp
If HbA1c at week 26 is <7.0%, the subject should continue on IAsp OD and titration according to 
Table 5.
If HbA1c at week 26 is J 7.0% IAsp treatment should be intensified with a second dose of IAsp. The 
second dose should be initiated at 4U. Titration should be performed according to Table 5.
If HbA1c at week 32 is J 7% IAsp treatment should be intensified with an additional dose of IAsp 
initiated at 4U. Titration should be performed according to Table 5.
3.7
Deviations from the algorithm
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust the insulin doses is based on all relevant information as described in Section 1. A reason for 
deviating from the algorithm should be entered into the eCRF.
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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 SMPG values measured since last visit/telephone
!
Date, time and doses of IDegAsp, IGlar and IAsp
!
Prescribed doses of IDegAsp, IGlar and IAsp
!
Reasons for deviation from the titration algorithms, if applicable
!
Hypoglycaemic episodes
CONFIDENTIAL


Trial ID: NN5401-4266
CONFIDENTIAL
Date:
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Novo Nordisk
Protocol - Appendix A
Version:
4.0
UTN: U1111-1175-7895
Status:
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EudraCT No.: 2015-004768-12
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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 blinded manner.
CONFIDENTIAL


Trial ID: NN5401-4266
CONFIDENTIAL
Date:
08 December 2016
Novo Nordisk
Protocol - Appendix A
Version:
4.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
11 of 11
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):408-416.
2. Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P. 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):1269-1274.
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):1569-1581.
4. Riddle et al. 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): 3080-3086.
5. Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, 
Endahl LA, Francisco AM, Hollander P: Insulin degludec, an ultra-long acting 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 Apr 21;379(9825):1498-507.
6. Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, 
Philotheou A, Francisco AM, Pei H, Bode B: Insulin degludec, an ultra-long acting 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 Apr 21;379(9825):1489-97.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02906917 
Sponsor trial ID: 
NN5401-4266 
Official title of study: 
A 38 week trial comparing effect and safety of insulin 
degludec/insulin aspart vs. insulin glargine plus insulin aspart 
in subjects with type 2 diabetes treated with basal insulin with 
or without oral antidiabetic treatment in need of treatment 
intensification 
Document date: 
22 June 2018 
 


Link
List of contents
Statistical analysis plan......................................................................................................................
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Date:
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Version:
Status:
IDegAsp
Trial ID: NN5401-4266
Clinical Trial Report
Appendix 16.1.9
22 June 2018
1.0
Final
16.1.9 Documentation of statistical methods
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Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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EudraCT No.: 2015-004768-12
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Statistical Analysis Plan
Trial ID: NN5401-4266
A 38 week trial comparing effect and safety of
insulin degludec/insulin aspart vs. insulin glargine plus insulin 
aspart in subjects with type 2 diabetes treated with basal 
insulin with or without oral antidiabetic treatment in need of
treatment intensification
Trial phase: 3b
Author:
 (
) 
Biostatistics Degludec and Devices
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
2 of 32
Table of contents                                                                                    Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................5
1.1
Trial information.......................................................................................................................5
1.2
Scope of the statistical analysis plan..........................................................................................7
2
Statistical considerations .....................................................................................................................7
2.1
Primary and secondary estimands..........................................................................................8
2.2
Sample size calculation............................................................................................................8
2.3
Definition of analysis sets......................................................................................................10
2.4
Primary endpoint ..................................................................................................................13
2.5
Supportive secondary endpoints ..............................................................................................15
2.5.1
Efficacy endpoints .................................................................................................15
2.5.2
Safety endpoints ....................................................................................................18
2.6
Health economics and/or patient reported outcomes.................................................................26
3
Changes to the statistical analyses planned in the protocol..............................................................26
3.1
Clarification of primary statistical analysis, primary estimand: ................................................26
3.2
Clarification of sensitivity analyses to secondary estimand for primary analysis,......................26
3.3
Changes to supportive secondary endpoints and explorative endpoints.....................................27
3.4
Statistical analyses of the following assessments will not be performed ...................................28
3.5
Statistical analyses based on the secondary estimand will not be performed for the 
following endpoints.................................................................................................................29
3.6
Changes to reporting of safety end points related to adverse events..........................................30
Below mentioned end point is added: ......................................................................................30
3.8
Change to reporting of laboratory assessments.........................................................................30
3.9
In-trial period and on-treatment period ....................................................................................31
3.10
Update of completer analyses set.............................................................................................31
4
References ..........................................................................................................................................32
CONFIDENTIAL


Statistical Analysis Plan
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Trial ID: NN5401-4266
Version:
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Status:
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EudraCT No.: 2015-004768-12
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine amino transferase
ANCOVA
analysis of covariance
AP
alkaline phosphatase
AST
aspartate aminotransferase
BG
blood glucose
BHQ
baseline hypo questionaire
BID
two times a day
CAS
Completer analysis set
CPMP
Committee for Proprietary Medicinal Products 
EOT
end of treatment
FAS
full analysis set
FPG
fasting plasma glucose
HbA1c
glycosylated haemoglobin
IAsp
insulin aspart
ICH
International Conference on Harmonisation
IDeg
insulin degludec
IDegAsp
insulin degludec/insulin aspart
IGlar
insulin glargine
ITT
intention-to-treat 
MMRM
mixed model for Repeated Measurement
NA
not applicable
NI
non-inferiority
OAD
oral antidiabetic drug
OD
once daily
PG
plasma glucose
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
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Trial ID: NN5401-4266
Version:
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PP
per protocol
REML
restricted maximum likelihood
SAP
statistical analysis plan
SD
standard deviation
SF-36v2®
Short-Form Health Survey 36 version 2
SMPG
self-measured plasma glucose
TEAE
treatment-emergent adverse event
TID
three times daily
TE
treatment effect
TRIM-D
Treatment Related Impact Measure-Diabetes
T2DM
type 2 diabetes mellitus
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Statistical Analysis Plan
CONFIDENTIAL
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Trial ID: NN5401-4266
Version:
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Status:
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EudraCT No.: 2015-004768-12
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1
Introduction
1.1
Trial information
Objectives and endpoints
The primary objective
!
To confirm the effect of insulin degludec/insulin aspart once daily versus insulin glargine 
once daily in combination with insulin aspart once daily in controlling glycaemia after 26 
weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
The secondary objectives
!
To compare other effect parameters and safety of insulin degludec/insulin aspart once daily 
versus insulin glargine once daily in combination with insulin aspart once daily after 26 
weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
!
To compare the effect and safety of insulin degludec/insulin aspart once daily or twice daily 
versus insulin glargine once daily in combination with insulin aspart (1-3 times daily) after 
38 weeks in subjects with type 2 diabetes mellitus treated with basal insulin with or without 
oral antidiabetic treatment in need of treatment intensification.
Primary endpoint
!
Change from baseline in glycosylated haemoglobin (HbA1c) (%) after 26 weeks
Supportive secondary efficacy endpoints:
!
Change from baseline in HbA1c(%) after 38 weeks
!
Change from baseline in fasting plasma glucose (FPG) after 26 weeks
!
Change from baseline in fasting plasma glucose (FPG) after 38 weeks
!
Responder (Yes/No) for HbA1c after 26 weeks: HbA1c < 7% 
!
Responder (Yes/No) for HbA1c after 38 weeks: HbA1c < 7% 
!
Responder (Yes/No) for HbA1c after 26 weeks: HbA1c < 7% without severe or BG 
confirmed symptomatic hypoglycaemia
!
Responder (Yes/No) for HbA1c after 38 weeks: HbA1c < 7% without severe or BG 
confirmed symptomatic hypoglycaemia
!
Self-measured plasma glucose measurements (SMPG) after 26 weeks: Mean pre-breakfast 
measurements used for titration
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN5401-4266
Version:
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EudraCT No.: 2015-004768-12
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!
Self-measured plasma glucose measurements (SMPG) after 38 weeks: Mean pre-breakfast 
measurements used for titration
!
Self-measured plasma glucose measurements (SMPG) after 26 weeks: 9-point profile - Post-
prandial increments
!
Self-measured plasma glucose measurements (SMPG) after 38 weeks: 9-point profile - Post-
prandial increments
Supportive secondary safety endpoints:
!
Incidence of treatment-emergent adverse events (TEAEs) from baseline to week 26
!
Incidence of treatment-emergent adverse events (TEAEs) during 38 weeks
!
Incidence of treatment-emergent adverse events (TEAEs) during intensification period 
(week 26-38)
!
Number of nocturnal, treatment-emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 26 weeks
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 38 weeks
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during maintenance (week 16-26)
!
Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during 26 weeks 
!
Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during 38 weeks 
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during maintenance (week 16-26)
!
Total insulin dose at week 26
!
Total insulin dose at week 38
!
Change in weight from baseline to week 26
!
Change in weight from baseline to week 38
Explorative endpoints
!
Change from baseline to week 26 for:
o
Health-related quality of life as evaluated by SF-36v2® Health Survey
o
Treatment related impact as evaluated by the Treatment Related Impact Measure-
Diabetes (TRIM-D)
!
Change from baseline to week 38 for:
o
Health-related quality of life as evaluated by the SF-36v2® Health Survey
CONFIDENTIAL


Statistical Analysis Plan
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Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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EudraCT No.: 2015-004768-12
Page:
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o
Treatment related impact as evaluated by the TRIM-D
Trial design:
This is a 38-week, multinational, open-label, two-arm, randomised (1:1), controlled, parallel-group, 
treat-to-target trial in subjects with type 2 diabetes mellitus treated with basal insulin with or
without oral antidiabetic drug(s) in need of treatment intensification. Subjects will be randomised in 
a 1:1 manner to receive either insulin degludec/insulin aspart (IDegAsp) OD or insulin glargine 
(IGlar) OD in combination with insulin aspart (IAsp) OD for the first 26 weeks followed by a 12-
weeks intensification period. The randomisation will be stratified based on the pre-trial basal insulin 
treatment regimen: OD or BID/TID (two/three times daily) dosing.
Subjects will remain in the same treatment arm throughout the trial, with the possibility of 
intensification of their treatment. At week 26 (V28), subjects not achieving sufficient glycaemic 
control (V27 HbA1c ≥ 7%) will be further intensified from either IDegAsp OD to IDegAsp BID or 
IGlar OD + IAsp OD to IGlar OD + IAsp BID, whereas subjects in good glycaemic control (V27 
HbA1c < 7%) will continue their insulin treatment regimen.
At week 32 (V34), glycaemic control will be evaluated again, and subjects in good glycaemic 
control (V33 HbA1c < 7%) will continue their insulin treatment regimen. Subjects on IDegAsp OD 
not reaching the glycaemic target (V33 HbA1c ≥ 7%) will be intensified to IDegAsp BID, whereas 
subjects in the IGlar arm not reaching glycaemic control will be intensified with one additional 
IAsp dose to IGlar OD + IAsp BID or TID daily for the remaining six weeks of the intensification 
period. 
Further details
For further details on trial design and endpoints please see the NN5401-4266 protocol version 4.0.
1.2
Scope of the statistical analysis plan
This SAP is based on the NN5401-4266 protocol version 4.0.
2
Statistical considerations
Novo Nordisk will analyse and report data from all sites together. 
Unless otherwise specified, all continuous measurements will be summarised descriptively at each 
visit by treatment using in-trial data. Endpoints that are analysed untransformed and endpoints that 
are not formally analysed are summarised by the arithmetic mean, standard deviation (SD), median, 
and minimum and maximum value. Endpoints that are analysed log-transformed are supplemented 
with the geometric mean and coefficient of variation. For measurements over time, mean values 
will be plotted to explore the trajectory over time. The geometric mean values will be plotted for 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
Status:
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EudraCT No.: 2015-004768-12
Page:
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endpoints that are analysed log-transformed. All descriptive summaries and plots will be based on 
in-trial data unless otherwise specified.
If an assessment has been made both at screening and randomisation, and if not otherwise specified, 
the value from the randomisation visit will be used as the baseline value. If the value measured at 
the randomisation visit is missing and the assessment has also been made at screening, then the 
screening value will be used as the baseline value. For summaries and statistical analysis of all 
endpoints the first non-missing values is used. The value should be taken according to the 
specification in the protocol, e.g. non-fasting FPG-values are not used. Re-tests of non-missing 
values are only included in subject specific listings.
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
for absolute values and change from baseline. The estimated means are either obtained by Rubin’s 
rule weighing together estimated means from multiple imputation or directly from estimation in a 
parameterized statistical model. In addition estimated mean treatment differences (or ratios) will be 
presented together with two-sided 95% confidence intervals and corresponding two-sided p-values.
2.1
Primary and secondary estimands
The primary estimand will be the difference in change from baseline at week 26 or week 38 
depending on the endpoint considered between IDegAsp OD and IGlar OD + IAsp OD, for all 
randomised subjects regardless of whether the subjects remained on initially assigned treatment 
until week 26 or week 38. This estimand is a de facto estimand addressing effectiveness.
The secondary estimand will be the difference in change from baseline at week 26  or week 38 
depending on the endpoint considered between IDegAsp OD and IGlar OD + IAsp OD if all 
randomised subjects had adhered to treatment until week 26 or week 38. This estimand is a de jure 
estimand addressing efficacy.
For hypoglycaemic episode endpoints, only the de jure estimand will be used. The reason for this is 
that data for hypoglycaemic episodes will not be systematically collected after treatment 
discontinuation.
2.2
Sample size calculation
The sample size is based on confirming non-inferiority of the primary estimand for the primary 
endpoint assessed at week 26 using the full analysis set (FAS). Sample sizes are also given for 
confirming non-inferiority for the primary estimand of the primary endpoint on the per-protocol set.
The primary objective is to confirm the effect of IDegAsp OD versus IGlar OD + IAsp OD in 
controlling glycaemia in basal insulin-treated subjects with T2DM.
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Statistical Analysis Plan
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Date:
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Trial ID: NN5401-4266
Version:
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This will be done by comparing the difference between IDegAsp OD and IGlar OD + IAsp OD in 
change from baseline in HbA1c after 26 weeks to a non-inferiority limit of 0.4%. The non-inferiority 
limit of 0.4% is aligned with the phase 3a programme and is considered appropriate to ensure a 
relevant effect of IDegAsp compared to placebo since a superior treatment effect of −0.85% [−1.04; 
−0.66] of IGlar versus placebo was reported in a placebo controlled clinical trial in T2DM    
subjects1. Supplementing IGlar with IAsp OD would further increase the treatment effect compared 
to placebo.
Formally, let D be the mean treatment difference (IDegAsp OD minus IGlar OD + IAsp OD) in 
change from baseline in HbA1c. The null-hypothesis of IDegAsp OD inferior by 0.4% or more will 
be tested against the alternative hypothesis of non-inferiority as given by
H0: D ≥0.40% against HA: D <0.40%
Non-inferiority will be considered confirmed if the upper bound of the two-sided 95% confidence 
interval for D is strictly below 0.4%. This is equivalent to using a one-sided test of size 2.5%, which 
means that the Type 1 error rate is controlled at 2.5% level.
Accordingly, the sample size is calculated using a t-statistic under the assumptions of a one-sided 
test of size 2.5%, a mean treatment difference of 0.0%, a standard deviation of SD=1.3%, and a 
non-inferiority limit of 0.40%. It is assumed that 15% of the randomised subjects will discontinue 
randomised treatment before week 26 or have missing data at week 26, and that 10% of the 
randomised subjects will be excluded from the per protocol (PP) analysis set. The assumptions are 
based on the results from a phase 3a trial (NN5401-3593). 
When estimating the primary estimand for the evaluation of the non-inferiority hypothesis, missing 
data will be imputed based on in-trial data. A penalty will be added to the change in HbA1c at week 
26 for all subjects in the IDegAsp OD arm who discontinued trial product prior to week 26 or who 
have missing data at week 26. The penalty corresponds to the non-inferiority limit of 0.4%.
In total an expected 15% will have missing on-treatment data at week 26, 10% will not be part of 
the PP analysis set. This means that 5/90*100%= 5.56% of the PP analysis set is expected to be 
non-completers, hence the expected treatment differences (adjusted treatment effect (TE) resulting 
from the applied penalty) for the non-inferiority hypothesis of the primary estimand is:
1) FAS: 0.15*0.4=0.06
2) PP: 0.0556*0.4=0.0222
The sample size assumptions for TE and the common SD are given in Table 2–1.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN5401-4266
Version:
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From these assumptions, and based on a 1:1 randomisation, the sample size is set to 264 subjects 
per treatment arm, in total 528 subjects. This will ensure a nominal power of at least 85% for 
confirming the primary objective based on the FAS as well as on the PP analysis set. The sample 
size calculation was done using SAS 9.4.
Table 2–1
Assumptions for sample size calculation
Primary 
Estimand
Analysis set 
Non-
inferiority 
margin 
SD
TE
Adjusted TE
Randomisation 
Scheme
Required 
Power
FAS 
0.4%
1.3%
0.0%
0.06%
1:1
85%
PP
0.4%
1.3%
0.0%
0.0222%
1:1
85%
Abbreviations: SD = standard deviation; TE = Treatment effect
Table 2–2
Sensitivity of sample size to variations in SD and power
#subjects in total
SD=1.1%
SD=1.2%
SD=1.3%
SD=1.4%
Power 80%
FAS
332
394
462
536
PP
300
356
416
482
Power 85%
FAS
378
450
528
612
PP
342
406
476
552
Power 90%
FAS
442
526
618
716
PP
400
474
556
644
Power 95%
FAS
546
650
762
884
PP
494
586
686
796
2.3
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E92.
!
Full Analysis Set (FAS): includes all randomised subjects. In exceptional cases, subjects 
may be excluded. In such cases the elimination will be justified and documented. The 
statistical evaluation of the FAS will follow the intention-to-treat (ITT) principle and 
subjects will contribute to the evaluation “as randomised”.
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Statistical Analysis Plan
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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!
Per-Protocol (PP) analysis set: includes all subjects in the Full Analysis Set who fulfils the 
following criteria:
o
Have not violated any inclusion criteria
o
Have not fulfilled any exclusion criteria
o
Have a non-missing HbA1c at screening or randomisation
o
Have at least one non-missing HbA1c after 12 weeks of exposure
o
Have at least 12 weeks of exposure
Subjects in the PP will contribute to the evaluation “as treated”.
!
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”.
!
Trial completer analysis set: Includes all randomised subjects who has attended either V40 
on treatment, or V40A, 38 weeks after randomisation according to protocol .
!
Treatment completer analysis set: Includes all randomised subjects who have completed the 
trial without discontinuation from randomised treatment. 
Before data are released for statistical analysis, a review of all data will take place to ensure a 
sufficient data quality and to ensure the planned statistical analysis are applicable. Any data 
decisions not foreseen in the protocol will be documented before database lock.
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. 
The decision to exclude any subject or observation from the statistical analysis is the joint 
responsibility of the study group. The subjects or observations to be excluded, and the reasons for 
their exclusion will be documented before database lock. The subjects and observations excluded 
from the analysis sets, and the reasons for this, will be described in the clinical trial report.
Definition of the observation periods:
In-trial: This observation period will include information collected at or after date of randomisation 
and up to the last scheduled subject-site contact. For subjects who withdraw their informed consent, 
or is lost to follow-up, the end of the in-trial period is defined as the date of the last scheduled 
subject-investigator contact (site or phone visit). In case a subject dies during the trial, the date of 
death will be the end-date of the in-trial observation period regardless of the above defined end-
dates. This observation period will be used for estimating the effectiveness estimand.
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN5401-4266
Version:
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UTN: U1111-1175-7895
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On-treatment: This observation period is a subset of the in-trial observation period and 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
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Statistical Analysis Plan
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Date:
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Novo Nordisk
Trial ID: NN5401-4266
Version:
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2.4
Primary endpoint
Primary statistical analysis for primary estimand
The primary estimand will be estimated based on the FAS using all post baseline HbA1c
measurements obtained on planned visits up until week 26, including week 26 measurements from 
subjects withdrawing from randomised treatment (in-trial observation period), mimicking an ITT 
scenario. To estimate this estimand for evaluation of non-inferiority of HbA1c, multiple imputation 
of missing values with separate imputation from each treatment arm will be applied. The use of data 
from prematurely treatment discontinued subjects in analyses will equalise treatment effects and the 
inclusion of a penalty equal to the non-inferiority margin will remedy this. Imputation will be done 
as follows:
!
In the first step, intermittent missing values are imputed using a Markov Chain Monte Carlo 
(MCMC) method, in order to obtain a monotone missing data pattern. This imputation is 
done for each treatment arm separately and 1000 copies of the dataset will be generated.
!
In the second step, for each of the 1000 copies of the dataset, an analysis of covariance 
(ANCOVA) for each treatment arm with region, sex, previous insulin regimen and previous 
OAD treatment as categorical fixed effects and baseline HbA1c measurement and age as a 
covariate will be fitted to the change in HbA1c from baseline to week 8 (visit 10). The 
estimated parameters and their variance from this model are used to impute missing values 
at week 8 for subjects in the respective treatment arms based on region, sex, previous insulin 
regimen, previous OAD treatment, age and HbA1c at baseline.
!
In the third step, for each of the 1000 copies of the dataset, an analysis of covariance model 
with region, sex, previous insulin regimen and previous OAD treatment as categorical fixed 
effects, and age, baseline HbA1c and HbA1c at week 8 (Visit 10) as covariates is fitted to the 
change in HbA1c from baseline to week 12 (Visit 14) for each treatment arm. The estimated 
parameters and their variances from this model are used to impute missing values at week 
12 for subjects in the respective treatment arms, based on region, sex, previous insulin 
regimen, previous OAD treatment, age and HbA1c at baseline and week 8.
!
Step three is repeated over the available planned visits, adding one visit at a time until week 
26. In each step the model is expanded to include a covariate from the previous visit.
!
Finally, a penalty equal to the non-inferiority margin 0.4% is added to the week 26 (visit 28)
HbA1c value for any prematurely treatment discontinued subject in the IDegAsp OD arm,
irrespective if the value was retrieved (V28A) data or an imputed value from the sequential 
imputation, as well as for other subject in IDegAsp arm with missing HbA1c measurement 
after 26 weeks.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
14 of 32
For each of the 1000 (now complete) imputed data sets the change from baseline to week 26 will be 
analysed using an ANCOVA with treatment, region, sex, previous insulin treatment regimen and 
previous OAD treatment as categorical fixed effects and baseline HbA1c and age as covariate. The 
estimates and standard deviations for the 1000 data sets are pooled to one estimate and associated 
standard deviation using Rubin’s rule. From these pooled estimates the confidence interval for the 
treatment differences and the associated p-value are calculated.
Non-inferiority of IDegAsp OD vs. IGlar OD + IAsp OD will be considered confirmed if the 95% 
confidence interval for the mean treatment difference lies entirely below 0.40%. A conclusion on 
non-inferiority will be based on the FAS and the primary estimand. The addition of the 0.4% 
penalty in the last imputation step corresponds to the non-inferiority null method, as described by
Koch3.
Sensitivity analyses for the primary estimand
The following sensitivity analyses will be performed:
!
The primary analysis will be repeated based on the PP analysis set in line with the 
Committee for Proprietary Medicinal Products (CPMP) Points to Consider 
(CPMP/EWP/482/99).
!
The primary analysis will be repeated on the FAS but without adding the penalty for 
subjects in the IDegAsp OD arm. The result of this analysis is regarded to give the most fair 
and unbiased estimate of the difference between the two treatments, in contrast to the 
primary analysis that due to the penalty is biased in favour of the IGlar treatment.
!
A tipping point analysis based on the FAS and the primary analysis for the primary estimand 
will be performed. In this analysis subjects who withdraw from the IDegAsp OD arm or 
have missing values at visit 26 are assumed to have an effect that is inferior to the de facto 
effect of IDegAsp OD. The extent of the inferiority (also termed a ‘penalty’) will be 
gradually increased to evaluate at which value IDegAsp OD is no longer non-inferior to 
IGlar OD + IAsp OD. This penalty value, also known as the tipping point, corresponds to 
the hypothetical degree of efficacy deterioration in withdrawn subjects that would change 
the conclusion of non-inferiority.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
15 of 32
Primary analysis for the secondary estimand
The secondary estimand will be estimated based on the FAS using post-baseline measurements up 
to and including week 26 from the on-treatment observation period. To estimate this estimand, the 
change from baseline in HbA1c after 26 weeks of treatment will be analysed using the mixed model 
for Repeated Measurement (MMRM) method with a restricted maximum likelihood (REML). The 
model will include treatment, sex, previous insulin treatment regimen, previous OAD treatment and 
region as factors and baseline HbA1c and age as covariates, all nested within visit. An unstructured 
covariance matrix for HbA1c measurements within the same subject will be employed, assuming 
measurements from different subjects are independent.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is missing at random (MAR). Under 
this assumption the statistical behaviour of the missing data (given the observed responses and 
model fixed effects and covariates) is assumed to be the same as the observed data. 
In a non-inferiority trial the efficacy estimand may be more appropriate than the effectiveness 
estimand, since it is not confounded by the effects of changing treatment from the randomised 
treatment to other treatments. 
Sensitivity analyses for the secondary estimand
The following sensitivity analyses will be performed:
!
The above MMRM analysis will be repeated on the PP using the on-treatment period, as 
well on the subset of subjects who remains on treatment up until week 26 visit. These 
analyses will be done to align with the reporting of the phase 3a trials. 
!
Using the FAS, the change in HbA1c from baseline after 26 weeks of treatment will be 
analysed using an analysis of variance (ANOVA) method with treatment, sex, previous 
insulin treatment regimen, previous OAD treatment and region as fixed factors, and age and
baseline HbA1c as covariates, and where missing values will be imputed using the Last 
Observation Carried Forward (LOCF) method. This is done to align with the reporting of the 
phase 3a trials.
2.5
Supportive secondary endpoints
2.5.1
Efficacy endpoints
For the following continuous supportive efficacy endpoints, analyses similar to those for the 
primary estimand of the primary endpoint will be done, with the adjustment that the non-inferiority-
penalty (NI-penalty) in step five of multiple imputation is not applied (this is only considered 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
16 of 32
relevant for non-inferiority testing). Continuous safety endpoints that are analysed statistically will 
also follow this procedure. A further change to the above specified model is that the model will 
include the baseline measurement of the endpoint as a covariate instead of the baseline HbA1c
measurement.
The following supportive secondary endpoints will be analysed through the statistical analysis 
described above.
HbA1c
Change from baseline in HbA1c (%) after 38 weeks.
In addition to the analysis specified for the primary estimand, the analysis specified for the 
secondary estimand will also be performed for this endpoint to align with analysis of HbA1c          
after 26 weeks.
Fasting plasma glucose
!
Change from baseline in FPG after 26 weeks
!
Change from baseline in FPG after 38 weeks
Self-measured plasma glucose measurements (SMPG)
!
SMPG after 26 weeks
o
Change from baseline in mean pre-breakfast measurements after 26 weeks
o
Change from baseline in post-prandial increments after 26 weeks
!
SMPG after 38 weeks
o
Change from baseline in mean pre-breakfast measurements after 38 weeks
Change from baseline in post-prandial increments after 38 weeks
Furthermore, the mean PG before breakfast used for dose-titration and the 9-point profile            
will be calculated at each visit using the available data.
Responder for HbA1c
!
Responder (Yes/No) for HbA1c after 26 weeks:
o
HbA1c < 7%
o
HbA1c < 7% without severe or BG confirmed symptomatic hypoglycaemia
!
Responder (Yes/No) for HbA1c after 38 weeks:
o
HbA1c < 7%
o
HbA1c < 7% without severe or BG confirmed symptomatic hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
17 of 32
Subjects with less than 16 weeks of treatment will be set as non-responders. Hypoglycaemic 
episodes will be based on the available data.
Analysis of each of the responder endpoints will be based on a logistic regression model which will
include treatment, sex, previous insulin treatment regimen, previous OAD treatment and region as
fixed factors, and age and baseline HbA1c as covariates. The analysis for the responder endpoints 
will be derived using the HbA1c values from the 1000 datasets originating from multiple imputation 
analysis of HbA1c, without applying the NI-penalty.
Each of these datasets will be analysed using the above logistic regression model and the results 
will then be pooled using Rubin’s rule.
Explorative endpoints 
The following endpoint will be analysed through the same statistical analysis for continuous 
endpoint:
!
SMPG after 38 weeks
o
Change from baseline in post-prandial increments after 38 weeks
!
Change from baseline to week 26 for:
o
Health-related quality of life as evaluated by SF-36v2® Health Survey
o
Treatment related impact as evaluated by the Treatment Related Impact Measure-
Diabetes (TRIM-D)
!
Change from baseline to week 38 for:
o
Health-related quality of life as evaluated by the SF-36v2® Health Survey
o
Treatment related impact as evaluated by the TRIM-D
Assessments
The following efficacy assessments will be summarised descriptively but with no statistical 
analyses performed:
!
Responder (Yes/No) for HbA1c after 26 weeks:
o
HbA1c < 7% without nocturnal (00:01-05:59) severe or BG confirmed symptomatic 
hypoglycaemia
!
Responder (Yes/No) for HbA1c after 38 weeks:
o
HbA1c < 7% without nocturnal (00:01-05:59) severe or BG confirmed symptomatic 
hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
18 of 32
2.5.2
Safety endpoints
Adverse events
The following endpoint on adverse events will be reported:
!
Incidence of treatment-emergent adverse events (TEAEs) from baseline to week 26
!
Incidence of treatment-emergent adverse events (TEAEs) during 38 weeks
!
Incidence of treatment-emergent adverse events (TEAEs) during intensification period 
(week 26-38)
The AEs will be coded using the most recent version of the Medical Dictionary for Regulatory
Activities coding.
A treatment-emergent adverse event (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 seven days after the last day of
randomised treatment. If the event has onset date before the first day of exposure on randomised
treatment and increases in severity during the treatment period and until seven days after the last
drug date, then this event should also be considered as a TEAE.
TEAEs are summarised descriptively, whereas non-treatment-emergent AE’s 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 serious TEAEs will be presented as an overview including all AEs,
serious AEs, number of deaths, AEs by severity, AEs by relation to treatment as assessed by the
investigator and AEs of special interest including AEs leading to withdrawal and AEs leading to
drug withdrawn. .
Furthermore summary tables based on system organ class and preferred terms are made for:
!
All TEAEs
!
Serious TEAEs
!
Possibly and probably related TEAEs
!
Severe, moderate and mild TEAEs
!
TEAEs reported by safety area of interest
!
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
!
TEAEs leading to withdrawal of subject or drug withdrawn
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
19 of 32
A listing of non-treatment-emergent events with onset date before the first day of exposure to
randomised treatment will be presented. A listing will also be presented for non-treatment-emergent
adverse events collected after the treatment-emergent period according to the definition of the
TEAE.
Hypoglycaemic episodes
The definition and classification of hypoglycaemic episodes is given after the description of the
statistical analysis.
Below assessments will be summarized descriptively.
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 26 weeks
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 26 
weeks
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during maintenance (week 16-26)
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 
maintenance (week 16-26)
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 38 weeks
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 38 
weeks
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 (R). Separate summaries are made by severity 
considering all confirmed hypoglycaemic episodes, nocturnal confirmed hypoglycaemic episodes 
and the ADA classification of hypoglycaemia.
In addition, to the extent where data allows, the following endpoints are analysed statistically.
During 26 weeks:
!
Number of nocturnal, treatment-emergent severe or blood glucose (BG) confirmed 
symptomatic hypoglycaemic episodes during 26 weeks
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 26 weeks
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during maintenance (week 16-26)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
20 of 32
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic
episodes during maintenance (week 16-26)
During 38 weeks:
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 38 weeks
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during 38 weeks
For endpoints addressing the hypoglycaemic rate in the 26 weeks or the 38 weeks period, a negative 
binomial model will be used, including treatment, previous insulin treatment regimen, previous 
OAD treatment, sex, and region as factors and age as covariate. The model will use a log-link 
function and the logarithm of the time period in which a hypoglycaemic episode was considered 
treatment emergent as offset. The treatment rate ratios will be estimated and 95% confidence 
intervals will be calculated.
The rationale for investigating the hypoglycaemic rate during the maintenance is to reflect long 
term use, as prior to this period (the titration period) the glycaemic control might be unstable. For 
endpoints addressing hypoglycaemic rate in the maintenance period, subjects that discontinue 
randomised treatment during the maintenance period will contribute with the available 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 maintenance period for subjects that discontinued randomised treatment during the maintenance 
period. For these subjects, the number of events will be imputed corresponding to a 10 weeks 
maintenance period as follows: 
!
In the first step, 1000 samples from the posterior distribution of model parameters are 
extracted. The model is fitted to the on-treatment maintenance data for subjects that 
discontinued randomised treatment during the maintenance period for each treatment arm 
separately. This is done using a Bayes negative binomial log-link model with the same 
factors, covariates and offset as in the analyses of hypoglycaemic episodes described above. 
The 1000 samples are used as sampled parameter estimates in the next step. 
!
For each sample of model parameters, the total number of hypoglycaemic events in the 
maintenance period for subjects that discontinued randomised treatment in the titration 
period is imputed as a random number of events from a negative binomial distribution using 
the sampled parameters. 
!
For each of the 1000 imputed data sets, that now have maintenance period data for all 
randomised subjects, the mean treatment ratio is estimated using the same negative binomial 
model as in the analyses of hypoglycaemic episodes described above. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
21 of 32
!
The estimates and standard deviations for the 1000 imputed data sets are pooled to one 
estimate and associated standard deviation using Rubin’s formula. From these the 95% 
confidence interval for the treatment ratio and the associated p-value are calculated.
If the above model cannot fit due to sparse data, the model in step 1 is fitted to the on-treatment data 
for subjects that discontinued randomised treatment during either titration or maintenance, i.e. do 
not complete the scheduled 26 weeks of treatment. 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 before 
week 26 in the following order, until a model fits:
!
sex
!
age
!
region
!
previous insulin treatment regimen
!
previous OAD treatment
The analyses and data presentations of hypoglycaemic events will be based on the hypoglycaemic 
episode form.
Classification of Hypoglycaemia:
Hypoglycaemic episodes are recorded by the subjects in their trial diaries throughout the trial. The 
information collected includes PG before treating the episode and whether the subject was able treat 
him/herself. This information is used by Novo Nordisk to classify episodes according to the 
confirmed hypoglycaemia definition and the ADA definition (severe, documented symptomatic, 
asymptomatic, probably symptomatic and pseudo).
!
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset 
of the episode occurs on or after the first day of trial product administration, and no later than 7 
calendar days after the last day on trial product 
!
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 2–1) and the ADA classification of hypoglycaemia (see Figure 2–2).
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
22 of 32
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)4. Therefore, Novo Nordisk has included hypoglycaemia with plasma 
glucose levels below this cut-off point in the definition of BG confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 2–1) in addition to the ADA 
classification: 
!
Severe hypoglycaemia according to the ADA classification5
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification5 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value <3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification5 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with or 
without symptoms consistent with hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
23 of 32
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–1
Novo Nordisk classification of hypoglycaemia
ADA classification5 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.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
24 of 32
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 2–2  ADA classification of hypoglycaemia
Insulin dose
!
Total insulin dose at week 26
!
Total insulin dose at week 38
Observed values of total insulin dose at week 26 and week 38 will be summarised by the arithmetic
mean, SD, median, and minimum and maximum value. Separate summaries will also be made for 
the basal insulin dose and the bolus insulin dose.
Weight
!
Change in weight from baseline to week 26
!
Change in weight from baseline to week 38
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
25 of 32
are summarised descriptively and analysed statistically using the primary statistical analysis for the 
primary estimand.
The following safety assessments will be reported:
Clinical evaluations at week 26 and week 38
!
Physical examination
!
Vital signs (blood pressure and pulse)
!
Dilated fundoscopy or fundus photography
!
12-lead electrocardiogram
will be summarised descriptively including:
!
Change from baseline to week 26
!
Change from baseline to week 38
Any findings in the physical examination evaluation at screening will be presented as listings. Any
clinically significant deterioration of a pre-existing condition after the screening visit, as well as any
new clinically findings will be recorded as adverse events.
Laboratory assessments
!
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, leucocytes)
!
Biochemistry (creatinine, ALT, AST, AP, sodium, potassium, albumin, total bilirubin)
!
Insulin antibodies
All laboratory parameters will be summarised descriptively.
The following tables will be presented based on observed data:
!
Shift tables from baseline to week 26
!
Shift tables from baseline to week 38
!
Change from baseline to week 26
!
Change from baseline to week 38
!
Proportion of subjects with measurements outside reference range by treatment and week.
For each laboratory parameter, individual values outside the reference range (abnormal values) will
be listed.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
26 of 32
2.6
Health economics and/or patient reported outcomes
The following patient reported outcome exploratory endpoints are included in the trial:
Change from baseline to week 26 for:
!
Health-related quality of life as evaluated by SF-36v2® Health Survey
!
Treatment related impact as evaluated by the Treatment Related Impact Measure-Diabetes 
(TRIM-D)
Change from baseline to week 38 for:
!
Health-related quality of life as evaluated by the SF-36v2® Health Survey
!
Treatment related impact as evaluated by the TRIM-D
The domain and overall scores for both SF-36 and TRIM-D will be summarised descriptively based
on observed data and explorative statistical analysis may be performed.
The data collected in the BHQ will not be included in the clinical trial report, nor will the data
collected in the hypoglycaemic resource use interview questionnaire. Data from the latter will be
used to assess costs associated with hypoglycaemia and provide information to be used in health
economic analyses.
3
Changes to the statistical analyses planned in the protocol
3.1
Clarification of primary statistical analysis, primary estimand:
In the protocol version 4.0 the penalisation of data from subjects on treatment but with missing data 
at week 26 is only described in the sample size section, not in section 17.4 when describing the 
analysis in details. This is updated to clarify that also imputed values for subjects in IDegAsp arm 
on treatment for 26 weeks but with missing HbA1c assessment at week 26 will be penalised.
Rationale:
Alignment of protocol sections. 
3.2
Clarification of sensitivity analyses to secondary estimand for primary analysis,
The sensitivity analysis for the secondary estimand specified in the protocol version 4.0 includes
subjects that complete the first 26 weeks of the trial on treatment and have on-treatment HbA1c
assessment at V28.
Rationale:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
27 of 32
This is in alignment with the declared aim for the sensitivity analysis, namely to align with the 
phase 3a program. 
3.3
Changes to supportive secondary endpoints and explorative endpoints
The following endpoints are considered secondary supportive and explorative endpoints, 
respectively:
Supportive secondary endpoints
Efficacy endpoints:
!
Change from baseline in HbA1c(%) after 38 weeks (defined as key supportive secondary 
efficacy endpoint in protocol)
!
Change from baseline in fasting plasma glucose (FPG) after 26 weeks
!
Change from baseline in fasting plasma glucose (FPG) after 38 weeks
!
Responder (Yes/No) for HbA1c after 26 weeks: HbA1c < 7% (defined as key supportive 
secondary efficacy endpoint in protocol)
!
Responder (Yes/No) for HbA1c after 38 weeks: HbA1c < 7% (defined as key supportive 
secondary efficacy endpoint in protocol)
!
Responder (Yes/No) for HbA1c after 26 weeks: HbA1c < 7% without severe or BG 
confirmed symptomatic hypoglycaemia
!
Responder (Yes/No) for HbA1c after 38 weeks: HbA1c < 7% without severe or BG 
confirmed symptomatic hypoglycaemia
!
Self-measured plasma glucose measurements (SMPG) after 26 weeks: Mean pre-breakfast 
measurements used for titration
!
Self-measured plasma glucose measurements (SMPG) after 38 weeks: Mean pre-breakfast 
measurements used for titration
!
Self-measured plasma glucose measurements (SMPG) after 26 weeks: 9-point profile - Post-
prandial increments
!
Self-measured plasma glucose measurements (SMPG) after 38 weeks: 9-point profile - Post-
prandial increments
Safety endpoints:
!
Incidence of treatment-emergent adverse events (TEAEs) from baseline to week 26
!
Incidence of treatment-emergent adverse events (TEAEs) during 38 weeks (defined as key 
supportive secondary safety endpoint in protocol)
!
Incidence of treatment-emergent adverse events (TEAEs) during intensification period 
(week 26-38)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
28 of 32
!
Number of nocturnal, treatment-emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 26 weeks
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during 38 weeks
!
Number of nocturnal, treatment emergent severe or BG confirmed symptomatic 
hypoglycaemic episodes during maintenance (week 16-26)
!
Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during 26 weeks (defined as key supportive secondary safety 
endpoint in protocol)
!
Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during 38 weeks (defined as key supportive secondary safety 
endpoint in protocol)
!
Number of treatment emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during maintenance (week 16-26)
!
Total insulin dose at week 26
!
Total insulin dose at week 38
!
Change in weight from baseline to week 26
!
Change in weight from baseline to week 38
Explorative endpoints
!
!
Change from baseline to week 26 for:
o
Health-related quality of life as evaluated by SF-36v2® Health Survey
o
Treatment related impact as evaluated by the Treatment Related Impact Measure-
Diabetes (TRIM-D)
!
Change from baseline to week 38 for:
o
Health-related quality of life as evaluated by the SF-36v2® Health Survey
o
Treatment related impact as evaluated by the TRIM-D
Remaining endpoints in protocol version 4.0 are considered assessments.
Rationale:
Clarification on distinction between supportive secondary and exploratory endpoints.
3.4
Statistical analyses of the following assessments will not be performed
Efficacy assessments:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
29 of 32
!
HbA1c < 7% without nocturnal (00:01-05:59) severe or BG confirmed symptomatic 
hypoglycaemia after 26 weeks
!
HbA1c < 7% without nocturnal (00:01-05:59) severe or BG confirmed symptomatic 
hypoglycaemia after 38 weeks
Safety assessments:
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 26 weeks
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 26 
weeks
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during maintenance (week 16-26)
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 
maintenance (week 16-26)
!
Number of nocturnal, treatment-emergent severe or BG confirmed hypoglycaemic episodes 
during 38 weeks
!
Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes during 38 
weeks
All above assessments will be summarized descriptively.
Rationale:
These assessments are supportive and no statistical analyses are needed.
3.5
Statistical analyses based on the secondary estimand will not be performed for the 
following endpoints
Efficacy endpoints:
!
Change from baseline in FPG after 26 weeks
!
Change from baseline in FPG after 38 weeks
!
Change from baseline in mean pre-breakfast measurements after 26 weeks
!
Change from baseline in post-prandial increments after 26 weeks
!
Change from baseline in mean pre-breakfast measurements after 38 weeks
!
Change from baseline in post-prandial increments after 38 weeks
!
Responder (Yes/No) for HbA1c< 7% after 26 weeks
!
Responder (Yes/No) for HbA1c < 7% without severe or BG confirmed symptomatic 
hypoglycaemia
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
30 of 32
!
Responder (Yes/No) for HbA1c< 7% after 38 weeks
!
Responder (Yes/No) for HbA1c < 7% without severe or BG confirmed symptomatic 
hypoglycaemia after 38 weeks
Safety endpoints:
!
Change in weight from baseline to week 26
!
Change in weight from baseline to week 38
Rationale:
For the above endpoints only the primary estimand are relevant.
3.6
Changes to reporting of safety end points related to adverse events
Below mentioned end point is added:
!
Incidence of treatment-emergent adverse events (TEAEs) during intensification period 
(week 26-38)
Rationale:
Safety when intensifying from OD to BID/TID is of interest for the trial.
The following sentence of protocol 4.0 will be deleted: “The EAC confirmed adverse events will be 
listed and summarised descriptively.”
Rationale:
Included in protocol by mistake, as no adjudication is done.
3.7
Changes to reporting of insulin dose
The following sentence of protocol 4.0 will be deleted: “and supplemented with the geometric mean 
and coefficient of variation”
Rationale:
Geometric mean and coefficient of variation for doses is not project standard anymore. 
3.8
Change to reporting of laboratory assessments
The following sentence of protocol 4.0 will be deleted: “Laboratory values will be presented 
graphically as box plots by treatment and week.”
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
31 of 32
Rationale:
Empirical distribution plots are evaluated as a better graphical presentation of laboratory data.
3.9
In-trial period and on-treatment period
The definition of in-trial period will be replaced by:”This observation period will include 
information collected at or after date of randomisation and up to the last scheduled subject-site 
contact. For subjects who withdraw their informed consent, or is lost to follow-up, the end of the in-
trial period is defined as the date of the last scheduled subject-investigator contact (site or phone 
visit). In case a subject dies during the trial, the date of death will be the end-date of the in-trial 
observation period regardless of the above defined end-dates. This observation period will be used 
for estimating the effectiveness estimand.”
The definition of On-treatment period will be replaced by: “This observation period is a subset of 
the in-trial observation period and 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.”
Rationale:
Alignment to current project standards.
3.10
Update of completer analyses set
The definition of completer analyses set (CAS) will be replaced by:
!
“Trial completer analysis set: Includes all randomised subjects who has attended either V40 
on treatment, or V40A, 38 weeks after randomisation according to protocol .”
!
Treatment completer analysis set: Includes all randomised subjects who have completed the 
trial without discontinuation from randomised treatment. “
Rationale:
The protocol does not give a clear definition for trial completers.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
23 January 2018
Novo Nordisk
Trial ID: NN5401-4266
Version:
1.0
UTN: U1111-1175-7895
Status:
Final
EudraCT No.: 2015-004768-12
Page:
32 of 32
4
References
1.
Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin 
glargine and placebo in combination with metformin and sulfonylurea therapy in
type 2 
diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial.
Diabetologia.
2009;52(10):2046-55.
2.
International Conference of Harmonisation. ICH Harmonised Tripartite Guideline E9.
Statistical Principles for Clinical Trials, Step 4 Version. 5 Feb 1998.
3.
Koch GG. Comments on 'Current issues in non -inferiority trials' by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med. 2008;27(3):333-42.
4.
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.
5.
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