Conditions: Diabetes Diabetes Mellitus, Type 1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 472
Healthy volunteers: no

Brief summary:
This trial is conducted in Europe and the United States of America (USA). The aim of this trial is to investigate efficacy and safety of Continuous Subcutaneous Insulin Infusion of Faster-acting Insulin Aspart compared to NovoRapid® in Adults with Type 1 Diabetes.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Faster-acting insulin aspart intervention 2: insulin aspart
Intervention descriptions: intervention 1: Injected s.c. /subcutaneously (under the skin) intervention 2: Injected s.c. /subcutaneously (under the skin)

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02825251 
Sponsor trial ID: 
NN1218-3854 
Official title of study: 
Efficacy and Safety of Continuous Subcutaneous Insulin 
Infusion of Faster-acting Insulin Aspart compared to 
NovoRapid® in Adults with Type 1 Diabetes 
Document date: 
08-Feb-2018 
 


Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol amendment 1 - RU ..............................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Fast-acting insulin aspart
Trial ID: NN1218-3854
Clinical Trial Report
Appendix 16.1.1
08 February 2018
1.0
Final
16.1.1 Protocol and protocol amendments
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CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
1 of 149
Protocol
Trial ID: NN1218-3854
Efficacy and Safety of Continuous Subcutaneous Insulin Infusion of 
Faster-acting Insulin Aspart compared to NovoRapid® in Adults with 
Type 1 Diabetes
onset® 5
Trial phase: 3b
Protocol originator
ClinOps, Insulin, GH & 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 No unpublished information contained herein may be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
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
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 No unpublished information contained herein may be 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 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
2 of 149
Table of Contents  
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................7
Table of Tables..................................................................................................................................................8
List of abbreviations.........................................................................................................................................9
1
Summary..................................................................................................................................................12
2
Flow chart ................................................................................................................................................16
3
Background information and rationale for the trial............................................................................20
3.1
Background information..............................................................................................................20
3.1.1
Therapeutic area.........................................................................................................20
3.1.2
Faster-acting insulin aspart ........................................................................................21
3.1.3
NovoRapid® (insulin aspart)......................................................................................22
3.2
Rationale for the trial...................................................................................................................22
4
Objectives and endpoints........................................................................................................................24
4.1
Objectives ....................................................................................................................................24
4.1.1
Primary objective.......................................................................................................24
4.1.2
Secondary objectives .................................................................................................24
4.2
Endpoints .....................................................................................................................................24
4.2.1
Primary endpoint........................................................................................................24
4.2.2
Confirmatory secondary endpoints............................................................................24
4.2.3
Supportive secondary endpoints ................................................................................24
4.2.3.1
Supportive secondary efficacy endpoints............................................25
4.2.3.2
Supportive secondary CGM and meal characteristics related 
endpoints excluding meal test .............................................................25
4.2.3.3
Supportive secondary endpoints CGM related endpoints 
excluding meal test..............................................................................26
4.2.3.4
Supportive secondary endpoints related to CGM and meal test..........26
4.2.3.5
Supportive secondary safety endpoints...............................................27
5
Trial design ..............................................................................................................................................27
5.1
Type of trial .................................................................................................................................27
5.2
Rationale for trial design..............................................................................................................29
5.2.1
Rational for choice of non-inferiority margin............................................................29
5.3
Treatment of Subjects..................................................................................................................30
5.3.1
Basal rate insulin adjustment .....................................................................................30
5.3.2
Bolus insulin titration.................................................................................................31
5.4
Titration review procedure...........................................................................................................31
5.5
Treatment after end of trial product.............................................................................................31
5.6
Rationale for treatment ................................................................................................................31
6
Trial population.......................................................................................................................................33
6.1
Number of Subjects .....................................................................................................................33
6.2
Inclusion criteria ..........................................................................................................................33
6.3
Exclusion criteria.........................................................................................................................34
CONFIDENTIAL


Protocol
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Date:
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Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
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6.4
Run-in failure criteria...................................................................................................................36
6.5
Randomisation criterion...............................................................................................................36
6.6
Criteria for premature discontinuation of trial product or withdrawal from trial ........................36
6.6.1
Premature discontinuation of trial product ................................................................36
6.6.2
Withdrawal from trial ................................................................................................37
6.7
Subject replacement.....................................................................................................................37
6.8
Rationale for trial population.......................................................................................................37
7
Milestones.................................................................................................................................................39
8
Methods and assessments .......................................................................................................................40
8.1
Visit procedures...........................................................................................................................40
8.1.1
Informed Consent ......................................................................................................40
8.1.2
Screening visit............................................................................................................40
8.1.2.1
Screening failures................................................................................41
8.1.2.2
Re-screening........................................................................................41
8.1.3
Run-in ........................................................................................................................41
8.1.3.1
Run-in failures.....................................................................................42
8.1.4
Randomisation ...........................................................................................................42
8.1.5
Site visits....................................................................................................................42
8.1.6
Phone contacts ...........................................................................................................43
8.1.7
Fasting visits ..............................................................................................................43
8.1.8
Withdrawal procedures..............................................................................................43
8.1.8.1
Premature discontinuation of trial product..........................................43
8.1.8.2
Withdrawal from trial..........................................................................46
8.1.9
End of treatment.........................................................................................................47
8.1.10
Follow-up...................................................................................................................47
8.1.10.1
Follow-up 1 (FU1, Visit 23)................................................................47
8.1.10.2
Follow-up 2 (FU2, Visit 24)................................................................47
8.2
Subject related information..........................................................................................................48
8.2.1
Demography and smoking status...............................................................................48
8.2.2
Diagnosis of Type 1 Diabetes Mellitus and diabetes complications..........................48
8.2.3
Concomitant illness and medical history...................................................................48
8.2.4
Childbearing potential................................................................................................49
8.2.5
Diabetes treatment history .........................................................................................49
8.3
Clinical assessments ....................................................................................................................49
8.3.1
Concomitant medication............................................................................................49
8.3.2
Use of Pumps and BG meters....................................................................................50
8.3.2.1
Insulin dose .........................................................................................50
8.3.2.2
Self-measured plasma glucose ............................................................52
8.3.2.3
Change of infusion set and reservoir...................................................54
8.3.2.4
Training in pump use...........................................................................57
8.3.2.5
Training in diabetes and carbohydrate counting .................................57
8.3.2.6
Back-up kit..........................................................................................58
8.3.3
Adverse events requiring special forms in the electronic case report form...............58
8.3.3.1
Hypoglycaemic episodes.....................................................................58
8.3.3.2
Unexplained hyperglycaemic episodes ...............................................62
8.3.3.3
Infusion site reactions..........................................................................63
8.3.4
Body measurements...................................................................................................64
8.3.5
12 lead-Electrocardiogram.........................................................................................65
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
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Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
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8.3.6
Eye examination ........................................................................................................65
8.3.7
Meal test.....................................................................................................................66
8.3.8
Physical examination.................................................................................................69
8.3.9
Vital signs ..................................................................................................................69
8.4
Laboratory assessments ...............................................................................................................70
8.4.1
1,5-anhydroglucitol....................................................................................................71
8.4.2
Biochemistry..............................................................................................................72
8.4.3
Fasting plasma glucose..............................................................................................72
8.4.4
Haematology..............................................................................................................72
8.4.5
HbA1c .........................................................................................................................72
8.4.6
Lipids .........................................................................................................................72
8.4.7
Pregnancy testing.......................................................................................................73
8.4.8
Urine samples ............................................................................................................73
8.5
Other assessments and procedures...............................................................................................73
8.5.1
Continuous glucose monitoring.................................................................................73
8.5.1.1
CGM Receiver setting and test upload................................................73
8.5.1.2
Eligibility for baseline continuous glucose monitoring.......................74
8.5.1.3
Fitting and removal of the continuous glucose monitoring device .....74
8.5.1.4
Wearing and calibration of the continuous glucose monitoring 
device ..................................................................................................76
8.5.1.5
Uploading of continuous glucose monitoring data..............................77
8.5.1.6
CGM Reports ......................................................................................78
8.5.1.7
The continuous glucose monitoring data.............................................78
8.5.1.8
Pump Data collected during CGM ......................................................79
8.5.2
Diary ..........................................................................................................................79
8.5.3
Patient reported outcomes (PRO) questionnaire........................................................80
8.6
Subject compliance......................................................................................................................80
9
Trial supplies ...........................................................................................................................................81
9.1
Trial products...............................................................................................................................81
9.2
Labelling......................................................................................................................................81
9.3
Storage .........................................................................................................................................82
9.4
Drug accountability and destruction............................................................................................82
9.5
Auxiliary supplies........................................................................................................................83
9.5.1
Auxiliaries supplied by Novo Nordisk ......................................................................83
9.5.2
Auxiliaries supplied by site........................................................................................83
9.5.3
Continuous glucose monitoring equipment supplies .................................................83
10 Interactive voice/web response system ..................................................................................................85
11 Randomisation procedure and breaking of blinded codes..................................................................86
11.1
Breaking of blinded codes ...........................................................................................................86
12 Adverse events, technical complaints and pregnancies .......................................................................87
12.1
Definitions ...................................................................................................................................87
12.1.1
Adverse events...........................................................................................................87
12.1.2
Serious adverse events...............................................................................................88
12.1.3
Non-serious adverse events........................................................................................89
12.1.4
Medical events of special interest..............................................................................89
12.1.5
Technical complaint...................................................................................................90
12.2
Reporting of adverse events.........................................................................................................90
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
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12.2.1
Timelines for initial reporting of adverse events .......................................................91
12.2.2
Reporting of trial product-related SUSARs by Novo Nordisk ..................................92
12.2.3
Novo Nordisk products used as concomitant medication..........................................92
12.3
Follow-up of adverse events........................................................................................................92
12.4
Technical complaints, and technical complaint samples .............................................................93
12.4.1
Reporting of technical complaints .............................................................................93
12.4.2
Collection, storage and shipment of technical complaint samples ............................94
12.5
Pregnancies..................................................................................................................................94
12.5.1
Pregnancies in female Subjects..................................................................................94
12.6
Precautions and/or overdose ........................................................................................................95
12.7
Committees related to safety........................................................................................................96
12.7.1
Novo Nordisk safety committee ................................................................................96
12.7.2
Data monitoring committee .......................................................................................96
13 Case report forms....................................................................................................................................97
13.1
Corrections to case report forms..................................................................................................97
13.1.1
Electronic case report form........................................................................................97
13.1.2
Paper case report form...............................................................................................98
13.2
Case report form flow..................................................................................................................98
14 Monitoring procedures ...........................................................................................................................99
14.1
Source data verification ...............................................................................................................99
14.1.1
CGM source data verification..................................................................................100
14.2
Continuous glucose monitoring procedures...............................................................................101
15 Data management..................................................................................................................................102
16 Computerised systems...........................................................................................................................104
17 Statistical considerations ......................................................................................................................105
17.1
Sample size calculation..............................................................................................................107
17.2
Definition of analysis sets..........................................................................................................109
17.3
Primary endpoint........................................................................................................................110
17.4
Secondary endpoints..................................................................................................................114
17.4.1
Confirmatory secondary endpoints..........................................................................114
17.4.2
Supportive secondary endpoints ..............................................................................116
17.4.2.1
Efficacy endpoints.............................................................................116
17.4.2.2
Safety endpoints................................................................................123
18 Ethics......................................................................................................................................................129
18.1
Summary of clinical pharmacology...........................................................................................129
18.2
Clinical benefits and risk considerations ...................................................................................129
18.2.1
Conclusion on clinical benefits and risk considerations..........................................131
18.3
Informed Consent ......................................................................................................................131
18.4
Data handling.............................................................................................................................132
18.5
Information to Subject during trial ............................................................................................132
18.6
Premature termination of the trial and/or trial site.....................................................................132
19 Protocol compliance..............................................................................................................................134
19.1
Protocol deviation......................................................................................................................134
19.2
Prevention of Missing Data .......................................................................................................134
20 Audits and inspections ..........................................................................................................................136
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
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21 Critical documents ................................................................................................................................137
22 Responsibilities......................................................................................................................................139
22.1
Investigator responsibilities .......................................................................................................139
22.2
Novo Nordisk responsibilities....................................................................................................140
23 Reports and publications......................................................................................................................141
23.1
Communication of results..........................................................................................................141
23.1.1
Authorship ...............................................................................................................142
23.1.2
Site-specific publication(s) by Investigator(s).........................................................142
23.2
Investigator access to data and review of results.......................................................................142
24 Retention of clinical trial documentation............................................................................................143
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............144
26 Indemnity statement .............................................................................................................................145
27 References..............................................................................................................................................146
Attachment I – Global list of key staff and relevant departments and vendors
Attachment II – Country list of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
7 of 149
Table of Figures   
Page
Figure 1–1
Trial design.............................................................................................................................13
Figure 5–1
Trial design.............................................................................................................................28
Figure 12–1
Initial reporting of AEs...........................................................................................................91
Figure 17–1
Novo Nordisk classification of hypoglycaemia....................................................................125
Figure 17–2
ADA classification of hypoglycaemia..................................................................................126
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
8 of 149
Table of Tables   
Page
Table 8–1
7-point profiles with the additional 9-point profile ................................................................54
Table 8–2
Meal test for Visit 6 and Visit 22............................................................................................68
Table 8–3
Overview of scheduled CGM sensor fitting and removal days relative to meal test based 
on two sensor periods .............................................................................................................75
Table 9–1
The following will be provided by Novo Nordisk A/S, Denmark..........................................81
Table 9–2
Storage of trial products..........................................................................................................82
Table 17–1
Specifications assumed for sample size calculation .............................................................108
Table 17–2
Sensitivity of sample size to power in step 1 and step 2.......................................................109
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
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List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
ANOVA
Analysis of variance
AP
alkaline phosphatase
AST
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
BMI
body mass index
CCDS
Company Core Data Sheet
CE
European Union European Conformity
CGM
Continuous Glucose Monitoring
CI
Confidence Interval 
CLAE
clinical laboratory adverse event
CRF
case report form
CRO
contract research organisation
CV
Coefficient of Variation
CSII
continuous subcutaneous insulin infusion
CT
computerised tomography
CTR
clinical trial report
DCCT
Diabetes Control and Complication Trial 
DCF
Data Clarification Form
DMC
Data monitoring committee
DUN
dispensing unit number
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
Estimated glomerular filtration rate
EDC
electronic data capture
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Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
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EMA
European Medicines Agency
EoT
End of trial
FAS
full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendment Act
FSFV
first Subject first visit
FPG
fasting plasma glucose
GCP
Good Clinical Practice
HbA1c
glycosylated haemoglobin
hCG
human chorion gonadotropin
HDL
high density lipoprotein
IB
Investigator’s Brochure
ICH
international conference on harmonisation
ICMJE
international committee of medical journal editors
ID
identification
IEC
independent ethics committee
IND
investigational new drug
IG
interstitial glucose 
IMP
investigational medicinal product
IRB
institutional review board
IV/WRS
interactive voice/web response system
LDL
low density lipoprotein
LSFV
last Subject first visit
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MedDRA
medical dictionary for regulatory activities
MIDF
monitor-Initiated Discrepancy Form
MRI
magnetic resonance imaging
NA
not applicable
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Trial ID: NN1218-3854
Version:
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Status:
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ND
not done
NYHA
New York heart association
PG
plasma glucose
PP
per protocol
PPG
postprandial (plasma) glucose
PRO
patient reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
s.c.
subcutaneous
SD
standard deviation
SDV
source data verification
SIF
Safety Information Form
SI/IC
Subject Information / Informed Consent Form
SmPC
Summary of Product Characteristics
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse reaction
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TEAE
Treatment Emergent Adverse Event
TMM
Trial Materials Manual
UKPDS
UK Prospective Diabetes Study 
UTN
Universal Trial Number
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Protocol
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Date:
04 February 2016
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
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1
Summary
Primary objective
To confirm the effect of continuous subcutaneous insulin infusion (CSII) treatment with faster-
acting insulin aspart in terms of glycaemic control by comparing it to CSII treatment with 
NovoRapid®, in adults with Type 1 Diabetes Mellitus (T1DM), using a non-inferiority approach.
Secondary objectives
To confirm superiority of CSII treatment with faster-acting insulin aspart compared to CSII 
treatment with NovoRapid® in adults with T1DM, in terms of:

Postprandial glucose (PPG) regulation (meal test)

Overall glycaemic control (HbA1c)

Postprandial glucose excursions (1,5-anhydroglucitol)

Time spent in low interstitial glucose (IG) (Continuous Glucose Monitoring (CGM))
To compare the effect and safety of CSII treatment with faster-acting insulin aspart vs CSII 
treatment with NovoRapid® in adults with T1DM.
Primary endpoint
Change from baseline in glycosylated haemoglobin (HbA1c) 16 weeks after randomisation.
Confirmatory secondary endpoints

Change from baseline in 1-hour PPG increment 16 weeks after randomisation (meal test).

Change from baseline in 1,5-anhydroglucitol 16 weeks after randomisation 

Change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) during CGM 16 
weeks after randomisation 
Trial design
This is a double-blind, randomised, multicentre, multinational, active controlled, treat-to-target, 
parallel group trial with a 4-week run-in and a 16-week treatment period comparing the effect and 
safety of CSII of faster-acting insulin aspart vs. NovoRapid® in adult Subjects with T1DM . 
Subjects entering the trial will stay on their own insulin pump, see Figure 17–1. 
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Trial ID: NN1218-3854
Version:
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Status:
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EudraCT no.: 2010-024054-11
Page:
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Figure 1–1
Trial design
The trial includes a screening visit to assess Subjects’ eligibility and additional weekly visits/phone 
contacts during the trial. All Subjects eligible for the trial will enter the 4-week run-in period; they 
will continue on their current insulin treatment and adhere to the protocol requirements as instructed 
by the Investigator. After the 4-week run-in period Subjects who, based on the Investigator’s 
discretion, have shown ability and willingness to adhere to the protocol and satisfactory handling of 
the pump will be randomised (1:1) to blinded NovoRapid® or faster-acting insulin aspart. After the 
16-week treatment period, the Subject will have a 7-day follow up (FU1) and 30-day (FU2) safety 
follow-up.
Up to 50% of the enrolled Subjects will be allowed to wear their own real-time CGM device during 
the entire course of the trial. The remaining enrolled Subjects will not be allowed to wear a CGM 
device except for three pre-specified periods. On specific days (11 to 13 days) a blinded CGM 
device will be handed out to all Subjects by the Investigator (provided by Novo Nordisk), including 
Subjects wearing their own real-time CGM. Randomisation will be stratified for the use of own 
real-time CGM.
Trial population
A total of approximately 666 Subjects with T1DM are planned to be screened, approximately 506 
Subjects to enter the run-in period, of which 450 are expected to enter randomised treatment.
Screening
Randomisation
Faster-acting insulin aspart CSII 
(225 Subjects)
NovoRapid® CSII             
(225 Subjects)
Weeks  -6       -4
                              0                                                                                                         16  +7d      +30d
Note: Prior to randomisation and after end of treatment Subjects are on marketed product. 
Baseline is defined as randomisation. 
FU2
CSII Continue
current Insulin 
treatment
16-week treatment period
FU1
CGM
CGM
CGM
4-week run-in 
period
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Protocol
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Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
Page:
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Key inclusion criteria

Male or female, age ≥18 years at the time of signing the informed consent 

Diagnosed with T1DM ≥1 year prior to the day of screening

Using the same Medtronic pump (Minimed 530G (551/751), Paradigm Veo (554/754), 
Paradigm Revel (523/723), Paradigm (522/722)) for CSII in a basal-bolus regimen with a 
rapid acting insulin analogue for at least six months prior to screening and willing to stay on 
the same pump model throughout the trial (if the model is changed the change should not 
exceed 7 consecutive days.) 

HbA1c 7.0-9.0% (53-75 mmol/mol) as assessed by central laboratory at screening

Body mass index (BMI) ≤35.0 kg/m2 at screening

Ability and willingness to take at least 3 daily meal-time insulin bolus infusions every day
throughout the trial
Key exclusion criteria

Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening 

Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening

History of hospitalization for ketoacidosis ≤180 days prior to 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 screening

Any condition which, in the opinion of the Investigator, might jeopardise a Subject’s safety 
or compliance with the protocol
Key efficacy assessments

HbA1c

PPG increments (meal test)

1,5-anhydroglucitol 

IG measurements (CGM)
Key safety assessments

Number of treatment emergent hypoglycaemic episodes

Number of adverse events
Trial products

Faster-acting insulin aspart, 100 U/mL solution for subcutaneous (s.c.) infusion provided in 
10 mL vial (Investigation Medicinal Product (IMP)– blinded) 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
15 of 149

Insulin aspart (NovoRapid®), 100 U/mL solution for s.c. infusion provided in 10 mL vial 
(Investigational Medicinal Product (IMP), comparator – blinded) 
CONFIDENTIAL


Protocol
UTN: U1111-1118-2480
Date:
04 February 2016
Status:
Final
Novo Nordisk
Trial ID: NN1218-3854
EudraCT no.: 2010-024054-11
Version:
4.0
Page:
16 of 149
2
Flow chart
NN1218-3854
Protocol section
Screening
4-week Run-in
Randomisation
0-16 weeks treatment period
Blinded trial product
End of treatment
Follow-up 1
Follow-up 2
Premature 
discontinuation 
of trial product
Visit (V)
Phone contact (P)
8.1.5
8.1.6
V
1
V
2
P
3
V
4
P
5
V
6
P
7
V
8
P
9
V
10
P
11
V
12
P
13
V
14
P
15
V
16
P
17
V
18
P
19
V
20
P
21
V
22
V
23
P
24
V
22A
V
22B8
Time of visit (weeks)
-6
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20
Visit window (days)1
+10
±3
±3
±3
±3
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
+3
+3
SUBJECT RELATED 
INFO/ASSESSMENTS
Informed consent
8.1.1
X
In/exclusion criteria
6.2, 6.3
X
X
Run-in failure criteria
6.4
X
X
X
X
X
Randomisation criteria
6.5
X
Criteria for premature discontinuation of 
trial product
6.6.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demography 
8.2.1
X
Tobacco use
8.2.1
X
Diagnosis of diabetes /diabetes complications
8.2.2
X
Diabetes treatment history
8.2.5
X
X
Concomitant illness
8.2.3
X
Medical history 
8.2.3
X
Concomitant medication
8.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLINICAL ASSESSMENTS
4-point profile (SMPG) 
8.3.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
7-7-9-point profile (SMPG)
8.3.2.2
X
X
X
X
Adverse events
12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycaemic episodes
8.3.3.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hyperglycaemic episodes6
8.3.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Protocol
UTN: U1111-1118-2480
Date:
04 February 2016
Status:
Final
Novo Nordisk
Trial ID: NN1218-3854
EudraCT no.: 2010-024054-11
Version:
4.0
Page:
17 of 149
NN1218-3854
Protocol section
Screening
4-week Run-in
Randomisation
0-16 weeks treatment period
Blinded trial product
End of treatment
Follow-up 1
Follow-up 2
Premature 
discontinuation 
of trial product
Visit (V)
Phone contact (P)
8.1.5
8.1.6
V
1
V
2
P
3
V
4
P
5
V
6
P
7
V
8
P
9
V
10
P
11
V
12
P
13
V
14
P
15
V
16
P
17
V
18
P
19
V
20
P
21
V
22
V
23
P
24
V
22A
V
22B8
Time of visit (weeks)
-6
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20
Visit window (days)1
+10
±3
±3
±3
±3
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
+3
+3
Infusion site reactions
8.3.3.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X4
X
X
Technical complaints
12.1.5
12.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
8.3.4
X
Body weight
8.3.4
X
X
X
X
X
Vital signs
8.3.9
X
X
X
X
X
Physical examination
8.3.8
X
X
X
X
X
ECG
8.3.5
X
X
X
Eye examination
8.3.6
X
X
X
Meal test
8.3.7
X
X
X
LABORATORY ASSESSMENTS
Fasting Plasma Glucose
8.4.3
X
X
X
X
HbA1c
8.4.5
X
X
X
X
X
X
X
1,5-anhydroglucitol
8.4.1
X
X
X
X
X
X
Biochemistry
8.4.2
X
X
X
X
X
Haematology
8.4.4
X
X
X
X
X
Lipids
8.4.6
X
X
X
X
X
Pregnancy testing
8.4.7
X7
X7
X7
X7
Urinalysis
8.4.8
X
X
X
X
X
OTHER ASSESSMENTS
CGM fitting
8.5.1.3, 
8.5.1.4
X
X
X
X
X
X
X8
CGM removal
8.5.1.3
X
X
X
X
X
X
X


Protocol
UTN: U1111-1118-2480
Date:
04 February 2016
Status:
Final
Novo Nordisk
Trial ID: NN1218-3854
EudraCT no.: 2010-024054-11
Version:
4.0
Page:
18 of 149
NN1218-3854
Protocol section
Screening
4-week Run-in
Randomisation
0-16 weeks treatment period
Blinded trial product
End of treatment
Follow-up 1
Follow-up 2
Premature 
discontinuation 
of trial product
Visit (V)
Phone contact (P)
8.1.5
8.1.6
V
1
V
2
P
3
V
4
P
5
V
6
P
7
V
8
P
9
V
10
P
11
V
12
P
13
V
14
P
15
V
16
P
17
V
18
P
19
V
20
P
21
V
22
V
23
P
24
V
22A
V
22B8
Time of visit (weeks)
-6
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20
Visit window (days)1
+10
±3
±3
±3
±3
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
+3
+3
CGM data transfer
8.5.1.5
X
X
X
X5
X
Change of infusion set and reservoir 
8.3.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PRO questionnaire
8.5.3
X
TRIAL MATERIAL
IV/WRS  
10
X
X
X
X
X
X
X
X
X
X
X
X
Dispensing visit (drug) 
9
X
X
X
X
X
X
X
X
X
Dosing2
X
X
X8
X
Drug accountability 
9.4
X
X
X
X
X
X
X
X
X
X
REMINDERS
Hand-out Subject participation card
8.1.2
X
Pairing of Subjects Pump and Subject Number in 
CareLink
8.1.3
X
Hand out and instruct in use of BG meter 
8.3.2.2
X
Hand out and instruct in use of back-up kit
8.3.2.6
X
X
X
X
X
X
X
X
X
X
X
Hand out and instruct in use of diary
8.5.2
X
X
X
X
X
X
X
X
X
X
X
X
Hand out of infusion set and reservoir
X
X
X
X8
Attend visit fasting
8.1.7
X
X
X
X
Training in diabetes and carbohydrate counting
8.3.2.5
X
X
Training in pump use (and trial procedures)
8.3.2.4
X
X
X
X
X
X
X
X
X
X
Remind Subjects to bring BG meter to site visit
8.3.1
X
X
X
X
X
X
X
X
X
X
X
Upload pump and BG meter data
8.3.2
X
X
X
X
X
X
X
X
X
X
X
X
Instruct in use of trial product
9.2, 9.3
X
X
X
X
X
X
X
X
End of treatment
8.1.9
X
X
X


Protocol
UTN: U1111-1118-2480
Date:
04 February 2016
Status:
Final
Novo Nordisk
Trial ID: NN1218-3854
EudraCT no.: 2010-024054-11
Version:
4.0
Page:
19 of 149
NN1218-3854
Protocol section
Screening
4-week Run-in
Randomisation
0-16 weeks treatment period
Blinded trial product
End of treatment
Follow-up 1
Follow-up 2
Premature 
discontinuation 
of trial product
Visit (V)
Phone contact (P)
8.1.5
8.1.6
V
1
V
2
P
3
V
4
P
5
V
6
P
7
V
8
P
9
V
10
P
11
V
12
P
13
V
14
P
15
V
16
P
17
V
18
P
19
V
20
P
21
V
22
V
23
P
24
V
22A
V
22B8
Time of visit (weeks)
-6
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20
Visit window (days)1
+10
±3
±3
±3
±3
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
+3
+3
End of trial
8.1.10.2
8.1.9
X
Casebook sign off 3
X
Key visits are highlighted in light blue.
1 Visit windows are relative to randomisation (Visit 6), except the two follow-up visits which are relative to Visit 22/22A. Visit 2 can take place as soon as the Subject
has been found eligible and must take place no later than 17 days after screening (Visit 1) 
2 Start/stop date of trial product (depending on when the Subject discontinues treatment)
3 The casebook should be signed of at the Subjects very last visit
4Infusion site reactions must be captured on the Adverse Event Form (no additional infusion site reaction information needs to be completed)
5Assessment not applicable if Subject prematurely discontinues treatment after Visit 12
6 Only unexplained Hyperglycaemic episodes
7 Blood pregnancy test 
8 For Subjects prematurely discontinuing treatment before Visit 12 


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
20 of 149
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, International Conference on 
Harmonisation 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
Data from the Diabetes Control and Complication Trial (DCCT) and United Kingdom Prospective 
Diabetes Study (UKPDS) shows that improvement in long term glucose control, as obtained with 
intensified insulin therapy, can reduce the incidence of complications and delay the progression of 
existing complications in Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus 
(T2DM)3,4. Control of postprandial hyperglycaemia significantly contributes to the glycosylated 
haemoglobin (HbA1c) level, and its treatment is essential for achieving the HbA1c target level5. 
Basal-bolus insulin therapy aims at approaching the physiological insulin secretion profile in the 
healthy state to the largest possible extent. For that purpose, faster-acting insulin analogues have 
been developed to more effectively control the postprandial glucose (PPG) excursions as compared 
to subcutaneously (s.c.) injected regular human insulin, primarily through offering a faster onset of 
action and shorter duration of action6. However, unmet needs exist within faster-acting insulin 
therapy. The current insulin analogues are not able to match the speed of the physiological post-
meal insulin secretion, and a faster onset of action is preferred for tighter PPG control. In addition, a 
more rapid delivery of the exogenous insulin to meet postprandial needs is likely to offer increased 
convenience and dosing flexibility for the patient7.
For an assessment of benefits and risks of the trial, see section 18.2.
3.1.1
Therapeutic area
The purpose of continuous subcutaneous insulin infusion (CSII) therapy in patients with diabetes is 
administration of insulin in a pattern which mimics physiological insulin secretion in people 
without diabetes. Basal insulin requirements are delivered by the pump in a continuous, slow 
infusion mode that is augmented by timed, meal-related bolus infusions. CSII offers advantages 
over multiple injection therapy, such as better flexibility and control over the basal insulin 
requirements and more predictable amounts of bolus insulin absorbed6. Results from clinical trials 
indicate that CSII for some patients is a more optimal therapy than multiple daily injections;
resulting in improved glycaemic control without an increased risk of hypoglycaemia8,9.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
21 of 149
3.1.2
Faster-acting insulin aspart
Faster-acting insulin aspart (also called faster aspart) is insulin aspart in a new formulation. Insulin 
aspart is marketed worldwide as NovoRapid® (in US it is NovoLog®). In the remainder of this 
document, the name NovoRapid® will be used. Faster-acting insulin aspart is being developed with 
the objective of achieving an increased early absorption of insulin aspart compared to NovoRapid®
thereby providing a faster insulin action. Faster-acting insulin aspart aims at mimicking the 
physiological prandial insulin secretion pattern better than currently available treatment and thereby 
more effectively controlling the PPG excursion and achieving a better PPG control, and increased 
flexibility in the time of dosing around meals compared with NovoRapid®. Results from clinical 
pharmacology trials in adults comparing pharmacokinetic and pharmacodynamic properties of 
faster-acting insulin aspart and NovoRapid® have shown that faster-acting insulin aspart elicited an 
earlier onset of appearance and a greater early exposure to insulin aspart than NovoRapid® in 
Subjects with T1DM, with the largest difference found within the first 15 minutes after injection. 
Faster-acting insulin aspart also elicited a greater early glucose-lowering effect than NovoRapid®, 
but no statistically significant difference between faster-acting insulin aspart and NovoRapid® in 
total glucose-lowering effect7. Similar results were found in a clinical pharmacology trial in a CSII 
pump setting, where the difference in onset of exposure and early insulin exposure were even 
greater for faster-acting insulin aspart compared with NovoRapid® than observed for single dose 
s.c. injection7.
In a therapeutic confirmatory basal-bolus trial in adult Subjects with T1DM, faster-acting insulin 
aspart taken with the meal effectively improved glycaemic control and the reduction in HbA1c was 
statistically significantly larger than with NovoRapid®. Mealtime faster-acting insulin aspart 
provided superior PPG control compared to NovoRapid®. No statistically significant difference was 
seen in overall rate of severe or blood glucose (BG) confirmed hypoglycaemic episodes between 
mealtime faster-acting insulin aspart and NovoRapid®. The rate during the first 1 hour after start of 
a meal, constituting a small fraction of all severe or BG confirmed hypoglycaemic episodes was 
statistically significantly higher for faster-acting insulin aspart compared to NovoRapid®. The 
overall safety profile for faster aspart and NovoRapid® was similar and as expected for insulin 
aspart. 
In a 6-week confirmatory pump compatibility trial, no microscopically confirmed episodes of 
infusion set occlusions (primary endpoint) were observed with either faster-acting insulin aspart or 
NovoRapid® in adult Subjects with type 1 diabetes7. 
In this trial, the safety profile of faster-acting insulin aspart is expected to be similar to that of 
NovoRapid®. The insulin aspart molecule has a well-known safety profile based on more than 15
years of clinical experience. Compared to NovoRapid®, faster-acting insulin aspart contains 
excipients which results in a faster initial absorption of insulin aspart following s.c. injection. The 
added excipients are included in the Food and Drug Administration´s (FDA) list for approved drug 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
22 of 149
products for injections and no toxicological concerns have been predicted for s.c. use in humans at
the proposed concentrations. 
For further details, please refer to the current version of the faster-acting insulin aspart 
Investigator´s Brochure (IB)7 and any updates hereto. 
3.1.3
NovoRapid® (insulin aspart)
Insulin aspart is homologous to human insulin, with the exception of the substitution of proline with 
aspartic acid at position B28. The rapid action of insulin aspart 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 to regular human insulin. Compared with human insulin, insulin aspart 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 T1DM10 and 
in Subjects with T2DM11-13. This also allows insulin aspart to be injected immediately before a 
meal, in contrast to regular human insulin. NovoRapid® is approved for use in CSII. 
For further details, please refer to the current version of the NovoRapid® EU Summary of Product 
Characteristics (SmPC)14, the U.S. NovoLog® Label Information15.
For an assessment of benefits and risks of the trial, see section 18.
3.2
Rationale for the trial
This trial aims to confirm the effect and to evaluate the safety of faster-acting insulin aspart with the 
use of CSII in adults with T1DM. In the European Medicines Agency (EMA) and FDA note for 
guidance on clinical investigation of medicinal products for the treatment of diabetes, HbA1c is 
considered the most widely accepted measure of overall, long-term glucose control. Consequently, 
change from baseline in HbA1c 16 weeks after randomisation will be included as the primary 
endpoint16,17.
The trial is intended to confirm that faster-acting insulin aspart, with a faster onset of action, is 
capable of demonstrating superior control of excessive postprandial glycaemic excursion during a 
standardised meal test and of demonstrating superiority of faster aspart in 1, 5-anhydroglucitol as 
another measure of PPG control, compared to NovoRapid®.
The trial also aims to confirm superiority and investigate the differences in interstitial glucose (IG)
of faster-acting insulin as compared to NovoRapid® based on data from continuous glucose 
monitoring (CGM) in adults with T1DM treated with CSII.
Further the trial is designed to confirm superiority of faster aspart in terms of overall glycaemic 
control measured as HbA1c when compared to NovoRapid®.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
23 of 149
The trial is a part of phase 3 clinical development program designed to meet the regulatory 
requirements for obtaining a CSII indication for faster-acting insulin aspart worldwide.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
24 of 149
4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To confirm the effect of continuous subcutaneous insulin infusion (CSII) treatment with faster-
acting insulin aspart in terms of glycaemic control by comparing it to CSII treatment with 
NovoRapid®, in adults with Type 1 Diabetes Mellitus (T1DM), using a non-inferiority approach.
4.1.2
Secondary objectives
To confirm superiority of CSII treatment with faster-acting insulin aspart compared to CSII 
treatment with NovoRapid® in adults with T1DM, in terms of:

Postprandial glucose regulation (meal test)

Overall glycaemic control (HbA1c)

Postprandial glucose excursions (1,5-anhydroglucitol)

Time spent in low interstitial glucose (CGM)
To compare the effect and safety of CSII treatment with faster-acting insulin aspart vs. CSII 
treatment with NovoRapid® in adults with T1DM.
4.2
Endpoints
Baseline is defined as randomisation (Visit 6).
4.2.1
Primary endpoint
Change from baseline in glycosylated haemoglobin (HbA1c) 16 weeks after randomisation.
4.2.2
Confirmatory secondary endpoints

Change from baseline in 1-hour PPG increment 16 weeks after randomisation (meal test)

Change from baseline in 1,5-anhydroglucitol 16 weeks after randomisation

Change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) during CGM 16 
weeks after randomisation
4.2.3
Supportive secondary endpoints
Supportive secondary endpoints are detailed in section 17.4.2 and are therefore only listed below 
without a detailed explanation. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
25 of 149
4.2.3.1
Supportive secondary efficacy endpoints
16 weeks after randomisation:

Change from baseline in fasting plasma glucose (FPG)

Percentage of Subjects reaching HbA1c targets

HbA1c <7.0% (53 mmol/mol) 

HbA1c <7.0 % (53 mmol/mol) without severe hypoglycaemic episodes

Change from baseline in 30- min, 1- hour, 2- hour, 3- hour and 4- hour PPG and in 30- min, 
2- hour, 3- hour and 4- hour PPG increment 16 weeks after randomisation (meal test)

Change from baseline in 7-7-9 point self-measured plasma glucose (SMPG) profile assessed 
by:

Mean of the 7-7-9 point SMPG profile

PPG and PPG increment (mean, breakfast, lunch and main evening meal)

Pre-prandial plasma glucose (PG) (mean, pre-breakfast, pre-lunch, pre-main evening 
meal)

Fluctuation in 7-7-9 point profile

Change in nocturnal SMPG measurements

Percentage of Subjects reaching PPG target (overall mean of daily post prandial glucose 
measurements in 7-7-9-point self-measured plasma glucose ):

Overall PPG (1 hour) ≤7.8 mmol/L [140 mg/dL]

Overall PPG (1 hour) ≤7.8 mmol/L [140 mg/dL] without severe hypoglycaemia 

Change from baseline in lipids-lipoproteins profile (total cholesterol, high density 
lipoproteins, low density lipoproteins)

Insulin dose (Units/day and Units/kg/day; total basal, total bolus, total daily insulin dose
and individual meal insulin dose): 

Insulin delivery pump parameters including insulin carbohydrate ratio, glucose sensitivity 
factor and active insulin time
4.2.3.2
Supportive secondary CGM and meal characteristics related endpoints
excluding meal test
16 weeks after randomisation:

Change from baseline in mean IG increment (0-30 min, 0-1 hour and 2 hours after 
start of meal)

Change from baseline in mean time to the IG peak after start of meal
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
Change from baseline in mean IG peak after start of meal 
4.2.3.3
Supportive secondary endpoints CGM related endpoints excluding meal test
16 weeks after randomisation:

Percentage of time spent with IG ≤2.5, 3.0, 3.5 mmol/L [45, 54, 63 mg/dL]) and IG >10.0, 
12.0 mmol/L [180, 216 mg/dL])

Incidence of episodes with IG ≤2.5, 3.0, 3.5, 3.9 mmol/L [45, 54, 63, 70 mg/dL]) and IG 
>10.0, 12.0 mmol/L [180, 216 mg/dL])

Change from baseline in mean of the IG profile

Percentage of time spent within target range 4.0-7.8 mmol/L (71-140 mg/dL)

Variation in the IG profile

Area under the curve (AUC3.9-IG) for IG ≤3.9 mmol/L [70 mg/dL]
4.2.3.4
Supportive secondary endpoints related to CGM and meal test
16 weeks after randomisation:

Change from baseline in AUCIG,0-15min

Change from baseline in AUCIG,0-30min

Change from baseline in AUCIG,0-1h

Change from baseline in AUCIG,0-2h

Change from baseline in AUCIG,0-4h  

Change from baseline in time to the IG peak after start of meal

Change from baseline in IG peak after start of meal
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4.2.3.5
Supportive secondary safety endpoints

Number of treatment emergent adverse events (AEs) during 16 weeks after randomisation

Number of treatment emergent infusion site reactions during 16 weeks after randomisation

Number of treatment emergent hypoglycaemic episodes classified both according to the 
American Diabetes Association definition and Novo Nordisk definition during 16 weeks 
after randomisation:

Overall

Daytime and nocturnal hypoglycaemic episodes (00:01-05:59 – inclusive)

Hypoglycaemic episodes from start of meal until 1, 2, 4 hours and from 2 hours 
(exclusive) to 4 hours (inclusive) after start of meal

Number of unexplained episodes of hyperglycaemia (confirmed by SMPG) during 16 
weeks after randomisation

Change from baseline 16 weeks after randomisation in clinical evaluations:

Physical examination 

Electrocardiogram (ECG)

Vital signs (blood pressure, pulse)

Fundus photography/fundoscopy

Change from baseline 16 weeks after randomisation in central laboratory assessments: 

Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, and 
leucocytes)

Biochemistry (total protein, creatinine, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (AP), sodium, potassium, albumin, 
and total bilirubin)

Urinalysis (for blood, protein, and ketones)

Change from baseline 16 weeks after randomisation in body weight and body mass index 
(BMI)

Number of change-of-infusion-sets per week during 16 weeks after randomisation 

Number of Subjects with at least one non-routine change-of-infusion-sets categorised by 
reasons for change-of-infusion-sets during 16 weeks after randomisation
5
Trial design
5.1
Type of trial
This is a double-blind, randomised, multicentre, multinational, active controlled, treat-to-target, 
parallel group trial with a 4-week run-in and a 16-week treatment period comparing the effect and 
safety of CSII of faster-acting insulin aspart vs. NovoRapid® in adult Subjects with T1DM. Subjects 
entering the trial will stay on their own insulin pump.
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The total duration of the trial is approximately 26 weeks split into the following periods (see Figure 
5–1):

≤2-week for screening period

A 4-week run-in period primarily for reinforcement of Subject training in trial procedures, 
diabetes education and collecting baseline assessments

A 16-week double-blinded treatment period 

A 7-day and 30-day follow-up period
Figure 5–1
Trial design
The trial includes a screening visit (Visit 1) to assess Subjects’ eligibility and additional weekly 
visits/phone contacts during the trial. All Subjects eligible for the trial will at Visit 2 enter the 4-
week run-in period, and they will continue on their currently prescribed insulin treatment. During 
the run-in period the Investigator will focus on reinforcement of training in pump use and diabetes 
as well as in trial procedures including the 4-point SMPG profiles, infusion set changes and 
completion of the diaries. Based on the Investigator’s discretion after the run-in period, Subjects
who have shown ability and willingness to adhere to the trial procedures and satisfactory handling 
of the pump will be randomised (Visit 6) in a 1:1 manner to NovoRapid® or faster-acting insulin 
aspart as described in section 11. After the 16-week treatment period, the Subject will have a 7-day 
follow-up (FU1, V 23) and 30-day (FU2, P 24) safety follow-up visit.
Up to 50% of the eligible Subjects will be allowed to wear their own real-time CGM device during 
the entire course of the trial. The remaining enrolled Subjects will not be allowed to wear a CGM 
device except for three pre-specified periods. During these periods a blinded CGM device will be 
Screening
Randomisation
Faster-acting insulin aspart CSII 
(225 Subjects)
NovoRapid® CSII             
(225 Subjects)
Weeks   -6       -4
                              0                                                                                             
        16  +7d      +30d
Note: Prior to randomisation and after end of treatment Subjects are on marketed product. 
Baseline is defined as randomisation. 
FU2
4-week run-in period
CSII Continue
current Insulin 
treatment
16-week treatment period
FU1
CGM
CGM
CGM
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handed out to all Subjects by the Investigator (provided by Novo Nordisk), including Subjects 
wearing their own CGM. 
5.2
Rationale for trial design
A 4-week run-in period has been included to ensure that the Subjects are being trained in the trial 
procedures and to collect 11 to 13 days baseline CGM measurements prior to randomisation.
A 16-week double-blinded, randomised treatment period is needed to obtain valid and adequate data 
regarding the effect and the safety. Treatment duration of 16 weeks is considered sufficient to reach 
a stable HbA1c level in a CSII setting.
By including at least 50% of the Subjects without their own real-time CGM it will allow for 
assessing safety data in a population that does not have the possibility to look and react on real-time 
CGM data. The Subjects who enter the trial without their own real-time CGM device must not start 
wearing one when enrolled in the trial. The other 50% wearing an own GGM device are included to 
comply with the still-growing insulin pump population wearing a real-time CGM without changing 
their current normal practice when entering the trial. Subjects wearing their own CGM are not 
allowed to use the low glucose suspend mode in the relevant pumps during the trial in order to 
assess the safety profile of faster-acting insulin aspart. Randomisation will be stratified according to
the use of own real-time CGM to ensure a comparable number of Subjects in each treatment group.
The rationale of the blinded CGM assessment is to obtain a thorough knowledge of the glycaemic 
control achieved with the different treatments in this trial.  
The rationale for the meal test is to evaluate PPG excursions after a standardised meal when 
infusing faster-acting insulin aspart compared to NovoRapid®.
A 7-day and 30-day follow-up visit is included in order to collect information on AEs occurring in 
the 30 days after discontinuation of trial drug. 
The treat-to-target approach, and thereby the very high frequency of contacts, has been chosen in 
order to ensure optimal titration of faster-acting insulin aspart and NovoRapid®.
This trial will be conducted at multiple centres to ensure that the required Subject population can be 
included.
5.2.1
Rational for choice of non-inferiority margin
Placebo controlled trials will usually be considered unethical to conduct in a T1DM diabetic 
population and it can therefore be difficult to assess the true insulin aspart effect. In a recently 
finalised faster-acting insulin aspart trial (NN1218-4049) in a bolus insulin naïve T2DM adult 
population comparing a basal insulin treatment in addition to metformin to a full basal bolus insulin 
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treatment in addition to metformin the estimated treatment difference in change from baseline 
HbA1c was - 0.94%-point [ -1.17; -0.72] (data on file). In that trial the addition of 3-times daily 
faster-acting insulin aspart lead to a reduction in HbA1c of 1.16%-point after 18 weeks of treatment. 
In a similar phase 4 trial19 investigating the stepwise addition of NovoRapid® to a full basal bolus 
regimen in bolus naïve T2DM adults the observed reduction in HbA1c after 21 weeks of treatment 
was 1.15%-point (data on file) with 3-times daily NovoRapid® added to basal insulin. This gives 
some indication that the effect of NovoRapid® versus placebo would be close to the 0.94%-point 
observed in trial NN1218-4049. Using a non-inferiority margin of 0.4, one of the suggested margins 
in the FDA guidance18, an improvement of approximately 0.54% would have been preserved using 
the 0.4% non-inferiority margin. It is also worthwhile to state that the T1DM population would not 
have any or limited endogenous insulin production and the true effect of NovoRapid® might be 
comparable to what is seen in a T2DM population.
5.3
Treatment of Subjects
At the start of the run-in period (Visit 2), Subjects will remain on their pre-trial insulin treatment. At 
randomisation (Visit 6), Subjects will be switched from their current insulin treatment to either 
faster-acting insulin aspart or NovoRapid® in a 1U:1U manner, keeping the current insulin delivery 
parameters in the pump. After the transfer to trial insulin treatment the insulin pump delivery 
parameters should be reviewed with regards to the need for adjustments. During the run-in period 
(Visit 2 to Visit 6), the basal rates and Bolus Wizard® should not be adjusted unless indicated for 
safety reasons.  
In the treatment period starting at randomisation (Visit 6), the Investigators must strive to achieve a 
glycaemic target of fasting and pre-prandial BG between 4.0-6.0 mmol/L [71-108 mg/dL] in a treat-
to-target fashion based on frequent SMPG profiles and safety. No maximum dose of insulin is 
specified. All Subjects will perform at least 4-point SMPG profiles on a daily basis, in accordance 
with section 8.3.2.2, throughout the trial. Guideline documents for the management of Insulin Pump 
Therapy will be provided both to the Investigators and the Subjects20,21. 
The dose adjustments must be done based on SMPG values only. No other anti-diabetic medication 
except the current insulin treatment is allowed during the trial after start of run-in period (Visit 2)
until randomisation (Visit 6). No other insulin products except the trial medication are allowed from 
start of the randomisation (Visit 6) until end of treatment (Visit 22).
5.3.1
Basal rate insulin adjustment
The purpose of adjusting the basal rates is to ensure that BG is kept in a stable range within 2 
mmol/L [35 mg/dL] in a fasting state and during the night. After randomisation (Visit 6), the 
Subjects should perform basal rate checks based on frequent measurements of SMPG values and the 
skipped meal principle, or similar, following instructions from the Investigator according to insulin 
adjustment guidelines for insulin pump users20,21.  
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During the treatment period, starting at randomisation (Visit 6), the Investigator must review and
adjust if necessary the individual basal rates at each site and phone visit and inform the Subject
accordingly. The Novo Nordisk insulin titration group will review the progress of treatment (please 
see section 5.4).
5.3.2
Bolus insulin titration
The Subjects should use meal-time boluses based on carbohydrate-counting using the Bolus 
Wizard® according to their usual practice and according to instructions from the Investigator. Meal-
time dosing is defined as bolus infusion initiated 0-2 minutes before a meal. At randomisation (Visit
6), the individual BG target should be set in the pump to a mean of the upper and lower value in the 
target range and the Bolus Wizard® settings should be evaluated by the Investigator after basal rates 
checks or adjustments. 
During the treatment period starting at randomisation (Visit 6), the Investigator must review and 
adjust if necessary the insulin to carbohydrate ratios and correction factors at each site and phone 
visit according to insulin adjustment guidelines for pump users20,21, and advise the Subject
accordingly. The Investigator should also review correction boluses and adjust the active insulin 
setting in case of any signs of incorrect settings. The Subject must be informed not to change the 
active insulin setting without discussing this with the Investigator. The Novo Nordisk insulin 
titration group will review the progress of treatment.
5.4
Titration review procedure
Surveillance of titration data will be performed centrally by Novo Nordisk in a blinded manner. 
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the 
glycaemic control. Novo Nordisk will 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 a blinded manner. When the Investigator receives an inquiry, a response should be 
received at Novo Nordisk within 24 hours (on weekdays). 
5.5
Treatment after end of trial product
When discontinuing trial products, either at end of treatment (Visit 22) or earlier, the Subject should 
be switched to a suitable marketed product at the discretion of the Investigator. Please see section
8.1.9.
5.6
Rationale for treatment
CSII treatment of adult patients with T1DM was introduced more than 30 years ago and found to 
generate improvements with respect to glucose control. Data from the DCCT show that intensive 
treatment is beneficial in terms of reducing the risk for long term complications3.
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Trial ID: NN1218-3854
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The currently available clinical pharmacology data demonstrates that injection with faster-acting 
insulin aspart formulations results in an increased early absorption of insulin aspart compared to 
NovoRapid® and thereby provides a faster onset of insulin action. 
A delay between the glucose measurements and the insulin absorption (so called lag-time) due to 
the s.c. route of insulin delivery can limit the possibility of reducing the excessive PPG excursions. 
The rapid action of faster-acting insulin aspart could prove more effective in achieving PPG control 
in a CSII regimen because of the shortened absorption time of faster-acting insulin aspart from the 
s.c. depot at the infusion site. 
NovoRapid® will be applied as a comparator to faster-acting insulin aspart in order to compare and 
confirm clinical effect and safety of faster-acting insulin aspart to the currently marketed insulin 
aspart formulation NovoRapid®. As the trial is double-blinded, faster-acting insulin aspart and 
NovoRapid® will be titrated following the same recommendations.
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6
Trial population
6.1
Number of Subjects 
Number of Subjects planned to be screened: 
666
Number of Subjects planned to be included in the run-in period:
506
Number of Subjects planned to be randomised: 
450 
Approximately a 24% screening failure rate and 11% run-in failure rate are expected for this trial.
6.2
Inclusion criteria
For an eligible Subject, all inclusion criteria must be answered "Yes".
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial
2. Male or female, age ≥18 years at the time of signing informed consent
3. Diagnosed with T1DM ≥1 year prior to the day of screening
4. Using the same Medtronic pump (Minimed 530G (551/751), Paradigm Veo (554/754), 
Paradigm Revel (523/723), Paradigm (522/722)) for CSII in a basal-bolus regimen with a 
rapid acting insulin analogue for at least six months prior to screening and willing to stay on 
the same pump model throughout the trial (if the model is changed the change should not 
exceed 7 consecutive days.) 
5. Ability and willingness to refrain from using low glucose suspend mode in the pump 
throughout the trial
6. Willingness to use one of the following types of infusion sets: Medtronic Quick-Set®, 
Medtronic Mio®, Medtronic Silhouette® or Medtronic Sure-T® (Easy-set®) throughout the 
trial
7. Willing to use CSII as the insulin treatment during the entire trial
8. Using the same insulin for at least 90 days prior to screening
9. HbA1c 7.0-9.0% (53-75 mmol/mol) inclusive as assessed by central laboratory at screening
10. BMI ≤35.0 kg/m2 at screening 
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11. Ability and willingness to take at least 3 daily meal-time insulin bolus infusions every day
throughout the trial
12. Ability and willingness to adhere to the protocol including performing SMPG profiles, 
CGM and meal test
6.3
Exclusion criteria
For an eligible Subject, all exclusion criteria must be answered "No".
1. Known or suspected hypersensitivity to trial products 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) 
For UK: Females of child-bearing potential who are pregnant, breast-feeding or intend to 
become pregnant and are sexually active and not using adequate contraceptive methods 
(Adequate contraceptive measures are defined as established use of oral, intravaginal, 
transdermal combined estrogen and progestogen hormonal methods of contraception; oral, 
injected or implanted progestogen only hormonal methods of contraception; placement of an 
intrauterine device or intrauterine hormone releasing system, bilateral tubal occlusion, 
barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository), female sterilisation, vasectomised partner (where partner 
is sole partner of Subject), or true abstinence (when in line with preferred and usual 
lifestyle))
For Belgium: Highly effective methods of birth control are defined as those, alone or in
combination, that result in a low failure rate (i.e., less than 1% per year) when used
consistently and correctly; such as implants, injectables, combined oral contraceptives, some 
IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments) or vasectomised partner.
For Germany: Adequate contraceptive measures are defined as implants, injectables, 
combined oral contraceptives, hormonal intrauterine device and sexual abstinence or 
vasectomised partner.
4. Participation in another clinical trial within 28 days before the screening visit. Participation 
is defined as having signed SI/IC. Note: clinical trials do not include non-interventional 
studies
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5. Anticipated significant change in lifestyle (e.g. eating, exercise or sleeping pattern) 
throughout the trial
6. Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening 
7. Subjects classified as being in New York Heart Association22 (NYHA) Class IV at screening
8. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening.
9. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (Systolic 
≥180 mmHg or diastolic ≥110 mmHg) at screening 
10. Impaired liver function, defined as ALT ≥ 2.5 times upper normal limit at screening
11. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
< 60 ml/min/1.73 m2 as defined by KDIGO 2012 classification using isotope dilution mass 
spectrometry (IDMS) for serum creatinine measured at screening. (KDIGO 201223 )
12. 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)
13. Proliferative retinopathy or maculopathy requiring acute treatment as verified by fundus 
photography or dilated fundoscopy performed within 90 days prior to the screening visit or 
as part of the screening assessments. Results must be present at Visit 2.
14. History of hospitalization for ketoacidosis ≤180 days prior to the day of screening
15. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within 90 days before screening 
16. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ is allowed.
17. Any condition which, in the opinion of the Investigator might jeopardise Subject’s safety or 
compliance with the protocol
18. Intention to start using a flash glucose monitoring or real-time CGM system device for 
personal use at any time after screening until the end of trial
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6.4
Run-in failure criteria
Subjects fulfilling any of the below listed criteria or withdrawing consent prior to randomisation are 
considered run-in failures and should follow the procedures described in section 8.1.3.1.
1. Included in the trial in violation of the inclusion and/or exclusion criteria 
2. Pregnancy
3. Intention of becoming pregnant
4. Participation in other clinical trials throughout the trial. Participation is defined as signed 
informed consent (note; clinical trials do not include non-interventional studies)
6.5
Randomisation criterion
To be randomised, the below randomisation criterion must be answered "Yes".
1. Subjects ability and willingness to adhere to the protocol and satisfactory handling of the 
pump, including regular changes of the infusion sets and adequate bolus dosing based on the 
Investigator’s judgment
6.6
Criteria for premature discontinuation of trial product or withdrawal from trial 
Efforts should be made to ensure Subjects attend and complete all scheduled visits and procedures. 
There will be a clear distinction between trial product discontinuation and withdrawal from trial by 
Subject.
6.6.1
Premature discontinuation of trial product 
The Subject may be discontinued from trial product at the discretion of the Investigator due to a 
safety concern.
The Subject must be discontinued from trial product if any of the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or randomised 
in violation of the randomisation criterion
2. Pregnancy
3. Intention of becoming pregnant
4. Participation in other clinical trials throughout the trial. Participation is defined as signed 
informed consent (note: clinical trials do not include non-interventional studies)
Discontinuations from trial product criteria are applicable from start of the randomisation (Visit 6)
throughout the trial until end of treatment (Visit 22).
Subject discontinued from trial product will be followed up as described in Section 8.1.8.1.
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6.6.2
Withdrawal from trial
The Subject may withdraw at will at any time. The Subject’s request to discontinue from the trial 
must always be respected.
If the Subject considers withdrawing the Informed Consent the Investigator must underline to the 
Subject the importance of continuing in the trial despite trial product discontinuation. If the Subject
agrees to discontinue trial product but stay in the trial, procedures described in Section 8.1.8.2
should be followed.
If a Subject decides to withdraw consent, the Subject should be encouraged to undergo procedures 
described in Section 8.1.8.2.
A Subject will be considered “lost to follow up” if the Subject repeatedly fails to attend the 
scheduled visits and the site is unable to establish contact to the Subject. The following actions must 
be taken by the site in relation to a Subject who fails to attend the site for a scheduled visit:

The site must attempt to contact the Subject and to reschedule the missed visit as soon as 
possible

The site must re-train the Subject in the importance of maintaining the scheduled visits

In cases where a Subject is deemed lost to follow up the Investigator must make every effort 
to regain contact to the Subject (by e.g. telephone calls, e-mails, certified letters or calls to 
family members or friends as applicable). These contact attempts should be documented in 
the Subject’s medical records. Only if the Subject continues to be unreachable after all 
contact attempts, the Subject should be considered to have withdrawn from the study with 
the primary reason being “lost to follow up”.
6.7
Subject replacement
Subjects who are withdrawn after randomisation (Visit 6) will not be replaced.
6.8
Rationale for trial population
The purpose of this trial is to assess the effect and safety of CSII of faster-acting insulin aspart in 
the treatment of adult Subjects with T1DM.
The trial population consists of adult Subjects with T1DM who have been treated with CSII for at 
least six months with the same pump and the same insulin for at least 90 days. This is to reduce 
pump user-related variability and to increase the likelihood that the Subjects will be able to adhere 
to the protocol requirements. To avoid potential influence on effect and safety data, at least 50% of 
the Subjects should consent to not use their own real-time CGM during the trial. Subjects entering 
the trial using own real-time CGM must switch off the low glucose suspend mode in order to avoid 
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potential impact of the safety results. This is only applicable for Subjects entering the trial using
own real-time CGM integrated with their pump. 
In diabetes, a likely cause of elevated HbA1c is poor compliance with treatment regimens or atypical 
course of the disease. Consequently individuals with an HbA1c greater than 9.0% (75 mmol/mol)
are not included in the trial. Subjects in good glycaemic control defined as HbA1c < 7.0% may not 
benefit from further optimisation of glucose control and therefor the lower cut-off value has been 
chosen. A BMI limit of ≤35.0 kg/m2 is chosen to include as broad a population as possible, while 
excluding exceedingly obese individuals. The trial protocol requires strict adherence and good 
Subject compliance. 
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7
Milestones
Planned duration of recruitment period, first Subject first visit (FSFV) – last Subject first Visit
(LSFV): 26 weeks
End of trial (EoT) is defined as last Subject last visit (LSLV) after 16 weeks of randomised 
treatment and a 30-day follow-up.
The recruitment period will depend on the screening rate and the screening/run-in failure rate.
Recruitment will be closed as soon as the total number of randomised Subjects is possible to reach,
taking into account the number of Subjects currently in screening/in the run-in period and the 
previous screening/run-in failure rate. All Subjects who are in screening/run-in when recruitment 
closes will be randomised if eligible. All Investigators will be notified immediately when the 
recruitment period ends and when the limit of 50% of the Subjects wearing their own CGM is met. 
When the recruitment period ends, no further Subjects may be screened and the interactive 
voice/web response system (IV/WRS) will be closed for further screening.
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 Disclosure, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)24, the Food and Drug Administration Amendment Act (FDAAA)25, 
European Commission Requirements26-28 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
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
40 of 149
8
Methods and assessments
8.1
Visit procedures
The following sections describe the assessments and procedures. Timing of the different 
assessments and procedures including type of visit and the visit windows are also described in the 
flowchart in section 2.
Throughout this section the term Investigator refers to Investigator or delegated personnel, unless 
otherwise stated.
8.1.1
Informed Consent
Before any screening activities take place, the Subjects must be provided with written and oral 
information about the trial, the procedures involved and their responsibilities and rights while 
participating in the trial, in accordance with ICH-GCP and local requirements. The Subjects will 
also be informed about possible advantages/disadvantages when being treated with trial products.
The Subjects will have the opportunity to ask questions and will have ample time to consider 
participation. 
Subjects who wish to participate in the trial will sign and date the Subject Information/Informed 
Consent (SI/IC) before any trial-related procedures commence. Trial-related activities are any 
procedures that would not have been performed during the normal management of the Subject. All 
Subjects must be provided with a copy of their own signed and dated SI/IC.
The process for providing trial information and obtaining informed consent is described further in 
section 18.3.
8.1.2
Screening visit
At screening (Visit 1), each Subjects will be assigned a unique 6-digit Subject number which will 
remain the same throughout the trial. A screening session must be performed in the IV/WRS.
Subjects will continue on their current diabetes treatment until start of randomisation (Visit 6) and 
they will not be supplied with any trial products until then.
Any abnormal and clinically significant findings at Visit 1 must be recorded on the medical 
history/concomitant illness form in the electronic case report form (eCRF).
At screening, Subjects will be provided with a card (Subject Participation Card) stating that they are 
participating in a trial and given contact address(es) and telephone number(s) of relevant trial site 
staff. Subjects should be instructed to return the card to the Investigator at last trial visit or to 
destroy the card after the last visit.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
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The Investigator must keep a Subject Screening Log, a Subject Identification Code List and a 
Subject Enrolment Log. The Subject Screening Log and Subject Enrolment Log may be combined 
in one list. 
For screening (Visit 1) procedures, please see flowchart in section 2.
8.1.2.1
Screening failures
If a Subject is not eligible to participate in the trial, the Subject will be considered a screening 
failure. Consequently, a Screening/Run-in Failure Session must be made in the IV/WRS.
For screening failures, the Screening Failure Form must be completed in the eCRF with the reason 
for not continuing in the trial. Serious adverse events (SAEs) from screening failures must be 
transcribed by the Investigator into the eCRF. Follow-up of SAEs must be carried out according to 
section 12.3.
When data has been monitored and queries have been resolved the case book must be signed in the 
eCRF.
8.1.2.2
Re-screening
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria 
related to laboratory parameters.
8.1.3
Run-in
If the Subject is found eligible to continue in the trial the Subject will enter a 4-week run-in period 
(Visit 2 to Visit 6). Visit 2 can take place as soon as the Subject has been found eligible and must 
take place no later than 17 days after screening (Visit 1). The results of all the screening 
assessments must be available (including central laboratory results) and must have been reviewed 
by the Investigator before the Subject can enter the run-in period.
A BG meter will be handed out to the Subjects, which needs to be coupled by site personnel with 
the Subjects pump by entering the BG meter serial number into the pump.
At the run-in visit (Visit 2) a pump data upload should be performed in order to pair the Subject’s 
pump with the Subject number created in CareLink Clinical.
The Subjects must be instructed to bring their BG meter to the site at every visit for data upload.
For procedures to be performed in the run-in period, please see flowchart in section 2.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
42 of 149
8.1.3.1
Run-in failures
If the Subject discontinues from the trial during the run-in period or is not eligible to be randomised 
(i.e. withdrawn their SI/IC, or not met the randomisation criterion, fulfils any of the run-in failure 
criteria, please see section 6.4), then the Subject will be considered a run-in failure. Consequently, a
Screening / Run-in Failure session must be made in the IV/WRS. A Run-in Failure Form must be 
recorded in the eCRF with the reason for not continuing in the trial. No end of treatment visit (Visit
22) and follow-up visits (Visit 23 and Visit 24) should take place. SAEs and non-serious AEs from 
run-in failures must be recorded in the eCRF. Follow-up of AEs should be carried out according to 
section 12.3. 
When data has been monitored and queries have been resolved the case book must be signed in the 
eCRF.
8.1.4
Randomisation 
Randomisation (Visit 6) should occur after the four-week run-in period has been completed.
The Subject must attend randomisation (Visit 6) fasting. For definition of fasting, please see section
8.1.7.
If the Subject meets the randomisation criterion at Visit 6, the Subject will be randomised into one 
of the two treatment arms by using IV/WRS; please see section 10. The Subject will undergo a meal 
test (please see section 8.3.7). When the meal test is completed the Subject will be instructed to 
discontinue their current insulin and start treatment with the trial product according to 
randomisation. A new infusion set and reservoir containing trial product must be inserted while the 
Subject is still at site. Stop date of the current insulin treatment and start date of the randomised trial 
product must be recorded in the eCRF.
Subjects will keep the same Subject number as allocated at screening.
For randomisation (Visit 6) procedures, please see flowchart in section 2.
8.1.5
Site visits
If a visit to the site is not performed as scheduled for any reason, then the Investigator should 
arrange for the visit to be performed as soon as possible and within the visit windows specified in 
section 2.
Scheduled dispensing of trial product should be performed at the visits indicated in the flowchart in 
section 2. A dispensing session must be performed in the IV/WRS when dispensing trial drug. Drug 
accountability should be performed at each dispensing visit from start of randomisation (Visit 6) 
until end of treatment (Visit 22)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
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Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
Page:
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For assessments performed at the site visits, please see flowchart in section 2.
8.1.6
Phone contacts
Before any phone contact, both the Investigator and Subject should agree on the date, timing and 
direction of the call. The Investigator remains responsible for ensuring that the phone contacts occur 
even if it is agreed that the Subject should call the site.
If a planned phone contact is, for some reason, not performed at the agreed time point, the 
Investigator must arrange for the phone contact to be performed as soon as possible and within the 
scheduled visit windows specified in section 2. A phone contact visit may be converted to a site
visit if needed.
The run-in failure/ discontinuation from trial product criteria must be reviewed during the phone 
contact to ensure the Subject is eligible to continue in the trial.
For assessments performed at the phone contacts please refer to the flowchart in section 2.
8.1.7
Fasting visits
Fasting is defined as no intake of drink or food for at least 8 hours prior to blood sampling (only 
water is allowed. The Subjects must attend the visits specified in section 2 in a fasting condition. 
Correction boluses are allowed until four hours before the measurement of the FPG. Subjects 
should not make any changes in the current basal rate setting 4 hours prior to the meal test.
Bolus insulin dosing and medication which should be taken with or after a meal should be withheld 
until blood sampling has been performed. Any other concomitant medication can be taken as usual.
If the Subject attends the fasting visits in a non-fasting condition, all blood samples, meal test and 
body weight measurements must be rescheduled within the visit window. The date of the meal test 
and body weight measurement in the eCRF should reflect the actual date of the meal test/body 
weight measurement (i.e. the actual visit date will differ from the assessment date under the same 
visit).
8.1.8
Withdrawal procedures
8.1.8.1
Premature discontinuation of trial product
If a Subject is discontinued from trial product, as described in Section 6.6.1 after randomisation 
(Visit 6), the Investigator must ensure that every possible effort is made to undertake the following 
procedures: 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
Page:
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Subjects discontinuing before or at Visit 12 (Week 6)

The Subject needs to be called in for a 22A including CGM fitting as soon as possible after
awareness of the trial product discontinuation intention. The meal test at Visit 22A should
be performed while the Subject still is on trial product according to randomisation unless
this is not feasible for safety reasons as judged by the Investigator. (Confirmation that the
meal test was performed on trial product will be recorded in the eCRF).

The Subject will be asked to remain on trial product until completion of Visit 22B
(Confirmation that the Subject was on trial product will be recorded in the eCRF)

The Visit 22B needs to be scheduled 7 days after Visit 22A and serves mainly for transfer 
of CGM data as specified in Section 2. No additional CGM fitting is needed for these 
Subjects at this visit.

The CGM assessment on visit 14 can be omitted for these Subjects
At Visit 22B a treatment discontinuation session must be made in IV/WRS and reason for 
discontinuation of trial product must be specified in the End of Treatment/Trial form in the eCRF. 
Final drug accountability must be performed even if the Subject is not able to come to the trial site.
At Visit 22B the Subject should be switched to a suitable marketed product at the discretion of the 
Investigator. The medication should be recorded on the diabetes treatment history form (please see 
8.2.5) in the eCRF.
If the Subject does not wish to continue on trial product until visit 22B (or if continuation on trial 
product is not possible due to a safety concern as judged by the investigator) then all assessments 
related to trial product discontinuation must be completed at visit 22A.
Subjects discontinuing after Visit 12 (Week 6)

The Subject needs to be called in for a 22A as soon as possible after awareness of the trial
product discontinuation intention. The meal test at Visit 22A should be performed while the
Subject still is on trial product according to randomisation unless this is not feasible for
safety reasons as judged by the Investigator. (Confirmation that the meal test was performed
on trial product will be recorded in the eCRF).

For Subjects discontinuing between Visit 12 and 14 the CGM and 7-7-9 profile assessment
on Visit 14 should be performed as planned, since the CGM has been fitted at Visit 12 for
these Subjects
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
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
For Subjects discontinuing between visit 14 and 20 the CGM assessment at visit 22A is not 
required and will be performed at the key Visit 22.

For Subjects discontinuing between Visit 20 and 22 the CGM and 7-7-9 profile assessment 
on Visit 22 should be performed as planned, since the CGM has been fitted at Visit 20 for 
these Subjects 
At Visit 22A a treatment discontinuation session must be made in IV/WRS and reason for 
discontinuation of trial product must be specified in the End of Treatment/Trial form in the eCRF. 
Final drug accountability must be performed even if the Subject is not able to come to the trial site.
At Visit 22A the Subject should be switched to a suitable marketed product at the discretion of the 
Investigator. The medication should be recorded on the diabetes treatment history form (please see 
8.2.5) in the eCRF.
All Subjects prematurely discontinuing the trial product
In addition, all Subjects prematurely discontinued from trial product should after Visit 22A (22B 
respectively) attend the FU1 and FU2 and continue in parallel with the per-protocol planned key 
visits: Visit 10, Visit 14, Visit 18 and Visit 22, after randomisation depending on when the Subject 
discontinues trial product. The following assessments are not applicable for prematurely 
discontinued Subjects at V22: 4-point SMPG profile, technical complaints, IWRS call.
Contact after premature discontinuation of trial product:
Subjects that prematurely discontinue trial product will be asked to attend an End of Treatment visit
(Visit 22A) and follow-up visit 1 (FU1) 7-12 days after visit 22A and follow-up visit 2 (FU2) 30-35 
days after V22A. In parallel they will continue with the per-protocol planned key visits: Visit 10, 
Visit 14, Visit 18 and Visit 22.
In the following situations, only one visit should take place:

If V22A is more than 12 weeks after randomisation and before the planned V22, only 
V22A should be performed instead of V22

If V14 /V18, and FU2 visit windows overlap according to visit schedule, only V14/V18
should be performed

If V22 and FU1 visit windows overlap according to visit schedule, only V22 should be 
performed
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
Final
EudraCT no.: 2010-024054-11
Page:
46 of 149

If V22 and FU2 visit windows overlap according to visit schedule, only V22 should be 
performed
Diary records after premature discontinuation of trial product:
The Subject will be handed out premature discontinuation diaries at Visit 22A to record the 
following:

Hypoglycaemic episodes. The following information should be recorded:

Start date and time of hypoglycaemic episode

Time and value of plasma glucose level before treating the episode (if available) and 
any follow up measurements

Whether the episode was symptomatic (Yes/No)

Whether the Subject was able to treat him/herself

Unexplained hyperglycaemic episodes (see section 8.3.3.2)

Change of Infusion sets and reservoirs (see section 8.3.2.3)

Meal dates and times (breakfast, lunch, main evening meal, other) in relation to 
performance of 7-7-9-point profiles and during the CGM period.(see section 8.5.1.4)
Hypoglycaemic and/or unexplained hyperglycaemic episode must be reported in the diary until 
Visit 22 has been completed.
8.1.8.2
Withdrawal from trial
If a Subject withdraws consent from the trial after randomisation (Visit 6), the Investigator must 
ensure every possible effort is made to undertake procedures same as those for end of treatment 
(Visit 22A) including the meal test, as soon as possible after decision of ending trial. The meal test 
should be performed with trial product according to randomisation unless this is not feasible due to 
safety reasons as judged by the Investigator.
The Subject should also complete the follow-up visits (Visit 23 and Visit 24). The End of 
Treatment/Trial form must be completed in the eCRF. A treatment discontinuation session must be 
made in IV/WRS and reason for withdrawing consent must be specified in the End of 
Treatment/Trial form in the eCRF. Final drug accountability must be performed even if the Subject
is not able to come to the trial site. 
Although a Subject is not obliged to give his/her reason(s) for withdrawing from a trial, the 
Investigator must make a reasonable effort to ascertain the reason(s), while fully respecting the 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
04 February 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
4.0
UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
Page:
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Subject's rights. Where the reasons are obtained, the primary reason for not completing the trial
must be specified on the End of Treatment/Trial form in the eCRF. 
8.1.9
End of treatment
At end of treatment (Visit 22), the trial product should be discontinued via a Completion session in
IV/WRS and stop date of trial product must be recorded in the eCRF.
The Subject should be switched to a suitable marketed product at the discretion of the Investigator
and this product should be recorded on the Concomitant Diabetes Medication form in the eCRF, as 
described in section 8.2.5. For procedures to be performed at end of treatment (Visit 22), please see
flowchart in section 2. 
At the End of Treatment Visit (Visit 22), the Investigator must fill out the End of Treatment/Trial 
Form in the eCRF.
8.1.10
Follow-up 
The follow-up period is covered by two visits, a 7-day follow-up (Visit 23, FU1) and a 30-day 
follow-up (Visit 24, FU2) both relative to the end of treatment visit (Visit 22). 
8.1.10.1
Follow-up 1 (FU1, Visit 23)
During the 7-day follow-up period (Visit 23) the following information will be collected and 
recorded in the eCRF:

AEs 

Concomitant medication

Concomitant diabetes medication

Hypoglycaemic events (collected in the Subjects’ diary and recorded in the eCRF)

Infusion site reaction (recorded in the eCRF)

Unexplained hyperglycaemic events (collected in the Subjects’ diary and recorded in the 
eCRF)
8.1.10.2
Follow-up 2 (FU2, Visit 24)
During the last follow-up period (from day 8 to day 30 after end of treatment) the following will be 
collected and recorded in the eCRF:

AEs (including infusion site reactions)

Concomitant medication

End of Treatment/ Trial Form
For procedures performed in the follow-up period (Visit 23 and Visit 24), please see flowchart in 
section 2. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
Page:
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8.2
Subject related information 
8.2.1
Demography and smoking status
The following demographic data will be obtained by the Investigator and recorded in the eCRF: 

Date of birth (if not permitted according to local laws the year of birth will be collected)

Age at screening

Ethnicity (if permitted according to local laws) 

Race (if permitted according to local laws) 

Sex

Smoking habits

Use of own CGM
Details of smoking status must be recorded at screening (Visit 1). Smoking is defined as smoking at 
least one cigarette, cigar or pipe daily. The collected information should include whether or not the 
Subject smokes or has smoked. For previous smokers, stop dates must be recorded. If the Subject
smokes or has smoked, the approximate duration of smoking and the average number of cigarettes
per day should be recorded in the Subjects medical records and the eCRF.
8.2.2
Diagnosis of Type 1 Diabetes Mellitus and diabetes complications
At screening (Visit 1) the date of diagnosis of T1DM and information regarding diabetes 
complications (i.e. diabetic retinopathy/neuropathy/nephropathy and macroangiopathy including 
peripheral vascular disease) will be obtained and recorded in the Diabetes History/Diabetes 
Complications Form in the eCRF. Information on diabetes complications, hypoglycaemia 
unawareness (according to Clarke questionnaire, question 8) and recurrent hypoglycaemia must also 
be recorded, if present. 
8.2.3
Concomitant illness and medical history
A concomitant illness is any illness, except T1DM, that is present at the start of the trial (i.e. at 
screening (Visit 1)) or found as a result of the screening procedures. 
Any change to a concomitant illness should be recorded on the Concomitant Illness form in the 
eCRF during the trial. A clinically significant worsening of a concomitant illness must be reported 
as an AE as described in section 12.
Medical history is a medical event that the Subject has experienced in the past. Only relevant 
medical history, as judged by the Investigator, should be reported. 
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset, date of resolution, or continuation, as applicable.
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Date:
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Trial ID: NN1218-3854
Version:
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Concomitant illness and medical history must be recorded on the corresponding pages of the eCRF.
8.2.4
Childbearing potential
It must be recorded in the eCRF whether female Subjects are of childbearing potential. 
Female of non-childbearing potential is defined as, but not limited to:

A 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 
Pregnancy testing must be performed on females with childbearing potential, as described in 
Section 8.4.7.
The Subjects must be instructed to use contraceptive methods, as described in Exclusion Criterion 
number 3, throughout the trial and until 1 week after end of treatment.
8.2.5
Diabetes treatment history
Any diabetes medication taken from run-in (Visit 2) to randomisation (Visit 6) must be recorded as 
diabetes medication in the eCRF including the trade name or generic name, and start date. Any 
initiation of diabetes treatment during the trial (e.g. in relation to hospitalisation) must be 
documented in the medical records and entered in the eCRF. 
At randomisation (Visit 6) all diabetes medication should be discontinued and a stop date recorded
in the eCRF. At end of treatment the marketed insulin product which the Subject is being switched 
to must be recorded as concomitant diabetes medication in the eCRF including the trade name or 
generic name, total daily dose and start date.
8.3
Clinical assessments
8.3.1
Concomitant medication
A concomitant medication is any medication, other than trial products and diabetes medication 
(which should be reported in accordance with section 8.2.5) which is taken during the trial, 
including in the screening, run-in, and follow-up periods.
Details of any concomitant medication must be recorded in the eCRF at screening (Visit 1). Any 
changes in concomitant medication must be recorded at each visit or phone contact as they occur. 
The information collected for each concomitant medication includes (at a minimum) trade name or 
generic name, indication, start date, and stop date (or continuation).
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Trial ID: NN1218-3854
Version:
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If a change is due to an AE, then this must be recorded and reported according to section 12. If the 
change influences the Subject’s eligibility to continue in the trial, then the monitor must be 
informed.
8.3.2
Use of Pumps and BG meters
During the trial, from start of the run-in period (Visit 2) until end of treatment (Visit 22), each time 
the Subjects attends a site visit the following data will be uploaded to CareLink Clinical (a web 
based database):

All BG meter data transferred to the pump

All pump data
Data uploaded from the insulin pump include SMPG values, insulin doses, dose calculation related 
data (e.g. carbohydrates, carbohydrate ratio and insulin sensitivity), primes and rewinds, alarms and 
other pump settings. Once data has been uploaded to CareLink Clinical the Investigator will use the 
reports generated to:

Check Subject treatment and compliance

Make adjustments to the Subject’s treatment 

Reconcile data entered in the Subjects diary 
Insulin pump data (including supporting metadata, i.e. pump type) to be used to address objectives 
and endpoints of the trial will be transferred from CareLink Clinical and stored in the trial database. 
Other pump data used for titration or medical surveillance and will be stored in a Novo Nordisk 
data repository.
8.3.2.1
Insulin dose
It is recommended that the bolus dose should be established by Subjects using the Bolus Wizard®
according to their usual practice based on instructions from the Investigator. 
During the trial, from start of the run-in period (Visit 2) until end of treatment (Visit 22), the below 
listed information will be transferred to the trial database. The remaining data will be transferred to 
a data repository at Novo Nordisk.
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN1218-3854
Version:
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Insulin dose data from one day prior to each visit:

Total daily insulin dose (units of insulin) and date for the day

Bolus doses

Date and time

Bolus delivered

Bolus programmed

Bolus type

Bolus duration 

Bolus Wizard® events

Insulin : carbohydrate ratio(s) 

Sensitivity factor(s) 

Active insulin 

Total bolus estimate

Total food estimate

Correction estimate

Carbohydrate input

BG input 

BG target ranges

Low target 

High target 
Insulin dose data from the day of each site visit:

Basal rate settings 

Basal delivery rates 

Date and start times of basal rates 
Insulin dose data from all days:

Temporary basal rate durations and types 

Insulin doses (bolus dose and basal rate) prior to each reported hypoglycaemic and 
unexplained hyperglycaemic episode (as described in section 8.3.3.1 and 8.3.3.2)
During the trial, from start of randomisation (Visit 6) until end of treatment (Visit 22), the 
Investigator must review and adjust the pump settings according to insulin dose adjustment 
guidelines for insulin pump users20,21 to achieve the Subjects’ set glycaemic target.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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Page:
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8.3.2.2
Self-measured plasma glucose
At the start of the run-in visit (Visit 2), the Subject will be provided with a BG meter, including 
lancets, plasma calibrated test stripes for BG meters. The Subject will be instructed verbally on how 
to use the device according to the manufacturer’s instructions. The Subject will also be provided 
with written instructions. Sites will, as necessary, go through the instructions of use with the Subject
during visits to the site. 
Throughout the trial, only the BG meter provided by Novo Nordisk must be used to measure the 
plasma glucose values and to calibrate the blinded CGM when in use, please see section 8.5.1.4.
The BG meter uses test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values (SMPG), 
which will be shown on the display. These are the values to be used for dose adjustments.
The BG meter and the pump should be linked by the site personnel at start of the run-in period 
(Visit 2) by entering the BG meters Identifications number into the pump to ensure SMPGs are 
automatically transferred to the pump. The BG meter must be set to transfer all SMPG values 
automatically.
The Subjects must be instructed to bring their BG meter to the site at every visit. The site personnel 
must upload the data from the BG meter into CareLink Clinical at every site visit.
The Investigator will be able to review the SMPG profiles in a number of CareLink Clinical reports
and use them to evaluate the Subject’s glycaemic control and make adjustments to the pump 
settings in order to optimise insulin titration.
Site personnel will review the diary data, compare it to the CareLink Clinical report, and enter the
reconciled SMPG values related to hypoglycaemic episodes and unexplained hyperglycaemic 
episodes into the eCRF during the site visit.
If clarification of entries is needed or discrepancies between diary and report are found, the Subject
must be questioned and a conclusion made in the Subject's medical record or in the CareLink 
Clinical Report.
For the following episodes additional information needs to be recorded in the diary:

If a SMPG value is ≤3.9 mmol/L [70 mg/dL], the Subject should record the hypoglycaemic 
episode, as detailed in section 8.3.3.1

If a SMPG value is > 3.9 mmol/L [70 mg/dL], but the Subject feels typical symptoms of 
hypoglycaemia and interprets those as indicative of hypoglycaemia but with a SMPG value
> 3.9 mmol/L [70 mg/dL], as detailed in section 8.3.3.1
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Novo Nordisk
Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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EudraCT no.: 2010-024054-11
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
If an SMPG value is ≥16.7 mmol/L [300 mg/dL], the Subject should record the 
unexplained hyperglycaemic episode, if applicable according to section 8.3.3.2
The Investigator needs to check whether the Subject has recorded the episodes in the 
hypoglycaemia and unexplained hyperglycaemia section of the diary, by comparing the diary with 
the CareLink Clinical report. If not, the missing information needs to be filled in by the Subject
during the visit. 
4-point self-measured plasma glucose profile 
Subjects will be instructed to perform 4-point profiles every day during the conduct of the trial 
(from Visit 2 to Visit 22). While wearing the CGM the Subject will continue to perform 4-point 
profiles and must be instructed to use at least two of these measurements for calibration of the 
CGM. The SMPGs should be measured at the following time points:

Before breakfast

Before lunch

Before main evening meal

At bedtime
SMPG measurements before breakfast should be performed in a fasting condition. SMPG 
measurements before lunch, main evening meal, and at bedtime should be performed before any 
bolus insulin infusion. The 4-point profile is part of the 7-7-9-point profiles.
The 4-point profiles will be recorded mainly for insulin titration purposes. 
7-7-9-point self-measured plasma glucose profile 
The Subject will be instructed to perform a 7-7-9-point profile before selected visits; please see the 
flowchart in section 2.
Measurement of the 7-7-9-point profile should be performed on the three consecutive days just 
before the visit as detailed in Table 8–1.
CONFIDENTIAL


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CONFIDENTIAL
Date:
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Trial ID: NN1218-3854
Version:
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Table 8–1
7-point profiles with the additional 9-point profile
Time point
Day -3
7-point 
profile
Day -2
7-point 
profile
Day -1
9-point 
profile
Day of 
visit
Before breakfast
X
X


60 mins after the start of 
breakfast
X
X


Before lunch
X
X


60 mins after the start of 
lunch
X
X


Before main evening meal
X
X


60 mins after the start of 
main evening meal
X
X


At bedtime
X
X


At 4 AM


(7-point profiles indicated as X and the 9-point profile indicated as )
The 7-7-9-point profiles will be used for effect analysis of the trial. The 7-7-9 profile will be 
identified based on Subject’s meal and bed time. An algorithm will be developed in order to select 
the appropriate SMPG measurements from the data transferred from CareLink Clinical using meal 
and bed times from the Subject’s diary.
The Investigator must review the CareLink Clinical report and ensure that SMPG values, that 
correspond to the mealtimes and bedtimes entered in the Subject’s diary, are present. If it is evident 
from the review that the Subject has only taken the daily required 4-point SMPG profile, then the 
Subject should be asked to perform the 7-7-9-point SMPG profile at the next possible opportunity 
along with recording the dates and times of the corresponding days’ meals and bedtimes. The 
review will be documented by signing and dating the CareLink Clinical reports.
8.3.2.3
Change of infusion set and reservoir
Infusion sets (Medtronic Quick-Set®, Medtronic Mio®, Medtronic Silhouette® or Medtronic SureT®
(Easy-set®)) and reservoirs (1.8/3.0 mL) will be provided by Novo Nordisk. Infusion sets and 
reservoirs will be dispensed at site visits indicated in the flowchart in section 2. The type of infusion 
set and size of reservoir should be recorded in the eCRF at each dispensing visit.
The Subjects should be instructed to routinely change infusion set in intervals not exceeding 3 days
(2 days for SureT® (Easy-set®)). Infusion set and reservoir should be changed at the same time. The 
trial products should preferably be administered in the abdominal wall. The Investigator should 
ensure that the Subject is instructed in the following:
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
The infusion region chosen should remain unchanged throughout the trial

The infusion site should be rotated within the same region

The infusion set should preferably be inserted in the same way
The Subject should change infusion set and reservoir at the site under supervision by the 
Investigator at randomisation (Visit 6) and at end of treatment (Visit 22) due to the change from 
pre-trial insulin to trial product. The Investigator should evaluate the skin for any local skin 
irritation or skin infection at every visit at the clinic. Any abnormal clinically significant findings 
should be recorded as an infusion site reaction, as detailed in section 8.3.3.3.
The Subject should be instructed to record all infusion set change in their diary. Investigator should 
ensure that instructions for change are being followed by reviewing the CareLink Report. The 
review must be documented by signing the CareLink Report. Infusion set changes can be 
considered as a ‘routine change’ or ‘non-routine change’.
Routine change
A routine change of the infusion set and reservoir is defined as a regular change performed in no 
more than 3-days intervals (2 days for SureT®(Easy-set®)). Infusion set change at site in the 
morning the day before randomisation (Visit 6) and end of treatment (Visit 22) are considered a 
routine change. All infusion set changes due to Subject’s decision and not due to any problem with 
the pump, the infusion set or glucose values (e.g. inconvenient location of infusion set) must be 
considered a routine change. 
Non-routine change
A non-routine change is defined as any change of infusion set and reservoir not fulfilling the criteria 
for a routine change.
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Infusion sets and reservoirs must be replaced if any change in the insulin solution or occlusion is 
perceived by the Subject, e.g. because of a pump alarm indicating an occlusion or other 
observations pointing towards obstruction of the insulin flow. For every perceived occlusion the 
Subject must:

Check the perceived occlusion with an air shot of at least 10 units of insulin performed 
using the pump’s manual bolus option 
Collection of infusion set change information
All infusion set changes from Visit 2 to Visit 22 will be collected in the Subjects’ diary. For all 
infusion set and reservoir changes the Subject must record the following in the diary:

The date and time of change 

Was the infusion set and reservoir change considered a routine change (Yes/No)? 
In case the above question is answered “Yes” and the infusion set is changed prior to the 3 days (2 
days for SureT®(Easy-set®), the Subject should confirm that the change was not due to any of the 
reasons listed below.
In case the above question is answered “No” the Subject must choose one main reason from the 
below (“a” to “f”) and record the following in the diary.
Was the change due to any of the following:
a) A perceived occlusion by the Subject

Was an air shot performed? (Yes/No)

Was there any insulin flow when an air-shot was performed (Yes/No)?

Did a ‘No delivery’ alarm sound (Yes/No)?

Was there a visible plug obstructing the flow (Yes/No)?
b) Changes in the insulin solution in the infusion set or reservoir (e.g. any visual change in 
colour or presence of particles) ?
c) Any problems related to the infusion set (e.g. leakages, dislodging of infusion set, large air 
bubbles etc.)?
d) Any infusion site reactions (The Subject should be instructed to contact the site in case of 
any infusion site reactions; please see section 8.3.3.3)
e) Any technical issues with the pump (Yes/No)

Did an alarm sound (Yes/No)? 

If “Yes”, specify the alarm
f)
Persistent high BG with no other explanation and not covered by any of the reasons above, 
which made the Subject change the infusion set (Yes/No)?  A persistent high BG is defined 
as a high SMPG level not decreasing by at least 2.8 mmol/L (50 mg/dL) an hour after a 
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN1218-3854
Version:
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Status:
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correction bolus. If the episode fulfils the criteria for unexplained hyperglycaemia an 
Unexplained Hyperglycaemia Form should be completed by the Subjects, as detailed in 
section 8.3.3.2. 
The Investigator or delegated site personnel must review all changes and verify that the time and 
date registered in the diary corresponds to the pump data.
The Investigator should check the CareLink Clinical reports for “no delivery alarms” and ensure 
infusion set changes performed due to “no delivery alarms” have been reported in the diary. 
8.3.2.4
Training in pump use 
At start of the run-in period (Visit 2), the Investigator should ensure that the Subject knows how to 
use the insulin pump and perform appropriate training. The Investigator will, as necessary, repeat 
the training at all visits (Visit 2 to Visit 22) to the site. The Investigator should ensure that the 
Subjects know about the following: 

How to set the time and date on their pump 

Importance of maintaining the correct time and date (e.g. when traveling or entering 
time changes due to daylight savings)

How to ensure the SMPG values are recorded in the pump

Pump settings including settings for basal rates and bolus doses

Dose adjustment of insulin and use of Bolus Wizard®

When to perform a routine and non-routine change of infusion set and reservoir

How to perform an air-shot 

How to report infusion set change information

Filling reservoir from vials including priming of infusion set and checking for air in the 
infusion set before insertion of reservoir

Carbohydrate counting

Troubleshooting in case of hypoglycaemia and hyperglycaemia

When and how to measure ketones (see section 8.3.3.2)

Troubleshooting in case of pump failure or any technical problems with the pump 
The Subjects should be instructed to call the site in case of any episodes of pump failures (e.g. 
technical problems or software problems) as well as to contact the pump manufacturer’s technical 
support. The Investigators should record this pump failure incident in the Subject medical record.
8.3.2.5
Training in diabetes and carbohydrate counting 
During the run-in period, all Subjects should have reinforced diabetes training including 
carbohydrate counting e.g. sessions with a diabetes educator, dietician or qualified site staff (i.e. 
diabetes specialised nurse) according to local practice. 
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It is the Investigators responsibility to ensure that the Subject is adequately trained during the trial 
and has a satisfactory knowledge in: 

Recognition of carbohydrates in commonly eaten foods 

Ability to count the carbohydrate content in typical portions of simple foods

Ability to interpret a nutrition label for carbohydrate content 

Glycaemic targets 

Preventing and treating hypoglycaemia using carbohydrate foods

Ability to sum up the carbohydrate content of a meal
8.3.2.6
Back-up kit
The Investigator must instruct the Subjects to always to carry a back-up kit containing medication 
and spare supplies to be used in case of pump failure. The Subject must be trained in how to use the 
back-up kit and what to bring when leaving home. The back-up kit consists of the following: 

Participation ID card with relevant phone numbers and contact details 

Extra infusion set (including inserter) and reservoir 

Syringes for injection of insulin (for use with vial)

Fast acting glucose preparation (e.g. tablets or powder)

Glucagon for injection (reimbursed by Novo Nordisk affiliate, or supplied by the central 
lab in Russia)

Extra vial with the Investigational Medical Product (IMP) the Subject is randomised to

Extra battery for the insulin pump

Urine sticks for ketone monitoring 
Subjects will also be encouraged to always carry their BG-meter and test strips. 
8.3.3
Adverse events requiring special forms in the electronic case report form
For some AEs the Investigator must fill in special forms in the eCRF. The AEs that require special 
forms in the eCRF are: 

Hypoglycaemic episodes; (section 8.3.3.1)

Unexplained hyperglycaemic episodes; (section 8.3.3.2)

Infusion site reactions; (section 8.3.3.3)

Medication errors (MESIs); (section 12.1.4)
8.3.3.1
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded by the Subject in the diary, when a 
hypoglycaemic episode is suspected. 
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All plasma glucose values:

≤3.9 mmol/L [70 mg/dL] or 

> 3.9 mmol/L [70 mg/dL] occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below throughout the trial from Visit 2 
to Visit 23.
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) or symptoms have been 
resolved in accordance to current guidelines29.
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
Hypoglycaemic Episode form to be completed by the Subjects in the diary. Repeated SMPG 
measurements and/or symptoms will per 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. One 
Hypoglycaemic Episode form is to cover these measurements and/or symptoms. However, each 
Hypoglycaemic Episode form will cover a period of maximum 60 minutes after onset of a 
hypoglycaemic episode.
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 symptom it is considered as a new hypoglycaemic 
episode and a new hypoglycaemic episode form is to be filled in.
Information on the hypoglycaemic episode will be collected partly in Subject’s diary (please refer to 
A in below bulleted text) and partly recorded by the pump automatically (please refer to B in below 
text) The Investigator or designated site personnel must complete the Hypoglycaemic Episode form
in the eCRF for each hypoglycaemic episode by collecting relevant data from the Subject’s diary 
and from the CareLink Clinical Reports. If for any reason the required data is not present in 
CareLink Clinical the Subject’s diary data can be considered as the source data.
At each contact the Investigator must review the CareLink Clinical Report showing low SMPG 
values to ensure consistency with the hypoglycaemic episodes reported in the Subject’s diary
(reconcile). For each hypoglycaemic episode identified in the CareLink Clinical report the 
Investigator must record a Hypoglycaemic Episode form in the eCRF. 
If clarification of entries is needed or discrepancies between diary and report are found, the Subject
must be questioned during the site visit and a conclusion recorded in the Subject's medical record or 
in the CareLink Clinical Report.
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The Subject must be questioned whether any of the low SMPG values listed in the CareLink 
Clinical report and not reported in the diary were severe i.e. whether the Subject was able to treat 
him/herself or not. If the Subject was not able to self-treat it has to be reported as a severe 
hypoglycaemic episode on a Hypoglycaemic Episode form in the eCRF.
Low SMPG values found in the CareLink Clinical report, for non-severe hypoglycaemic episodes 
not having a Hypoglycaemic Episode form comple1ted within 7 days since the SMPG measurement 
should be reported on a Hypoglycaemic Episode form with as much information as possible. Novo 
Nordisk will not query for additional data except for the date, SMPG value and whether the Subject
was able to self-treat or not, due to decreased validity of such data30,31.
The Subject must be re-trained in how to report hypoglycaemic episodes if the Investigator
identifies low SMPG values not reported as hypoglycaemic episodes. The CareLink Clinical report 
must be signed and dated by the Investigator to document that the cross-checking with the diary has 
been performed.
The eCRF Hypoglycaemic Episode form should include the following information:

Start date and time of hypoglycaemic episode A

The SMPG value before treating the episode (if available) and any follow up 
measurementsB
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode.

Whether the episode was symptomatic (Yes/No) A
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if
the Subject experience symptoms later during the episode. 

Whether the Subject was able to treat him/herself A
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode 
should be reported reflecting the most severe degree of hypoglycaemia. 

Date and time of last main meal prior to episode A

Whether the episode occurred in relation to physical activity A

Any sign of fever or intercurrent disease? A

Whether the Subject was asleep when the episode occurred? A
o
If “Yes”, whether the symptoms of the episode woke up the Subject
A collected on the Subjects diary and entered in the eCRF
B to be retrieved from the CareLink Clinical report and entered in the eCRF
The following information related to each hypoglycaemic event will be retrieved directly from the 
insulin dose data transferred from the pump into the trial database:
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Trial ID: NN1218-3854
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
Date and time and dose of last basal rate change prior to episode

Date, time, type (meal bolus, correction or combination) and dose of last bolus insulin 
administration prior to episode
The answer to the question: "Was Subject able to treat him/herself?" must be answered "No" for an 
episode requiring assistance of another person to actively administer carbohydrate, glucagon or take 
other corrective actions. SMPG concentrations may not be available during an event, but 
neurological recovery following the return of SMPG to normal is considered sufficient evidence 
that the event was induced by a low SMPG concentration. 
Oral carbohydrates should not be given if the Subject is unconscious.
If the question "Was Subject able to treat him-/herself?" is answered "No", the following 
information should be recorded (recorded in the Subjects’ diary, to be entered in the eCRF):

Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-
medical person)? A

Where the treatment was administered (i.e. in clinic/emergency room/hospital or other if the 
Subject was treated in a clinic/emergency room/hospital, whether they were transported in 
an ambulance or not)? A

Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, intravenous 
glucose or other)?A

Were symptoms alleviated after administration of treatment? A

Factors contributing to the episode (i.e. physical activity, missed meal, diet changed, 
medication error (i.e. overdose, mix-up between products), miscalculation of insulin dose, 
other factors not listed, or unknown)? A

Did the Subject experience seizure? A

Was the Subject unconscious/comatose? A

Did the Subject experience any of the following symptoms (layman term used in the diary is 
specified in brackets if different from the protocol term)32? A

Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart 
beat)

Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate 
movement)

General malaise: headache or malaise (feeling discomfort/unease)

Other symptoms? A
In the Subjects diary the above questions will be formulated in layman language which is indicated 
in brackets. 
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If the Subject experiences a severe hypoglycaemic episode the Subject should be instructed to 
contact the site staff as soon as possible after recovery for further guidance on titration.
If the hypoglycaemic episode fulfils the criteria for an SAE and/or a medical event of special 
interest (MESI) then an AE form and a safety information form (SIF) must also be filled in, see 
section 12.On the SIF, the following information must be reported by the investigator:

Date and time and dose of last basal rate change prior to episode

Date, time, type (meal bolus, correction or combination) and dose of last bolus insulin 
administration prior to episode
8.3.3.2
Unexplained hyperglycaemic episodes
Any unexplained hyperglycaemic episode with SMPG values ≥16.7 mmol/L [300 mg/dL] and no 
apparent explanation (i.e. no apparent medical, dietary, insulin dosage, or pump failure reason) must 
be recorded in the Subjects’ diary. Symptoms should be treated in accordance with instructions 
from Investigator. If the Subject is referred to any clinic/hospital, elevated urine ketone levels 
should be confirmed by blood ketone measurements and the result should be recorded in the eCRF.
Information on the hyperglycaemic episode will be collected partly in Subject’s diary (please refer 
to A in below text), partly recorded by the pump automatically and entered by the Investigator into 
the eCRF (please refer to B in below text) from Visit 2 to Visit 23. If for any reason the required 
data is not present in CareLink Clinical the Subject’s diary data can be considered as the source 
data.
The Investigator must review the CareLink Clinical Reports in conjunction with the Subjects diary 
(reconcile) and ensure that the unexplained hyperglycaemic episodes reported in the diary are 
present in the report. For each unexplained hyperglycaemic episode (present in the diary and the 
report) the Investigator must complete the Unexplained Hyperglycaemic Episode form in the eCRF.
To document this reconciliation the Investigator must date and sign the CareLink Clinical Report.
If clarification of entries is needed or discrepancies between diary and report are found, the Subject
must be questioned and a conclusion made in the Subject's medical record or in the CareLink 
Clinical Report.
The Unexplained Hyperglycaemic Episode Form should include:
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
Date and time of unexplained hyperglycaemic episode A

The SMPG level before treating the episode (if available) B
The highest value measured during the hyperglycaemic episode will be reported as the 
plasma glucose value for the episode.

Result from urine ketone test, if available (trace, small, moderate, and large) or negative A

Date and time of last main meal prior to episode A
A collected on the Subjects diary, to be entered in the eCRF
B to be retrieved from the CareLink Clinical report and entered in the eCRF
The following information related to each unexplained hyperglycaemic event will be retrieved 
directly from the insulin dose data transferred from the pump into the trial database:

Date and time and dose of last basal rate change prior to episode

Date, time, type (meal bolus, correction or combination) and dose of last bolus insulin 
administration prior to episode
If the unexplained hyperglycaemic episode fulfils the criteria for an SAE, then a SIF must also be 
filled in accordance to section 12. On the SIF, the following information must be reported by the 
investigator:

Date and time and dose of last basal rate change prior to episode

Date, time, type (meal bolus, correction or combination) and dose of last bolus insulin 
administration prior to episode
Multiple (>1) unexplained hyperglycaemic values of SMPG ≥16.7 mmol/L (300 mg/dL) are
considered as one unexplained hyperglycaemic episode until the SMPG is <16.7 mmol/L (300
mg/dL). One episode is set to a maximum of 24 h for the first SMPG ≥ 16.7 mmol/L (300 mg/dL)
All hyperglycaemic episodes that are not unexplained should be reported as AEs in accordance to 
section 12 if the Investigator judges that the hyperglycaemic episode is clinically significant.
8.3.3.3
Infusion site reactions
If suspicion of an infusion site reaction occurs, the Subject should be instructed to call the site staff 
as soon as possible for further guidance.
Infusion site reactions at the site of trial product(s) administration must be recorded as an AE and 
on an Infusion Site Reaction form in the eCRF throughout the trial from start of run-in period (visit
2) to 7-day follow-up (visit 23) and as AEs at follow-up phone contact (visit 24). By questioning the 
Subject the Investigator should obtain the following information and record it in the eCRF:
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
Previous allergy. If “Yes”, specify

History of current reaction(s):

Was the skin normal before the event? (Yes/No) If “No”, specify

Time of appearance of the reaction after infusion set change 

Associated local symptoms (burning, pain, numbness, itching etc.)

Duration of reaction

Have the symptoms been relieved? (Yes / No)

The time and date of the last infusion set change prior to the episode

Clinical evaluation and detailed description including:

The time between appearance of infusion site reaction and Investigator inspection of 
the reaction

The anatomical site of reaction

Size of the reaction at time of examination (widest diameter in cm/in)

Was any treatment(s) given for this condition? (Yes/No, if Yes: antihistamines, 
corticosteroids, analgesics, other)

Was the product stored according to recommendations

Was the infusion site reaction related to the tape/adhesive

Dermatological description of the reaction (redness, swelling, macula, haematoma, bleeding 
etc.)

Were there any risk/confounding factors?(Yes/No)

If yes, personal history of allergies or intolerance (specify), family history of 
allergies or intolerance (specify), other (specify) 
The Investigator has to evaluate whether further actions are needed (e.g. extra visits, discontinuation 
from trial product, dermatologist consultation).
8.3.4
Body measurements
All values of the body measurements will be recorded in the eCRF. 
Height (without shoes) will be measured by the Investigator at screening (Visit 1) only and 
recorded rounded to the nearest centimetre (cm) or inch (in). 
Body weight should be measured in kilograms (kg) or pounds (lb) without overcoat and shoes, and 
wearing only light clothing. Body weight will be recorded to one decimal place. 
The body weight should be assessed on the same calibrated weighing scale equipment throughout 
the trial, if possible. 
BMI will automatically be calculated by the eCRF. 
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8.3.5
12 lead-Electrocardiogram
An ECG-12 lead must be performed locally. The ECG must be interpreted by the Investigator, and 
documented by Investigator signature and date on the ECG print-out. The Investigator must write 
the interpretation of the ECG in the eCRF.
The evaluation must follow the categories:

Normal

Abnormal

Clinically significant? (Yes/No)
Any abnormal and/or clinically significant findings at screening (Visit 1) must be recorded on the 
Concomitant Illness/Medical History form in the eCRF.
Any clinically significant deterioration as well as any new clinically significant signs or symptoms 
should be reported as an AE in accordance with section 12.
If an ECG-12 lead has already been performed within three weeks before screening (Visit 1), and if 
the results are available at the screening visit, the procedure does not need to be repeated. However, 
if clinically warranted as judged by the Investigator, the ECG-12 lead should be repeated. If 
performed before the Subject consents to participate in the trial it must also be stated in the 
Subject’s medical records that this procedure was not performed in relation to the trial.
ECGs performed three weeks in advance of the remaining visits as specified in the flowchart in 
section 2 are acceptable if the results are available at the scheduled visit.
8.3.6
Eye examination
Fundus photography or dilated fundoscopy must be performed by the Investigator, a local 
ophthalmologist, or an optometrist according to local practice. The result of the fundus photography
or dilated fundoscopy will be interpreted locally by the Investigator and must be available prior to 
run-in (Visit 2). To document this, the Investigator must sign and date the result page and write the 
interpretation in the eCRF. 
The evaluation must follow the categories:

Normal

Abnormal

Clinically significant? (Yes/No)
Any abnormal and/or clinically significant findings at screening must be recorded on the Medical 
History/Concomitant Illness Form in the eCRF.
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Any clinically significant deterioration as well as any new clinically significant signs or symptoms 
should be reported as an AE in accordance with section 12.
If fundus photography or dilated fundoscopy has been performed within 90 days before screening 
(Visit 1) and if the results are available at the screening visit, the procedure does not need to be 
repeated. However, if clinically warranted the fundus photography or dilated fundoscopy should be 
repeated at screening (Visit 1). If performed before the Subject consents to participate in the trial, it 
must also be stated in the Subject’s medical records that this procedure was not performed in 
relation to the trial.
Fundus photography or dilated fundoscopy performed within three weeks in advance of Visit 22 is 
acceptable if the results are available at the scheduled visit.
8.3.7
Meal test
The Subject will undergo a standardised liquid meal test at certain visits (see section 2) and will 
have their 30 minute and 1 to 4 hour PPG measured. During that time 6 blood samples will be 
drawn, as specified in the Table 8–2. The samples will be analysed by the central laboratory and the 
values transferred directly into the trial database.
The Subject must attend the meal test visits in a fasting condition, as detailed in section 8.1.7. Bolus 
infusion and other medication which should be taken before, in a relation to or after a meal should 
be withheld until the meal test has been performed. 
The Subject should before the meal test be instructed to: 

Follow normal routine regarding eating and exercise habits on the day prior to the meal test

Refrain from intake of alcohol and use of medications that affect motility (i.e. prokinetics, 
anticholinergics, tricyclic antidepressants) on the day prior to the meal test, unless the 
Subject was on this medication at trial entry and does not change the product or product 
dose

Not to make any changes in the current basal rate setting 4 hours prior to the meal test

Measure a SMPG value at 4 AM the night before and in the morning before the meal test. 
The 4 AM SMPG value and before-meal-test SMPG value is part of the 9-point profile

Change infusion set and reservoir in the morning the day before the meal test

Continue to wear the CGM device until end of meal test

Take a correction bolus according to guidance from Bolus Wizard® if the PG value above 
the target level
There should be a minimum of four hours between any correction bolus dose and the start of the 
meal test. 
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Any hypoglycaemic episodes from midnight before the meal test should be treated and the 
hypoglycaemic episode should be recorded in the diary, please see section 8.3.3.1. In this case, the 
meal test should be re-scheduled within the visit window and at Visit 6 before randomisation to trial 
product.
The Subject should have SMPG values within a range of 4.0-8.8 mmol/L [71-160 mg/dL] before
beginning the meal test and bolus insulin dosing. The SMPG values should be verified and recorded
at the site before starting the meal test. If the Subject is not fasting or the SMPG value is outside the 
range, the meal test should be rescheduled within the visit window.
At randomisation (Visit 6) the Investigator must evaluate the Subjects’ eligibility to continue in the 
trial before the meal test is performed. Only Subjects eligible for randomisation should have the 
Visit 6 meal test performed. Thus, this assessment should not be performed for run-in failure 
Subjects. Randomisation (Visit 6) should not take place until the meal test has ended.
The Subject’s body weight must be measured and a blood sample must be drawn two minutes 
before intake of the standardised liquid meal. The bolus insulin dose should be calculated by the 
Investigator based on the dose level of 0.1 unit/Kg body weight. The calculated dose should be 
rounded to the nearest whole unit. The 0.1 unit/kg dose is chosen as an approximation of a clinically 
relevant bolus dose needed for the given size of a standardised meal for T1DM. Only a normal 
bolus type is allowed. The Investigator must review the pump settings before the start of the meal in 
accordance to section 8.3.2.1. The start of bolus infusion will be defined as time point 0. The 
Subject will have a carbohydrate-rich standardised meal served immediately after bolus infusion 
and must consume this as quickly as possible (within 12 minutes). The Investigator should confirm 
that the Subject consumed the required volume of the standardised liquid meal in the eCRF and 
actual clock time of start of infusion and meal consumption should be noted. 
The standardised meal will be provided by Novo Nordisk. The volume of the standardised meal to 
be consumed should be measured out by the Investigator to be the equivalent to 78 grams of 
carbohydrate.
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Table 8–2
Meal test for Visit 6 and Visit 22
Time point – minutes
Bolus insulin infusion
/ Standardised meal
Blood sample (PG)*
SMPG values
Before start of meal test
X (within target range 4.0-8.8 
mmol/L [71-160 mg/dL])
   -2
X
X (as appropriate to ensure 
Subject’s safety)
   0
X
  30
X
  60
X
120
X
180
X
240
X
End of meal test
X ( Subject’s safety)
*All blood samples must be sent to the central laboratory for analysis
Laboratory results from meal test data will be loaded directly into the trial database by the central 
laboratory. The meal test results will not be provided to the Investigator until after EoT (Visit 24).
The Subject should wait in the clinic to have the blood samples drawn after 30 minutes, 1, 2, 3 and 
4 hours from the start of the standardised meal, as detailed in Table 8–2. During the meal test the 
Subject should be resting in a chair. No smoking or intake of meals and liquids will be allowed 
during the meal test, except for water, which is allowed two hours after intake of the standardised 
meal.
If SMPG values ≤3.9 mmol/L [70 mg/dL] are measured then the hypoglycaemia should be treated 
according to local practice and the meal test should continue according to the Investigator’s 
discretion. The hypoglycaemic episode must be reported. Please see section 8.3.3.1.
The following must be recorded in the eCRF in relation to the meal test: 

Fasting status

Time and value of SMPG measurement confirming that the Subject’s glucose is within the 
target of 4.0-8.8 mmol/L (71-160 mg/dL)

Body weight

Start and end-time of standardised meal

Volume and carbohydrate content of standardised meal consumed

Confirmation that the Subject consumed the required volume of the standardised meal

Batch number of standardised meal consumed

Time of blood samples

Hypoglycaemic episode number, if relevant

Time of intervention and amount of glucose rescue treatment
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After the meal test, the Investigator should make sure that the Subject is safe to leave the site 
confirmed by an additional SMPG value.
When the meal test is finished, the Novo Nordisk provided CGM device should be removed and 
data uploaded to the computer by the Investigator, please see section 8.5.1.5. 
When the meal test at randomisation (Visit 6) is completed, the Subject will be instructed to 
discontinue their current insulin and start treatment with randomised trial product. When the meal 
test at the end of treatment (Visit 22) is completed, the Subject will be switched to a marketed 
insulin product according to Investigator's discretion as detailed in section 5.5.
The treatment should be initiated after the meal test and the Subjects must change infusion set and 
reservoir before the Subject leaves the site. 
8.3.8
Physical examination
The physical examination will be performed as outlined in the flow chart (section 2). Physical 
examination will include examination of:

The respiratory system

The cardiovascular system

The central and peripheral nervous system

The gastrointestinal system, including the mouth

The musculoskeletal system

The skin

The head, ears, eyes, nose, throat and neck
Any abnormal and/or clinically significant findings at screening (Visit 1) must be recorded on the 
Concomitant Illness Form/Medical History in the eCRF, please see section 8.2.3, and the 
Investigator must add a comment in the Subject’s medical record.
Any clinically significant worsening from screening, as well as any new abnormal and clinically 
significant findings, must be reported as an AE in accordance with section 12.
8.3.9
Vital signs
Diastolic blood pressure, systolic blood pressure and pulse should be assessed while the Subject is 
in a sitting position after five minutes of rest. If the Subject is using antihypertensive medication to 
control the blood pressure, then the medication should be taken as usual prior to assessing vital 
signs. 
Vital signs will be assessed according to the flow chart, please see section 2. At screening (Visit 1) 
blood pressure needs to be measured three times and all values should be recorded in the eCRF. The 
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mean value will be calculated by the eCRF, and must be evaluated against the relevant exclusion 
criterion; please see section 6.3.
Any abnormal and/or clinically significant findings at screening (Visit 1) must be recorded on the 
Concomitant Illness/Medical History form in the eCRF.
Any clinically significant deterioration of a pre-existing condition, as well as any new clinically 
significant signs or symptoms, should be reported as an AE in accordance with section 12.
8.4
Laboratory assessments
Except for urine pregnancy testing, ketone measurements (blood/urine, in case of a hyperglycaemic 
episode) which will be performed locally, all laboratory analyses will be performed by a central 
laboratory contracted by Novo Nordisk. The central laboratory will provide all laboratory supplies 
for the sampling and transportation of all blood and urine samples taken during the trial. The central 
laboratory may utilise subcontractors.
A detailed description of the assay methods, reference ranges and procedures for obtaining the 
samples, handling, storage and shipment of the samples are specified in a trial-specific laboratory 
manual provided to the sites by the central laboratory. Information regarding laboratory materials 
such as tubes and labels are also described in there. 
Laboratory samples can be drawn on another day than on the day of the actual visit, as long as it is 
within the visit window, as stated in the flowchart in section 2. 
If laboratory samples need to be retaken due to missing result(s) (e.g. haemolysed, sample leaked 
during transit, sample not being conclusive, lost in transit, etc.), the Subject should be called in for 
resampling. Please see the laboratory manual for further guidance. The repeated blood sampling 
must be marked with the related visit number and missing lab measurements. The laboratory sample
date must be recorded in the eCRF should reflect the actual date of sampling (i.e. the actual visit
date will differ from the assessment date under the same visit.)
Only laboratory samples specified in the protocol should be sent to the central laboratory for 
analysis. If additional laboratory sampling is needed, e.g. to follow up on AEs, this should be done 
at the local laboratory. Samples for the central laboratory will be coded in order to keep Subject’s 
identity anonymous.
Laboratory results will be made available by the central laboratory. 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.
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Final laboratory reports must be reviewed, dated and signed by the Investigator on the day of 
evaluation. It must be specified by the Investigator whether out of range results are clinically 
significant.
If any clinically significant abnormalities occur at screening (Visit 1) and for lipids at randomisation 
(Visit 6), then these must be recorded on the Concomitant Illness/Medical History form in the 
eCRF. Any clinically significant deterioration of a pre-existing condition as well as any new 
clinically significant signs or symptoms should be reported as an AE in accordance with section 12.
Laboratory equipment in the central laboratories may provide standard 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 available laboratory results for concomitant illnesses and AEs and report these according 
to this protocol. The review of laboratory reports must be documented either on the front page of 
the documents and/or in the Subject's medical record.
Laboratory samples will be destroyed after analysis on an ongoing basis. 
8.4.1
1,5-anhydroglucitol 
Blood samples will be drawn to determine the level of 1,5-anhydroglucitol in order to evaluate 
postprandial glycaemic fluctuations. The analysis will be performed by the central laboratory. 
Sampling timings are indicated in the flow chart, please see section 2.
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8.4.2
Biochemistry
Blood samples for biochemistry will be analysed to determine:

ALT

AST

Albumin

AP

Creatinine

Estimated glomerular filtration rate (eGFR)

Potassium

Sodium

Total bilirubin

Total protein
8.4.3
Fasting plasma glucose
FPG is measured in order to evaluate glycaemic control. The Subject must attend visits fasting. 
Please see section 2. For definition of fasting, please see section 8.1.7.
A FPG result ≤3.9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as a 
clinical laboratory adverse event (CLAE) at the discretion of the investigator (see Section 12.1.1).
8.4.4
Haematology
Blood samples for haematology will be collected as indicated in the flow chart (section 2) and 
analysed to determine:

Erythrocytes

Haematocrit

Haemoglobin

Leucocytes

Thrombocytes 
8.4.5
HbA1c
Blood samples will be drawn as specified in the flow chart (section 2) to determine the HbA1c level 
in order to evaluate glycaemic control. 
8.4.6
Lipids
Blood samples for lipids will be as specified in the flow chart (section 2) analysed to determine:
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
Total cholesterol

High density lipoprotein (HDL)

Low density lipoprotein (LDL)
8.4.7
Pregnancy testing
For females of childbearing potential (for definition please see section 8.2.4), a blood human 
Chorionic Gonadotropin (hCG) pregnancy test will be performed at the visits, as detailed in the 
flowchart in section 2. In addition, urine pregnancy tests will be performed locally during the trial if 
a menstrual period is missed or if deemed necessary by the Investigator or required by local law. A 
positive urine pregnancy test should be followed by a confirmatory serum-hCG (central laboratory).
The central laboratory will provide the pregnancy kits for urine testing performed locally at the site.
8.4.8
Urine samples
A urine dipstick microscopic analysis of the following parameters will be performed:

Albumin/creatinine ratio   

Erythrocytes

Protein

Ketones
In case of a clinically significant positive outcome of the dipstick analysis, a microscopic urine 
analysis will be performed. 
8.5
Other assessments and procedures
8.5.1
Continuous glucose monitoring
As indicated in the flow chart in section 2, all Subjects will have CGM profiles generated for 11 to 
13 consecutive days in three periods during the trial. The profiles will be generated by a FDA 
approved and European Union European Conformity (CE) labelled CGM device, developed for 
continuous monitoring of glucose levels in persons with diabetes mellitus.
The CGM device will be blinded to the Subject during the CGM period. Upon upload of CGM data 
at site, the Investigator or delegated staff should review the CGM data and document this according 
to section 8.5.1.5. The CGM data must remain blinded to the Subject prior to End of Treatment visit
(V22). The CGM values generated must not be used for insulin dose titration or for hypoglycaemic 
event reporting, unless otherwise supported by SMPG values.
8.5.1.1
CGM Receiver setting and test upload
The CGM Receiver must be set up before use. The set up includes: date and time setting, entry of 
CGM Transmitter ID and blinding of the CGM Receiver. Upon set up of the CGM Receiver a test 
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upload must be performed by the site personnel to verify correct installation of CGM software and 
correct set up of the CGM Receiver.
Upon set-up of the test upload a CGM device status report will be available in the CGM Software 
system. The CGM device status report shows the CGM Receiver serial number, the CGM 
Transmitter Id, the blinded status, the clock accuracy and verification that no data exists on the 
CGM Receiver prior to use.
The CGM device status report should be printed out, dated and signed by the Investigator and filed 
as a source document in the Investigator’s trial master file. 
8.5.1.2
Eligibility for baseline continuous glucose monitoring
The first fitting visit in the first CGM period (during run-in period Visit 2 - 6) has to be planned 
from 11 to 13 days prior to the randomisation visit in order to register baseline CGM data while the 
meal test is performed at Visit 6.
If the Subject is not eligible to continue the meal test should not be performed at randomisation 
(Visit 6).
At the first fitting visit, the Investigator must ensure that the Subject is eligible to continue in the 
trial, before the CGM device is fitted. 
8.5.1.3
Fitting and removal of the continuous glucose monitoring device
The first fitting visit in the second CGM period (during treatment Visit 6 - 14) has to be planned 
from 11 to 13 days prior to Visit 14 in order to register treatment CGM data while the meal test is 
performed at Visit 14.The CGM device should be fitted to the Subject at the site. The Subject
should perform CGM calibration with SMPG values beginning two hours after the device is fitted.
The fist fitting visit in the third CGM period (during treatment Visit 14- 22) has to be planned from 
11 to 13 days prior to Visit 22 in order to register treatment CGM data while the meal test is 
performed at Visit 22.The CGM device should be fitted to the Subject at the site. The Subject
should perform CGM calibration with SMPG values beginning two hours after the device is fitted. 
If a Subject withdraws consent, a site visit must be scheduled in order to stop the CGM sensor 
measurement and have the CGM device removed from the Subject. 
The CGM sensor has an in-use period of seven days. The CGM device will automatically stop 
recording data exactly 7 days after sensor insertion. Therefore a second sensor will have to be fitted 
to the Subjects after the first seven days period in order to obtain 11 to 13 days data. This should be 
taken into account when scheduling the Subject visits. The CGM device should be worn for at least 
11 days by each Subject and should be planned so the Subject wear the CGM during the meal test. 
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Additional fitting of sensors can be planned if the meal test assessment has to be rescheduled more 
than seven days after the second fitting visit, which means the Subject can be on CGM for more 
than 13 days. If the sensor is dislodged and needs to be replaced or if a visit window must be 
accommodated, additional fitting of sensors can be planned as well. In case of sensor is dislodged, 
the Subject must contact site in order to schedule a new fitting at site or at home according to the 
Investigator’s judgement.
The meal test must not be scheduled on the first or seventh day after having fitted the second 
sensor. Hence the fitting of the sensors must be scheduled accordingly and as a minimum one day 
before the meal test visit; please see Table 8–3. The rationale for this is: firstly, the sensor will not 
start measuring IG until after the 2-hour start-up calibration on the first day, and the Subject will 
have to wait two hours after the sensor insertion before the meal test can start. Secondly, the risk of 
the CGM device stopping before or during the meal test is possible as the CGM device will 
automatically stop recording data exactly seven days after sensor insertion.
Table 8–3
Overview of scheduled CGM sensor fitting and removal days relative to meal 
test based on two sensor periods
Visit
V4/V12/V20 (±3 days)
P5/P13/P21 (±3 days)
V 6/ V22(A*)
Days
-17
-16
-15
-14
-13
-12
-11
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Procedure
Schedule Fitting 1
Schedule Removal 
1 and Fitting 2
Meal test
and Removal 2
*Fitting and removal need to be scheduled as soon as the Investigator becomes aware of premature discontinuation of 
trial product of a Subject.
During the fitting visit, the Investigator will insert a glucose sensor under the Subject’s skin, 
measuring the concentration of glucose in the interstitial fluid every five minutes. The sensor is 
attached to a transmitter and both are worn by the Subject. The transmitter will transfer the IG data 
automatically to the receiver where data is stored.
Removal of the first sensor and fitting of the second sensor can be performed at home by the 
Subject if the Subject has been trained and is able to perform it correctly; according to the 
Investigator judgment.
In order to ensure that the CGM device is measuring correctly the abdominal insulin infusions site 
must be in a distance of minimum 7.6 cm (three inches) from where the CGM sensor has been 
inserted. This will also ensure that local skin reactions, if any, may be related to the correct trial 
product and/or device. 
The Subject should be instructed to remove the CGM device prior to any x-ray, computerised 
tomography (CT) scan or magnetic resonance imaging (MRI).
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After wearing the device for 11 to 13 days, and having performed the meal test assessment, the 
Subject should have the device removed during the scheduled visit; please see flowchart in section
2.
Inserting the sensor and wearing the adhesive patch might cause infection, bleeding, pain or skin 
irritations (redness, swelling, bruising, itching, scarring or skin discoloration). On rare occasions the 
sensor may fracture on rare occasion and a sensor fragment may remain under the skin. Adequate 
medical care must then be provided to the Subject.
For further information on preparing, fitting, and removal of the CGM device, please refer to the
CGM manufacturer’s user guide and quick user guide.
It is not considered an unscheduled visit when Subjects visit the site for a CGM fitting between 
visits. This needs to be documented in the Subject’s medical record.
8.5.1.4
Wearing and calibration of the continuous glucose monitoring device
The CGM assessment should be performed on days representing the Subject’s daily life. Subjects 
should be instructed to avoid:

Changing their diet during the CGM period of 11 to 13 consecutive days unless absolutely 
required

Unusual strenuous exercise during the CGM period

Medications with acetaminophen/paracetamol while wearing the CGM device (these 
medications may affect the performance and readings of the CGM (e.g. false high CGM 
readings))
The accuracy of the CGM system is dependent on calibration values from the Subject. It is therefore 
essential that Subject and site personnel are fully trained in the use of the CGM device according to 
the CGM manufacturer’s user guide or quick user guide. Start-up calibration should be performed 
two hours after fitting the device; two SMPG values are needed for start-up calibration. While 
wearing the device, the Subjects will continue to perform the 4-point and in some cases 7-7-9-point
profiles, (according to section 8.3.2.2) and to use at least two of these SMPG values for calibration
as required according to the CGM manufacturer’s user guide. The SMPG value for calibration 
should be entered directly into the CGM receiver within five minutes of performing the SMPG
value measurement. The device will give an alert if calibration values are missing after 12 hours. 
Some additional measurement may be required for calibration if the SMPG value entered in the 
device is very different from the sensor glucose reading.
The SMPG values used for calibration must be in the range of 2.2 - 22.2 mmol/L [40 - 400 mg/dL].
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The Subjects must be instructed to enter the following into the CGM receiver when wearing the 
CGM device: 

2-hour start-up: Two SMPG values used for calibration and for starting the CGM measuring 
(two hours after the sensor has been inserted)

12 hour update: Two SMPG values used for calibration per day (every 12 hours after the 2-
hour start-up calibration)
The following data should be recorded in the diary when wearing the CGM device: 

Date and time of meals (breakfast, lunch, main evening meal and other meals)
The meal times recorded during the CGM periods should match the timings in the 4-point profile. 
The receiver battery will need to be charged by the Subject during the 11 to 13 day periods, this 
should be done taking into account the transmission range from the transmitter to the receiver (i.e.
six meters (20 feet)).
For further information on wearing and calibrating the CGM device, please refer to the CGM 
manufacturer’s user guide.
8.5.1.5
Uploading of continuous glucose monitoring data
Each CGM period is made up of two sensor periods. Uploading data after the first sensor period is 
optional, but data from both sensor periods must be uploaded within three days after randomisation 
(Visit 6), Visit 14, and end of treatment (Visit 22 / 22A), respectively. The upload will be 
documented by the system directly.
A CGM software program will be provided to allow upload of the CGM data. The following 
information must be entered in the CGM software program when uploading CGM data:

Trial identification (ID)

Subject ID

Visit ID
The following information must be recorded and transferred into the trial database for every CGM 
assessment:
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
Serial number of the CGM device
8.5.1.6
CGM Reports
CGM data capture report
Upon each data upload a CGM data capture report will be available in the CGM Software system. 
The CGM data capture report shows the CGM data capture in percentage and the daily SMPG 
calibration values entered into the CGM receiver for each CGM period.
The CGM data capture in percentage shows whether the Subject has kept the CGM Receiver within 
the required transmission range of six meters (20 feet) from the CGM transmitter and that the 
wireless communication between the transmitter and receiver has worked well. Deviation from this 
requirement should lead to re-training of the Subject or technical troubleshooting.
The daily SMPG calibration values shows whether the Subject has entered their SMPG value twice 
per day (every 12 hour) into the CGM Receiver. Deviation from this requirement should lead to re-
training of the Subject.
The CGM data capture report should be printed out, dated and signed by the Investigator and filed 
as a source document. 
CGM trend pattern report
Upon each data upload a CGM trend pattern report will be available in the CGM Software system. 
The CGM trend pattern report shows the CGM data values measured by the CGM sensor during 
each CGM period.

The CGM data value shows any trends or patterns which could lead to consideration 
whether additional plasma glucose measurements may be needed. 
The CGM trend pattern report should be printed out, dated and signed by the Investigator and filed 
as a source document.
8.5.1.7
The continuous glucose monitoring data 
During the data recording period the CGM device, in which the data is “born”, is regarded as an 
intermediate media, as the data cannot be accessed until uploaded to an electronic system. Data will 
be transferred from the CGM device to an electronic system, and then to the trial database. During 
each CGM period the Subject will be blinded to the CGM data. The Investigator will be able to 
review the CGM data upon data upload at site but the CGM data must remain blinded to the Subject
prior to End of Treatment visit (V22). After the end of the trial, all CGM data for all Subjects at the 
site will be provided to the Investigator and then stored and archived on site.
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8.5.1.8
Pump Data collected during CGM
During all 3 CGM periods the following data will be collected by the pump and electronically 
transferred to the trial database:
Bolus per meal:

Date and time

Carbohydrate counts

Bolus dose
8.5.2
Diary 
Diaries will be used in this trial and handed out to the Subjects as specified in section 2. At Visit 23 
the Subjects have to return their last diaries.
The Investigator must carefully instruct the Subject in how to fill out the diary. The Subject should 
bring the diary at each visit to the site and there the Investigator or delegated site personnel must 
review the diary together with the Subject to ensure consistency/compliance. The information in the 
diary must be transferred into the eCRF by the trial personnel. Review of diaries must be 
documented either on the front page of the diary and/or in the Subject's medical record. If 
clarification of entries is needed or discrepancies in the diary are found, the Subject must be 
questioned and a conclusion made in the Subject's medical record or in the CareLink Clinical 
Report. Care must be taken not to bias the Subject.
The following data will be captured by the Subject in the diary:

Hypoglycaemic episodes

Unexplained hyperglycaemic episodes (including any urine/blood ketone values measured, 
if available)

Change of infusion set and reservoir 

Meal dates and times (breakfast, lunch, main evening meal, other) in relation to 
performance of 7-7-9-point profiles and during the CGM period.
It is the Investigator responsibility to ensure that relevant information from the diary and the 
medical record is transcribed into the eCRF. Furthermore the site personnel must ensure to cross-
check the diary content with the information in the CareLink Clinical Reports.
Any incomplete diary data older than 7 days should not be queried for completeness by the 
Investigator due to decreased validity of such data30,31. Exceptions being safety questions as 
specified in section 8.3.3.1.
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8.5.3
Patient reported outcomes (PRO) questionnaire
Baseline information regarding eating habits, level of exercise, diabetes management and glucose 
levels will be collected at visit 2 (Diet and Activity Information for Type 1 Diabetes). 
It is the responsibility of the Investigator to review the questionnaires for completeness and possible 
AEs (refer to section 12 for AE reporting) immediately following completion. The review must be 
documented either on the documents and/or the Subjects’ medical record. The Investigator should 
solely review the questionnaire for possible AEs and blank fields. If clarification of entries or 
discrepancies in PRO questionnaire 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.
Data from the questionnaire will be transferred into the eCRF by the Investigator, and the 
questionnaire should be kept as source documentation at the site
8.6
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: To ensure treatment compliance, the Investigator will at each visit assess the 
Subject’s compliance by evaluating the drug accountability, glycaemic control, adherence to the 
visit schedule, completion of the Subject’s diary, and the SMPG values in the CareLink Clinical 
Report. If a Subject is being non-compliant with the treatment, then the Investigator must discuss 
this with the Subject and emphasise the importance of being in compliance. 
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
Trial product must not be used if it does not appear clear and colourless. 
9.1
Trial products
Table 9–1
The following will be provided by Novo Nordisk A/S, Denmark
Trial product
Strength
Dosage form
Route of 
administration
Faster aspart 
(IMP, blinded )*
100 U/mL
Solution for 
injection in vial,
10 mL
s.c.
Insulin aspart (NovoRapid®)
(IMP, blinded ) 
100 U/mL
Solution for 
injection in vial,
10 mL
s.c.
* Faster aspart is the short name for faster-acting insulin aspart and only the short name will be used as text on the 
labels. Trial products are visually identical.
9.2
Labelling
Labelling of the trial products will be in accordance with Annex 1333, 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 IV/WRS. Dispensing unit numbers (DUNs) will be distributed to the sites 
according to enrolment and randomisation. 
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9.3
Storage
Table 9–2
Storage of trial products
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use time*
Faster aspart
Store in refrigerator (2°C – 8°C)
Do not freeze
Protect from light
Store below 30°C
Do not refrigerate
Do not freeze
Protect from light
Use within 4 weeks
Insulin aspart 
(NovoRapid®) 
Store in refrigerator (2°C – 8°C)
Do not freeze
Protect from light
Store below 30°C
Do not refrigerate
Do not freeze
Protect from light
Use within 4 weeks
* In-use time starts when vial is removed from refrigerator (dispensing at site).
When the IMP is in the pump reservoir the in-use condition is to keep it below 37°C for a maximum 
of 6 days. Therefore the IMPs in the pump reservoir should be discarded after no more than 6 days 
of use or after exposure to temperatures that exceeds 37°C15.
The Investigator must ensure the availability of proper storage conditions, and also 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).
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.
Sensors for the CGM system should not be exposed to excessive heat or direct sunlight. Sensors not 
in use must be stored in accordance with the manufacturer instructions and must be temperature 
monitored according to the temperature range on the labelling. If the sensors are stored in a cool 
environment, allow the sensors to warm to room temperature for about 15 minutes to prevent 
condensation before insertion. Discard sensors past the expiration date on label, if the package is 
damaged, or the seal is broken.
9.4
Drug accountability and destruction
Drug accountability is the responsibility of the Investigator. The Investigator will perform the drug 
accountability using the IV/WRS Drug Accountability Module.
Subjects are instructed to return all used, partly used and unused trial product at each dispensing 
visit, and then finally at end of treatment (Visit 22/22A). Please see flowchart in section 2 for 
timing of the dispensing visits.
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Returned trial product (used, partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
The monitor will reconcile the drug accountability using the IWRS Drug Accountability Module.
The monitor is responsible for ensuring that there is a process for the destruction of used and 
unused trial product. The destruction of trial product will be recorded on a Destruction Form, which 
will be signed by the person responsible for destruction. Destruction of product must be 
documented.
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
9.5
Auxiliary supplies
The Subject will use their own insulin pump during the trial.
9.5.1
Auxiliaries supplied by Novo Nordisk

Bayer Contour® Next Link meters (CE approved), and strips, lancets and control solution
for BG meters

Insulin reservoirs (1.8/3.0 mL) 

Infusion sets (Medtronic Mio®, Medtronic Silhouette®, Medtronic Quick-set® or Medtronic 
Sure-T® (Easy-set®) will be reimbursed or supplied by Novo Nordisk according to local 
regulations

Standardised liquid meal (for the meal test)

CGM supplies (please see section 9.5.3)

Urine sticks for ketone measurement 

Syringes for injection of insulin (for use with vial)

Extra vial with the IMP the Subject is randomised to

Extra battery for the insulin pump

A fast-acting glucose preparation (e.g. tablets or powder)
9.5.2
Auxiliaries supplied by site

Glucagon for injection (reimbursed by Novo Nordisk affiliate, supplied by the central lab in 
Russia)
9.5.3
Continuous glucose monitoring equipment supplies
Novo Nordisk will provide the following:
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
CGM device (receiver and transmitter) 

CGM user guide and quick user guide (for site use) 

Instructions for Subjects
CGM equipment should be returned to Novo Nordisk at end of treatment (Visit 22). 
The CGM manufacturer will provide the following:

CGM installation link to CGM software

CGM sensors (customs clearance must be expected)

CGM training (webinar or on-site)
A PC with internet connection must available at site (same PC as used for the eCRF system can be 
utilised). For further instruction and requirements, please see CGM manufacturer’s user guide.
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10
Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS is used for:

Screening

Screening / Run-in failure

Randomisation

Medication arrival

Dispensing

Discontinuation from trial product

Completion

Code break

Drug accountability

Data change
IV/WRS user manuals will be provided to each trial site.
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11 Randomisation procedure and breaking of blinded codes
At randomisation (Visit 6) the Subject will be randomised to either faster-acting insulin aspart or 
NovoRapid® in a 1:1 manner to the two different treatment arms described below using the 
IV/WRS:

Faster-acting insulin aspart

NovoRapid® 
The randomisation will be stratified based on the following factor:

Use of own CGM (Yes/No)
11.1
Breaking of blinded codes
The code for a particular Subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the Subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document.
The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) immediately 
after the code is broken.
When the code is broken, the treatment allocation will be accessible to the Investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at the time of code break the 
IV/WRS helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken the Subject must be discontinued from trial product and a 
discontinuation session must be completed in IV/WRS.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse events
An AE is any untoward medical occurrence in a Subject administered a product, and which does not 
necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:

A clinically significant worsening of a concomitant illness

A clinical laboratory AE (CLAE): a clinical laboratory abnormality which is clinically 
significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due 
to the abnormality
The following should not be reported as AEs:

Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness)

Pre-planned procedures unless the condition for which the procedure was planned has 
worsened from signing the SI/IC

Non-serious hypoglycaemia is an AE but is reported on a Hypoglycaemic Episode Form
instead of on an AE Form; please see section 8.3.3.1

Non-serious unexplained hyperglycaemias are AEs, but are reported on a Unexplained 
Hyperglycaemic Form instead of on an AE Form; please see section 8.3.3.2
The following three definitions are used when assessing an AE:

Severity 

Mild - no or transient symptoms, no interference with the Subject's daily activities

Moderate - marked symptoms, moderate interference with the Subject's daily 
activities

Severe - considerable interference with the Subject's daily activities; unacceptable

Causality 
The following terms are used when assessing the relationship between an AE and the relevant 
trial product(s): 
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
Probable - good reason and sufficient documentation to assume a causal 
relationship

Possible - a causal relationship is conceivable and cannot be dismissed

Unlikely - the event is most likely related to aetiology other than the trial product

Final outcome:

Recovered/resolved - the Subject has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related 
activity after the Subject signed the informed consent

Recovering/resolving - the condition is improving and the Subject is expected to 
recover from the event. This term is only applicable if the Subject has completed the 
trial or has died from another AE

Recovered/resolved with sequelae - the Subject has recovered from the condition, 
but with lasting effect due to a disease, injury, treatment or procedure. If a sequela 
meets an SAE criterion, the AE must be reported as an SAE

Not recovered/not resolved - the condition of the Subject has not improved and the 
symptoms are unchanged, or the outcome is not known

Fatal - this term is only applicable if the Subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a Subject before he/she died should 
be assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved 
with sequelae" or "not recovered/not resolved". An AE with fatal outcome must be 
reported as an SAE

Unknown - this term is only applicable if the Subject is lost to follow-up
12.1.2
Serious adverse events
A 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
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The following adverse events must always be reported as a Serious Adverse Event 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 ALT or AST >3 x UNL and total bilirubin > 2 x UNL, where 
no alternative aetiology exists (Hy’s law)
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 active of physical stay, or 

Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial-related and social 
purposes do not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital 
admissions for surgical procedures, planned before trial inclusion, are not considered AEs or 
SAEs
c. A substantial disruption of a Subject's ability to conduct normal life functions (e.g. following the 
event or clinical investigation the Subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life)
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse
12.1.3
Non-serious adverse events
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medical events of special interest
A MESI is an event which, in the evaluation of safety, has a special focus. A MESI is an AE (SAE 
or non-serious AE) which fulfils the below defined MESI criteria.

Medication errors concerning trial products:

Administration of wrong drug (Note: Use of wrong DUN is not considered a 
medication error.)

Wrong route of administration, such as intramuscular instead of s.c.

Administration of an overdose with the intention to cause harm (e.g. suicide attempt)
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
Accidental administration of a lower or higher dose than intended.  The
administered dose must deviate from the intended dose to an extend where clinical 
consequences for the trial Subject were likely to happen as judged by the 
Investigator, although not necessarily did happen
12.1.5
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:

The physical or chemical appearance of trial products in the vials (e.g. discoloration, 
particles or contamination)

The 10 mL vial packaging material (e.g. leakage, cracks, rubber membrane issues or errors 
in labelling text)
However, colour change, particle or crystal formation in the infusion set and reservoir are not 
considered as a technical complaint and thereby not to be reported to Customer Complaint Centre, 
Novo Nordisk.
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 SI/IC until the last phone 
contact/site visit. The events must be recorded in the applicable eCRF form in a timely manner; see 
timelines below and in Figure 12–1.
During each contact with the trial site staff, the Subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
All AEs, observed by the Investigator or Subject, must be reported by the Investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: 

Faster-acting insulin aspart: IB, current version7and updates thereof

Insulin aspart (NovoRapid®): Company Core Data Sheet (CCDS) Current version 
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 SIF must be completed in addition to the AE Form. If several symptoms or diagnoses 
occur as part of the same clinical picture, one SIF can be used to describe all the SAEs. 
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MESIs, regardless of seriousness, must be reported using the AE Form, the SIF and a MESI Form. 
The MESI Form is a form tailored to collect specific information related to the individual MESI. 
The AE Form for a non-serious AE not fulfilling the MESI criteria should be signed when the event 
is resolved or at the end of the trial.
12.2.1
Timelines for initial reporting of adverse events
The Investigator must complete the following forms in the eCRF within the specified timelines:

SAEs - The AE Form within 24 hours and the SIF within five calendar days of the 
Investigator's first knowledge of the SAE
Both forms must be signed within seven calendar days from the date the information was entered in 
the eCRF:

SAEs fulfilling the MESI criteria - In addition to above, the MESI Form within 14 
calendar days of the Investigator's first knowledge of the AE

Non-serious AE fulfilling the MESI criteria - The AE Form, SIF and MESI Form within 
14 calendar days of the Investigator's first knowledge of the event
If the eCRF is unavailable, the concerned AE information must be reported on paper forms and sent 
to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available, the Investigator must transcribe the information on the appropriate forms 
in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the Investigators trial file. 
Figure 12–1
Initial reporting of AEs 
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12.2.2
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 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 
Institutional Review Boards/Independent Ethics Committees (IRBs/IECs) of trial product-related 
SUSARs in accordance with local requirement and GCP1, unless locally this is an obligation of the
Investigator.
12.2.3
Novo Nordisk products used as concomitant medication
If a SAE and/or MESI is considered to have a causal relationship with a Novo Nordisk marketed 
product used as concomitant medication in the trial, it is important that the suspected relationship is 
reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. 
Novo Nordisk may need to report this 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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
Non-serious AE fulfilling the MESI criteria - Non-serious AE fulfilling the MESI criteria 
must be followed as specified for non-serious AEs. Follow-up information on MESIs 
should only include new (e.g. corrections or additional) information and must be reported 
within 14 calendar days of the Investigator’s first knowledge of the information. This is 
also the case for previously reported non-serious AEs which subsequently fulfil the MESI 
criteria. 

The Investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. A worsening of an unresolved AE must be reported as follow-up with 
re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
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: 

Faster-acting insulin aspart, 100 U/mL, 10 mL vial

Insulin aspart (NovoRapid®), 100 U/mL, 10 mL vial
which occur from the time of first usage of the product until the time of the last usage of the product
in the treatment period must be collected and sent to Customer Complaint Centre, 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, SAEs, and/or 
MESI.
Technical complaints must be reported on a separate Technical Complaint Form in the eCRF for 
each product listed. If the technical complaint involves more than one batch/code number or more 
than one DUN, a Technical Complaint Form for each batch/code number or for each DUN must be 
completed in the eCRF.
The Investigator must complete the Technical Complaint Form within the following timelines of the 
trial site obtaining knowledge of the technical complaint:

Technical complaint assessed as related to an SAE within 24 hours

All other technical complaints within five 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 
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Centre, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available, the Investigator must re-enter the information on the appropriate forms in the eCRF.
Technical complaints related to pumps should be addressed to the pump manufacturer, please see 
section 8.3.2.4.
12.4.2
Collection, storage and shipment of technical complaint samples
The Investigator must collect the technical complaint sample and notify the monitor within five 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Centre, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the Technical Complaint Form must 
be sent with the sample.
The Investigator must ensure that the technical complaint sample contains the batch/code number 
and, if available, the DUN.
If the technical complaint sample is unobtainable, the Investigator must specify on the Technical 
Complaint Form in the eCRF why it is unobtainable.
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage, as detailed in section 9. 
12.5
Pregnancies
12.5.1
Pregnancies in female Subjects
Female Subjects must be instructed to notify the Investigator immediately if they become pregnant
during the trial (e.g. from start of the run-in period (Visit 2) until end of treatment (Visit 22)). The 
Investigator must report any pregnancy in Subjects who have received trial product(s).
The Investigator must follow the pregnancy until the pregnancy outcome and the new-born infant is 
one month of age.
The Investigator must report information about the pregnancy, pregnancy outcome, and health of 
the new-born infant(s), as well as AEs in connection with the pregnancy and AEs in the foetus and 
new-born infant.
The following must be collected and reported by the Investigator to Novo Nordisk electronically 
(e.g. in PDF format) or by fax or courier:
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
Reporting of pregnancy information - Information about the pregnancy and pregnancy 
outcome/health of the new-born infant(s) has to be reported on Maternal Form 1A and 1B, 
respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, 
further information has to be reported for the female Subject on Maternal Form 2. In 
addition, information from the male partner has to be reported on the Paternal Form, after an 
informed consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
Investigator's first knowledge of initial or follow-up information

Reporting of AE information - The Investigator has to report AEs in connection with the 
pregnancy as well as in the foetus and new-born infant(s). The SAEs that must be reported 
include abnormal outcome, such as foetal death (including spontaneous abortion), and 
congenital anomalies (including those observed at gross examination or during autopsy of 
the foetus), as well as other pregnancy complications fulfilling the criteria of an SAE
Forms and timelines for reporting AEs:

Non-serious AEs:

Paper AE Form* within 14 calendar days of the Investigator's first knowledge of 
the initial or follow-up information to the non-serious AE

SAEs: 

Paper AE Form* within 24 hours of the Investigator's first knowledge of the SAE

Paper SIF within five calendar days of the Investigator's first knowledge of the 
SAE

SAE follow-up information to the AE Form and/or SIF within 24 hours of the 
Investigator's first knowledge of the follow-up information
* It must be clearly stated in the AE diagnosis field on the AE Form if the event occurred in the 
Subject, foetus or new-born infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and Pregnancy 
Forms must be responded to by the Investigator within 14 calendar days from the date of receipt 
of the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
During treatment with insulin, there is a risk of hypoglycaemia (see section 8.3.3.1). Symptoms of 
hypoglycaemia usually occur suddenly and may include cold sweat, nervousness or tremor, anxious 
feelings, unusual tiredness, confusion, difficulty in concentration, excessive hunger, temporary 
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vision changes, headache, nausea and palpitation. Prolonged or severe hypoglycaemia can lead to a 
loss of self-control, spasms, and/or unconsciousness and, in extreme cases, death.
Asymptomatic hypoglycaemia and symptoms of hypoglycaemia should be treated with 
carbohydrates. Mild to moderate symptoms can be treated by ingestion of carbohydrate (for 
example, juice). Severe hypoglycaemia resulting in the loss of consciousness should be treated with 
parenteral glucose, glucagon or dextrose.
For further details, please refer to the current version of faster-acting insulin aspart IB7 and for 
NovoRapid® EU Summary of product characteristics, please refer to the current versions of the 
SmPC14 or U.S. Novolog® Label Information15.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal faster-acting insulin aspart safety committee to perform
ongoing safety surveillance. The faster-acting insulin aspart safety committee may recommend 
unblinding of any data for further analysis, and in this case an independent ad hoc group will be 
established in order to maintain the blinding of the trial personnel.
12.7.2
Data monitoring committee
The independent data monitoring committee (DMC) is established to review and evaluate 
accumulating data from an ongoing clinical trial in order to protect the safety of the Subjects and to 
evaluate the evolving risk-benefit if required. The DMC will perform an interim evaluation of the 
relevant safety data on an ongoing basis including possible infusion set occlusions.
The DMC is composed of permanent members who are independent of Novo Nordisk and will 
cover relevant medical and biostatistics specialities, and they may request assistance from 
additional ad hoc members, if needed. The DMC will review relevant safety data on an ongoing 
basis, and will recommend to Novo Nordisk whether to continue, modify, or terminate the trial, as 
necessary. The composition of the DMC, objectives of the surveillance, meeting frequency, data to 
be analysed at the meetings, time-point for interim evaluations and responsibilities with regard to 
information (such as meeting minutes) will be described in a DMC charter.
The DMC members will only have direct contact with the Novo Nordisk Global Safety department 
through the safety surveillance representatives, and will have no direct interaction with those in trial 
management. The DMC recommendations should be addressed directly to the Novo Nordisk Global 
Safety department and the internal Novo Nordisk safety committee for faster aspart. It is the 
responsibility of the Novo Nordisk internal safety committee for faster aspart to take action(s) for 
Subject safety based on the DMC recommendations. DMC concerns relating to trial processes 
should be communicated to trial management via the Novo Nordisk Global Safety department.
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13 Case report forms
Novo Nordisk will provide a system for an eCRF. This system and support services to the system 
will be supplied by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:

Pregnancy Form

Technical Complaint Form
In addition paper AE Forms, Safety Information Form will be provided. These must only be used 
when access to the eCRF is revoked. 
Print legibly on the paper CRF forms 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
13.1.1
Electronic case report form
Corrections to the eCRF data may be made by the Investigator or the Investigator's delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the Investigator's delegated staff after the date the Investigator has signed 
the case book, the case book must be signed and dated again by the Investigator.
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13.1.2
Paper case report form
Corrections to the data in CRFs 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). 
Corrections necessary after the CRFs have been removed from the trial site must be documented on 
a Data Clarification Form (DCF) or on a Monitor-Initiated Discrepancy Form (MIDF). 
13.2
Case report form flow 
The Investigator must ensure that data is recorded in the eCRF/paper CRF as soon as possible, 
preferably within five days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
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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 (SDV) and to 
monitor drug accountability. The first monitoring visit will be performed as soon as possible after 
FSFV at the trial site and no later than 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 GCP1, but will not exceed 8 weeks.
14.1
Source data verification
The monitor must be given direct access to 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).
Further, it must be possible to verify the Subject’s diabetes history (diagnosis of diabetes and 
diabetes treatment) in source documents 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 records from relevant party e.g. primary physician or diabetes clinic.
All data must be verifiable in source documentation other than the eCRF.
Unless specified otherwise all data recorded in the PRO and the Subject diary is considered source 
data including:

Hypoglycaemic episodes

Unexplained hyperglycaemic episodes (including any urine/blood ketone values measured, 
if available)

Change of infusion set and reservoir 

Meal dates and times (breakfast, lunch, main evening meal)
CareLink Clinical is considered source for all data captured from the pump and the BG meter.
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All data recorded in the CGM is considered source including:

Sensor time, sequence no.

IG, calibrated

Calibration value

Serial no.
For all data recorded, the source document must be defined in a source document agreement at each 
trial site. There should 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 diaries and/or PROs must not be removed from the trial site.
The monitor will ensure that the eCRF is completed and that paper CRFs are collected.
Monitors must 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 CRF. 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 addressing any actions to be taken.
14.1.1
CGM source data verification 
The following should be monitored from the diary data:

Date and actual clock time of meals (breakfast, lunch, main evening meal and other meals)
The following should be monitored from the CGM reports:

The CGM device status report has been printed, dated and signed by site staff

The CGM data capture report has been printed, dated and signed by site staff

The unblinded CGM trend reports have been printed, dated and signed by site staff

The CGM receiver serial number in the CGM device status report has been recorded in the 
eCRF

The CGM receiver mode in the CGM data capture report must be blinded

Any SMPG values ≤ 3.9 mmol/L (70 mg/dL) in the CGM data capture report has been 
recorded as a hypoglycaemic episode in the eCRF
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14.2
Continuous glucose monitoring procedures
During the course of the trial, the monitor will ensure that: (a) the CGM procedures have been 
adhered to, (b) all issues have been recorded and (c) monitoring and SDV has taken place. The 
monitor will have to verify that CGM data has been recorded and uploaded in accordance with the 
CGM manufacturer’s user guide.
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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 an external Clinical Research Organisation (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 from the laboratory performing the 
analyses. 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 identification number. 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.
Data collection
Insulin pumps, BG meters and CGM devices have made it possible to collect and transfer data 
electronically. The technology has been developed with the aim of ensuring optimal treatment and 
data driven decision between patient and physician. However, these devices create and collect many 
data designed for the surveillance and adjustment of patient’s treatment that are not specified for 
collection of data specifically for this clinical trial. 
This has led to the necessity to specify:

Which data points are collected by the device (insulin pump, BG meter and CGM device) 
that will be used for statistical analysis (inferential and descriptive) in order to address the 
objectives and endpoints of the trial 

Which data points are collected/transferred that are not required or used per protocol (and 
therefore not cleaned but only stored at a data repository) 

Which data points are collected by the device that are used for daily surveillance and 
adjustment of patient’s treatment only (and therefore not cleaned but only stored at a data 
repository)

Which data points required by the protocol will have to be captured in other sources if not 
captured by the device
Any required data points not captured by the device (insulin pump, BG meter or CGM device) will 
have to be collected from another source such as a paper diary. As paper diary data will be 
supportive to the data collected by the device it may require data points to be present in more than 
one location in order for the paper diary data to be linked with the device data. 
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It has been defined for cases where the same data point exists in more than one location which data 
point should be considered the source. Additional details regarding collection and handling of data 
can be found in the Data collection and handling strategy document34.
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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. 
CareLink Clinical is a computerised system provided by Medtronic to be used to capture and 
process insulin pump data. This system is described in a data collection and handling strategy. The 
use and control of this system will be documented. 
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17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock. 
General considerations
In general, for endpoints evaluated as a change from baseline and/or where a baseline adjustment is 
made, baseline is defined as information collected at randomisation (Visit 6). In case a measurement 
is not available at randomisation, the most recent measurement prior to randomisation will be used 
as baseline.
Two observation periods are defined, “in-trial” and “on-treatment”, and it will be specified which 
period each analysis will use.

In-trial: the observation period from date of randomisation and until last trial-related 
Subject-site contact. The in-trial observation period includes data collected after 
discontinuation of randomised treatment.

On-treatment: the observation period from date of first dose of randomised 
NovoRapid®/faster-acting insulin aspart and no later than 7 days after the day of last dose of 
randomised NovoRapid®/faster-acting insulin aspart. The on-treatment observation period 
includes data collected up to and including 7 days after discontinuation of randomised 
treatment.
All efficacy endpoints will be summarised and analysed using the full analysis set (FAS), unless 
otherwise stated. Safety endpoints will be summarised using the safety analysis set and analysed 
using the FAS.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(LSMeans) for change from baseline, if applicable. Estimated mean treatment differences (or ratios) 
will be presented together with two-sided 95% confidence interval (CI) for all endpoints analysed 
statistically. 
For endpoints measured over time, mean values will be plotted to explore the trajectory over time. 
For survival endpoints (e.g. drop-out pattern) Kaplan-Meier plots are presented for each treatment. 
Data collected before randomisation (Visit 6) will only be summarised descriptively.
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Estimands
The primary objective, to confirm the effect of CSII treatment with faster-acting insulin aspart in
terms of glycaemic control by comparing it to CSII treatment with NovoRapid®, in adults with 
T1DM, will be assessed by the change from baseline in HbA1c using a non-inferiority approach. 
More specifically the upper limit of the 95% confidence interval for the difference between faster-
acting insulin aspart and NovoRapid® should be compared to a non-inferiority margin of 0.4%. If it 
is below or equal to 0.4% non-inferiority will be considered established and effect demonstrated. 
The trial also aims to compare CSII treatment with faster-acting insulin aspart to NovoRapid® for a 
number of confirmatory secondary endpoints. The family-wise type I error rate will be controlled in 
the strong sense using a hierarchical (fixed sequence) testing procedure. This is based on a priority 
ordering of the null-hypotheses, and testing them in this order using the two-sided 95% confidence 
interval approach until an insignificant result appears. The effect is that rejection of a null 
hypothesis only will be considered for analyses where all previous null-hypotheses have been 
rejected in favour of faster-acting insulin aspart. 
The steps in the hierarchical testing procedure are as follows:
Step 1 (Primary analysis): HbA1c non-inferiority of faster-acting insulin aspart versus NovoRapid®
Step 2: 1-hour PPG increment (meal test) superiority of faster-acting insulin aspart versus 
NovoRapid®
Step 3: HbA1c superiority of faster-acting insulin aspart versus NovoRapid®
Step 4: 1,5-Anhydroglucitol superiority of faster-acting insulin aspart versus NovoRapid®
Step 5: time spent in low IG (≤3.9 mmol/L [70 mg/dL]) superiority of faster-acting insulin aspart 
versus NovoRapid®
Primary estimand (de facto)
The primary estimand is defined as the treatment difference between Subjects randomised to CSII 
treatment with faster-acting insulin aspart and CSII treatment with NovoRapid® in adults with 
T1DM assessed by change from baseline in HbA1c 16 weeks after randomisation for all randomised 
Subjects regardless of treatment discontinuation or use of ancillary therapies. This estimand is a de 
facto estimand addressing effectiveness.
The primary estimand assesses the expected benefit that a Subject can achieve if prescribed to CSII
treatment with faster-acting insulin aspart as compared to CSII treatment with NovoRapid® in 
adults with T1DM. By not putting any restrictions on the randomised treatment adherence, this 
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estimand aims at a difference as close as possible to the one that can be expected in real-world 
clinical practice, provided that the treatment adherence and use of ancillary therapies reflects 
clinical practice. Thereby the primary estimand provides a clinically relevant treatment difference 
for clinicians concerning the glycaemic effect of CSII treatment with faster-acting insulin aspart as 
compared to CSII treatment with NovoRapid® in the day to day life in adults with T1DM.
Secondary estimand (de jure)
Unlike the primary estimand, the secondary estimand is defined as the treatment difference in 
change from baseline in HbA1c 16 weeks after randomisation between CSII treatment with faster-
acting insulin aspart and CSII treatment with NovoRapid® in adult Subjects with T1DM if Subjects 
continue on-treatment until 16 weeks. This estimand is a de jure estimand, addressing efficacy. 
As an alternative to the primary estimand, this estimand provides a more hypothetical treatment 
difference, but may also be the most sensitive for a non-inferiority comparison, since the marketed 
product that Subjects discontinuing from randomised treatment are switched to may equalize the 
treatment effect. 
The two estimands will be repeated for the endpoints:

1-hour PPG increment (meal test)

1,5-Anhydroglucitol

time spent in low IG (≤3.9 mmol/L [70 mg/dL]) (CGM)
17.1
Sample size calculation
The primary objective of the trial is to confirm the effect of CSII treatment with faster-acting insulin 
aspart in terms of glycaemic control by comparing it to CSII treatment with NovoRapid® in adults 
with T1DM, using a non-inferiority approach. The non-inferiority margin of 0.4% (absolute) was 
chosen as described in section 5.2.1. The statistical evaluation will be done as described in section 
17.3. 
The trial also aims to confirm superiority of CSII treatment with faster-acting insulin aspart for a 
number of secondary confirmatory endpoints using the hierarchical testing procedure as described 
in section 17 (General considerations).
The sample size is determined to ensure sufficient power for the first step and second step in the 
hierarchical testing procedure. 
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In previous exploratory trials where CSII treatment with faster aspart has been investigated, the 
completion rates have been high. Therefor it will not be unexpected that treatment discontinuation 
might be as low as 4% where trial discontinuation constitutes half of these.
The power for the non-inferiority step is based on a t-statistic under the assumption of a one-sided 
test of size 2.5 %. A mean treatment difference of -0.1% for the comparison between faster-acting 
insulin aspart and NovoRapid® is expected. As trials in this population where Subjects are using 
insulin pumps and where data from treatment withdrawn subjects is retrieved is limited, a 
conservative estimate of the standard deviation (SD) in change from baseline in HbA1c of 0.8% was 
chosen.
For determination of power in the second step in the hierarchical testing, where change from 
baseline in 1-hour PPG increment 16 weeks after randomisation is compared between faster-acting 
insulin aspart and NovoRapid® a t-statistic with a two-sided test of size 5.0% is used, where the 
treatment difference is expected to be at least 0.9 mmol/L [16 mg/dL]. The SD=3.4 mmol/L [62 
mg/dL] in change from baseline in 1-hour PPG increments 16 weeks after randomisation based on 
laboratory analysed PG in a standardised meal test will be considered reasonable, based on prior 
trials. 
The power calculation is done using proc power in SAS Version 9.4. Please refer to Table 17–1 for 
assumption of the sample size calculation. 
Table 17–1
Specifications assumed for sample size calculation
Statistical 
test
Significance
Level
Analysis 
Population
Non-inferiority 
Margin
SD
Mean 
Difference
Randomisation
Scheme
Step 1
2-group t-test
One-sided 2.5%
FAS
0.4% (absolute) 0.8
-0.1
1:1
Step 2
2-group t-test
Two-sided 5.0%
FAS
NA
3.4
0.9
1:1
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In Table 17–2, the sensitivity of the sample size to the power in Step 1 and Step 2 is shown for three 
different sizes of FAS. Three different choices of the mean difference are used to calculate the 
power in Step 2.
Table 17–2
Sensitivity of sample size to power in step 1 and step 2
Step 1
Step 2
N 
Total
N per 
arm
Mean 
Diff
SD
Step 1 
Power 
(%)
Null 
Diff
Mean 
Diff
SD
Step 2 
Power 
(%)
FAS
FAS
-0.1
0.80 >99.9
0
0.8
3.4
52.8
300
150
-0.1
0.80 >99.9
0
0.9
3.4
62.7
-0.1
0.80 >99.9
0
1.0
3.4
71.9
-0.1
0.80 >99.9
0
0.8
3.4
70.2
450
225
-0.1
0.80 >99.9
0
0.9
3.4
80.0
-0.1
0.80 >99.9
0
1.0
3.4
87.6
-0.1
0.80 >99.9
0
0.8
3.4
82.0
600
300
-0.1
0.80 >99.9
0
0.9
3.4
89.9
-0.1
0.80 >99.9
0
1.0
3.4
94.9
In conclusion, with 450 Subjects in the FAS (225 Subjects per group) will ensure a power of 
>99.9% to conclude HbA1c non-inferiority in the first step. This sample size gives 80.0% marginal 
power to conclude 1 hour PPG increment superiority in the second step.
Assuming a screening failure rate of 24% and run-in failure rate of 11%, 666 Subjects should be 
screened for inclusion in the trial.
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance1:
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
Full Analysis Set (FAS) includes all randomised Subjects. In exceptional cases, randomised 
Subjects may be excluded from the FAS. In such cases, the reason for exclusion will be 
justified and documented. Subjects in the FAS will contribute to the evaluation “as 
randomised”    

Per Protocol (PP) Analysis Set includes all Subjects in the full analysis set, excluding 
Subjects who:

Have violated any inclusion criteria

Have fulfilled any exclusion criteria
Subjects in the PP set will contribute to the evaluation “as treated”

Safety Analysis Set includes all Subjects receiving at least one dose of the IMP or its 
comparator. Subjects in the safety analysis set will contribute to the evaluation “as treated”. 
Randomised Subjects who are lost to follow-up, and where no exposure information of the trial 
product or its comparator is available after randomisation, will be handled as unexposed.
Before data are released for statistical review, a blinded review of all data will take place to identify 
serious non-adherence to the protocol that may potentially affect the results. Furthermore, extreme 
values and outliers will be identified by the statistician during programming and data review, 
according to ICH-E91. This will be performed by using a fake randomisation.
The Subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before database lock. The Subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report
(CTR).
17.3
Primary endpoint
The primary endpoint is the change from baseline in HbA1c 16 weeks after randomisation.
Primary analysis
1) The primary estimand will be addressed by the below primary analysis based on all Subjects
included in the FAS and using the in-trial observation period. Note that if Subjects withdraw 
consent to contribute additional information or are completely lost to follow-up, missing 
data will still occur. The primary analysis will be implemented as a statistical model using 
multiple imputations where the Subjects without any available HbA1c measurements at 
scheduled visits will have their HbA1c value imputed from the available information from 
the treatment the Subject has been randomised to. Note that this resembles in essence a 
mixed model of repeated measurements analysis, but Subjects without post-randomisation 
measurements contribute to the analysis, as the missing values will be imputed. The analysis 
will be implemented as follows:
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
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 group separately and 100 copies of the dataset will 
be generated. 

In the second step, for each of the 100 copies of the dataset, an analysis of variance 
model with strata (two levels based on use of own CGM or not), previous insulin use 
(three levels: NovoRapid®, Apidra® (insulin glulisin), Humalog® (insulin lispro) and 
region as factors, and baseline HbA1c as a covariate is fitted to the change in HbA1c
from baseline to week 4 for each treatment group separately. The estimated 
parameters, and their variances, from these models are used to impute missing values 
at week 4 for Subjects in each treatment group, based on strata, previous insulin use, 
region and baseline HbA1c.

In the third step, for each of the 100 copies of the dataset, missing values at week 8 
are imputed in the same way as for week 4. The imputations are based on an analysis 
of variance model with strata, previous insulin use and region as a factors and 
baseline HbA1c and change from baseline in HbA1c at week 4 as covariates.

This stepwise procedure is then repeated sequentially for week 12 and 16

For each of the complete data sets, the change from baseline to week 16 is analysed 
using an analysis of variance model with treatment, strata, previous insulin use and 
region as factors, and baseline HbA1c as a covariate. 

The estimates and standard deviations for the 100 data sets are pooled  using Rubin’s 
formula:
 =
1
100 
 ,   


, 
 =  1
100 
 



+ 1 + 1
100 
1
100 −1 
( −)


where mi and SDi are the estimated means and standard deviations for the 100 
copies of the dataset, and mMI and SDMI are the pooled estimates.
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
From mMI  and  SDMI, the 95% confidence interval for the treatment differences is 
calculated.
Non-inferiority of faster-acting insulin aspart will be considered confirmed if the upper boundary of 
the two-sided 95% CI is below or equal to 0.4% or equivalent if the p-value for the one-sided test of
H0: D >0.4%     against HA: D ≤0.4%,
is less than or equal to 2.5%, where D is the mean treatment difference (faster-acting insulin aspart 
minus NovoRapid®). 
Note that as the anticipated number of Subjects discontinuing treatment, but not trial is low, 
imputations based on such Subjects will not be suitable.
Provided that the hierarchical testing allows, the evaluation of superiority will be based on the same 
statistical model, as the primary analysis 1). The associated sensitivity analysis that follows will 
investigate the robustness of non-inferiority and superiority (analysis 3b and 3c) as well.
Sensitivity analyses for the primary analysis addressing the primary estimand
All sensitivity analyses for the primary analysis addressing the primary estimand will use the in-trial 
observation period.
2) First the primary analysis in 1) will be repeated, but excluding all factors except from 
treatment in the model. This analysis will explore the influence of the different factors.
3) The primary analysis approach chosen for this trial relies on the assumption that missing 
data is missing at random (MAR). This assumption implies that the HbA1c for Subjects 
leaving the trial, after their withdrawal, develops in a similar way as the HbA1c for similar 
Subjects that remain in the trial (not necessarily on treatment) and had similar development 
of HbA1c before withdrawal. The MAR assumption may be questionable for Subjects 
withdrawing at own will. Therefore the statistical models using multiple imputation will be 
repeated with the following alterations:
a) Imputations will be done from the treatment arm that the Subject was randomised to 
and a value of 0.4% (non-inferiority margin) is added to the change from baseline in 
HbA1c at week16 for Subjects randomised to faster-acting insulin aspart who 
withdrew from the trial35. 
b) Imputations will be done from the comparator arm (NovoRapid®). This will serve as 
a sensitivity analysis for the superiority analysis. It does not rely on the MAR 
assumption, but assumes that all Subjects who withdraw from the trial in the faster-
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acting insulin aspart arm shift to NovoRapid®. The imputation will be done such that 
the treatment effect diminishes gradually after trial discontinuation (copy reference). 
c) Imputation will be done from the comparator arm (NovoRapid®). This will serve as a 
supplementary sensitivity analysis for the superiority analysis. It does not rely on the 
MAR assumption, but assumes that all Subjects that withdraw the trial in the faster-
acting insulin aspart arms responded as if they had been on NovoRapid® for the 
entire trial. The imputation will be done such that the treatment effect diminishes 
immediately after trial discontinuation (jump to reference). 
Analyses addressing the secondary estimand
All analyses addressing the secondary estimand will use the on-treatment observation period.
4) The secondary estimand will be analysed using the same statistical model using multiple 
imputations as the primary analysis in 1) except using the on-treatment observation period. 
5) A tipping point analysis based on a statistical model using multiple imputation model 
similar to 1), using the on-treatment observation period, will be made. In this analysis 
observations for Subjects that discontinue randomised treatment are imputed based on the 
treatment arm they were randomised to and Subjects discontinuing treatment in the faster-
acting insulin aspart group are given a penalty. This is done to investigate the robustness of 
the conclusion in the primary analysis with respect to the MAR assumption and mimics a 
scenario where the HbA1c of the Subjects discontinuing treatment in the faster-acting insulin 
aspart groups evolve less favourably than predicted. As a first step imputations will be done 
without penalty assuming MAR in the treatment group. Second, the imputed values for 
week 16 in the faster-acting insulin aspart group will be added a penalty. This is done 
repeatedly, gradually increasing the penalty until the conclusion from the non-inferiority 
analysis no longer holds. This will serve as a sensitivity analysis for the non-inferiority 
analysis and the specific value of the penalty that changes the conclusion will be used to 
evaluate the robustness of the conclusion of the non-inferiority analysis.
6) A tipping point analysis based on a statistical model using multiple imputation, similar to 5) 
but with the modification that Subjects discontinuing treatment due to non-eligibility 
(Subjects discontinuing faster-acting insulin aspart/NovoRapid® prematurely due to criteria 
1, 2, 3, and 4) in the faster-acting insulin aspart group will not have a penalty added. These 
analyses are motivated by the fact that data from Subjects prematurely discontinuing faster-
acting insulin aspart/NovoRapid® due to non-eligibility can reasonably be assumed to be 
missing completely at random. 
7) The same statistical model using multiple imputations as the analysis in 4), but using the PP 
analysis set and analysed using the on-treatment observation period. This analysis will 
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investigate the situation that Subjects might have deviated from the inclusion and exclusion 
criteria and will serve as sensitivity analysis for the non-inferiority analysis.
17.4
Secondary endpoints
17.4.1
Confirmatory secondary endpoints
If the effect of CSII treatment with faster-acting insulin aspart can be confirmed in the primary 
analysis, the trial also aims to confirm the superiority of CSII treatment with faster-acting insulin 
aspart, for a number of secondary confirmatory endpoints. 
The steps used in the hierarchical testing procedure are as follows:
Step 1 (Primary analysis): HbA1c non-inferiority of faster-acting insulin aspart versus 
NovoRapid®
Step 2: 1-hour PPG increment (meal test) superiority of faster-acting insulin aspart versus 
NovoRapid®
Step 3: HbA1c superiority of faster-acting insulin aspart versus NovoRapid®
Step 4: 1,5-anhydroglucitol superiority of faster-acting insulin aspart versus NovoRapid®
Step 5: time spent in low IG (≤3.9 mmol/L [70 mg/dL]) superiority of faster-acting insulin aspart 
versus NovoRapid®
The primary estimand for the primary endpoint will be repeated for the confirmatory secondary 
endpoints, change from baseline in 1-hour PPG increment (meal test), change from baseline in 1,5-
anhydroglucitol and change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) 
during CGM 16 weeks after randomisation. The analyses related to these estimands are defined 
below and will be used for the decisions to continue or not, throughout the hierarchical testing 
procedure. These analyses will be based on the FAS and use the in-trial observation period.
As sensitivity analyses the secondary analysis associated with the secondary estimand for the 
primary endpoint will also be repeated for the confirmatory secondary endpoints. The analyses will 
be based on the FAS and using the on-treatment observation period.
Change from baseline in 1-hour PPG increment 16 weeks after randomisation (meal test)
(Step 2)
As the second step of the hierarchical testing procedure, change from baseline in 1-hour PPG 
increment 16 weeks after randomisation will be tested for superiority of faster-acting insulin aspart 
compared to Novo Rapid®.
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The 1-hour PPG increment will be analysed based on the laboratory measured values in the meal 
test. 
The 1-hour PPG increment endpoint will be analysed using the FAS and the in-trial observation 
period based on a multiple imputation technique where the change from baseline in 1-hour PPG 
increment at week 16 for subjects withdrawn from trial are imputed based on data from completers 
in the NovoRapid® arm. Multiple copies (100 copies) of the full dataset will be generated by 
imputing missing values based on estimated parameters as follows: 

An analysis of variance model with strata (two levels based on use of own CGM or not), 
previous insulin use (three levels: NovoRapid®, Apidra®, Humalog®), and region as factors 
and baseline 1-hour PPG increment as covariate is fitted to the change from baseline in 1-
hour PPG increment at week 16 for the NovoRapid® group only. The estimated parameters, 
and the variance, from this model are used to impute missing values using stochastic 
simulation at week 16 for subjects in both treatment groups in order to generate 100 
complete datasets.

For each of the complete data sets, the change from baseline to week 16 is analysed using 
an analysis of variance model with treatment, strata (two levels based on use of own CGM 
or not), previous insulin use (three levels: NovoRapid®, Apidra®, Humalog®), and region as 
factors, and baseline 1-hour PPG increment as covariate.

The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
associated standard deviation using Rubins formula. From this, the pooled estimates and 
95% confidence interval for the treatment difference is calculated.
The superiority will be assessed by comparing the upper limit of the 95% CI to 0. If the upper 95% 
CI is below 0 then superiority will be confirmed.
Change from baseline in HbA1c 16 weeks after randomisation (Step 3)
As the third step in the hierarchical testing, superiority of HbA1c 16 weeks after randomisation with
faster-acting insulin aspart compared to NovoRapid® is to be confirmed. 
The confidence interval from the primary analysis 1) will be used to determine superiority. 
Superiority will be confirmed if the upper boundary of the two-sided 95% confidence interval of the 
mean treatment difference (faster-acting insulin aspart minus NovoRapid®) is below 0%.
Change from baseline in 1,5-anhydroglucitol 16 weeks after randomisation (Step 4)
Step 4 in the hierarchical testing procedure is to confirm superiority of change from baseline in 1,5-
anhydroglucitol 16 weeks after randomisation with faster-acting insulin aspart compared to 
NovoRapid®.
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The change from baseline in 1,5-anhydroglucitol will be analysed using a model similar to 1), but 
with baseline 1,5-anhydroglucitol as a covariate. 
Superiority will be confirmed if the upper boundary of the two-sided 95% confidence interval of the 
mean treatment difference (faster-acting insulin aspart minus NovoRapid®) is below 0.
Change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) during CGM 16 
weeks after randomisation (Step 5)
The time spent in low IG is defined for each Subject at each CGM period as the accumulated time 
in hours spent below or equal to 3.9 mmol/L [70 mg/dL] from the first valid sensor value divided by 
the actual duration of the profile. To report the endpoint in minutes per 24 hours the ratio is 
multiplied by 1440.
Step 5 of the hierarchical testing procedure is to confirm superiority of change from baseline of time 
spent in low IG (≤3.9 mmol/L [70 mg/dL]) during CGM 16 weeks after randomisation with faster-
acting insulin aspart compared to NovoRapid®. 
The change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) will be analysed with 
a model similar to 1), but with the baseline value of time in hypoglycaemia as covariate. 
17.4.2
Supportive secondary endpoints
17.4.2.1
Efficacy endpoints
All endpoints except insulin dose and insulin pump parameters in this section will be assessed using 
the FAS and the in-trial observation period and repeated using the on-treatment observation period. 
Insulin dose and insulin pump parameters will be presented using the safety analysis set and will 
therefore only use the on-treatment observation period.
Change from baseline in FPG to 16 weeks after randomisation
Change from baseline in FPG 16 weeks after randomisation will be analysed on all planed post-
baseline measurements until or at 16 weeks with a model similar to 1) except with baseline FPG as 
covariate. 
Percentage of Subjects reaching HbA1c target 16 weeks after randomisation:
HbA1c < 7.0% 
A dichotomous (responder/non-responder) endpoint will be defined based on whether a Subject has 
met the HbA1c target (HbA1c <7.0% (53 mmol/mol)) 16 weeks after randomisation.  
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This responder endpoint will be analysed based on a logistic regression model using treatment, 
strata (two levels based on use of own CGM or not), previous insulin use (three levels: 
NovoRapid®, Apidra®, Humalog®), and region as factors, and baseline HbA1c as covariate. In 
analysis of the in-trial observation period Subjects without an HbA1c measurement at week 16 will 
be treated as non-responders. In the on-treatment observation period analysis both Subjects who 
discontinue faster-acting insulin aspart/NovoRapid® or withdraw from trial is included as non-
responders. 
HbA1c <7.0 % without severe hypoglycaemia
A dichotomous (responder/non-responder) endpoint will be defined based on whether a Subject has 
met the HbA1c target (HbA1c <7.0% (53 mmol/mol)) 16 weeks after randomisation without 
treatment emergent severe hypoglycaemic episodes. 
This responder endpoint will be analysed based on a logistic regression model using treatment, 
strata (two levels based on use of own CGM or not), previous insulin use (three levels: 
NovoRapid®, Apidra®, Humalog®), and region as factors and baseline HbA1c as covariate. In the 
analysis of the in-trial observation period Subjects without an HbA1c measurement at week 16 will 
be treated as non-responders. In the on-treatment observation period analysis both Subjects who 
discontinue faster-acting insulin aspart/NovoRapid® or withdraw from trial will be included as non-
responders.
Change from baseline in 30- min, 1- hour, 2- hour, 3- hour and 4- hour PPG and in 30- min, 2-
hour, 3- hour and 4- hour PPG increment after 16 weeks after randomisation (meal test)
Laboratory measured PG from the meal test will be analysed for 30 minutes, 1-hour, 2-hours, 3-
hours and 4-hours PPG separately. The corresponding PPG increments will be derived separately 
using each PPG measurement minus the pre-prandial PG.
Change from baseline in PPG and PPG increment 16 weeks after randomisation will be analysed 
separately using a model similar to the model used in hierarchical testing procedure step 2 for 1-
hour PPG increment 16 weeks after randomisation (meal test) except with the corresponding 
baseline value as covariate.
Change from baseline in endpoints derived from the 7-7-9 point SMPG profile 16 weeks after 
randomisation
PPG and PPG increments based on the 7-7-9-point SMPG profiles will be derived separately for PG 
measurements made 1 hour after the meal. In the following section this distinction will be 
considered implicit and without further explanation.
Pre-prandial PG and PPG will be recorded by the Subjects as part of the 7-7-9 point SMPG profile 
prior to three defined visits. Individual mean mealtime PPG (post-breakfast, post-lunch, post-main 
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evening meal) will be derived from the three profiles. Overall mean PPG will be derived from the 
individual derived mealtime PPG values.
PPG increment for each meal (breakfast, lunch, main evening meal) will be derived from the 7-7-9 
point SMPG profile as the difference between PPG values and the PG value before meal in each 
separate profile. The mean of the derived increments will then be calculated separately for each 
meal. Mean 1 hour PPG increments over all meals will be derived as the mean of all corresponding 
mean meal increments. 

Change from baseline in mean of the 7-7-9-point SMPG profile
The mean of the 7-7-9-point SMPG profile is defined as the area under the curve profile 
divided by the measurement time, and is calculated using the linear trapezoidal technique.
Change from baseline in the mean of the 7-7-9-point SMPG profile 16 weeks after 
randomisation will be analysed using a model similar to 1) except with the corresponding 
baseline value as covariate.

Change from baseline in mean pre-prandial PG, PPG and PPG increment over all three 
meals
Change from baseline in mean pre-prandial PG, PPG and PPG increment 16 weeks after 
randomisation will be analysed separately using a model similar to 1), except with the 
corresponding baseline value as covariate. 

Change from baseline in individual meal (breakfast, lunch and main evening meal) PPG,
PPG increment and pre-prandial PG (pre-breakfast, pre-lunch, pre-main evening meal) 
Change from baseline in PPG, PPG increment and pre-prandial PG endpoints 16 weeks after 
randomisation for the individual meals will be analysed separately using a model similar to 
1) except with the corresponding baseline value as covariate.

Change from baseline in fluctuation in 7-7-9-point profile
The fluctuation in the 7-7-9-point profile is defined as:
dt
PG
t
PG
T
T


0
)
(
1
,
where T, PG(t) and PG denotes the length of the profile, the PG value at time t and the 
mean of the profile, respectively. 
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Fluctuation in the 7-7-9-point profile will be logarithmically transformed and analysed in the 
same way as mean of the profile is analysed except with the corresponding log-transformed 
baseline value as covariate. 
Estimated treatment means and the estimated treatment difference with corresponding 95% 
CI will be back-transformed to the original scale, resulting in estimated geometric means, a 
treatment ratio and a 95% CI for the treatment ratio.

Change in nocturnal SMPG measurements
Change from baseline in nocturnal SMPG measurements will be assessed by considering the 
differences between PG values available at bedtime, at 4 AM and the before breakfast value 
the following day: (4 AM PG value minus at bedtime PG value), (before breakfast PG value 
minus at bedtime PG value) and (before breakfast PG value minus 4 AM PG value). 
Change from baseline in nocturnal SMPG measurements 16 weeks after randomisation will 
be analysed in the same way as mean of the profile is analysed, except with the 
corresponding baseline values as covariate. .
PPG responders (based on mean of PPG measurements in SMPG) 16 weeks after 
randomisation:

Overall PPG (1 hour) 7.8 mmol/L [140 mg/dL]
A dichotomous (responder / non-responder) endpoint will be defined based on whether a 
Subject has reached an overall mean 1 hour PPG 7.8 mmol/L [140 mg/dL] 16 weeks after 
randomisation, where PPG is derived from the 7-7-9 point SMPG profile. 
This responder endpoint will be analysed based on a logistic regression model using 
treatment, strata (two levels based on use of own CGM or not), previous insulin use (three 
levels: NovoRapid®, Apidra®, Humalog®), and region as factors, and baseline overall 1-hour 
mean PPG as covariate. In analysis of the in-trial observation period Subjects without an 
overall mean 1 hour PPG at week 16 will be treated as non-responder. In the on- treatment 
observation period analysis both Subjects who discontinue faster-acting insulin 
aspart/NovoRapid® or withdraw from trial will be included as non-responders.

Overall PPG (1-hour ) 7.8 mmol/L [140 mg/dL] without severe hypoglycaemia
A dichotomous (responder / non-responder) endpoint will be defined based on whether a 
Subject has reached an overall 1-hour PPG 7.8 mmol/L [140 mg/dL] 16 weeks after 
randomisation without any treatment emergent severe hypoglycaemic episodes. 
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This responder endpoint will be analysed based on a logistic regression model using 
treatment, strata (two levels based on use of own CGM or not), previous insulin use (three 
levels: NovoRapid®, Apidra®, Humalog®) and region as factors, and baseline mean 1-hour 
PPG as covariate. In analysis of the in-trial observation period Subjects without an overall 
mean 1 hour PPG at week 16 will be treated as non-responders. In the on- treatment 
observation period analysis both Subjects who discontinue faster-acting insulin 
aspart/NovoRapid® or withdraw from trial will be included as non-responders. 
Change from baseline in lipids-lipoproteins profile 16 weeks after randomisation
Change from baseline in lipid endpoints (LDL, HDL, and total cholesterol) will be analysed 
separately using a model similar to 1). The lipid endpoints will be log-transformed before they are 
analysed including the corresponding baseline measurement which is included in the analysis as a 
covariate. The treatment difference and associated 95% confidence intervals will be back-
transformed providing results in terms of ratios of geometric means on the original scale. 
Insulin dose (Units/day and Units/kg/day; total basal, total bolus, total daily insulin dose and 
individual meal insulin dose) 
The insulin doses will be summarised descriptively by treatment week according to regimen, both 
by meal type and as total daily dose in units and units/kg (total daily and separately for each meal 
time dose). The total daily basal dose will be derived from the total daily dose and bolus doses 
including correction doses. Insulin doses will be summarised using the on-treatment observation 
period and using the safety analysis set.
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Insulin delivery pump parameters 
The insulin pump parameters including insulin carbohydrate ratio, glucose sensitivity factor and 
active insulin time will be summarised descriptively by treatment week. They will be summarised 
using the on-treatment observation period and using the safety analysis set.
Supportive secondary CGM-related endpoints 
All following endpoints will be assessed 16 weeks after randomisation:

Percentage of time spent with IG ≤2.5, 3.0, 3.5 mmol/L [45, 54, 63 mg/dL]) and IG >10.0,
12.0 mmol/L [180, 216 mg/dL])

Incidence of episodes with IG ≤2.5, 3.0, 3.5, 3.9 mmol/L [45, 54, 63, 70 mg/dL]) and IG 
>10.0, 12.0 mmol/L [180, 216 mg/dL])

Percentage of time spent within IG target range 4.0-10.0mmol/L (71-180 mg/dL)

Change from baseline in mean of the IG profile
The mean of the IG profile will be defined as:
dt
t
IG
T
IG
T


0
)
(
1
,
where T is the time length of the profile and IG(t) is the IG value at time t. (Here t=0 
represents the time point for the start of the profile.) This mean will be calculated by means 
of the linear trapezoidal technique.

Variation in the IG profile
The variation in the IG profile will be defined as:
dt
IG
t
IG
T
T


0
)
(
1
,
where T is the time length of the profile, IG(t) is the IG value at time t, and IG is the mean 
of the IG profile as defined above. (Again, here t=0 represents the time point for the start of 
the profile.) The integral will be calculated by the linear trapezoidal technique. The 
coefficient of variation (CV%) will also be calculated to describe the IG variation.

Change from baseline in the AUC(3.9-IG) for IG 3.9 mmol/L [70 mg/dL]
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The AUC (3.9-IG) is defined for each Subject at each CGM period as the AUC (3.9-IG) when IG 
is below or equal to 3.9 mmol/L [70 mg/dL] from the first valid sensor value divided by the 
actual duration of the profile. The AUC will be calculated by the linear trapezoidal 
technique. If the profile has missing censor values, then the AUC should be calculated for 
each profile part consisting of non-missing censor values. The endpoint is then calculated as 
the sum of the AUCs for all profile parts divided by the sum of the duration of the profile 
parts for which AUC is calculated. 
IG measurements during meal test will be excluded.
All CGM endpoints will be summarised descriptively by treatment.
Supportive secondary CGM and meal-characteristics endpoints
The following endpoints will be assessed 16 weeks after randomisation:

Change from baseline in mean IG increment (0-30 min, 0-1 hour and 0-2 hours after 
start of the meal)
The mean IG (meal) increment will be defined as the mean across main meals of the 
prandial increments, i.e. the difference between IG 30 (1 or 2 hours, respectively) after the 
meal and IG before the meal

Change from baseline in mean IG peak after start of meal
The mean IG peak after start of meal will be derived as mean across main meals of the IG 
maximum values within 4 hours after start of the meal. 

Change from baseline in mean time to the IG peak after meal
The mean time to the IG peak after meal is derived as the mean time to the IG peak across 
main meals. 
These endpoints will also be derived for each main meal separately (breakfast, lunch and main 
evening meal). IG measurements during meal test will be excluded. All endpoints will be analysed 
separately, using a model similar to 1) except with the corresponding baseline value as covariate.
All CGM endpoints will be summarised descriptively by treatment.
Supportive secondary efficacy endpoints related to CGM and meal test 
Endpoints listed below will be assessed during meal test and based on CGM measurements.
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Date:
04 February 2016
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The following endpoints will be assessed 16 weeks after randomisation:

Change from baseline in AUCIG,0-15min 

Change from baseline in AUCIG,0-30min

Change from baseline in AUCIG,0-1h

Change from baseline in AUCIG,0-2h

Change from baseline in AUCIG,0-4h

Change from baseline in time to the IG peak after start of meal

Change from baseline in IG peak after start of meal
AUCIG,0-15 min, AUCIG,0-30 min, AUCIG,0-1h, AUCIG,0-2h, and AUCIG,0-4h will be calculated as the AUC 
IG using the linear trapezoidal technique. The endpoint will be analysed using an analysis of 
variance model including treatment, previous insulin use (three levels: NovoRapid®, Apidra®, 
Humalog®), region and strata as factors, and the corresponding baseline value as covariate. 
The IG peak after start of meal will be derived as the IG maximum values within 4 hours after start 
of the meal-test meal. 
Change from baseline in IG peak and time to IG peak 16 weeks after randomisation will be 
compared separately between treatments using an analysis of variance model including treatment, 
strata (two levels based on use of own CGM or not), previous insulin use (three levels: 
NovoRapid®, Apidra®, Humalog®), and region as factors, and the corresponding baseline value as 
covariate.
17.4.2.2
Safety endpoints
All safety endpoints will be compared using the on-treatment observation period. In terms of 
adverse events, as a minimum, serious adverse events will be tabulated separately also using the in-
trial observation period.
All events in the in-trial observation period will be listed with information about whether it 
appeared in the on-treatment observation period or not.
Number of treatment emergent Adverse Events (AEs)
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
presented based on system organ class and preferred terms. 
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has an 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.
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TEAEs are summarised descriptively, whereas AE’s not defined as treatment emergent are 
presented in listings, including AEs reported in the 30-day follow-up period. The summaries of 
TEAEs are made displaying the number of Subjects with at least one event, the percentage of 
Subjects with at least one event, the number of events and the event rate per 100 patient years of 
exposure. These summaries are done by seriousness, severity, relation to insulin treatment, relation 
to device, premature treatment discontinuation due to AEs and outcome.
Furthermore, summary tables based on system organ class and preferred terms are made for:

All TEAEs

Serious TEAEs

Possibly or probably related TEAEs

Severe TEAEs

TEAEs with preferred term that are experienced by at least 5% of the Subjects in any 
treatment arm or by at least 5% of all Subjects
For AEs where additional information is recorded, this will be listed.
AEs occurring during the run-in period are considered non-treatment emergent and will be 
summarised separately.
Number of treatment emergent infusion site reactions
Infusion site reactions occurring during the trial will be summarised using the on-treatment
observation periods, and listed.
Classification of Hypoglycaemia
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of IMP administration after randomisation and no later 
than one day after the last day on IMP.
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the American Diabetes Association (ADA) classification of 
hypoglycaemia (see Figure 17–2).
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Date:
04 February 2016
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Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L [56 
mg/dL]36. Therefore, Novo Nordisk has included hypoglycaemia with PG 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 classification29

Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification29 or BG confirmed by a PG value <3.1 mmol/L [56 mg/dL] with or without
symptoms consistent with hypoglycaemia
Figure 17–1
Novo Nordisk classification of hypoglycaemia 
ADA classification29 of hypoglycaemia 

Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may 
not be available during an event, but neurological recovery following the return of PG to 
normal is considered sufficient evidence that the event was induced by a low PG
concentration

Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L [70 mg/dL]
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
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG 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 PG 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 PG determination but that was presumably caused 
by a PG concentration ≤3.9 mmol/L [70 mg/dL]
Figure 17–2
ADA classification of hypoglycaemia
Data on-treatment emergent hypoglycaemic episodes are presented in terms of the number of 
Subjects with at least one event (N), the percentage of Subjects with at least one event (%), the 
number of events (E) and the event rate per 100 years of exposure (R). Separate summaries are 
made by severity considering all episodes, nocturnal and daytime episodes using Novo Nordisk and 
ADA classified episodes. All episodes will also be summarised by category, including summaries in 
relation to time since start of meal, as occurring during first 1, 2, and 2 (inclusive) to 4 hours
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(exclusive) after start of meal, respectively. Non-treatment emergent hypoglycaemic episodes will 
be listed.
The number of treatment emergent severe or BG confirmed hypoglycaemic episodes (all, daytime, 
nocturnal, 1 hour, 2 hour, 4 hour and 2 (inclusive) to 4 hours (exclusive) after start of the meal) will 
be analysed based on the FAS using a negative binomial regression model with a log-link function 
and the logarithm of the time period in which a hypoglycaemic episode is considered treatment 
emergent as offset. The model will include treatment, strata (two levels based on use of own CGM 
or not), previous insulin use (three levels: NovoRapid®, Apidra®, Humalog®), and region as factors. 
To the extent where data allow, separate analyses will be performed for severe episodes.
Number of unexplained episodes of hyperglycaemia (confirmed by SMPG)
The number of unexplained episodes of hyperglycaemia will be summarised in a frequency table. 
Unexplained hyperglycaemia is defined as a confirmed PG value ≥16.7 mmol/L (300 mg/dL) and is 
unexplained (i.e. no apparent medical, dietary, insulin dosage or pump failure reason). The 
percentage of Subjects with unexplained hyperglycaemia will be presented.
Physical examination 
The physical examination parameters (head, ears, eyes, nose, throat, neck, respiratory system, 
cardiovascular system, gastrointestinal system incl. mouth, musculoskeletal system, central and 
peripheral nervous system, skin), and their change from baseline, will be summarised descriptively. 
All findings will be listed.
Electrocardiogram
ECG findings will be summarised descriptively including summaries of the change from baseline. 
Change from baseline will be summarised as normal/abnormal not clinically significant/abnormal 
clinically significant categorisation in shift tables.
Vital signs (blood pressure, pulse)
Vital signs include diastolic blood pressure, systolic blood pressure and pulse. The measurements 
will be summarised descriptively using both the actual values as mean change.
Fundus photography/fundoscopy
Fundus photography/fundoscopy findings and the change from baseline will be summarised 
descriptively.
Clinical laboratory assessments
Change from baseline 16 weeks after randomisation in central laboratory assessments: 
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
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, and leucocytes)

Biochemistry (total protein, creatinine, ALT, AST, AP, sodium, potassium, albumin, and 
total bilirubin)

Urinalysis (albumin/creatine ratio, erythrocytes, protein, and ketones)
Individual laboratory values will be compared to their relevant reference range (when existing) and 
flagged as being below or above the range. The measurements and their change from baseline will 
be summarised descriptively. Change from baseline will be summarised descriptively using both the 
actual values and the low/normal/high categorisation in shift tables. 
Change from baseline in body weight and BMI 16 weeks after randomisation 
The measurements will be summarised descriptively using the actual values as mean change.
Change from baseline in body weight will be analysed using a statistical model similar to 1), except 
with the corresponding baseline measurement as covariate. The analysis will be based on the safety 
analysis set and the on-treatment observation period.
Number of change-of-infusion-sets per week during 16 weeks after randomisation
For each Subject this is calculated as the total number of infusion sets used divided by the actual 
duration of the randomised treatment period in days, multiplied by seven. It will be summarised for 
each treatment using descriptive statistics.
Number of Subjects with at least one non-routine change categorised by reasons for change
The percentage of Subjects with at least one non-routine change will be presented, categorised by 
reasons for change, in a frequency table by treatment.
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Date:
04 February 2016
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Version:
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18 Ethics
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2.
All Subjects included in the trial will be treated with their pre-trial insulin in the run-in period and 
thereafter be randomised to either faster-acting insulin aspart or NovoRapid®.
The most common side effect of all available insulin preparations is hypoglycaemia. The 
Investigator will explain to the Subject how they should check their BG with the BG meter provided 
by Novo Nordisk, and what precautions to take. 
Subjects randomised in the trial will be transferred to a treatment regimen anticipated to be either 
better than or equal to the treatment they receive at the time they entered the trial. However, 
participation in the study will mean additional visits to the clinic and additional assessments as 
some of the assessments required for the study are not performed in normal practice or are 
performed less frequently. 
At the end of treatment (Visit 22), the Subject and Investigator will decide on the best available 
treatment on the market. It will not be possible for the Subjects to continue using faster-acting 
insulin aspart trial product.
18.1
Summary of clinical pharmacology
Results from clinical pharmacology trials comparing pharmacokinetic and pharmacodynamic
properties of faster-acting insulin aspart and NovoRapid® have shown that faster-acting insulin 
aspart elicited an earlier onset of insulin exposure and a greater early exposure to insulin aspart than 
NovoRapid® in Subjects with T1DM, with the largest difference found within the first 15 minutes 
after injection7. Faster-acting insulin aspart also elicited a greater early glucose-lowering effect than 
NovoRapid®, but no statistically significant difference between faster-acting insulin aspart and 
NovoRapid® in total glucose-lowering effect7.
In an exploratory insulin pump trial a greater BG lowering effect during 2 hours after a standardised 
meal test was seen. In this trial the mean prandial IG increments measured by CGM at 60 and 120 
minutes after all meals were statistically significantly lower for faster aspart when compared to 
NovoRapid®.
No safety concerns were raised during any of the trials.
18.2
Clinical benefits and risk considerations 
The current trial will compare the effect and safety of faster-acting insulin aspart versus 
NovoRapid® in CSII. The currently available data demonstrate that treatment with faster-acting 
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insulin aspart results in an increased early absorption of faster-acting insulin aspart compared to 
NovoRapid®, thereby providing a faster action.
For the individual Subjects, the personal health-related benefits are related to the medical 
examination and the benefit from an intensified insulin treatment regimen anticipated to be better 
than or equal to the treatment they receive at the time they enter the trial. However, they will have 
to spend some extra time monitoring and recording data and on additional visits to the clinic and 
phone contacts. 
The very high frequency of contacts between the trial population and the Investigator and the 
thorough evaluation of basal rates, insulin sensitivity and insulin to carbohydrate-ratio will provide 
the opportunity for optimising the titration of basal and bolus insulin based on SMPG values and 
thereby may contribute to obtaining improved HbA1c results. All Subjects will have reinforced 
pump and diabetes training regarding carbohydrate counting. 
For the individual Subject, the anticipated risks include hypoglycaemia, hyperglycaemia,  infusion 
site reactions, CGM related inconveniences, systemic allergic reactions and antibody development. 
Frequent site visits, close monitoring and supervision, as well as frequent measurement of BG 
levels will enable the site to react in a timely manner if the Subject should be affected by the 
described risks.
A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia 
occurs, it may occur earlier after an injection than with soluble human insulin. Similarly, it should 
be kept in mind that the onset of action of faster aspart is expected to be faster than with 
NovoRapid®.
The small s.c. depot at the infusion site could be seen as a potential risk leading to shortened time to 
hypoinsulinaemia, hyperglycaemia and potentially diabetic ketoacidosis in case of technical 
problems with the pump.
Infusion site reactions can occur. The nature of the infusion site reactions is expected to be mild, 
transient and more of a visual character and is not expected to be of concern to the Subject’s safety. 
In the periods where a blinded CGM is being worn, inconvenience from the CGM sensor due to 
local skin irritation or pain from the attached small recorder might happen but is considered to be 
transient and not to be of any safety concerns to the Subject. 
The blood samples taken during meal tests might be inconvenient to the Subjects but is not of any 
safety concern. 
No maximum dose of insulin is specified as doses are titrated individually. All Subjects will 
perform at least 4-point profiles on a daily basis throughout the trial for safety purposes and for the 
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Date:
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purpose of insulin titration. More frequently sampled SMPG profiles can be expected in a shorter 
period after randomization for adjustment of the basal rates and pump adjustments.
All Subjects will have diabetes training regarding carbohydrate counting and handling of the insulin 
pump including training in use of the Bolus Wizard® and assessment of the basal rates.
Insulin aspart is marketed as NovoRapid®. NovoRapid® is approved for pump use. Please refer to 
the local labelling for a description of risks and benefits. 
All treatments are contraindicated in case of hypersensitivity to the active substances or any of the 
excipients.
When discontinuing trial treatment, the Subject will be switched to a suitable marketed product at 
the discretion of the Investigator.
18.2.1
Conclusion on clinical benefits and risk considerations 
Subjects in this trial will benefit from an intensified insulin treatment in a CSII regimen in a treat-
to-target setting under close supervision.
The safety profile of insulin aspart is well established from the market use of NovoRapid®. The data 
available for faster-acting insulin aspart in non-clinical and clinical studies taken together with 
review of the additional excipients in the faster-acting insulin aspart formulation have not revealed 
any safety issues that would prohibit the administration of faster-acting insulin aspart formulations 
in accordance with the planned trial.
It is therefore concluded that the clinical benefits from the trial as well as the contribution to the 
development of a new faster-acting insulin aspart outweigh the potential risks of participating in the 
trial. 
18.3
Informed Consent
In seeking and documenting SI/IC, the Investigator must comply with applicable regulatory 
requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of Helsinki2.
Before any trial-related activity, the Investigator must give the Subject verbal and written 
information about the trial and the procedures involved in a form that the Subject can read and 
understand. 
The Subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
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The Investigator must ensure the Subject has ample time to come to a decision whether or not to 
participate in the trial. A voluntary, signed, and personally dated SI/IC must be obtained from the 
Subject before any trial-related activity.  
The responsibility for seeking SI/IC must remain with the Investigator, but the task may be 
delegated by the Investigator to a medically qualified person, in accordance with local 
requirements. The SI/IC must be signed and personally dated by the person who seeks the SI/IC
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 revised
SI/IC must be provided and a new SI/IC must be obtained.
18.4
Data handling
If the Subject is discontinued from treatment, withdraws consent, or is lost to follow-up, then the 
Subject's data will be handled as follows:

Data already collected and data collected at the EoT visit will be retained by Novo Nordisk, 
entered into the database and used for the trial report 

Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.5
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 for your participation letter" at the end of the 
trial. Further the Subject may receive trial letters during the trial period. 
All written information given to Subjects must be sent to IRB/IEC for approval/favourable opinion 
and to regulatory authorities for approval or notification according to local regulations.
18.6
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs, or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If a trial is suspended or prematurely terminated, the Investigator must inform the Subjects 
promptly and ensure appropriate therapy and follow-up. The Investigator and/or Novo Nordisk 
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must also promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant 
regulatory authorities must be informed.
If, after the termination of the trial, the risk/benefit 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 deviation
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's trial master file and Novo 
Nordisk trial master file.
19.2
Prevention of Missing Data
A significant proportion of missing data can be potential source of bias when analysing data in 
clinical trials leading to a risk of misinterpretation of the trial results. Missing data may affect both 
estimation of treatment effect and the confidence interval that surrounds it as well as the 
representativeness of the sample size in relation to the target population.  
The run-in period in this trial will reduce the likelihood of drop-outs as only those who adhere to the 
protocol requirements will undergo randomisation. Subjects will during the run-in period get an 
understanding of what is expected from them when taking part in the trial and thereby minimise 
discontinuation form trial product post randomisation. In addition, only absolutely necessary criteria 
for premature discontinuation of trial product primarily focusing on Subjects safety are included 
and thereby reducing the number of discontinuations and securing maximum amount of data.
Close surveillance of retention rate will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal from trial (e.g. 
adverse events, Subject withdrawing consent or due to any of the criteria for premature 
discontinuation of trial product). In case of decreasing retention rate at a site, the site will be re-
trained in the importance of emphasising to the Subject the importance of continuing in the trial and 
adhering to trial procedures.
Investigators must make every effort to ensure 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) and trends will be monitored on an on-going basis throughout the trial followed by 
appropriate actions (e.g. training of Subjects and site staff).
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It should be noted that there is no universal best statistical method for handling missing data. The 
assumptions that go into the primary statistical analysis will be investigated by further sensitivity 
analysis. Considerably consistent results from sensitivity analyses and from the primary analysis 
will provide assurance of the overall trial conclusions. In the final clinical trial report, results for all 
pre-specified analyses and any substantial differences between the analyses will be the Subject of 
explicit discussion.
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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, 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, SI/IC, any other written information to be 
provided to the Subject and Subject recruitment materials

List of IRB/IEC members and/or constitution(or a general assurance number/statement of 
compliance)

Curricula vitae of Investigator and sub-Investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)

Signed receipt of Investigator's Brochure 

SMPC for NovoRapid®

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 agreemeazxsnt

Central laboratory certification and normal ranges

Insurance statement, if applicable

Financial Disclosure Form from Investigator and sub-Investigator(s)

For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest

For US trial sites: FDA Form 1572 must be completed and signed by the Investigator at 
each site
FDA Form 1572
For US sites:

Intended for US sites

Conducted under the Investigational New Drug (IND)

All US Investigators, as described above, will sign FDA Form 1572
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For sites outside the US:

Intended for participating sites outside of the US

Not conducted under the IND

All Investigators outside the US will not sign the FDA Form 1572
Novo Nordisk will analyse and report data from all sites together.
By signing the protocol, each Investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol, each Investigator also agrees to allow Novo Nordisk to make Investigator's 
name and information about site name and address publically available if this is required by 
national or international regulations.
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22 Responsibilities
All staff (Novo Nordisk, site, laboratory, CRO etc.) will conduct the trial in compliance with ICH 
GCP1, applicable regulatory requirements and the Declaration of Helsinki2.
22.1
Investigator responsibilities 
The Investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the Investigator must maintain a list of appropriately qualified persons to whom he/she has 
delegated specified significant trial-related duties. The Investigator must ensure that there is 
adequate training for all staff participating in the conduct of the trial. It is the Investigator's 
responsibility to supervise the conduct of the trial and to protect the rights, safety, and well-being of 
the Subjects.
A qualified physician, who is an Investigator or a sub-Investigator for the trial, must be responsible 
for all trial-related medical decisions.
The Investigator must ensure adequate supervision of the conduct of the trial at the trial site. 
The Investigator will follow instructions from Novo Nordisk when processing data.
The Investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the Investigator's trial file. The documents including the subject identification code list 
should be kept in a secure locked facility, so no unauthorized persons can get access to the data. 
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 tasks.
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22.2
Novo Nordisk responsibilities
Novo Nordisk will be responsible for the preparation of the protocol and any updates, the eCRF, the 
supply of trial products and auxiliary supplies as defined in section 9, monitoring, data 
management, and statistics, the CTR as documented by Novo Nordisk procedures and internal 
specific agreements as well as the current GCP guidelines1. 
Novo Nordisk will provide an electronic system for electronic data capture (EDC). This system, and 
the support services to the system, will be supplied by a clinical services vendor. The activities of 
the clinical services vendor will be under the direction and supervision of Novo Nordisk. 
Furthermore, Novo Nordisk will be responsible for the IV/WRS.
Surveillance of insulin titration will be performed by Novo Nordisk. The titration deviations will be 
reviewed by titration surveillance consultants from Novo Nordisk.
A central laboratory will be responsible for providing all laboratory supplies for the analysis of all 
blood and urine samples taken during the trial. 
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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 CTR (signatory 
Investigator) on behalf of all participating Investigators. The signatory Investigator will be 
appointed based upon the criteria defined by the ICMJE for research publications37.
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 Disclosure.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up t0 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced, and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
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statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the Investigators' and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the Investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any Investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within one month from 
receipt of the planned communication. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors (ICMJE37, 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 with the 
randomisation code after results are available.
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Date:
04 February 2016
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Trial ID: NN1218-3854
Version:
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24 Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The Investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The Investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the Investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the Investigator to an independent archive provider that has a system in place to allow 
only the Investigator to access the files.
The Investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other Subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the Investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the Investigator
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the trial site/institution must be retained for 15 years after the completion of the trial, 
or longer if required by local regulations or Novo Nordisk. In any case trial files cannot be 
destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.  
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
Institutional Review Boards/Independent Ethics Committees 
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 CTR synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the Subjects.
The Investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the Investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the CTR according to national requirements.
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Date:
04 February 2016
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Trial ID: NN1218-3854
Version:
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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.
Novo Nordisk accepts liability in accordance with: 
For Belgium: Law concerning experiments on the human person of 07 May 2004 – Article 29: 
§ Even if without fault, the sponsor is liable for the damage which the Subject and/or his rightful 
claimants sustain and which shows either a direct or an indirect connection with the trial
For Netherlands: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 juli 2007 
(Medicines Law, 1 July 2007).
De Wet Medisch-wetenschappelijk Onderzoek met mensen (WMO), 1 maart 2006 (Medical 
Research Involving Human Subjects Act, 1 March 2006).
Besluit verplichte verzekering bij medisch-wetenschappelijk onderzoek met mensen 2015, 24 
november 2014 (Decree compulsory insurance in medical research involving human Subjects 2015, 
24 November 2014). 
For France: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 2004 
art. 88 I,IX, Journal Officiel of 11 August 2004. 
"The sponsor is responsible for identification of the harmful consequences of the biomedical the 
research for the person lending himself thereto and for indemnification of his beneficiaries, except 
in case of proof, incumbent on it, that the prejudice is not attributable to his fault or if the fault of 
any intervening party, without the sponsor's being entitled to call on acts by a third party or the 
voluntary withdrawal of the person who had initially consented to cooperating in the research".
For Russia: Federal law “On Medical Products” #86-FZ dated 22 June 1998 (last amendments 
dated 30 December 2008.  Federal Law of 12 April 2010 No. 61-FZ "On Medicinal Drugs' 
Cerculation".
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27 References
1 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Guideline 
for Good Clinical Practice E6 (R1), Step 4. 10 Jun 1996.
2 World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. Last amended by the 64th WMA General Assembly, Fortaleza, 
Brazil.  2013. 
3 The Diabetes Control and Complications Trial Research Group. The effect of intensive 
treatment of diabetes on the development and progression of long-term complications in 
insulin-dependent diabetes mellitus. New Engl J Med 1993; 329(14):977-986.
4 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131):837-853.
5 Woerle HJ, Neumann C, Zschau S, Tenner S, Irsigler A, Schirra J et al. Impact of fasting and 
postprandial glycemia on overall glycemic control in type 2 diabetes. Importance of 
postprandial glycemia to achieve target HbA1c levels. Diabetes Res Clin Pract 2007; 77:280-
285.
6 Lauritzen T, Pramming S, Deckert T, Binder C. Pharmacokinetics of continuous subcutaneous 
insulin infusion. Diabetologia 1983; 24(5):326-329.
7 Novo Nordisk A/S. Investigator's Brochure, Faster-acting insulin aspart (8th Edition) and any 
updates hereof.  2015. 
8 Implementation of treatment protocols in the Diabetes Control and Complications Trial. 
Diabetes Care 1995; 18(3):361-376.
9 Hirsch IB, Bode BW, Garg S, Lane WS, Sussman A, Hu P et al. Continuous subcutaneous 
insulin infusion (CSII) of insulin aspart versus multiple daily injection of insulin aspart/insulin 
glargine in type 1 diabetic patients previously treated with CSII. Diabetes Care 2005; 
28(3):533-538.
10 Home PD, Lindholm A, Riis A. Insulin aspart vs. human insulin in the management of long-
term blood glucose control in type 1 diabetes mellitus: a randomized controlled trial. Diabet 
Med 2000; 17(11):762-770.
11 Bretzel RG, Arnolds S, Medding J, Linn T. A direct efficacy and safety comparison of insulin 
aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 
diabetes. Diabetes Care 2004; 27(5):1023-1027.
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04 February 2016
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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12 Gallagher A, Home PD. The effect of improved post-prandial blood glucose control on post-
prandial metabolism and markers of vascular risk in people with type 2 diabetes. Diabetes Res 
Clin Pract 2005; 67(3):196-203.
13 Perriello G, Pampanelli S, Porcellati F, Avogaro A, Bosi E, Petrella G et al. Insulin aspart 
improves meal time glycaemic control in patients with type 2 diabetes: a randomized, 
stratified, double-blind and cross-over trial. Diabet Med 2005; 22(5):606-611.
14 NovoRapid - EU Summary of product characteristics. 2015. 
15 Food and Drug Administration. NovoLog - U.S. label information. 17-Apr-2015.
16 European Medicines Agency. Guideline on clinical investigation of medicinal products in the 
treatment of diabetes mellitus, Committee for Medicinal Products for Human Use (CHMP).  
20 Jan 2010. 
17 U.S.Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Guidance for Industry, Diabetes Mellitus: 
Developing Drugs and Therapeutic Biologics for Treatment and Prevention.  1 Feb 2008. 
18 U.S.Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Guidance for Industry, Diabetes Mellitus: 
Developing Drugs and Therapeutic Biologics for Treatment and Prevention. 1 Feb 2015. 
19 Rodbard HW, Visco VE, Andersen H, Hiort LC, Shu DH. Treatment intensification with 
stepwise addition of prandial insulin aspart boluses compared with full basal-bolus therapy 
(FullSTEP Study): a randomised, treat-to-target clinical trial. Lancet Diabetes Endocrinol 
2014; 2(1):30-37.
20 Joslin Diabetes Center. Management of Insulin Pump Therpy, Adult Provider Study 
Guidebook, current version.  
21 Joslin Diabetes Center. Management of Insulin Pump Therpy, Adult Subject Study 
Guidebook, current version.  
22 New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart 
and great vessels. 9 ed. 1994.
23 KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney 
Disease. Official Journal of the International Society of Nephrology 2012; 3(1).
24 International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts 
submitted to Biomedical Journals.  2012. 
25 Food and Drug Administration. Food and Drug Administration Amendments Act. 2007.
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Trial ID: NN1218-3854
Version:
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26 The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal 
products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 
2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. Official 
Journal of the European Communities. December 2006.  
27 The European Parliament and the Council of the European Council. Directive 2001/20/EC of 
the European Parliament and the Council of 4 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the Member States relating to the implementation 
of good clinical practice in the conduct of clinical trials on medicinal products for human use, 
article 11. Official Journal of the European Communities. May.  2001. 
28 The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Councel of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Agency, article 57. Official Journal 
of the European Communities. April.  2001. 
29 Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al. Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care 2013; 36(5):1384-1395.
30 U.S.Department of Health and Human Services - FDA. Guidance for Industry, Patient-
Reported Outcome Measures: Use in Medical Product Development to Support Labeling 
Claims.  Dec 9 A.D. 
31 Stull DE, Leidy NK, Parasuraman B, et al. Optimal recall periods for patient-reported 
outcomes: challenges and potential solutions. Current Medical Research and Opinion 25[4], 
929-942. 
32 McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet 
Med 2001; 18(9):690-705.
33 European Union. The rules govering medicinal products in the European Union, volume 4, 
Annex 13, Manufacture of Investigational Medicial Products.  Feb 2010. 
34 Novo Nordisk A/S. NN1218-3854/4100 - Data collection and handling strategy for Insulin 
Pump, Blood Glucose Meter and Paper Diary Data, current version.  
35 Koch G. Comments on 'Current issues in non-inferiority trials'. Statistics in Medicine 2008; 
27(3):333-342.
36 Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 
79(3):777-781.
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Version:
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37 Clever L, Colaianni LA, Davidoff F, Horton R, Kassirer JP, Angell M et al. Uniform 
requirements for manuscripts submitted to biomedical journals. New Engl J Med 1997; 
336(4):309-315.
CONFIDENTIAL


Global and country key Novo Nordisk staff
Attachments I and II (if applicable) to the protocol are located in the Trial Master File.
Content: Global key staff and Country key staff
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Fast-acting insulin aspart
Trial ID: NN1218-3854
Clinical Trial Report
Appendix 16.1.1
08 February 2018
1.0
Final
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
15 September 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
1 of 5
Protocol Amendment
no 1
to Protocol, final version 4
dated 04 February 2016
Trial ID: NN1218-3854
Efficacy and Safety of Continuous Subcutaneous Insulin Infusion of
Faster-acting Insulin Aspart compared to NovoRapid® in Adults with
Type 1 Diabetes
onset® 5
Trial phase: 3b
Applicable to Russia
Amendment originator:
TrialOps 5 , 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:
15 September 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
2 of 5
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
Table of Figures   
Page
No table of figures entries found.
Table of Tables   
Page
No table of figures entries found.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
15 September 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
3 of 5
1
Introduction including rationale for the protocol amendment
This local protocol amendment is being generated for Russia to ensure that it is clear to all parties 
involved in the execution of this trial that the blood glucose meter Ascensia Contour® Next Link 
used in this trial is not approved in Russia and will therefore be used as a device for investigational
use in Russia.
Further, this protocol amendment specifies how the technical complaints for this device for 
investigational use will be collected in Russia. 
In this protocol amendment:

Any new text is written in italics.

Any text deleted from the protocol is written using strike through.
2
Changes
Section 8.3.2.2 Self-measured plasma glucose
At the start of the run-in visit (Visit 2), the Subject will be provided with a BG meter, including 
lancets, the corresponding lancing device and plasma calibrated test stripes for BG meters. The 
Subject will be instructed verbally on how to use the device according to the manufacturer’s 
instructions. The Subject will also be provided with written instructions in local language. Sites 
will, as necessary, go through the instructions of use with the Subject during visits to the site. It is 
the site’s responsibility to ensure that the subject is familiar with the use of the device, as the 
device’s display will be in English.
The BG meter used in this trial will be the Ascensia Contour® Next Link blood glucose monitoring 
system (Ascensia Diabetes Care, Basal, CH). The Ascensia Contour® Next Link blood glucose 
monitoring system is CE marked in the European Union, but is not marketed, licensed or approved 
in Russia. Accordingly, the device will be marked as “for investigational use only” in Russia. 
Novo Nordisk A/S will be responsible for ensuring subjects’ safety when using this device for 
investigational use during this trial.
All technical complaints, AEs and SAEs related to the BG meters must be reported to Novo Nordisk.
using a separate Technical Complaint Form for BG meters and on the AE Form and SIF according 
to the process and reporting timelines specified in Section 12. The Investigator must inform the 
local Ethics Committees of such events according to local legislation.
Section 8.3.2.6 Back-up kit
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
15 September 2016
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Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
4 of 5

Glucagon for injection (reimbursed by Novo Nordisk affiliate, or supplied by the Novo 
Nordisk affiliate central lab in Russia)
Section 9.5.1 Auxiliaries supplied by Novo Nordisk

Bayer Ascensia Contour® Next Link meters blood glucose monitoring system (CE approved 
marked in EU) marked as “for investigational use only”, and strips, lancets and control 
solution for BG meters
9.5.2 Auxiliaries supplied by site

Glucagon for injection (reimbursed by Novo Nordisk affiliate, supplied by the Novo Nordisk
affiliate central lab in Russia)
12.1.5 Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device for investigational use in Russia) 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 in the vials (e.g. discoloration, 
particles or contamination)

The 10 mL vial packaging material (e.g. leakage, cracks, rubber membrane issues or errors 
in labelling text)

Any technical malfunction of the BG meter
12.4.1 Reporting of technical complaints
All technical complaints on any of the following trial products and devices for investigational use:

Faster-acting insulin aspart, 100 U/mL, 10 mL vial

Insulin aspart (NovoRapid®), 100 U/mL, 10 mL vial

Ascensia Contour® Next Link blood glucose monitoring system (BG meter)
Technical complaints must be reported on a separate Technical Complaint Form in the eCRF for 
each Novo Nordisk product listed. If the technical complaint involves more than one batch/code 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
15 September 2016
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
5 of 5
number or more than one DUN, a Technical Complaint Form for each batch/code number or for 
each DUN must be completed in the eCRF.
Technical complaints concerning the BG meters must be reported using the paper based Technical 
Complaint Form for BG meters.
12.4.2 Collection, storage and shipment of technical complaint samples
The Investigator must collect the technical complaint BG meter and notify the monitor within five 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Ascensia, (the address is provided in Attachment I) and ensure that the BG is sent as soon as 
possible. A print or copy of the Technical Complaint Form for BG meters must be sent with the 
sample.
13 Case report forms
The following will be provided as paper CRFs:

Pregnancy Form

Technical Complaint Form

Technical Complaint Form for BG meters
CONFIDENTIAL


Novo Nordisk A/S 
Electronic Signature Page 
 
 
 
 
Documentum ObjectID :
 
 
This is a representation of an electronic record that was signed electronically and this page is the 
manifestation of the electronic signature. 
Document signed by: 
Initials           
Full Name 
Meaning 
Date and Time of Signature
(Server Time) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 Sep 2016
13:23:22
3854-local-protocol-amendment-ru
Clinical Approval
15-Sep-2016 11:58 GMT+0000
Author Approval
15-Sep-2016 12:26 GMT+0000
Clinical Approval
15-Sep-2016 13:22 GMT+0000
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02825251 
Sponsor trial ID: 
NN1218-3854 
Official title of study: 
Efficacy and Safety of Continuous Subcutaneous Insulin 
Infusion of Faster-acting Insulin Aspart compared to 
NovoRapid® in Adults with Type 1 Diabetes 
Document date: 
08-Feb-2018 
 


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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
1 of 31
Statistical Analysis Plan
Trial ID: NN1218-3854
Efficacy and Safety of Continuous Subcutaneous Insulin 
Infusion of Faster-acting Insulin Aspart compared to 
NovoRapid® in Adults with Type 1 Diabetes
Onset® 5
Author:
Name: 
Department: Biostatistics Aalborg 2
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
Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 
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:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
2 of 31
Table of contents   
Page
Table of contents.........................................................................................................................................2
List of abbreviations ...................................................................................................................................3
1
Introduction .........................................................................................................................................4
1.1
Trial information.......................................................................................................................4
1.2
Scope of the statistical analysis plan..........................................................................................5
2
Statistical considerations .....................................................................................................................5
2.1
Sample size calculation .............................................................................................................8
2.2
Definition of analysis sets........................................................................................................10
2.3
Primary endpoint.....................................................................................................................10
2.4
Secondary endpoints ...............................................................................................................14
2.4.1
Confirmatory secondary endpoints.........................................................................14
2.4.2
Supportive secondary endpoints.............................................................................16
2.4.2.1
Efficacy endpoints............................................................................16
2.4.2.2
Safety endpoints...............................................................................23
3
Changes to the statistical analyses planned in the protocol..............................................................29
4
References ..........................................................................................................................................31
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
3 of 31
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AP
alkaline phosphatase
AST
aspartate aminotransferase
AUC
area under the curve
BG
blood glucose
BMI
body mass index
CGM
continuous glucose monitoring
CI
confidence interval
CSII
continuous subcutaneous insulin infusion
CTR
clinical trial report
CV
coefficient of variation
ECG
electrocardiogram
FAS
full analysis set
FPG
fasting plasma glucose
HDL
high density lipoprotein
ICH
international council on harmonisation
IG
interstitial glucose
IMP
investigational medicinal product
LDL
low density lipoprotein
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
PG
plasma glucose
PP
per protocol
PPG
postprandial glucose
SAP
statistical analysis plan
SD
standard deviation
SMPG
self-measured plasma glucose
T1DM
type 1 diabetes mellitus
TEAE
treatment emergent adverse event
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
4 of 31
1
Introduction
1.1
Trial information
This is a double-blind, randomised, multicentre, multinational, active controlled, treat-to-target, 
parallel group trial with a 4-week run-in and a 16-week treatment period comparing the effect and 
safety of continuous subcutaneous insulin infusion (CSII) of fast-acting insulin aspart versus 
NovoRapid® in adult subjects with type 1 diabetes mellitus (T1DM). Subjects entering the trial will 
stay on their own insulin pump.
The total duration of the trial is approximately 26 weeks split into the following periods (see Figure 
1–1):
!
≤ 2-week for screening period
!
A 4-week run-in period primarily for reinforcement of subject training in trial procedures, 
diabetes education and collecting baseline assessments
!
A 16-week double-blinded treatment period 
!
A 7-day and 30-day follow-up period
Figure 1–1
Trial design
Up to 50% of the eligible subjects will be allowed to wear their own real-time continuous glucose 
monitoring (CGM) device during the entire course of the trial. The remaining enrolled Subjects will 
not be allowed to wear a CGM device except for three pre-specified periods. During these periods a 
Screening
Randomisation
Fast-acting insulin aspart CSII (225 
subjects)
NovoRapid
® CSII             
(225 subjects)
Weeks   -6        -4                               0
                                                                                                 16  +7d     +30d
Note: Prior to randomisation and after end of treatment subjects are on marketed product. 
Baseline is defined as randomisation. 
FU2
4-week run-in period
CSII Continue
current Insulin 
treatment
16-week treatment period
FU1
CGM
CGM
CGM
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
5 of 31
blinded CGM device will be handed out to all subjects by the Investigator, including subjects 
wearing their own CGM. Randomisation is stratified according to the use of own real-time CGM.
The primary objective is to confirm the effect of continuous subcutaneous insulin infusion (CSII) 
treatment with fast-acting insulin aspart in terms of glycaemic control by comparing it to CSII 
treatment with NovoRapid®, in adults with Type 1 Diabetes Mellitus (T1DM), using a non-
inferiority approach.
The secondary objectives are to confirm superiority of CSII treatment with fast -acting insulin aspart 
compared to CSII treatment with NovoRapid ® in adults with T1DM, in terms of:
!
Postprandial glucose regulation (meal test)
!
Overall glycaemic control (HbA1c)
!
Postprandial glucose excursions (1,5-anhydroglucitol)
!
Time spent in low interstitial glucose (CGM)
To compare the effect and safety of CSII treatment with fast -acting insulin aspart vs. CSII treatment 
with NovoRapid® in adults with T1DM.
For further details see the trial protocol.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the statistical considerations of NN1218-3854 as 
planned in the trial protocol Efficacy and Safety of Continuous Subcutaneous Insulin Infusion of 
Faster-acting Insulin Aspart compared to NovoRapid® in Adults with Type 1 Diabetes, version 4.0 
(dated 04 February 2016). It contains a more detailed description for deriving and calculation of 
endpoints. Furthermore, it details changes to the statistical considerations presented in the protocol.
The changes to the statistical considerations proposed in this SAP and the reasons for the changes 
will be reported in the clinical trial report (CTR).
2
Statistical considerations
General considerations
In general, for endpoints evaluated as a change from baseline and/or where a baseline adjustment is 
made, baseline is defined as information collected at randomisation (Visit 6). In case a measurement 
is not available at randomisation, the most recent measurement prior to randomisation will be used 
as baseline. 
Two observation periods are defined, “in-trial” and “on-treatment”, and it will be specified which 
period each analysis will use.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
6 of 31
!
In-trial: the observation period from date of randomisation and until last trial -related 
Subject-site contact. The in-trial observation period includes data collected after 
discontinuation of randomised treatment.
!
On-treatment: the observation period from date of first dose of randomised 
NovoRapid®/fast-acting insulin aspart and no later than 7 days after the day of last dose of 
randomised NovoRapid®/fast-acting insulin aspart. The on-treatment observation period 
includes data collected up to and including 7 days after discontinuation of randomised 
treatment.
All efficacy endpoints will be summarised and analysed using the full analysis set (FAS), unless 
otherwise stated. Safety endpoints will be summarised using the safety analysis set and analysed 
using the FAS.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(LSMeans) for change from baseline, if applicable. Estimated mean treatment differences (or ratios) 
will be presented together with two-sided 95% confidence interval (CI) for all endpoints analysed 
statistically. 
For endpoints measured over time, mean values will be plotted to explore the trajectory over time. 
For survival endpoints (e.g. drop-out pattern) Kaplan-Meier plots are presented for each treatment. 
Data collected before randomisation (Visit 6) will only be summarised descriptively.
Subjects that prematurely discontinue from treatment or withdraw from trial will attend end of 
treatment visits called visit 22A and 22B. Data collected at these visits will be reallocated to the 
next scheduled visit where the given assessment is planned. As a general rule, all observed values 
from randomised subjects will be used in all statistical analyses, but in case two different values are 
associated to the same visit in time, the use of a given value will depend on the estimand of interest. 
For the primary estimand the reallocated on-treatment value will not be used and for the secondary 
estimand the reallocated on-treatment value will be used. The estimands will be defined in the next 
section.
Testing strategy and estimands
The primary objective, to confirm the effect of CSII treatment with fast-acting insulin aspart in 
terms of glycaemic control by comparing it to CSII treatment with NovoRapid ®, in adults with 
T1DM, will be assessed by the change from baseline in HbA1c using a non-inferiority approach. 
More specifically the upper limit of the 95% confidence interval for the difference between fast-
acting insulin aspart and NovoRapid® should be compared to a non-inferiority margin of 0.4%. If it 
is below or equal to 0.4% non-inferiority will be considered established and effect demonstrated. 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
7 of 31
The trial also aims to compare CSII treatment with fast-acting insulin aspart to NovoRapid® for a 
number of confirmatory secondary endpoints. The family-wise type I error rate will be controlled in 
the strong sense using a hierarchical (fixed sequence) testing procedure for the primary estimand. 
This is based on a priority ordering of the null-hypotheses, and testing them in this order using the 
two-sided 95% confidence interval approach until an insignificant result appears. The effect is that 
rejection of a null hypothesis only will be considered for analyses where all previous null-
hypotheses have been rejected in favour of fast-acting insulin aspart.
The steps in the hierarchical testing procedure are as follows:
Step 1 (Primary analysis): HbA1c non-inferiority of fast-acting insulin aspart versus NovoRapid®
Step 2: 1-hour postprandial glucose (PPG) increment (meal test) superiority of fast-acting insulin 
aspart versus NovoRapid®
Step 3: HbA1c superiority of fast-acting insulin aspart versus NovoRapid®
Step 4: 1,5-Anhydroglucitol superiority of fast -acting insulin aspart versus NovoRapid®
Step 5: time spent in low interstitial glucose (IG) (≤3.9 mmol/L [70 mg/dL]) superiority of fast -
acting insulin aspart versus NovoRapid®
Primary estimand (de facto)
The primary estimand is defined as the treatment difference between Subjects randomised to CSII 
treatment with fast-acting insulin aspart and CSII treatment with NovoRapid® in adults with T1DM 
assessed by change from baseline in HbA1c 16 weeks after randomisation for all randomised 
Subjects regardless of treatment discontinuation or use of ancillary therapies. This estimand is a de 
facto estimand addressing effectiveness.
The primary estimand assesses the expected benefit that a Subject can achieve if prescribed to CSII 
treatment with fast-acting insulin aspart as compared to CSII treatment with NovoRapid® in adults 
with T1DM. By not putting any restrictions on the randomised treatment adherence, this estimand 
aims at a difference as close as possible to the one that can be expected in real-world clinical 
practice, provided that the treatment adherence and use of ancillary therapies reflects clinical 
practice. Thereby the primary estimand provides a clinically relevant treatment difference for 
clinicians concerning the glycaemic effect of CSII treatment with fast-acting insulin aspart as 
compared to CSII treatment with NovoRapid® in the day to day life in adults with T1DM.
Secondary estimand (de jure)
Unlike the primary estimand, the secondary estimand is defined as the treatment difference in 
change from baseline in HbA1c 16 weeks after randomisation between CSII treatment with fast-
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
8 of 31
acting insulin aspart and CSII treatment with NovoRapid® in adult Subjects with T1DM if Subjects 
continue on-treatment until 16 weeks. This estimand is a de jure estimand, addressing efficacy. 
As an alternative to the primary estimand, this estimand provides a more hypothetical treatment 
difference, but may also be the most sensitive for a non-inferiority comparison, since the marketed 
product that Subjects discontinuing from randomised treatment are switched to may equalize the
treatment effect. 
The two estimands will be repeated for the endpoints:
!
1-hour PPG increment (meal test)
!
1,5-Anhydroglucitol
!
time spent in low IG (≤3.9 mmol/L [70 mg/dL]) (CGM)
2.1
Sample size calculation
The primary objective of the trial is to confirm the effect of CSII treatment with fast-acting insulin 
aspart in terms of glycaemic control by comparing it to CSII treatment with NovoRapid® in adults 
with T1DM, using a non-inferiority approach. The non-inferiority margin of 0.4% (absolute) was 
chosen as described in section 5.2.1 of the protocol. The statistical evaluation will be done as 
described in section 2.3. 
The trial also aims to confirm superiority of CSII treatment with fast -acting insulin aspart for a 
number of secondary confirmatory endpoints using the hierarchical testing procedure as described 
in section 2 (General considerations). 
The sample size is determined to ensure sufficient power for the first step and second step in the 
hierarchical testing procedure. 
In previous exploratory trials where CSII treatment with faster aspart has been investigated, the 
completion rates have been high. Therefore it is expected that treatment discontinuation might be as 
low as 4% where trial discontinuation constitutes half of these.
The power for the non-inferiority step is based on a t-statistic under the assumption of a one-sided 
test of size 2.5 %. A mean treatment difference of -0.1% for the comparison between fast-acting 
insulin aspart and NovoRapid® is expected. As trials in this population where Subjects are using 
insulin pumps and where data from treatment withdrawn subjects is retrieved are limited, a 
conservative estimate of the standard deviation (SD) in change from baseline in HbA1c of 0.8% was 
chosen.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
9 of 31
For determination of power in the second step in the hierarchical testing, where change from 
baseline in 1-hour PPG increment 16 weeks after randomisation is compared between fast-acting 
insulin aspart and NovoRapid® a t-statistic with a two-sided test of size 5.0% is used, where the 
treatment difference is expected to be at least 0.9 mmol/L [16 mg/dL]. The SD=3.4 mmol/L [62 
mg/dL] in change from baseline in 1-hour PPG increments 16 weeks after randomisation based on 
laboratory analysed plasma glucose (PG) in a standardised meal test is considered reasonable, based 
on prior trials. 
The power calculation is done using proc power in SAS Version 9.4. Please refer to Table 2–1 for 
assumption of the sample size calculation. 
Table 2–1
Specifications assumed for sample size calculation
Statistical 
test
Significance
Level
Analysis 
Population
Non-inferiority 
Margin
SD
Mean 
Difference
Randomisation
Scheme
Step 1
2-group t-test
One-sided 2.5%
FAS
0.4% (absolute) 0.8
-0.1
1:1
Step 2
2-group t-test
Two-sided 5.0%
FAS
NA
3.4
0.9
1:1
In Table 2–2, the sensitivity of the sample size to the power in Step 1 and Step 2 is shown for three 
different sample sizes of FAS. Three different choices of the mean difference are used to calculate 
the power in Step 2.
Table 2–2
Sensitivity of sample size to power in step 1 and step 2
Step 1
Step 2
N 
Total
N per 
arm
Mean 
Diff
SD
Step 1 
Power 
(%)
Null 
Diff
Mean 
Diff
SD
Step 2 
Power 
(%)
FAS
FAS
-0.1
0.80 >99.9
0
0.8
3.4
52.8
300
150
-0.1
0.80 >99.9
0
0.9
3.4
62.7
-0.1
0.80 >99.9
0
1.0
3.4
71.9
-0.1
0.80 >99.9
0
0.8
3.4
70.2
450
225
-0.1
0.80 >99.9
0
0.9
3.4
80.0
-0.1
0.80 >99.9
0
1.0
3.4
87.6
-0.1
0.80 >99.9
0
0.8
3.4
82.0
600
300
-0.1
0.80 >99.9
0
0.9
3.4
89.9
-0.1
0.80 >99.9
0
1.0
3.4
94.9
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
10 of 31
In conclusion, a sample size of 450 Subjects in the FAS (225 Subjects per group) will ensure a 
power of >99.9% to conclude HbA1c non-inferiority in the first step. This sample size gives 80.0% 
marginal power to conclude 1 hour PPG increment superiority in the second step.
Assuming a screening failure rate of 24% and run-in failure rate of 11%, 666 Subjects should be 
screened for inclusion in the trial.
2.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance:1
!
Full Analysis Set (FAS) includes all randomised Subjects. In exceptional cases, randomised 
Subjects may be excluded from the FAS. In such cases, the reason for exclusion will be 
justified and documented. Subjects in the FAS will contribute to the evaluation “as 
randomised”    
!
Per Protocol (PP) Analysis Set includes all Subjects in the full analysis set, excluding 
Subjects who:
!
Have violated any inclusion criteria
!
Have fulfilled any exclusion criteria
Subjects in the PP set will contribute to the evaluation “as treated” 
!
Safety Analysis Set includes all Subjects receiving at least one dose of the IMP or its 
comparator. Subjects in the safety analysis set will contribute to the evaluation “as treated”. 
Randomised Subjects who are lost to follow-up, and where no information on exposure to the trial 
product or its comparator is available after randomisation, will be handled as unexposed.
Before data are released for statistical review, a blinded review of all data will take place to identify 
serious non-adherence to the protocol that may potentially affect the results. Furthermore, extreme 
values and outliers will be identified by the statistician during programming and data review, 
according to ICH-E9.1 This will be performed using a fake randomisation.
The Subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before database lock. The Subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report 
(CTR).
2.3
Primary endpoint
The primary endpoint is the change from baseline in HbA1c 16 weeks after randomisation.
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Statistical Analysis Plan
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Trial ID: NN1218-3854
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Primary analysis
1) The primary estimand will be addressed by the below primary analysis based on all Subjects 
included in the FAS and using the in-trial observation period. Note that if Subjects withdraw 
consent to contribute additional information or are completely lost to follow-up, missing 
data will still occur. The primary analysis will be implemented as a statistical model using 
multiple imputations where the Subjects without any available HbA1c measurements at 
scheduled visits will have their HbA1c value imputed from the available information from 
the treatment the Subject has been randomised to. Note that this resembles in essence a 
mixed model of repeated measurements analysis, but Subjects without post-randomisation 
measurements contribute to the analysis, as the missing values will be imputed. The analysis 
will be implemented 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 group separately and 100 copies of the dataset will 
be generated.
!
In the second step, for each of the 100 copies of the dataset, an analysis of variance 
model with strata (two levels based on use of own CGM or not), previous insulin use 
(three levels: NovoRapid®, Apidra® (insulin glulisine), Humalog® (insulin lispro) and 
region as factors, and baseline HbA1c as a covariate is fitted to the change in HbA1c
from baseline to week 4 for each treatment group separately. The estimated
parameters, and their variances, from these models are used to impute missing values 
at week 4 for Subjects in each treatment group, based on strata, previous insulin use, 
region and baseline HbA1c.
!
In the third step, for each of the 100 copies of the dataset, missing values at week 8 
are imputed in the same way as for week 4. The imputations are based on an analysis 
of variance model with strata, previous insulin use and region as factors and baseline 
HbA1c and change from baseline in HbA1c at week 4 as covariates.
!
This stepwise procedure is then repeated sequentially for week 12 and 16
!
For each of the complete data sets, the change from baseline to week 16 is analysed 
using an analysis of variance model with treatment, strata, previous insulin use and 
region as factors, and baseline HbA1c as a covariate. 
!
The estimates and standard deviations for the 100 data sets are pooled using Rubin’s 
formula:
 =
1
100
 ,


,
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Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
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Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
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EudraCT No.: 2010-024054-11
Page:
12 of 31
 =  1
100
 



+ 1 + 1
100
1
100 −1 
( −)


where mi and SDi are the estimated means and standard deviations for the 100 
copies of the dataset, and mMI and SDMI are the pooled estimates.
!
From mMI  and  SDMI, the 95% confidence interval for the treatment differences is 
calculated. 
Non-inferiority of fast-acting insulin aspart will be considered confirmed if the upper boundary of 
the two-sided 95% CI is below or equal to 0.4% or equivalent if the p-value for the one-sided test of
H0: D >0.4%     against HA: D ≤0.4%,
is less than or equal to 2.5%, where D is the mean treatment difference (fast-acting insulin aspart 
minus NovoRapid®). 
Note that as the anticipated number of Subjects discontinuing treatment, but not trial is low, 
imputations based on such Subjects will not be suitable.
Provided that the hierarchical testing allows, the evaluation of superiority will be based on the same 
statistical model, as the primary analysis 1). The associated sensitivity analysis that follows will 
investigate the robustness of non-inferiority and superiority (analysis 3b and 3c) as well.
Sensitivity analyses for the primary analysis addressing the primary estimand
All sensitivity analyses for the primary analysis addressing the primary estimand will use the in-trial 
observation period.
2) First the primary analysis in 1) will be repeated, but excluding all factors except from 
treatment from the multiple imputation and analysis of variance models while still including 
baseline HbA1c as a covariate. This analysis will explore the influence of the different 
factors.
3) The primary analysis approach chosen for this trial relies on the assumption that missing 
data is missing at random (MAR). This assumption implies that the HbA1c for Subjects 
leaving the trial, after their withdrawal, develops in a similar way as the HbA 1c for similar 
Subjects that remain in the trial (not necessarily on treatment) and had similar development 
of HbA1c before withdrawal. The MAR assumption may be questionable for Subjects 
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Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
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EudraCT No.: 2010-024054-11
Page:
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withdrawing at own will. Therefore the statistical models using multiple imputation will be 
repeated with the following alterations:
a) Imputations will be done from the treatment arm that the Subject was randomised to 
and a value of 0.4% (non-inferiority margin) is added to the change from baseline in 
HbA1c at week16 for Subjects randomised to fast-acting insulin aspart with an 
imputed value at week 16.2
b) Missing values at week 16 will be imputed from the comparator arm (NovoRapid®). 
This will serve as a sensitivity analysis for the superiority analysis. It does not rely 
on the MAR assumption, but assumes that Subjects on fast-acting insulin aspart with 
an imputed value at week 16 switch to NovoRapid®. The imputation will be done 
such that the treatment effect diminishes gradually (conditional imputation).
c) Missing values at week 16 will be imputed from the comparator arm (NovoRapid®). 
This will serve as a supplementary sensitivity analysis for the superiority analysis. It 
does not rely on the MAR assumption, but assumes that Subjects on fast-acting 
insulin aspart with missing value at week 16 switch to NovoRapid®. The imputation 
will be done such that the treatment effect diminishes immediately (unconditional 
imputation). 
Analyses addressing the secondary estimand
All analyses addressing the secondary estimand will use the on-treatment observation period.
4) The secondary estimand will be analysed using the same statistical model using multiple 
imputations as the primary analysis in 1) except using the on-treatment observation period. 
5) A tipping point analysis based on a statistical model using multiple imputation model 
similar to 1), using the on-treatment observation period, will be made. In this analysis 
observations for Subjects without a measurement are imputed based on the treatment arm 
they were randomised to and Subjects without a measurement in the fast-acting insulin 
aspart group are given a penalty. This is done to investigate the robustness of the conclusion 
in the primary analysis with respect to the MAR assumption and mimics a scenario where 
the HbA1c of the Subjects without a measurement in the fast-acting insulin aspart group
evolve less favourably than predicted. As a first step imputations will be done without 
penalty assuming MAR in the treatment group. Second, a penalty will be added to the 
imputed values for week 16 in the fast-acting insulin aspart group. This is done repeatedly, 
gradually increasing the penalty until the conclusion from the non -inferiority analysis no 
longer holds. This will serve as a sensitivity analysis for the non-inferiority analysis and the 
specific value of the penalty that changes the conclusion will be used to evaluate the 
robustness of the conclusion of the non-inferiority analysis.
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Statistical Analysis Plan
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Date:
11 August 2017
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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EudraCT No.: 2010-024054-11
Page:
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6) A tipping point analysis based on a statistical model using multiple imputation, similar to 5) 
but with the modification that Subjects without a measurement that discontinued treatment 
due to non-eligibility (Subjects discontinuing fast-acting insulin aspart/NovoRapid®
prematurely due to criteria 1, 2, 3, and 4) in the fast-acting insulin aspart group will not have 
a penalty added to the imputed values. These analyses are motivated by the fact that data 
from Subjects prematurely discontinuing fast-acting insulin aspart/NovoRapid® due to non-
eligibility can reasonably be assumed to be missing completely at random. 
7) The same statistical model using multiple imputations as the analysis in 4), but using the PP 
analysis set and analysed using the on-treatment observation period. This analysis will 
investigate the situation that Subjects might have deviated from the inclusion and exclusion 
criteria and will serve as sensitivity analysis for the non-inferiority analysis.
2.4
Secondary endpoints
2.4.1
Confirmatory secondary endpoints
If the effect of CSII treatment with fast-acting insulin aspart can be confirmed in the primary 
analysis, the trial also aims to confirm the superiority of CSII treatment with fast-acting insulin 
aspart, for a number of secondary confirmatory endpoints. 
The steps used in the hierarchical testing procedure are as follows:
Step 1 (Primary analysis): HbA1c non-inferiority of fast-acting insulin aspart versus NovoRapid®
Step 2: 1-hour PPG increment (meal test) superiority of fast-acting insulin aspart versus 
NovoRapid®
Step 3: HbA1c superiority of fast-acting insulin aspart versus NovoRapid®
Step 4: 1,5-anhydroglucitol superiority of fast -acting insulin aspart versus NovoRapid®
Step 5: time spent in low IG (≤3.9 mmol/L [70 mg/dL]) superiority of fast -acting insulin aspart 
versus NovoRapid®
The primary estimand for the primary endpoint will be repeated for the confirmatory secondary 
endpoints, change from baseline in 1-hour PPG increment (meal test), change from baseline in 1,5-
anhydroglucitol and change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) 
during CGM 16 weeks after randomisation. The analyses related to these estimands are defined 
below and will be used for the decisions to continue or not, throughout the hierarchical testing 
procedure. These analyses will be based on the FAS and use the in-trial observation period.
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Statistical Analysis Plan
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Date:
11 August 2017
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Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
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The secondary analysis 4) will also be repeated for the confirmatory secondary endpoints. The 
analysis will be based on the FAS and using the on-treatment observation period.
Change from baseline in 1-hour PPG increment 16 weeks after randomisation (meal test) 
(Step 2)
As the second step of the hierarchical testing procedure, change from baseline in 1-hour PPG 
increment 16 weeks after randomisation will be tested for superiority of fast-acting insulin aspart 
compared to Novo Rapid®.
The 1-hour PPG increment will be analysed based on the laboratory measured values in the meal
test, and is derived as the 1-hour PPG measurement minus the pre-prandial PG. 
The 1-hour PPG increment endpoint will be analysed using the FAS and the in-trial observation 
period based on a multiple imputation technique where the change from baseline in 1-hour PPG 
increment at week 16 for subjects with missing value are imputed based on data from subjects in the 
NovoRapid® arm with non-missing values at week 16. Multiple copies (100 copies) of the full 
dataset will be generated by imputing missing values based on estimated parameters as follows: 
!
An analysis of variance model with strata (two levels based on use of own CGM or not), 
previous insulin use (three levels: NovoRapid®, Apidra®, Humalog®), and region as factors 
and baseline 1-hour PPG increment as covariate is fitted to the change from baseline in 1-
hour PPG increment at week 16 for the NovoRapid® group only. The estimated parameters, 
and their variances, from this model are used to impute missing values using stochastic 
simulation at week 16 for subjects in both treatment groups in order to generate 100 
complete datasets.
!
For each of the complete data sets, the change from baseline to week 16 is analysed using 
an analysis of variance model with treatment, strata (two levels based on use of own CGM 
or not), previous insulin use (three levels: NovoRapid®, Apidra®, Humalog®), and region as 
factors, and baseline 1-hour PPG increment as covariate. The estimates and standard 
deviations for the 100 data sets are pooled to one estimate and associated standard deviation 
using Rubin’s formula. From this, the pooled estimate and 95% confidence interval for the 
treatment difference are calculated.
The superiority will be assessed by comparing the upper limit of the 95% CI to 0. If the upper 95% 
CI is below 0 then superiority will be confirmed.
Change from baseline in HbA1c 16 weeks after randomisation (Step 3)
The third step in the hierarchical testing is to confirm superiority of fast-acting insulin aspart 
compared to NovoRapid® with respect to HbA1c 16 weeks after randomisation. 
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Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
Version:
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The confidence interval from the primary analysis 1) will be used to determine superiority.  
Superiority will be confirmed if the upper boundary of the two-sided 95% confidence interval of the 
mean treatment difference (fast-acting insulin aspart minus NovoRapid®) is below 0%.
Change from baseline in 1,5-anhydroglucitol 16 weeks after randomisation (Step 4)
Step 4 in the hierarchical testing procedure is to confirm superiority of change from baseline in 1,5-
anhydroglucitol 16 weeks after randomisation with fast-acting insulin aspart compared to 
NovoRapid®.
The change from baseline in 1,5-anhydroglucitol will be analysed using a model similar to 1), but 
with baseline 1,5-anhydroglucitol as a covariate. 
Superiority will be confirmed if the upper boundary of the two-sided 95% confidence interval of the 
mean treatment difference (fast-acting insulin aspart minus NovoRapid®) is below 0.
Change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) during CGM 16 
weeks after randomisation (Step 5)
The time spent in low IG is defined for each Subject at each CGM period as the accumulated time 
in hours spent below or equal to 3.9 mmol/L [70 mg/dL] from the first valid sensor value divided by 
the actual duration of the profile. To report the endpoint in minutes per 24 hours the ratio is 
multiplied by 1440.
Step 5 of the hierarchical testing procedure is to confirm superiority of change from baseline of time 
spent in low IG (≤3.9 mmol/L [70 mg/dL]) during CGM 16 weeks after randomisation with fast-
acting insulin aspart compared to NovoRapid®. 
The change from baseline of time spent in low IG (≤3.9 mmol/L [70 mg/dL]) will be analysed with 
a model similar to 1), but with the corresponding baseline value as covariate. 
2.4.2
Supportive secondary endpoints
2.4.2.1
Efficacy endpoints
All endpoints except insulin dose and insulin pump parameters in this section will be assessed using 
the FAS and the in-trial observation period and repeated using the on-treatment observation period. 
Insulin dose and insulin pump parameters will be presented using the safety analysis set and will 
therefore only use the on-treatment observation period.
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Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
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Change from baseline in FPG to 16 weeks after randomisation
Change from baseline in FPG 16 weeks after randomisation will be analysed on all planned post-
baseline measurements until or at 16 weeks with a model similar to 1) except with baseline FPG as 
covariate. 
Percentage of Subjects reaching HbA1c target 16 weeks after randomisation:
HbA1c < 7.0% 
A dichotomous (responder/non-responder) endpoint will be defined based on whether a Subject has 
met the HbA1c target (HbA1c <7.0% (53 mmol/mol)) 16 weeks after randomisation.  
This responder endpoint will be analysed based on a logistic regression model using treatment, 
strata (two levels based on use of own CGM or not), previous insulin use (three levels: 
NovoRapid®, Apidra®, Humalog®), and region as factors, and baseline HbA1c as covariate. In 
analysis of the in-trial observation period Subjects without an HbA1c measurement at week 16 will 
be treated as non-responders. In the on-treatment observation period analysis Subjects who 
discontinue fast-acting insulin aspart/NovoRapid®, withdraw from trial, and/or have no HbA1c
measurement at week 16 are included as non-responders.
HbA1c <7.0 % without severe hypoglycaemia 
A dichotomous (responder/non-responder) endpoint will be defined based on whether a Subject has 
met the HbA1c target (HbA1c <7.0% (53 mmol/mol)) 16 weeks after randomisation without 
treatment emergent severe hypoglycaemic episodes. 
This responder endpoint will be analysed based on a logistic regression model using treatment, 
strata (two levels based on use of own CGM or not), previous insulin use (three levels: 
NovoRapid®, Apidra®, Humalog®), and region as factors and baseline HbA1c as covariate. In the 
analysis of the in-trial observation period Subjects without an HbA1c measurement at week 16 will 
be treated as non-responders. In the on-treatment observation period analysis Subjects who 
discontinue fast-acting insulin aspart/NovoRapid®, withdraw from trial, or have no HbA1c
measurement at week 16 are included as non-responders.
Change from baseline in 30- min, 1- hour, 2- hour, 3- hour and 4- hour PPG and in 30- min, 2-
hour, 3- hour and 4- hour PPG increment after 16 weeks after randomisation (meal test)
Laboratory measured PG from the meal test will be analysed for 30 minutes, 1-hour, 2-hours, 3-
hours and 4-hours PPG separately. The corresponding PPG increments will be derived separately 
using each PPG measurement minus the pre-prandial PG.
Change from baseline in PPG and PPG increment 16 weeks after randomisation will be analysed 
separately using a model similar to the model used in hierarchical testing procedure step 2 for 1-
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Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
Version:
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hour PPG increment 16 weeks after randomisation (meal test) except with the corresponding 
baseline value as covariate.
Change from baseline in endpoints derived from the 7-7-9 point self-measured plasma glucose 
(SMPG) profile 16 weeks after randomisation
PPG and PPG increments based on the 7-7-9-point SMPG profiles will be derived separately for PG 
measurements made 1 hour after the meal. In the following section this distinction will be 
considered implicit and without further explanation.
Pre-prandial PG and PPG will be recorded by the Subjects as part of the 7-7-9 point SMPG profile 
prior to three defined visits. Individual mean mealtime PPG (post-breakfast, post-lunch, post-main 
evening meal) will be derived from the three profiles. Overall mean PPG will be derived from the 
individual derived mealtime PPG values.
PPG increment for each meal (breakfast, lunch, main evening meal) will be derived from the 7-7-9 
point SMPG profile as the difference between PPG values and the PG value before meal in each 
separate profile. The mean of the derived increments will then be calculated separately for each 
meal. Mean 1 hour PPG increments over all meals will be derived as the mean of all corresponding 
mean meal increments. 
!
Change from baseline in mean of the 7-7-9-point SMPG profile
The mean of the 7-7-9-point SMPG profile is defined as the area under the curve profile 
divided by the measurement time, and is calculated using the linear trapezoidal technique.
Change from baseline in the mean of the 7-7-9-point SMPG profile 16 weeks after 
randomisation will be analysed using a model similar to 1) except with the corresponding 
baseline value as covariate.
!
Change from baseline in mean pre-prandial PG, PPG and PPG increment over all three 
meals
Change from baseline in mean pre-prandial PG, PPG and PPG increment 16 weeks after 
randomisation will be analysed separately using a model similar to 1), except with the 
corresponding baseline value as covariate. 
!
Change from baseline in individual meal (breakfast, lunch and main evening meal) PPG, 
PPG increment and pre-prandial PG (pre-breakfast, pre-lunch, pre-main evening meal) 
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Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
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Change from baseline in PPG, PPG increment and pre-prandial PG endpoints 16 weeks after 
randomisation for the individual meals will be analysed separately using a model similar to 
1) except with the corresponding baseline value as covariate.
!
Fluctuation in 7-7-9-point profile
The fluctuation in the 7-7-9-point profile is defined as:

 ∫|() −
    |!


,
where T, PG(t) and 
    denotes the length of the profile, the PG value at time t and the mean 
of the profile, respectively. 
Fluctuation in the 7-7-9-point profile will be logarithmically transformed and analysed in the 
same way as mean of the profile is analysed except with the corresponding log-transformed 
baseline value as covariate. 
Estimated treatment means and the estimated treatment difference with corresponding 95% 
CI will be back-transformed to the original scale, resulting in estimated geometric means, a 
treatment ratio and a 95% CI for the treatment ratio.
!
Change in nocturnal SMPG measurements 
Change from baseline in nocturnal SMPG measurements will be assessed by considering the 
differences between PG values available at bedtime, at 4 AM and the before breakfast value 
the following day: (4 AM PG value minus at bedtime PG value), (before breakfast PG value 
minus at bedtime PG value) and (before breakfast PG value minus 4 AM PG value). 
Change from baseline in nocturnal SMPG measurements 16 weeks after randomisation will 
be analysed in the same way as mean of the profile is analysed, except with the 
corresponding baseline values as covariate. .
Percentage of subjects reaching PPG target (based on mean of PPG measurements in SMPG) 
16 weeks after randomisation:
!
Overall PPG (1 hour) ∀7.8 mmol/L [140 mg/dL]
A dichotomous (responder / non-responder) endpoint will be defined based on whether a 
Subject has reached an overall mean 1 hour PPG ∀7.8 mmol/L [140 mg/dL] 16 weeks after 
randomisation, where PPG is derived from the 7-7-9 point SMPG profile. 
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Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
Version:
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UTN: U1111-1118-2480
Status:
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This responder endpoint will be analysed based on a logistic regression model using 
treatment, strata (two levels based on use of own CGM or not), previous insulin use (three 
levels: NovoRapid®, Apidra®, Humalog®), and region as factors, and baseline overall 1-hour 
mean PPG as covariate. In analysis of the in-trial observation period Subjects without an 
overall mean 1 hour PPG at week 16 will be treated as non-responder. In the on-treatment 
observation period analysis Subjects who discontinue fast-acting insulin aspart/NovoRapid®,
withdraw from trial, or have no 1-hour mean PPG measurement at week 16 will be included 
as non-responders.
!
Overall PPG (1-hour ) ∀7.8 mmol/L [140 mg/dL] without severe hypoglycaemia
A dichotomous (responder / non-responder) endpoint will be defined based on whether a 
Subject has reached an overall 1-hour PPG ∀7.8 mmol/L [140 mg/dL] 16 weeks after 
randomisation without any treatment emergent severe hypoglycaemic episodes. 
This responder endpoint will be analysed based on a logistic regression model using 
treatment, strata (two levels based on use of own CGM or not), previous insulin use (three 
levels: NovoRapid®, Apidra®, Humalog®) and region as factors, and baseline mean 1-hour 
PPG as covariate. In analysis of the in-trial observation period Subjects without an overall 
mean 1 hour PPG at week 16 will be treated as non-responders. In the on- treatment 
observation period analysis Subjects who discontinue fast-acting insulin aspart/NovoRapid®,
withdraw from trial, or have no 1-hour PPG measurement at week 16 will be included as 
non-responders. 
Change from baseline in lipids-lipoproteins profile 16 weeks after randomisation
Change from baseline in lipid endpoints (low density lipoprotein (LDL), high density lipoprotein
(HDL), and total cholesterol) will be analysed separately using a model similar to 1). The lipid 
endpoints will be log-transformed before they are analysed including the corresponding baseline 
measurement which is included in the analysis as a covariate. The treatment difference and 
associated 95% confidence intervals will be back-transformed providing results in terms of ratios of 
geometric means on the original scale. 
Insulin dose (Units/day and Units/kg/day; total basal, total bolus, total daily insulin dose and 
individual meal insulin dose) 
The insulin doses will be summarised descriptively by treatment week according to regimen, both 
by meal type and as total daily dose in units and units/kg (total daily and separately for each meal 
time dose). The total daily basal dose will be derived from the total daily dose and bolus doses 
including correction doses. Insulin doses will be summarised using the on-treatment observation 
period and using the safety analysis set.
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Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
Version:
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Insulin delivery pump parameters 
The insulin pump parameters including insulin carbohydrate ratio, glucose sensitivity factor and 
active insulin time will be summarised descriptively by treatment week. They will be summarised 
using the on-treatment observation period and using the safety analysis set.
Supportive secondary CGM-related endpoints 
All following endpoints will be assessed 16 weeks after randomisation:
!
Percentage of time spent with IG ≤2.5, 3.0, 3.5, 3.9 mmol/L [45, 54, 63, 70 mg/dL] and IG 
>10.0, 12.0, 13.9 mmol/L [180, 216, 250 mg/dL]
!
Incidence of episodes with IG ≤2.5, 3.0, 3.5, 3.9 mmol/L [45, 54, 63, 70 mg/dL] and IG 
>10.0, 12.0, 13.9 mmol/L [180, 216, 250 mg/dL]
!
Percentage of time spent within IG target range 4.0-10.0mmol/L (71-180 mg/dL)
!
Change from baseline in mean of the IG profile
The mean of the IG profile will be defined as:
"
   =

 ∫"()!


,
where T is the time length of the profile and IG(t) is the IG value at time t. (Here t=0 
represents the time point for the start of the profile.) This mean will be calculated by means 
of the linear trapezoidal technique.
!
Variation in the IG profile
The variation in the IG profile will be presented by the fluctuation, which is defined as:

 ∫|"() −"
   |!


,
where T is the time length of the profile, IG(t) is the IG value at time t, and "
   is the mean 
of the IG profile as defined above. (Again, here t=0 represents the time point for the start of 
the profile.) The integral will be calculated by the linear trapezoidal technique. The 
coefficient of variation (CV%) will also be calculated to describe the IG variation.
CONFIDENTIAL


Statistical Analysis Plan
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Date:
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Trial ID: NN1218-3854
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EudraCT No.: 2010-024054-11
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!
Change from baseline in the area under the curve (AUC)(3.9-IG) for IG ∀3.9 mmol/L [70 
mg/dL]
The AUC (3.9-IG) is defined for each Subject at each CGM period as the AUC (3.9-IG) when IG 
is below or equal to 3.9 mmol/L [70 mg/dL] from the first valid sensor value divided by the 
actual duration of the profile. The AUC will be calculated by the linear trapezoidal 
technique. If the profile has missing censor values, then the AUC should be calculated for 
each profile part consisting of non-missing censor values. The endpoint is then calculated as 
the sum of the AUCs for all profile parts divided by the sum of the duration of the profile 
parts for which AUC is calculated. 
IG measurements during meal test will be excluded.
All CGM endpoints will be summarised descriptively by treatment.
Supportive secondary CGM and meal-characteristics endpoints
The following endpoints will be assessed 16 weeks after randomisation:
!
Change from baseline in mean IG increment (0-30 min, 0-1 hour and 0-2 hours after 
start of the meal)
The mean IG (meal) increment will be defined as the mean across main meals of the 
prandial increments, i.e. the difference between IG 30 min (1 or 2 hours, respectively) after 
the meal and IG before the meal
!
Change from baseline in mean IG peak after start of meal
The mean IG peak after start of meal will be derived as mean across main meals of the IG 
maximum values within 4 hours after start of the meal. 
!
Change from baseline in mean time to the IG peak after meal
The mean time to the IG peak after meal is derived as the mean time to the IG peak across 
main meals. 
These endpoints will also be derived for each main meal separately (breakfast, lunch and main 
evening meal). IG measurements during meal test will be excluded. All endpoints will be analysed 
separately, using a model similar to 1) except with the corresponding baseline value as covariate.
All CGM endpoints will be summarised descriptively by treatment.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
23 of 31
Supportive secondary efficacy endpoints related to CGM and meal test 
Endpoints listed below will be assessed during meal test and based on CGM measurements.
The following endpoints will be assessed 16 weeks after randomisation:
!
Change from baseline in AUCIG,0-15min 
!
Change from baseline in AUCIG,0-30min
!
Change from baseline in AUCIG,0-1h
!
Change from baseline in AUCIG,0-2h
!
Change from baseline in AUCIG,0-4h
!
Change from baseline in time to the IG peak after start of meal
!
Change from baseline in IG peak after start of meal
AUCIG,0-15 min, AUCIG,0-30 min, AUCIG,0-1h, AUCIG,0-2h, and AUCIG,0-4h will be calculated as the AUC 
IG using the linear trapezoidal technique and weighted by duration. From these endpoints the 
increments will also be calculated where an average of the IG concentrations immediately before 
the meal is subtracted from the weighted AUC. Each endpoint and derived increment will be 
analysed using an analysis of variance model including treatment, previous insulin use (three levels: 
NovoRapid®, Apidra®, Humalog®), region and strata as factors, and the corresponding baseline 
value as covariate. 
The IG peak after start of meal will be derived as the IG maximum values within 4 hours after start 
of the meal-test meal. 
Change from baseline in IG peak and time to IG peak 16 weeks after randomisation will be 
compared separately between treatments using an analysis of variance model including treatment, 
strata (two levels based on use of own CGM or not), previous insulin use (three levels: 
NovoRapid®, Apidra®, Humalog®), and region as factors, and the corresponding baseline value as 
covariate.
2.4.2.2
Safety endpoints
All safety endpoints will be compared using the on-treatment observation period. In terms of 
adverse events, as a minimum, serious adverse events will be tabulated separately also using the in-
trial observation period.
All events in the in-trial observation period will be listed with information about whether it 
appeared in the on-treatment observation period or not.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
24 of 31
Number of treatment emergent Adverse Events (AEs) 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
presented based on system organ class and preferred terms. 
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has an 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.
TEAEs are summarised descriptively, whereas AEs not defined as treatment emergent are presented 
in listings, including AEs reported in the 30-day follow-up period. The summaries of TEAEs are 
made displaying the number of Subjects with at least one event, the percentage of Subjects with at 
least one event, the number of events and the event rate per 100 patient years of exposure. These 
summaries are done by seriousness, severity, relation to insulin treatment, relation to technical 
complaint, premature treatment discontinuation due to AEs, AEs leading to withdrawal from trial
and outcome.
Furthermore, summary tables based on system organ class and preferred terms are made for:
!
All TEAEs
!
Serious TEAEs
!
Possibly or probably related TEAEs
!
Severe TEAEs
!
TEAEs with preferred term that are experienced by at least 5% of the Subjects in any 
treatment arm or by at least 5% of all Subjects
For AEs where additional information is recorded, this will be listed.
AEs occurring during the run-in period are considered non-treatment emergent and will be 
summarised separately.
Number of treatment emergent infusion site reactions
Infusion site reactions occurring during the trial will be summarised using the on-treatment 
observation periods, and listed.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
25 of 31
Classification of Hypoglycaemia
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of IMP administration after randomisation and no later 
than one day after the last day on IMP.
Nocturnal hypoglycaemic episodes: are episodes occurring between 00:01 and 05.59 both inclusive.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 2–1) and the American Diabetes Association (ADA) classification of 
hypoglycaemia (see Figure 2–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L [56 
mg/dL].3 Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-off 
point in the definition of blood glucose (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 classification4
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification4 or BG confirmed by a PG value <3.1 mmol/L [56 mg/dL] with or without
symptoms consistent with hypoglycaemia
Figure 2–1
Novo Nordisk classification of hypoglycaemia 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
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ADA classification4 of hypoglycaemia 
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may 
not be available during an event, but neurological recovery following the return of PG to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤3.9 mmol/L [70 mg/dL]
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG 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 PG 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 PG determination but that was presumably caused 
by a PG concentration ≤3.9 mmol/L [70 mg/dL]
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
27 of 31
Figure 2–2
ADA classification of hypoglycaemia
Data on-treatment emergent hypoglycaemic episodes are presented in terms of the number of 
Subjects with at least one event (N), the percentage of Subjects with at least one event (%), the 
number of events (E) and the event rate per 100 years of exposure (R). Separate summaries are 
made by severity considering all episodes, nocturnal and daytime episodes using Novo Nordisk and 
ADA classified episodes. All episodes will also be summarised by category, including summaries in 
relation to time since start of meal, as occurring within the following time intervals:
!
During first 1, 2 and 4 hours after the start of the meal
!
Between 1 (exclusive) to 2 hours (inclusive) after start of meal
!
Between 2 (exclusive) to 3 hours (inclusive) after start of meal
!
Between 3 (exclusive) to 4 hours (inclusive) after start of meal
!
Between 2 (exclusive) to 4 hours (inclusive) after start of meal 
Non-treatment emergent hypoglycaemic episodes will be listed.
The number of treatment emergent severe or BG confirmed hypoglycaemic episodes (all, daytime, 
nocturnal, 1 hour, 2 hour, 4 hour, 1 (exclusive) to 2 hours (inclusive), 2 (exclusive) to 3 hours 
(inclusive), 3 (exclusive) to 4 hours (inclusive), and 2 (exclusive) to 4 hours (inclusive) after start of 
the meal) will be analysed based on the FAS using a negative binomial regression model with a log -
link function and the logarithm of the time period in which a hypoglycaemic episode is considered 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
28 of 31
treatment emergent as offset. The model will include treatment, strata (two levels based on use of 
own CGM or not), previous insulin use (three levels: NovoRapid®, Apidra®, Humalog®), and region 
as factors. To the extent where data allow, separate analyses will be performed for all severe 
episodes.
Number of unexplained episodes of hyperglycaemia (confirmed by SMPG)
The number of unexplained episodes of hyperglycaemia will be summarised in a frequency table. 
Unexplained hyperglycaemia is defined as a confirmed PG value ≥16.7 mmol/L (300 mg/dL) and is 
unexplained (i.e. no apparent medical, dietary, insulin dosage or pump failure reason). The 
percentage of Subjects with unexplained hyperglycaemia will be presented.
Unexplained hyperglycaemic episodes will be defined as treatment emergent if the onset of the 
episode occurs on or after the first day of IMP administration after randomisation and no later than 
one day after the last day on IMP.
Physical examination 
The physical examination parameters (head, ears, eyes, nose, throat, neck, respiratory system, 
cardiovascular system, gastrointestinal system incl. mouth, musculoskeletal system, central and 
peripheral nervous system, skin), and their change from baseline, will be summarised descriptively. 
All findings will be listed.
Electrocardiogram
Electrocardiogram (ECG) findings will be summarised descriptively including summaries of the 
change from screening. Change from screening will be summarised as normal/abnormal not 
clinically significant/abnormal clinically significant categorisation in shift tables.
Vital signs (blood pressure, pulse)
Vital signs include diastolic blood pressure, systolic blood pressure and pulse. The measurements 
will be summarised descriptively using both the actual values as mean change.
Fundus photography/fundoscopy
Fundus photography/fundoscopy findings and the change from screening will be summarised 
descriptively.
Clinical laboratory assessments
Change from baseline 16 weeks after randomisation in central laboratory assessments: 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
29 of 31
!
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, and leucocytes)
!
Biochemistry (total protein, creatinine, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (AP), sodium, potassium, albumin, and total 
bilirubin)
!
Urinalysis (albumin/creatinine ratio, erythrocytes, protein, and ketones)
Individual laboratory values will be compared to their relevant reference range (when existing) and 
flagged as being below or above the range. The measurements and their change from baseline will 
be summarised descriptively. Change from baseline will be summarised descriptively using both the 
actual values and the low/normal/high categorisation in shift tables. 
Change from baseline in body weight and body mass index (BMI) 16 weeks after 
randomisation 
The measurements will be summarised descriptively using the actual values as mean change.
Change from baseline in body weight will be analysed using a statistical model similar to 1), except 
with the corresponding baseline measurement as covariate. The analysis will be based on the safety 
analysis set and the on-treatment observation period.
Number of change-of-infusion-sets per week during 16 weeks after randomisation
For each Subject this is calculated as the total number of infusion sets used divided by the actual 
duration of the randomised treatment period in days, multiplied by seven. It will be summarised for 
each treatment using descriptive statistics.
Number of Subjects with at least one non-routine change categorised by reasons for change
The percentage of Subjects with at least one non-routine change will be presented, categorised by 
reasons for change, in a frequency table by treatment.
3
Changes to the statistical analyses planned in the protocol
General considerations
It has been clarified how data collected at visit 22A and 22B are handled.
Statistical analysis
It has been clarified that type 1 error will only be controlled for the primary estimand.
In the sensitivity analysis 2) for change from baseline in HbA1c it has been clarified that baseline 
HbA1c is still included in the analysis as a covariate.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
30 of 31
In the statistical analysis in the protocol it is not clear if missing values or values for subjects 
discontinuing treatment/withdraw from trial should be imputed. Some of the following changes 
have been implemented to account for this issue.
In the sensitivity analysis for change from baseline in HbA1c it has been changed from subjects 
withdrawing from trial to subjects with an imputed value at week 16 to be aligned with the primary 
analysis.
In the statistical sensitivity analysis 3b) for change from baseline in HbA1c copy reference has been 
changed to conditional imputation, and for 3c) jump to reference has been changed to unconditional 
imputation to clarified the method used.
It has been clarified that the statistical analysis 4) will be repeated as for the confirmatory secondary 
endpoints.
For change from baseline in 1-hour PPG increment (meal test) it has been clarified how the 
endpoint is derived, which is aligned with the other endpoints derived from the meal test. To align 
with the primary analysis it has been changed so values at week 16 are imputed for subjects with 
missing values instead of imputing values for subjects withdrawn from trial, and the imputations are 
based on subjects in the NovoRapid® arm with non-missing values instead of completers in the 
NovoRapid® arm.
For the statistical analysis of change from baseline of time spent in low IG (≤3.9 mmol/L) it has 
been clarified that the corresponding baseline value will be included as covariate.
In the statistical analysis for subjects reaching HbA1c or PPG (SMPG) targets it has been clarified 
that subjects without an HbA1c measurement or 1-hour mean PPG measurement at week 16 will be 
handled as non-responders in the on-treatment observation period analysis. 
Change from baseline has been removed for fluctuation in the 7-7-9-point SMPG profile as it is 
analysed logarithmically transformed and change from baseline values could be negative.
CGM endpoints
Percentage of time spent with IG ≤3.9 mmol/L [70 mg/dL] has been added to align with the 
thresholds for IG for the endpoints incidence of episodes.
The percentage of time spent with IG >13.9 mmol/L [250 mg/dL] and incidence of episodes with 
IG >13.9 mmol/L [250 mg/dL] has been added to further evaluate the effect and safety of fast-
acting insulin aspart.
It has been clarified the variation in the IG profile will be presented by the fluctuation.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
11 August 2017
Novo Nordisk
Trial ID: NN1218-3854
Version:
1.0
UTN: U1111-1118-2480
Status:
Final
EudraCT No.: 2010-024054-11
Page:
31 of 31
The change from baseline in ΔAUCIG,0-15min, ΔAUCIG,0-30min, ΔAUCIG,0-1h, ΔAUCIG,0-2h and 
ΔAUCIG,0-4h are added to further evaluate the effect and safety of fast-acting insulin aspart.
It has been clarified that the endpoints related to CGM and meal test derived as AUCs will be 
weighted by the duration.
Adverse events
For adverse events summaries by relation to device has been change to relation to technical 
complaint to align with what is reported on the case report forms. Summaries for AEs leading to 
withdrawal from trial have been added to further investigate the safety of fast -acting insulin aspart.
Hypoglycaemic episodes
The endpoints treatment emergent hypoglycaemic episodes occurring within 1 (exclusive) to 2 
hours (inclusive), 2 (exclusive) to 3 hours (inclusive), 3 (exclusive) to 4 hours (inclusive) after start 
of the meal has been added to further investigate the safety of fast-acting insulin aspart.
It has been clarified that separate statistical analysis will only be for all severe hypoglycaemic 
episodes as the number is expected to be very low.
Unexplained hyperglycaemic episodes
The treatment emergent definition for unexplained hyperglycaemic episodes has been clarified.
Assessments not collected at baseline
ECG and fundus photography/fundoscopy is not collected at baseline, hence change from screening 
will be summarised for these endpoints instead. 
4
References
1.
ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials: dated 05 
February 1998.
2.
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.
3.
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.
4.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
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