Clinical trial NCT02670915
Conditions: Diabetes Diabetes Mellitus, Type 1
Sponsor: Novo Nordisk A/S
Start date: 2016-05-04; Completion date: 2018-03-03
Enrollment: 834 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of the trial is to investigate efficacy and safety of faster-acting insulin aspart compared to NovoRapid® both in combination with insulin degludec in children and adolescents with type 1 diabetes.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Faster-acting insulin aspart intervention 2: insulin aspart intervention 3: insulin degludec
Intervention descriptions: intervention 1: For subcutaneous (s.c., under the skin) injection once daily. intervention 2: For subcutaneous (s.c., under the skin) injection once daily. intervention 3: For subcutaneous (s.c., under the skin) injection once daily.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02670915 
Sponsor trial ID: 
NN1218-4101 
Official title of study: 
Efficacy and Safety of Faster-acting Insulin Aspart compared 
to NovoRapid® both in Combination with Insulin Degludec in 
Children and Adolescents with Type 1 Diabetes 
Document date: 
17 August 2018 
 


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


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
1 of 128
Protocol
Trial ID: NN1218-4101
Efficacy and Safety of Faster-acting Insulin Aspart compared to 
NovoRapid® both in Combination with Insulin Degludec in Children 
and Adolescents with Type 1 Diabetes 
onset®7
Trial phase: 3b
Protocol originator
 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 No unpublished information contained herein may be 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
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 No unpublished information contained herein may be 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:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
2 of 128
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................7
Table of Tables..................................................................................................................................................7
List of abbreviations.........................................................................................................................................8
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................13
3
Background information and rationale for the trial............................................................................17
3.1
Background information..............................................................................................................17
3.2
Therapeutic area...........................................................................................................................17
3.3
NovoRapid®.................................................................................................................................18
3.4
Faster-acting insulin aspart ..........................................................................................................18
3.5
Insulin degludec...........................................................................................................................19
3.6
Rationale for the trial...................................................................................................................20
4
Objectives and endpoints........................................................................................................................21
4.1
Objectives ....................................................................................................................................21
4.1.1
Primary objective.......................................................................................................21
4.1.2
Secondary objectives .................................................................................................21
4.2
Endpoints .....................................................................................................................................21
4.2.1
Primary endpoint........................................................................................................21
4.2.2
Secondary endpoints..................................................................................................21
4.2.2.1
Supportive secondary efficacy endpoints............................................22
4.2.2.2
Supportive secondary CGM related efficacy endpoints 
(subgroup): ..........................................................................................22
4.2.2.3
Supportive secondary CGM and meal-characteristics efficacy 
endpoints (subgroup):..........................................................................22
4.2.2.4
Supportive secondary meal test related efficacy endpoints 
(subgroup): ..........................................................................................23
4.2.2.5
Supportive secondary CGM and meal test related efficacy 
endpoints (subgroup):..........................................................................23
4.2.2.6
Supportive secondary safety endpoints...............................................23
5
Trial design ..............................................................................................................................................25
5.1
Type of trial .................................................................................................................................25
5.2
Rationale for trial design..............................................................................................................26
5.2.1
Rationale for the CGM and meal test subgroup.........................................................27
5.2.2
Rationale for choice of non-inferiority margin..........................................................27
5.3
Treatment of Subjects..................................................................................................................27
5.3.1
Basal insulin titration.................................................................................................28
5.3.2
Bolus insulin titration.................................................................................................28
5.4
Treatment after discontinuation of trial product ..........................................................................29
5.5
Rationale for treatment ................................................................................................................29
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
3 of 128
6
Trial population.......................................................................................................................................30
6.1
Number of Subjects .....................................................................................................................30
6.2
Inclusion criteria ..........................................................................................................................30
6.2.1
Additional inclusion criteria for the CGM and meal test subgroup...........................31
6.3
Exclusion criteria.........................................................................................................................31
6.4
Run-in failure criteria...................................................................................................................32
6.5
Randomisation criteria.................................................................................................................32
6.5.1
Additional randomisation criterion for the CGM and meal test subgroup.................32
6.6
Criteria for premature discontinuation of trial product................................................................33
6.7
Withdrawal from trial ..................................................................................................................33
6.8
Subject replacement.....................................................................................................................34
6.9
Rationale for trial population.......................................................................................................34
7
Milestones.................................................................................................................................................36
8
Methods and assessments .......................................................................................................................37
8.1
Visit procedures...........................................................................................................................37
8.1.1
Informed Consent and child assent............................................................................37
8.1.2
Screening visit............................................................................................................38
8.1.2.1
Screening failures................................................................................38
8.1.2.2
Re-screening........................................................................................39
8.1.3
Run-in ........................................................................................................................39
8.1.3.1
Run-in failures.....................................................................................39
8.1.4
Randomisation ...........................................................................................................39
8.1.5
Site visits....................................................................................................................40
8.1.6
Phone contacts ...........................................................................................................40
8.1.7
Fasting visits ..............................................................................................................41
8.1.8
Rescheduled visits......................................................................................................41
8.1.9
End of Treatment .......................................................................................................41
8.1.10
Follow-up periods......................................................................................................41
8.1.10.1
Follow-up Visit 1 ................................................................................41
8.1.10.2
Follow-up Visit 2 ................................................................................42
8.2
Premature discontinuation of trial product ..................................................................................42
8.3
Withdrawal from trial ..................................................................................................................44
8.4
Subject related information..........................................................................................................45
8.4.1
Demography...............................................................................................................45
8.4.2
Diagnosis of type 1 diabetes mellitus ........................................................................45
8.4.3
Concomitant illness and medical history...................................................................45
8.4.4
Concomitant medication............................................................................................45
8.4.5
Diabetes treatment history .........................................................................................46
8.5
Clinical Assessments ...................................................................................................................46
8.5.1
Adverse events requiring special forms in the eCRF.................................................46
8.5.1.1
Hypoglycaemic episodes.....................................................................46
8.5.1.2
Hyperglycaemic episodes....................................................................49
8.5.1.3
Injection site reactions.........................................................................50
8.5.2
Body measurements...................................................................................................51
8.5.3
Continuous glucose monitoring (CGM) and meal test in a subgroup........................51
8.5.4
Insulin dose................................................................................................................52
8.5.5
Physical examination.................................................................................................52
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
4 of 128
8.5.5.1
Pubertal status (Tanner staging)..........................................................52
8.5.6
Self-measured plasma glucose...................................................................................53
8.5.6.1
4-point profile......................................................................................53
8.5.6.2
8-point profile......................................................................................54
8.5.7
Vital signs ..................................................................................................................55
8.6
Laboratory assessments ...............................................................................................................55
8.6.1
Blood volumes for blood sampling............................................................................56
8.6.2
1,5-anhydroglucitol....................................................................................................57
8.6.3
Biochemistry..............................................................................................................58
8.6.4
Fasting plasma glucose..............................................................................................58
8.6.5
Haematology..............................................................................................................59
8.6.6
HbA1c .........................................................................................................................59
8.6.7
Insulin antibodies.......................................................................................................59
8.6.8
Lipids .........................................................................................................................59
8.6.9
Pregnancy testing.......................................................................................................60
8.7
Other assessments and procedures...............................................................................................60
8.7.1
Diary ..........................................................................................................................60
8.7.2
Training in diabetes and carbohydrate counting........................................................61
8.7.3
Training in trial product and pen handling ................................................................62
8.7.4
Safety precautions......................................................................................................62
8.8
Subject compliance......................................................................................................................63
9
Trial supplies ...........................................................................................................................................64
9.1
Trial products...............................................................................................................................65
9.2
Labelling......................................................................................................................................66
9.3
Storage .........................................................................................................................................67
9.4
Drug accountability and destruction............................................................................................68
9.5
Auxiliary supplies........................................................................................................................68
9.5.1
Auxiliaries supplied by Novo Nordisk A/S ...............................................................68
10 Interactive voice/web response system ..................................................................................................69
11 Randomisation procedure and breaking of blinded codes..................................................................70
11.1
Breaking of blinded codes ...........................................................................................................70
12 Adverse events, and technical complaints and pregnancies................................................................71
12.1
Definitions ...................................................................................................................................71
12.1.1
Adverse event ............................................................................................................71
12.1.2
Serious adverse event.................................................................................................73
12.1.3
Non-serious adverse event.........................................................................................74
12.1.4
Medical event of special interest................................................................................74
12.1.5
Technical complaint...................................................................................................74
12.2
Reporting of adverse events.........................................................................................................75
12.2.1
Timelines for initial reporting of AEs:.......................................................................76
12.2.2
Reporting of trial product-related SUSARs by the sponsor:......................................77
12.2.3
Novo Nordisk products used as concomitant medication:.........................................77
12.3
Follow-up of adverse events........................................................................................................77
12.4
Technical complaints, and technical complaint samples .............................................................78
12.4.1
Reporting of technical complaints .............................................................................78
12.4.2
Collection, storage and shipment of technical complaint samples ............................79
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
5 of 128
12.5
Pregnancies..................................................................................................................................79
12.5.1
Pregnancies in female Subjects..................................................................................79
12.6
Precautions and/or overdose ........................................................................................................81
12.7
Committees related to safety........................................................................................................81
12.7.1
Novo Nordisk safety committee ................................................................................81
12.7.2
Data Monitoring Committee......................................................................................81
13 Case report forms....................................................................................................................................82
13.1
Corrections to case report forms..................................................................................................82
13.2
Case report form flow..................................................................................................................83
14 Monitoring procedures ...........................................................................................................................84
14.1
Source data verification ...............................................................................................................84
15 Data management....................................................................................................................................86
16 Computerised systems.............................................................................................................................87
17 Statistical considerations ........................................................................................................................88
17.1
Sample size calculation................................................................................................................90
17.1.1
Sample size calculation for the CGM and meal test subgroup ..................................91
17.2
Definition of analysis sets............................................................................................................91
17.3
Primary endpoint..........................................................................................................................92
17.4
Secondary endpoints....................................................................................................................95
17.4.1
Supportive secondary endpoints ................................................................................95
17.4.1.1
Change from baseline refers to the change from randomisation to 
26 weeks after randomisation.Efficacy endpoints...............................96
17.4.1.2
Safety endpoints................................................................................100
18 Ethics......................................................................................................................................................107
18.1
Clinical benefits and risk assessments.......................................................................................107
18.2
Informed consent .......................................................................................................................110
18.2.1
Child Assent Form...................................................................................................110
18.3
Data handling.............................................................................................................................111
18.4
Information to Subject during trial ............................................................................................111
18.5
Premature termination of the trial and/or trial site.....................................................................111
19 Protocol compliance..............................................................................................................................112
19.1
Protocol deviations ....................................................................................................................112
19.2
Prevention of missing data.........................................................................................................112
20 Audits and inspections ..........................................................................................................................114
21 Critical documents ................................................................................................................................115
22 Responsibilities......................................................................................................................................117
23 Reports and publications......................................................................................................................118
23.1
Communication of results..........................................................................................................118
23.1.1
Authorship ...............................................................................................................119
23.1.2
Site-specific publications by Investigators ..............................................................119
23.2
Investigator access to data and review of results.......................................................................119
24 Retention of clinical trial documentation and human biospecimens................................................121
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
6 of 128
24.1
Retention of clinical trial documentation...................................................................................121
24.2
Retention of human biospecimens.............................................................................................121
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............122
26 Indemnity statement .............................................................................................................................123
27 References..............................................................................................................................................124
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:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
7 of 128
Table of Figures   
Page
Figure 1–1
Trial design.............................................................................................................................11
Figure 5–1
Trial design.............................................................................................................................26
Figure 12–1
Initial reporting of AEs...........................................................................................................76
Figure 17–1
Novo Nordisk classification of hypoglycaemia in paediatrics .............................................102
Figure 17–2
ADA/ISPAD classification of hypoglycaemia in paediatrics...............................................103
Table of Tables
Page
Table 8–1
8-point SMPG profile (8-point profile) ..................................................................................54
Table 8–2
Approximate blood volumes collected during the trial...........................................................57
Table 9–1
Trial Products .........................................................................................................................65
Table 9–2
Storage of trial products..........................................................................................................67
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
8 of 128
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BG
blood glucose
CGM
continuous glucose monitoring
CRO
contract research organisation
DUN
dispensing unit number
eCRF
electronic case report form
EMA
European Medicines Agency
EoT
End of treatment
FAS
full analysis set
FDA
Food and Drug Administration
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
HbA1c
glycosylated haemoglobin
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
I:Carb
insulin:carbohydrate ratio
IB
Investigator’s Brochure
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
IG
interstitial glucose
IRB
Institutional Review Board
ISPAD
International Society for Paediatric and Adolescent 
Diabetes 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
9 of 128
IV/WRS
interactive voice/web response system
LAR
legally acceptable representative
LDL
low density lipoprotein
LSLV
last subject last visit
MAR
missing at random
NPH
Neutral Protamine Hagedorn
PG
plasma glucose
PP
per protocol
PPG
postprandial glucose
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set 
s.c
subcutaneous
SmPC
summary of product characteristics
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent adverse event
T1DM
type 1 diabetes mellitus
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
10 of 128
1
Summary
Primary objective:
To confirm the effect of treatment with meal-time faster-acting insulin aspart in terms of glycaemic 
control by comparing it to meal-time NovoRapid®, both in combination with insulin degludec using 
a non-inferiority approach in children and adolescents with type 1 diabetes.  
Secondary  objectives
To confirm the effect of treatment with post-meal faster-acting insulin aspart in terms of glycaemic 
control by comparing it to meal-time NovoRapid®, both in combination with insulin degludec, 
using a non-inferiority approach in children and adolescents with type 1 diabetes.
To confirm superiority of treatment with meal-time faster-acting insulin aspart in terms of 
glycaemic control by comparing it to meal-time NovoRapid®, both in combination with insulin 
degludec in children and adolescents with type 1 diabetes.
To compare the effect and safety of treatment with meal-time faster-acting insulin aspart vs. meal-
time NovoRapid® both in combination with insulin degludec in children and adolescents with type 
1 diabetes. 
To compare the effect and safety of treatment with post-meal faster-acting insulin aspart vs. meal-
time NovoRapid® both in combination with insulin degludec in children and adolescents with type 
1 diabetes.
Primary endpoint
!
Change from baseline in HbA1c 26 weeks after randomisation
Key secondary endpoints
26 weeks after randomisation:
Change from baseline in 8-point self-measured plasma glucose (SMPG) profile (8-point 
profile):
!
Mean postprandial glucose (PPG) and PPG increment over all three meals
!
Change from baseline in fasting plasma glucose (FPG)
!
Number of treatment emergent adverse events (AEs)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
11 of 128
Trial design
This is a 26-week randomised, partly double-blind, multicentre, multinational, active controlled, 
treat-to-target, three-armed parallel group trial with a 12-week run-in period comparing the effect
and safety of meal-time faster-acting insulin aspart vs. meal-time NovoRapid® both in combination 
with insulin degludec once daily in a basal-bolus regimen in type 1 diabetes mellitus Subjects from
1 year to less than 18 years of age. The trial will also include a 26-week open-label post-meal 
faster-acting insulin aspart dosing arm in combination with insulin degludec.
Figure 1–1
Trial design
Trial population:
A total of 833 Subjects with type 1 diabetes mellitus are planned to enter the run-in period, of which 
750 are expected to enter randomised treatment.
Key inclusion criteria:
!
Male or female, 1 ≤ age < 18 years at the time of signing informed consent and < 18 years at 
the time of randomisation
!
Diagnosed with type 1 diabetes mellitus (based on clinical judgement and supported by
laboratory analysis as per local guidelines)
!
Ongoing daily treatment with a basal-bolus insulin regimen using basal insulin analogue or 
NPH insulin for at least 90 days prior to the screening visit
!
HbA1c ≤ 9.5% (80 mmol/mol) analysed by the central laboratory at the screening visit
Screening
Randomisation
Meal-time faster-acting insulin aspart and insulin degludec        
(250 Subjects)
Meal-time NovoRapid® and insulin degludec                  
(250 Subjects)
Week  -14       -12
   
     0                                                                                             
    26   27            30
Note: Prior to run-in and after End of Treatment Subjects are on marketed products
FU1
12-week run-in period
Meal-time 
NovoRapid® and 
insulin degludec
26-week treatment period
FU2
Post-meal faster-acting insulin aspart and 
insulin degludec  (250 Subjects)
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
12 of 128
Key exclusion criteria:
!
More than one episode of diabetic ketoacidosis requiring hospitalisation within the last 90 
days prior to the screening visit
!
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
Key randomisation criterion:
!
HbA1c ≤ 9.5% (80 mmol/mol) (at Visit 12 analysed by the central laboratory )
Key efficacy assessments:
!
HbA1c
!
Mean postprandial glucose (PPG) and PPG increment (assessed from 8-point profile) over 
three meals
!
Fasting plasma glucose (FPG)
Key safety assessment:
!
Number of adverse events (AEs)
Trial product(s):
For this trial the following trial products will be provided:
!
Faster-acting insulin aspart, 100 U/mL solution for subcutaneous (s.c.) injection
(investigational medicinal product) administered with NovoPen Echo®
!
NovoRapid®, 100 U/mL solution for s.c. injection (investigational medicinal product) 
administered with NovoPen Echo®
!
Insulin degludec, 100 U/mL solution for s.c. injection (investigational medicinal product)
administered with a pre-filled PDS290 pen-injector (FlexTouch®)
CONFIDENTIAL


Protocol
UTN: U1111-1158-1170 
Date:
10 November 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN1218-4101
EudraCT no.: 2014-002568-33 
Version:
2,0
Page:
13 of 128
2
Flow chart
NN1218-4101
Protocol section
Screening
12-week run-in period
Randomisation
26-week treatment period
Follow-up 1c
Follow-up 2c
Premature 
Discontinuationc
Visit (V)
Phone contact (P)
V1
V2
P3
V4
P5
V6
P7
V8
P9
V10 P11 V12 P13
V14
P15
V16
P17
V18
P19
P20
P21
V22
P23
P24
P25
V26
P27
P28
P29
V30
P31
P32
P33
V34
P35
P36
P37
V38
P39
V40
V41
P42
V40A
Time of visit (week)
-14
-12
-11
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
+7 
days
after 
EoT
+30 
days
after 
EoT
Visit window (days)a
+10 ±3b
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
SUBJECT RELATED 
INFO/ASSESSMENTS
Informed consent
8.1.1
18.2
x
Informed assent
8.1.1
18.2
x
In/exclusion criteria 
6.2 6.3
x
x
Randomisation criteria
6.5
x
Run-in failure criteria
6.4
x
x
x
x
x
x
x
x
x
x
x
x
Criteria for premature 
discontinuation of trial 
product 
6.6
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Demography
8.4.1
x
xd
Diagnosis of diabetes 
8.4.2
x
Diabetes treatment history
8.4.5
x
x
x
x
x
x
Concomitant illness/medical 
history 
8.4.3
x
Concomitant medication 
8.4.4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
CLINICAL 
ASSESSMENTS
4-point profile (SMPG)
8.5.6.1
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
x
xe
x
8-point profile (SMPG)
8.5.6.2
x
x
x
x
Hypoglycaemic episodes
8.5.1.1
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
x
x
x
x
x
Hyperglycaemic episodes
8.5.1.2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
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
x
x
x
x
x
x
Injection site reactions
8.5.1.3
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
x
x
x
x
xf
x
Technical complaints
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
x
x
x
x
xe
Height 
8.5.2
x
x
x
x
x
Body weight 
8.5.2
x
x
x
x
x


Protocol
UTN: U1111-1158-1170 
Date:
10 November 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN1218-4101
EudraCT no.: 2014-002568-33 
Version:
2,0
Page:
14 of 128
NN1218-4101
Protocol section
Screening
12-week run-in period
Randomisation
26-week treatment period
Follow-up 1c
Follow-up 2c
Premature 
Discontinuationc
Visit (V)
Phone contact (P)
V1
V2
P3
V4
P5
V6
P7
V8
P9
V10 P11 V12 P13
V14
P15
V16
P17
V18
P19
P20
P21
V22
P23
P24
P25
V26
P27
P28
P29
V30
P31
P32
P33
V34
P35
P36
P37
V38
P39
V40
V41
P42
V40A
Time of visit (week)
-14
-12
-11
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
+7 
days
after 
EoT
+30 
days
after 
EoT
Visit window (days)a
+10 ±3b
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
Vital signs
8.5.7
x
x
x
x
x
Physical examination 
8.5.5
x
x
x
x
x
Pubertal status (Tanner 
staging)
8.5.5.1
x
x
x
x
CGMg
8.5.3
x
x
x
x
x
xe
x
Meal testg
8.5.3
x
xe
x
LABORATORY 
ASSESSMENTS
Fasting plasma glucoseh
8.6.4
x
x
x
x
HbA1c
8.6.6
x
x
x
x
x
x
1,5-anhydroglucitol
8.6.2
x
x
x
x
Biochemistry 
8.6.3
x
x
x
x
x
Haematology 
8.6.5
x
x
x
x
x
Antibodies
8.6.7
x
x
x
x
Lipids 
8.6.8
x
x
x
x
x
Pregnancy test
8.6.9
x
x
x
x
TRIAL MATERIAL
IV/WRS call
10
x
x
x
x
x
x
x
x
x
x
x
xe
x
Dispensing visit 
8.1.3
8.1.5
x
x
x
x
x
x
x
x
x
x
Dosingi
8.5.4
x
x
x
Doses of trial insulin on the 
3 days before visit
8.5.4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
New doses of trial
Insulin
8.5.4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Drug accountability
9.4
x
x
x
x
x
x
x
x
x
x
x
REMINDERS
Hand out ID Card 
8.1.2
x
Training in diabetes and 
carbohydrate counting
8.7.2
x
x
x
x
x
x
x
x


Protocol
UTN: U1111-1158-1170 
Date:
10 November 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN1218-4101
EudraCT no.: 2014-002568-33 
Version:
2,0
Page:
15 of 128
NN1218-4101
Protocol section
Screening
12-week run-in period
Randomisation
26-week treatment period
Follow-up 1c
Follow-up 2c
Premature 
Discontinuationc
Visit (V)
Phone contact (P)
V1
V2
P3
V4
P5
V6
P7
V8
P9
V10 P11 V12 P13
V14
P15
V16
P17
V18
P19
P20
P21
V22
P23
P24
P25
V26
P27
P28
P29
V30
P31
P32
P33
V34
P35
P36
P37
V38
P39
V40
V41
P42
V40A
Time of visit (week)
-14
-12
-11
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
+7 
days
after 
EoT
+30 
days
after 
EoT
Visit window (days)a
+10 ±3b
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
+5
Training in trial products
and pen handling
8.7.3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Handout direction for use
9.2
x
Handout and instruct in BG 
meter use
8.5.6
x
Supply and instruct in 
diary/collection of diary
8.7.1
8.2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xj
x
Handout FPG home blood 
sampling kit
8.6.4
x
x
x
xk
Instruct in safety precautions 
and hand out supplies
8.7.4
x
End of Treatment
8.1.9
x
x
End of trial
8.1.9,
8.2, 8.3
xl
xm
Sign off case book
13
xl
xm


Protocol
UTN: U1111-1158-1170 
Date:
10 November 2015
Status:
Final
1RYR1RUGLVN
Trial ID: NN1218-4101
EudraCT no.: 2014-002568-33 
Version:
2,0
Page:
16 of 128
a)
Visit windows are relative to the randomisation visit (Visit 14), except for the follow-up visits which are relative to last day on trial product
b)
Visit 2 can take place as soon as the Subject has been found eligible and must take place no later than 13 days after the screening visit (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
c)
Subjects who prematurely discontinue trial product will be asked to attend the premature discontinuation visit and subsequently FU1 and FU2 according to 
section 8.2
d)
For Germany only: The only demographic data to be collected at Visit 14 is the Subject’s age at randomisation (to be used for stratification)
e)
The assessment is not applicable for premature discontinued Subjects, see section 8.2
f)
Injection site reactions must be captured on the AE form (no additional injection site reaction information needs to be completed)
g)
Only applicable for a subgroup of Subjects. In case of premature discontinuation please see Appendix B
h)
Using the FPG home blood sampling kit
i)
Start and stop date of trial product 
j)
Only collection of diary. For Subjects who prematurely discontinue trial product a new diary will be handed out at this visit
k)
Site staff should provide FPG home blood sample kits to the Subject prior to the visit
l)
Only for Subjects prematurely discontinuing trial product  
m) Only for Subjects completed the full visit schedule. Subjects who prematurely discontinue trial product must have Visit 40 planned according to section 8.2


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
17 of 128
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH Good Clinical Practice (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
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 mellitus3,4. Postprandial hyperglycaemia contributes 
significantly to the glycosylated haemoglobin (HbA1c) level, and its control is essential for 
achieving the HbA1c target level5. Basal-bolus insulin therapy aims at mimicking the normal 
physiological insulin response. Rapid-acting insulin analogues were developed to more effectively 
control the postprandial glucose (PPG) excursions than subcutaneously injected human regular 
insulin, primarily through offering a faster onset and shorter duration of action6. However, unmet 
needs still exist within prandial insulin therapy for people with diabetes and an exogenous insulin 
with a faster glucose lowering effect is needed for tighter PPG control. A faster glucose lowering 
effect is also likely to offer greater flexibility in the time of dosing around meals thus increasing 
convenience for the patients and may allow the patients to better match the insulin taken to the 
meal. Although several insulin products are available on the market and can be used by paediatric 
patients, there is still a need for improvement of the treatment options to more closely resemble the 
physiological action profile of endogenous insulin and to reduce unwanted side effects such as 
hypoglycaemia. The pathophysiology of T1DM appears to be comparable between adults and 
paediatric patients, and consequently, the potential benefits of faster-acting insulin aspart for 
children and adolescents are believed to be similar to those for adults. 
3.2
Therapeutic area
T1DM is among the most common chronic diseases in childhood and adolescence and the children 
and adolescents with T1DM are dependent on insulin for survival. Intensive treatment is beneficial 
in terms of reducing the risk for long term complications. The International Society for Paediatric 
and Adolescent Diabetes (ISPAD) recommends an HbA1c range for all age groups of < 7.5% (58 
mmol/mol), and that each child should have their target individually determined with the goal of 
achieving a value as close to normal as possible while avoiding severe hypoglycaemia as well as 
frequent mild to moderate hypoglycaemia7. This treatment target was recently supported by the 
American Diabetes Association (ADA)8.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
18 of 128
3.3
NovoRapid®
Insulin aspart is marketed worldwide as NovoRapid® (marketed as NovoLog® in the US) and is a 
fast-acting insulin analogue indicated for the treatment of diabetes. In the remainder of this 
document the name NovoRapid® will be used.
NovoRapid® 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 human insulin. Compared with regular 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 T1DM9,10,11
and in Subjects with type 2 diabetes mellitus12-14. This also allows NovoRapid® to be injected 
immediately before a meal, in contrast to regular human insulin. NovoRapid® can be used in 
children in preference to regular human insulin when a rapid onset of action might be beneficial, 
e.g. in the timing of the injections in relation to meals. No studies have been performed in children 
below the age of 2 years. In line with current practice NovoRapid® will only be used in this age 
group under careful medical supervision. 
For further details see the current version of the NovoRapid® summary of product characteristics
(SmPC)15or the U.S. NovoLog® Label information16.
3.4
Faster-acting insulin aspart
Faster-acting insulin aspart (also called faster aspart) is insulin aspart in a new formulation. 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
excursions 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 effect17. Results 
from a clinical pharmacology trial comparing the pharmacokinetic and pharmacodynamic properties 
of faster-acting insulin aspart and NovoRapid® during a meal test in children (6-11 years), 
adolescents (12-17 years) and adults (18-64 years) with T1DM have shown that faster-acting insulin 
aspart elicited an earlier onset of exposure and a higher early insulin exposure whilst maintaining a 
similar total exposure and maximum concentration compared to NovoRapid® across all age groups. 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
19 of 128
Faster-acting insulin aspart had a larger glucose-lowering effect compared to NovoRapid® during 
the meal-test in children. In adolescents, a larger glucose-lowering effect for faster-acting insulin 
aspart was not demonstrated during the meal-test, despite a greater early insulin exposure. In adults, 
the glucose-lowering effect tended to be larger for faster-acting insulin aspart than for NovoRapid®
during a meal-test. Overall, the glucose-lowering effect was comparable between age groups17.
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®. For post-meal faster-acting insulin aspart, 
non-inferiority to meal-time NovoRapid® regarding lowering of HbA1c was also confirmed. Meal-
time faster-acting insulin aspart provided superior PPG control compared  with NovoRapid® based 
on 2-hour PPG increment during a meal test. A statistically significant difference was also 
demonstrated for 1-hour PPG increment (meal test) in favour of meal-time faster-acting insulin 
aspart. No statistically significant difference was seen in overall rate of severe or blood glucose
confirmed hypoglycaemic episodes between meal-time faster-acting insulin aspart and 
NovoRapid®.The rate during the first 1 hour after start of a meal, constituting a smaller fraction of 
all severe or blood glucose (BG) confirmed hypoglycaemic episodes, was statistically significantly 
higher for meal-time faster-acting insulin aspart compared to NovoRapid®. The overall safety 
profile for faster-acting insulin aspart and NovoRapid® was similar and as expected for insulin 
aspart17. 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 10 
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 
products for injections, and no toxicological concerns have been predicted from s.c. use in humans 
at the proposed concentrations. For further details see the current version of the faster-acting insulin 
aspart Investigator Brochure (IB)17.
3.5
Insulin degludec
Insulin degludec (marketed as Tresiba®) is a basal insulin with an ultra-long duration of action for 
once-daily s.c. administration at any time of the day, preferably at the same time every day. After 
s.c. injection, soluble and stable multi-hexamers are formed creating a depot of insulin in the s.c.
tissue. Insulin degludec monomers gradually separate from the multi-hexamers thus resulting in a 
slow and continuous delivery of insulin degludec into the circulation, leading to the observed ultra-
long pharmacokinetic and pharmacodynamic profiles and thereby a flat and stable glucose-
lowering-effect. The duration of action of insulin degludec is beyond 42 hours within the 
therapeutic dose range. A clinical pharmacology study in children and adolescents with T1DM 
confirmed that the ultra-long acting properties of insulin degludec seen in adults are preserved in 
children and adolescents. Extent of exposure after a single fixed dose tends to be greater in 
children/adolescents than in adults; but as with other insulin products, insulin degludec should 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
20 of 128
always be titrated according to individual requirements18. In a recent study conducted in a paediatric 
population insulin degludec was shown to be safe and to effectively improve long-term glycaemic 
control in all Subjects19. Insulin degludec was recently approved for use in children and adolescents 
aged 1 to less than 18 years old in the EU.
For further details see the current version of the Tresiba® EU SmPC20 or the U.S. Tresiba® Label 
information21 and if not approved in the country of interest detailed information for insulin degludec 
is available in the current edition and any updates of the Investigator’s Brochure (IB)22. 
At the time of this protocol issuance, degludec is approved in more than 60 countries, including
USA, all of the EU countries, and marketed in 26 countries.
3.6
Rationale for the trial
This trial aims to confirm that the efficacy and safety profile of faster-acting insulin aspart can be 
demonstrated in the paediatric population 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, HbA1c will be included as the primary endpoint23,24.
The trial is also designed to investigate differences in glycaemic control between faster-acting 
insulin aspart and NovoRapid® based on data from a standardised meal test and continuous glucose 
monitoring (CGM) in a subgroup of Subjects. 
In addition, this trial includes a post-meal faster-acting insulin aspart dosing arm in order to assess 
whether post-meal administration could prove effective in achieving glucose control to offer a 
clinically acceptable treatment option.
Together with the clinical pharmacology trial in children and adolescents, the current trial is 
conducted in order to fulfil the regulatory requirements for obtaining a paediatric indication for 
faster-acting insulin aspart25.
For an assessment of benefits and risks of the trial, see section 18.1.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2,0
UTN: U1111-1158-1170 
Status:
Final
EudraCT no.: 2014-002568-33 
Page:
21 of 128
4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To confirm the effect of treatment with meal-time faster-acting insulin aspart in terms of glycaemic 
control by comparing it to meal-time NovoRapid® both in combination with insulin degludec using 
a non-inferiority approach in children and adolescents with type 1 diabetes.
4.1.2
Secondary objectives
To confirm the effect of treatment with post-meal faster-acting insulin aspart in terms of glycaemic 
control by comparing it to meal-time NovoRapid® both in combination with insulin degludec,
using a non-inferiority approach in children and adolescents with type 1 diabetes.
To confirm superiority of treatment with meal-time faster-acting insulin aspart in terms of 
glycaemic control by comparing it to meal-time NovoRapid®, both in combination with insulin 
degludec in children and adolescents with type 1 diabetes.
To compare the effect and safety of treatment with meal-time faster-acting insulin aspart vs. meal-
time NovoRapid® both in combination with insulin degludec in children and adolescents with type 
1 diabetes.
To compare the effect and safety of treatment with post-meal faster-acting insulin aspart vs. meal-
time NovoRapid® both in combination with insulin degludec in children and adolescents with type 
1 diabetes.
4.2
Endpoints
4.2.1
Primary endpoint
!
Change from baseline in HbA1c 26 weeks after randomisation 
4.2.2
Secondary endpoints
Change from baseline refers to the change from randomisation to 26 weeks after randomisation.
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4.2.2.1
Supportive secondary efficacy endpoints
The following endpoints will be assessed 26 weeks after randomisation. 
Change from baseline in 8-point self-measured plasma glucose (SMPG) profile (8-point 
profile):
!
Mean PPG and PPG increment over all three meals*
!
Individual meal (breakfast, lunch and main evening meal) PPG and PPG
increment 
!
Mean of the 8-point profile
!
Fluctuation in the 8-point profile
!
Change from baseline in fasting plasma glucose (FPG)*
!
Change from baseline in 1,5-anhydroglucitol
!
Percentage of Subjects reaching HbA1c target (HbA1c<7.5 %) according to ISPAD 
guidelines
!
Percentage of Subjects reaching HbA1c target (HbA1c<7.5 %) according to ISPAD 
guidelines, without severe hypoglycaemia
!
Insulin dose (Units/day and Units/kg/day; total basal, total bolus and individual meal insulin 
dose)
4.2.2.2
Supportive secondary CGM related efficacy endpoints (subgroup):
26 weeks after randomisation:
!
Change from baseline of time spent in low interstitial glucose (IG) (IG ≤ 3.9 mmol/L [70 
mg/dL])
!
Incidence of episodes and percentage of time spent with IG ≤2.5, 3.0, 3.9 mmol/L [45, 54, 
70 mg/dL] and IG >10.0, 12.0 mmol/L [180, 216 mg/dL]
!
Percentage of time spent within IG target 4.0-10.0 mmol/L [71-180 mg/dL] both included
4.2.2.3
Supportive secondary CGM and meal-characteristics efficacy endpoints
(subgroup):
26 weeks after randomisation:
!
Change from baseline in mean IG increment (0-1 hours and 0-2 hours after start of the meal)
!
Change from baseline in mean IG peak after start of meal
!
Change from baseline in mean time to the IG peak after meal
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Date:
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Version:
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4.2.2.4
Supportive secondary meal test related efficacy endpoints (subgroup): 
26 weeks after randomisation:
!
Change from baseline in 30-minute PPG and PPG increment 
!
Change from baseline in 1-hour PPG and PPG increment 
!
Change from baseline in 2-hour PPG and PPG increment
4.2.2.5
Supportive secondary CGM and meal test related efficacy endpoints (subgroup):
26 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
4.2.2.6
Supportive secondary safety endpoints
26 weeks after randomisation:
!
Number of treatment emergent hypoglycaemic episodes
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
!
Number of treatment emergent hypoglycaemic episodes subdivided into daytime and 
nocturnal (23:00-7:00, both included) 
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
!
Number of treatment emergent meal related (from start of meal until 1, 2, and 4 hours 
after start of meal and from 2-4 hours after start of meal, respectively) hypoglycaemic 
episodes 
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
!
Number of treatment emergent adverse events (AEs)* 
!
Number of treatment emergent injection site reactions 
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Protocol
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Date:
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Version:
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!
Change from baseline in clinical evaluations:
!
Physical examination 
!
Vital signs 
!
Change from baseline in body weight, height, body mass index and SD score of body weight 
and body mass index (z score)
!
Change from baseline in laboratory assessments: 
!
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, and 
leucocytes)
!
Biochemistry (creatinine, alanine aminotransferase [ALT], aspartate
aminotransferase [AST], alkaline phosphatase [AP], sodium, potassium, albumin, 
and total bilirubin)
!
Lipid profile (total cholesterol, high density lipoproteins [HDL], low density 
lipoproteins [LDL])
!
Change from baseline in anti-insulin aspart (specific and cross-reacting with human insulin
and total of these) antibody development 
*Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov
and EudraCT).
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Protocol
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Date:
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Version:
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5
Trial design
5.1
Type of trial
This is a 26-week randomised, partly double-blind, multicentre, multinational, active controlled, 
treat-to-target, parallel group trial with a 12-week run-in period comparing the efficacy and safety 
of meal-time faster-acting insulin aspart vs. meal-time NovoRapid® both in combination with 
insulin degludec once daily in a basal-bolus regimen in Subjects with T1DM from 1 year to less 
than 18 years of age. The trial will also include a 26-week open-label post-meal faster-acting insulin 
aspart dosing arm in combination with insulin degludec.
The randomisation will be stratified by age group (1 ≤ age < 3 years, 3 ≤age < 6 years, 6 ≤ age < 12
years and 12 ≤ age < 18 years) based on Subject’s age at randomisation.
For each Subject, the total trial duration is approximately 45 weeks consisting of the following 
periods:
!
Up to 2 weeks for screening 
!
A 12-week run-in period primarily with the aim of optimising the insulin degludec dose
!
A 26-week treatment period 
!
A 7-day and a 30-day follow-up period 
Throughout the run-in and treatment period there will be weekly site visits/phone contacts.
A subgroup of Subjects (150 in total), age ≥ 8 years old at screening (Visit 1) will have blinded 
CGM and a standardised meal test at two occasions during the trial leading up to Visit 14 and Visit 
40. The Subjects will have the blinded CGM for at least 11 days and up to 13 days before 
randomisation and up to 13 days before the end of the 26-week treatment period. The standardised 
meal test will be performed at baseline (Visit 14) and at the End of Treatment. The CGM and meal
test subgroup and procedures are described in Appendix B. 
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Version:
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Figure 5–1
Trial design
The trial includes a screening visit to assess the Subject’s eligibility. At Visit 2, the eligible Subjects 
will be enrolled in a 12-week run-in period where all Subjects will be switched from their previous 
insulin treatment to insulin degludec once daily and meal-time NovoRapid®. During the 12-week 
run-in period the Investigator will focus on optimisation of the basal insulin on a weekly basis to 
individual fasting plasma glucose (FPG) targets. After the run-in period, Subjects with HbA1c ≤
9.5% (80 mmol/mol) who based on the Investigator’s judgement have shown ability and willingness 
to adhere to the trial protocol will be randomised (1:1:1) to receive meal-time faster-acting insulin
aspart, post-meal faster-acting insulin aspart or meal-time NovoRapid®, all in combination with 
insulin degludec. In the 26-week treatment period, the Investigator should focus on optimising 
bolus insulin to individual pre-meal targets, in accordance with the titration guideline, as described 
in Appendix A. Adjustment of basal insulin dose should be minimized during the treatment phase. 
However, if necessary, basal insulin dose may be adjusted at the Investigator’s discretion. The 
Investigator must attempt to achieve the glycaemic pre-meal target of 4.0 – 8.0 mmol/L (71 – 145 
mg/dL), and the bedtime target of 6.7 – 10 mmol/L (120 – 180 mg/dL) as described in 
Appendix A7.
5.2
Rationale for trial design
The 12-week run-in period has been included to ensure that the Subjects are being trained in the 
trial procedures and that the basal insulin titration is optimised safely. The randomisation will be 
stratified by age group (1 ≤ age < 3 years, 3 ≤age < 6 years, 6 ≤ age < 12 years and 12 ≤ age < 18 
years) to ensure a comparable number of Subjects in each treatment group for each strata. The 26-
week treatment period (double-blind with open-label arm) is needed to obtain as valid and unbiased 
effect and safety data as possible and the duration is considered sufficient to reach a stable HbA1c
Screening
Randomisation
Meal-time faster-acting insulin aspart and insulin degludec        
(250 Subjects)
Meal-time NovoRapid® and insulin degludec          
(250 Subjects)
Week  -14       -12
   
     0                                                                                             
    26   27            30
Note: Prior to run-in and after End of Treatment Subjects are on marketed products
FU1
12-week run-in period
Meal-time 
NovoRapid® and 
insulin degludec
26-week treatment period
FU2
Post-meal faster-acting insulin aspart and 
insulin degludec  (250 Subjects)
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Date:
10 November 2015
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Version:
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UTN: U1111-1158-1170 
Status:
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level in a basal-bolus setting. The post-meal dosing arm is open-label due to the difference in 
dosing timing from the two blinded arms. The high frequency of contacts has been chosen in order 
to ensure optimal titration of faster-acting insulin aspart and NovoRapid®.
A 30 days follow up visit is introduced in order to collect information on adverse events (AEs)
occurring in the follow up period. 
5.2.1
Rationale for the CGM and meal test subgroup
The rationale for the meal test is to evaluate PPG excursions after a standardised liquid meal when 
injecting faster-acting insulin aspart compared to NovoRapid®. The rationale for the CGM 
assessment is to get a thorough evaluation of the glycaemic control achieved with the different 
treatments in this trial, including during the meal test.  
5.2.2
Rationale for choice of non-inferiority margin
Placebo control 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 
treatment in addition to metformin the estimated treatment effect in change from baseline HbA1c
was - 0.94% [ -1.17; -0.72] (data on file). In this trial the addition of 3 times daily faster-acting 
insulin aspart lead to a reduction in HbA1c of 1.16% after 18 weeks of treatment. In a similar phase 
4 trial 26 investigating the stepwise addition of insulin aspart to a full basal bolus regimen in bolus 
naïve T2DM adults the observed reduction in HbA1c after 21 weeks of treatment was 1.15% (data 
on file) with 3 times daily insulin aspart added to basal insulin. This gives some indication that the 
effect of NovoRapid® versus placebo would be close to the 0.94% observed in trial NN1218-4049. 
Using a non-inferiority margin of 0.4, one of the suggested margins in the FDA guidance27, 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 endogenous 
insulin production and the true effect of insulin aspart might be even higher than what is seen in a 
T2DM population.
5.3
Treatment of Subjects
All Subjects will record 4-point SMPG profiles (4-point profiles) on the three days prior to a site 
visit/phone contact, in accordance with section 8.5.6.1, throughout the trial for the purpose of 
insulin titration. In the 26-week treatment period, the Investigator should focus on optimising bolus 
insulin on a weekly basis to individual pre-meal and bedtime targets. Adjustment of basal insulin 
dose should be minimised during the treatment phase. However, if necessary, basal insulin dose 
may be adjusted at the Investigator’s discretion. Insulin doses should be titrated according to plasma 
glucose (PG) values as described in the titration guideline (Appendix A). No maximum dose is 
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Date:
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specified. The Novo Nordisk insulin titration team will review glycaemic parameters during 
treatment and is blinded to Subject’s trial treatment.
No concomitant diabetes medication except the trial products are allowed during the trial after Visit 
2.
The Subjects must not wear their own real time CGM during the run-in and treatment periods.
5.3.1
Basal insulin titration
At Visit 2 Subjects will be switched from their previous basal insulin analogue or Neutral 
Protamine Hagedorn (NPH) insulin to insulin degludec, as described in the titration guideline 
(Appendix A). Insulin degludec should be administered once daily at any time of the day, 
preferably at the same time every day. During the 12-week run-in period the basal insulin will be 
titrated by the Investigator on a weekly basis to the pre-breakfast glycaemic target of 4.0 - 8.0 
mmol/L (71 - 145 mg/dL) in accordance with the titration guideline (Appendix A). Further 
adjustments of the insulin degludec dose during the treatment period should be done at the 
discretion of the Investigator, if needed. 
5.3.2
Bolus insulin titration
At Visit 2 Subjects will be switched from their pre-trial bolus insulin to meal-time NovoRapid®, as 
described in the titration guideline, see Appendix A. All Subjects should have additional diabetes 
training including training in carbohydrate counting as described in section 8.7.2. NovoRapid® will 
not be adjusted during the run-in period unless the Investigator finds it necessary to adjust the bolus 
insulin for safety reasons. 
At randomisation (Visit 14) Subjects will be randomised to receive meal-time faster-acting insulin 
aspart, or post-meal faster-acting insulin aspart or to continue using meal-time NovoRapid®.
According to the discretion of the Investigator the Subjects will be instructed to titrate the bolus 
insulin doses using the principles of flexible bolus dosing based on the meal carbohydrate content 
or to use the pre-defined bolus dosing algorithms during the treatment period, see Appendix A. It is 
recommended that the Subjects use the method that they are most familiar with throughout the trial. 
The Subjects should continue using the dosing method that they use when they enter the trial, 
however if switching dosing method is to the benefit of the Subjects, as judged by the Investigator,
the Subjects may change dosing method during the trial. In the treatment period the bolus insulin 
will be titrated to the pre-meal target of 4.0 – 8.0 mmol/L (71 – 145 mg/dL), and the bed-time target
of 6.7 – 10 mmol/L (120 – 180 mg/dL) in a treat-to-target fashion.
Throughout the trial the bolus insulin (faster-acting insulin aspart or NovoRapid®) will be 
administered for each three main meals i.e. breakfast, lunch and main evening meal. Additional 
bolus dosing is allowed at the discretion of the Investigator. 
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Timing of dosing should be according to randomisation and should be as described:
!
Meal-time dosing is defined as injecting 0 - 2 minutes before the meal. 
!
Post-meal dosing, is defined as injecting 20 minutes after the start of the meal
Timing of bolus insulin injection should be part of the “training in trial products and pen handling”
and should be reinforced at each contact.
Details regarding titration of bolus insulin (pre-defined dosing algorithm and principles of flexible 
bolus dosing) are described in the titration guideline, see Appendix A.
5.4
Treatment after discontinuation of trial product
When discontinuing trial products the Subject should be switched to suitable marketed products at 
the discretion of the Investigator. Doses of subsequent antidiabetic treatment should be carefully 
titrated based on blood glucose measurements, considering the stable effect and long half-life of 
insulin degludec. Doses of subsequent antidiabetic treatment should be captured in the eletronic 
case report form (eCRF) according to section 8.4.5 at each contact after discontinuation.
5.5
Rationale for treatment
Based on the currently available pharmacokinetic data on faster-acting insulin aspart it is 
anticipated that treatment with faster-acting insulin aspart as a meal-time insulin will enable insulin 
therapy to more closely mimic a physiologic insulin secretory pattern. Consequently, the PPG 
excursions may be more effectively controlled. For further details see the current version of the 
faster-acting insulin aspart IB17.  
NovoRapid® will be used as a comparator to faster-acting insulin aspart in order to compare the
effect and safety of faster-acting insulin aspart to the currently marketed insulin aspart formulation. 
For further details see the current version of the NovoRapid® SmPC15 or the U.S. NovoLog® Label 
information16. As this is a partly double-blind trial, NovoRapid® and faster-acting insulin aspart will 
be titrated following the same recommendations. 
Insulin degludec has been chosen as the basal insulin because it is a once-daily basal insulin and as 
efficacy and safety has been studied in adult Subjects and recently in a paediatric population19. The 
flat and stable glucose-lowering effect of insulin degludec makes it an optimal insulin when 
assessing the properties of bolus insulin (faster-acting insulin aspart compared to NovoRapid®). For 
further details see the current version of the Tresiba® EU SmPC20 and if not approved in the country 
of interest see the insulin degludec IB22.
The treatment targets are aligned with the current ISPAD Clinical Practice Consensus Guidelines7.
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Protocol
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Date:
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6
Trial population
6.1
Number of Subjects 
Number of Subjects planned to be screened: 1004
Number of Subjects planned to be included in the run-in period: 833
Number of Subjects planned to be randomised: 750
A screening failure rate of approximately 17 % and a run-in failure rate of approximately 10% are
anticipated for this trial. The Investigators must strive to include Subjects in the youngest age 
groups (age < 6), to enable investigation of the efficacy and safety of faster-acting insulin aspart in 
these age groups. It will be attempted to include at least 20 Subjects below 6 years of age in each 
treatment arm.
6.2
Inclusion criteria
For an eligible Subject, all inclusion criteria must be answered "yes".
1. Informed consent and child assent, as age-appropriate, 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. Legally Acceptable Representative
(LAR) of the Subject must sign and date the Informed Consent Form (according to local 
requirements). The child must sign and date the Child Assent Form or provide oral assent, if 
required according to local requirements
2. Male or female, 1 ≤ age < 18 years at the time of signing informed consent and < 18 years at the 
time of randomisation
3. Diagnosed with type 1 diabetes mellitus (based on clinical judgement and supported by 
laboratory analysis as per local guidelines)
4. Ongoing daily treatment with a basal-bolus insulin regimen using a basal insulin analogue or 
NPH insulin for at least 90 days prior to the screening visit
5. Ability and willingness to take at least 3 daily meal-time related bolus insulin injections 
throughout the trial (Subject and LAR(s) should be evaluated as a unit)
6. Total daily dose of insulin ≤ 2.0 U/kg prior to the screening visit
7. HbA1c ≤ 9.5% (80 mmol/mol) analysed by the central laboratory at the screening visit
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8. Ability and willingness to adhere to the protocol, including performing self-measured plasma 
glucose profiles (Subject and LAR(s) should be evaluated as a unit)
9. Willingness to NOT use real time CGM during the trial
6.2.1
Additional inclusion criteria for the CGM and meal test subgroup
For a Subject to be eligible for the CGM and meal test subgroup, all the below additional inclusion 
criteria must be answered "yes".
10. Male or female, age ≥ 8 years at the time of screening (Visit 1)
11. Weight ≥ 20.0 kg (44.0 lbs) measured at the time of screening (Visit 1)
12. Ability and willingness to use the principles of flexible bolus dosing based on carbohydrate 
counting, as judged by the Investigator (Subject and LAR(s) should be evaluated as a unit)
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 EU only: Adequate contraceptive measures are implants, injectable, combined oral 
contraceptives, hormonal IUD, sexual abstinence or vasectomised partner.
For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, 
condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.
4. Participation in another clinical trial within 28 days before the screening visit
Note: Clinical trials do not include non-interventional studies
5. Anticipated initiation or change in concomitant medication in excess of 14 days known to affect 
weight or glucose metabolism (e.g. orlistat, thyroid hormones, corticosteroids)
6. Any condition, which, in the opinion of the Investigator, might jeopardise the Subject's safety or 
compliance with the protocol (Subject and LAR(s) should be evaluated as a unit)
7. Diagnosis of malignant neoplasms within the last five years prior to the screening visit
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8. Known hypoglycaemic unawareness or recurrent severe hypoglycaemic episodes as judged by 
the Investigator
9. More than one episode of diabetic ketoacidosis requiring hospitalisation within the last 90 days
prior to the screening 
10. 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
6.4
Run-in failure criteria
The Subject must be withdrawn from the trial during the run-in period if the following applies: 
1. Included in the trial in violation of the inclusion and/or exclusion criteria.
2. Pregnancy
3. Intention of becoming pregnant
4. Participation in another clinical trial throughout the run-in period
Subjects fulfilling any of the above criteria or withdrawing consent prior to randomisation are 
considered as run-in failures and should be completed as described in section 8.1.3.1.
6.5
Randomisation criteria
To be randomised, the below randomisation criteria must be answered “yes”.
1. Age < 18 years at the time of randomisation
2. HbA1c ≤ 9.5% (80 mmol/mol) (at Visit 12 analysed by the central laboratory )
3. Subjects must have demonstrated ability and willingness to adhere to the protocol during the 
run-in period, based on the Investigator’s judgement (Subject and LAR(s) should be evaluated 
as a unit)
6.5.1
Additional randomisation criterion for the CGM and meal test subgroup
For a Subject to be eligible for the CGM and meal test subgroup, the below additional
randomisation criterion must be answered "yes".
4. Subject has shown ability and willingness to use the principles of flexible bolus dosing based on 
carbohydrate counting throughout the run-in period, as judged by the Investigator (Subject and 
LAR(s) should be evaluated as a unit)
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Protocol
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Date:
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Version:
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6.6
Criteria for 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 the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion and/or randomised in violation 
of the randomisation criteria
2. Pregnancy
3. Intention of becoming pregnant
4. Participation in another clinical trial throughout the trial
Subjects discontinued from trial product after randomisation will be followed as described in 
section 8.2.
6.7
Withdrawal from trial 
The Subject may withdraw at will at any time either by the Subject or by the Subject's LAR(s). The 
Subject's request to discontinue must always be respected. 
If the Subject considers withdrawing consent the Investigator must underline to the Subject the 
importance of continuing in the trial despite trial product discontinuation. If the Subject agrees to 
discontinue trial product but to stay in the trial, procedures similar to those described in section 8.2
must be followed. 
If a Subject decides to withdraw informed consent the Subject should be encouraged to undergo 
procedures as described in section 8.3
A Subject included in the trial in violation of the inclusion and/or exclusion criteria and/or 
randomised in violation of the randomisation criteria must discontinue treatment with trial product, 
but will not be withdrawn from the trial and will be followed as described in section 8.2
A subject will be considered lost to follow-up if he/she repeatedly fails to attend the scheduled visits 
and the site staff is unable to establish contact with the subject.
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Date:
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The following actions must be taken in relation to a subject who fails to attend the site for a 
required visit:
!
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible
!
The site must re-train the subject in the importance of maintaining the scheduled visits 
!
In cases in which the subject is deemed lost to follow-up the investigator must make every 
effort to regain contact with the subject (e.g. telephone calls to friends or family members, e-
mails or certified letter to the subject as applicable). These contact attempts should be 
documented in the subject’s medical records. Should the subject continue to be unreachable, 
only then will he/she be considered to have withdrawn from the trial with the primary reason 
being “lost to follow-up”
6.8
Subject replacement
Subjects who are withdrawn will not be replaced.
6.9
Rationale for trial population
For children and adolescents diagnosed with T1DM, insulin therapy is indicated, and data from the 
The Diabetes Control and Complications Trial Research Group (DCCT) show that intensive 
treatment is beneficial in terms of the risk of developing long term complications3. As the disease 
usually presents in early childhood and adolescence, the assessment of safety and efficacy of new 
insulins is appropriate in all ages including childhood and adolescence. 
The trial population consist of children and adolescents with T1DM, 1 ≤ age < 18 years with an 
HbA1c ≤ 9.5 % (80 mmol/mol) at screening and at randomisation. Infants below the age of 1 year 
are not eligible for this trial since most cases of diabetes diagnosed at this very young age are cases 
of neonatal diabetes. Neonatal diabetes is a distinct form of diabetes requiring specialized diagnosis 
and management beyond the scope of this trial. 
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 9.5% (80 mmol/mol) are 
not included in this trial. The HbA1c limit is also expected to select a population that can achieve 
adequate basal insulin coverage in the 12-week run-in basal insulin titration period where focus is 
not on bolus titration.
During the last 3 months prior to Visit 1 the Subjects must have been on an ongoing daily treatment 
with a basal-bolus insulin regimen using basal insulin analogue or NPH insulin in order to ensure a 
smooth switch from prior treatment to trial treatment, and to ensure that optimal adjustment of basal 
insulin can be done during the 12-week run-in period. 
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For safety reasons, Subjects with more than one episode of diabetic ketoacidosis requiring 
hospitalisation within the last 90 days prior to the screening visit are not eligible for this trial.
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7
Milestones
Planned duration of recruitment period(FSFV –LSFV): 38weeks
End of trial is defined as Last Subject Last Visit (LSLV).
The duration of the recruitment period will depend on the screening rate, and the screening-and 
run-in failure rates.
Recruitmentwill be followed closely via the interactive voice/web response system (IV/WRS) in 
order to estimate when to stop the screening, taking into account the number of Subjects currently 
in screening/run-in, and previous screening/run-in failure rates. 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, after which no further Subjects may be 
screened, and the IV/WRS will be closed for further screening.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, novonordisk-trials.comand the 
Clinical Trials Information JapicCTI site clinicaltrials.jp. According to the Novo Nordisk Code of 
Conduct for Clinical Trial Disclosure28, it will also be disclosed according to other applicable 
requirements such as those of the International Committee of Medical Journal Editors (ICMJE)29
the Food and Drug Administration Amendment Act (FDAAA)30, European Requirements31-33and 
other relevant recommendations or regulations. If a Subject requests to be included in the trial via 
the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may disclose the Investigator’s 
contact details to the Subject. As a result of increasing requirements for transparency, some 
countries require public disclosure of Investigator names and their affiliations.
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Protocol
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Date:
10 November 2015
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Version:
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UTN: U1111-1158-1170 
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8
Methods and assessments
In order to safeguard the Subjects and to prevent discomfort to the largest extent possible, the 
number of assessments and blood samplings for analysis during the trial will be kept to a minimum. 
From section 8.1.2 and throughout the protocol, Subject refers to the Subject and LAR(s) as a 
whole, if applicable, depending on the age and the capability of the Subject to perform the required 
trial procedures. 
If applicable and agreed with the LAR(s), other Family members, relatives or persons close to the 
Subject are allowed to support the Subject with performing the trial related procedures as well as to
accompany the Subject to site visits.
8.1
Visit procedures
Procedures for the visits and phone contacts are described in the section below. Timing of the 
different assessments and the visit windows are described in the flowchart in section 2.
8.1.1
Informed Consent and child assent 
Before any screening activities take place, the Subject and the LAR(s) must be provided with 
written and oral information about the trial and the procedures involved. The Subject and LAR(s)
must be fully informed, orally and in writing about their responsibilities and rights while 
participating in the trial, in accordance with local requirements. The Subject and LAR(s) will also 
be informed about possible advantages and disadvantages when being treated with trial products. 
All information will be presented to the Subject in an age-appropriate language. The Subject and 
LAR(s) will have the opportunity to ask questions and have ample time to consider participation. 
The informed consent form must be signed and dated by one or both Parents/LAR(s) according to
local requirements 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. If 
required according to local legislation, oral assent must be provided by the Subject, or if required a 
child assent form must be dated and signed by the Subject, as age-appropriate. The Subject and 
LAR(s) must be provided with a copy of their own signed and dated Subject information/ informed 
consent form and child assent form.
If the minor reaches legal age during the conduct of the trial, the Subject has to re-consents to the 
standard (adult) SI/IC. This is done by using the SI/IC signature sheet for Subject turning legal age 
included in the standard (adult) SI/IC form. 
If the Investigator is not the Subject’s primary physician the Investigator should if possible notify 
the primary physician about the Subject’s trial participation. If required, permission must be given 
by the Subject and the LAR(s).
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The process for providing trial information and obtaining informed consent is described further in 
section 18.2.
8.1.2
Screening visit
Screening will take place within 17 days prior to the run-in visit (Visit 2). Before any screening 
related trial procedures are performed informed consent must be obtained by the Subject, according 
to section 8.1.1 and 18.2.
Each Subject 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 the run-in visit (Visit 2), 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 eCRF.
After Visit 1, 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.
At screening, Subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the Investigator at the last trial visit or to destroy the card after the 
last visit.
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 procedures (Visit 1), see flowchart, section 2. 
8.1.2.1
Screening failures
If the Subject is not eligible to participate in the trial the Subject will be considered a screening 
failure. Consequently, a screening failure session must be made in the IV/WRS.
For screening failures the screening failure form in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events (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.
When data has been monitored and queries have been resolved the case book must be signed by the 
Investigator in the eCRF. 
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8.1.2.2
Re-screening
Rescreening is NOT allowed.
8.1.3
Run-in
If the Subject is found eligible to continue in the trial the Subject will enter a 12-week run-in period 
(Visit 2). Visit 2 can take place as soon as the Subject has been found eligible and must take place 
no later than 17 days after the screening visit (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.
At Visit 2 the Subject will receive trial products and no other anti-diabetic treatment is allowed 
from Visit 2 until the End of Treatment visit .
A run-in dispensing session must be performed in the IV/WRS when entering the run-in period.
For procedures to be performed in the run-in period see flowchart, section 2.
8.1.3.1
Run-in failures
If the Subject decides to discontinue from the trial during the run-in period, or is fulfilling one of 
the run-in failure criteria, or has not met the randomisation criteria then the Subject will be 
considered a run-in failure. Consequently, a run-in failure session must be made in the IV/WRS and 
a run-in failure form must be completed in the eCRF together with the reason for not continuing in 
the trial. No further visits or assessments should take place, however the Subject should be 
instructed to return all used, unused and partly used trial product to the site. Final drug 
accountability must be performed in the IV/WRS.
Medical events of special interest (MESIs), SAEs and non-serious AEs from run-in failures must be 
transcribed by the Investigator into the eCRF. Follow-up of AEs should be carried out according to 
section 12.3. The last date of trial product treatment must be captured in the IV/WRS. 
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 14) should occur after the 12-week run-in period has been completed. If the 
Subject meets the randomisation criteria and none of the run-in failure criteria, the Subject will be 
randomised into one of the three treatment arms by using IV/WRS, as described in section 10. The 
Subject will keep the same Subject number as allocated at screening. Stop date of NovoRapid® from 
run-in and start date of the randomised trial product will be recorded in the eCRF.
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Date:
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Version:
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In the morning of Visit 14 the Subject should collect a capillary blood sample for FPG central 
laboratory analysis using the FPG home sampling kit provided at Visit 12. The Subject must be 
fasting for the capillary FPG blood sample, as described in section 8.6.4. If the Subject has 
performed the FPG blood sampling at home fasting is not required for Visit 14. Subjects 
participating in the CGM and meal test subgroup must attend Visit 14 fasting, as described in 
section 8.1.7 and in Appendix B. 
Subjects must attend Visit 14 without having taken any insulin for at least 8 hours prior to the visit 
as required for insulin antibody blood sampling.
For randomisation visit procedures (Visit 14), see flowchart, 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 
the flowchart in section 2.
Scheduled dispensing of trial products should be performed at the visits indicated in the flowchart 
section 2. A dispensing session must be performed in the IV/WRS when dispensing. Drug 
accountability must be performed at each dispensing visit after Visit 2 and at the End of Treatment 
visit.
The discontinuation from trial product criteria must be reviewed to ensure the Subject’s eligibility 
to continue in the trial. 
For assessments performed at the site visits see the flowchart in section 2.
8.1.6
Phone contacts
Before any phone contacts both the Investigator and Subject should agree on the timing and 
direction of the call. The Investigator remains responsible for ensuring that the contacts occur even 
if it is agreed that the Subject should call the site.
If a planned phone contact is, for any 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 visit may be converted into a site visit e.g. if further 
titration is needed.
The premature discontinuation from trial product criteria must be reviewed to ensure the Subject’s 
eligibility to continue in the trial. For assessments performed at the phone contacts see flowchart 
section 2.
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Date:
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Version:
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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). Medication which should be taken with or after a meal should be withheld until 
blood sampling has been performed. No insulin must be taken for at least 8 hours prior to insulin 
antibody blood sampling. Any other concomitant medication can be taken as usual.
If the Subject has performed the FPG blood sampling at home fasting is not required for any site 
visits, except for Subjects included in the CGM and meal test subgroup. 
The Subjects included in the CGM and meal test subgroups must attend Visit 14 and Visit 40
fasting. 
8.1.8
Rescheduled visits
If the Subjects included in the CGM and meal test subgroup attend Visit 14 and Visit 40 in a non-
fasting condition, the visit should be rescheduled within the visit window, see Appendix B. 
8.1.9
End of Treatment
At End of Treatment, the randomised treatment with trial product should be discontinued and a 
Completion session must be performed in the IV/WRS.
The Subject should be switched to suitable marketed product(s) at the discretion of the Investigator 
and should be recorded on the concomitant diabetes medication form in the eCRF, as described in 
section 8.4.4 . 
For procedures to be performed at End of Treatment, see flowchart in section 2.
Subjects in the CGM and meal test subgroup should undergo the meal test before discontinuing trial 
product.
8.1.10
Follow-up periods
Follow-up visit 1 (FU1) (Visit 41) is a site visit and must take place 7-12 days after the actual date 
of an End of Treatment. Follow-up visit 2 (FU2) (Phone Contact 42) must take place 30-35 days 
after the End of Treatment.
8.1.10.1
Follow-up Visit 1 
After the first follow-up period (7 days) the following data will be collected:
!
AEs 
!
Concomitant medication
!
Current diabetes medication
!
Hypoglycaemic episodes
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Date:
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Version:
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!
Hyperglycaemic episodes
!
Injection site reactions
The diary, handed out at the End of Treatment visit for collection of hypoglycaemic and 
hyperglycaemic episodes, should be returned by the Subject at this visit.
8.1.10.2
Follow-up Visit 2
After the last follow-up period (30 days) the following data will be collected during the phone 
contact:
!
AEs
!
Concomitant medication
!
Current diabetes medication
8.2
Premature discontinuation of trial product
If a Subject is prematurely discontinued from trial product after randomisation (Visit 14), the 
Investigator must ensure every possible effort is made to undertake procedures for Visit 40A, as 
soon as possible. 
A ”treatment discontinuation” session must be made in the IV/WRS and reason for discontinuation 
of trial product must be specified in the first part of the End-of-Treatment/Trial form in the eCRF. 
For CGM and Meal test subgroup the ”treatment discontinuation” session must be performed after 
the meal test has been finalised.
Final drug accountability must be performed. The Subject should be switched to a suitable marketed 
product at the discretion of the Investigator. The medication should be recorded on the concomitant 
diabetes medication form in the eCRF, as described in 5.4 and 8.4.4 at each contact after 
discontinuation.
The Subject should also complete the follow-up visits (Visit 41 and Phone Contact 42).
In addition, Subjects prematurely discontinued from trial product should continue with the per 
protocol planned visits after 12 weeks (Visit 26) and 26 weeks (Visit 40) from randomisation
depending on when the Subject discontinues trial product. The following assessments are not 
applicable for prematurely discontinued Subjects at V40: 4-point profile, technical complaints, 
CGM and meal test, IV/WRS call.
Phone contact after premature discontinuation of trial product:
The Investigator must establish telephone contact with the Subject at least once halfway through the 
premature discontinuation visit period, if the Subjects discontinue the trial treatment prior to Visit 
30. Phone contact will only be recorded in source data and will not be captured in eCRF. 
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Date:
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Version:
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The Subject should be notified that they will be contacted according to the protocol.  
All attempts to contact the Subject must be documented in the source document.
At each contact the Investigator should as a minimum capture/evaluate: 
!
Any assessment of hypo/hyperglycaemic episodes
!
Adverse events
!
Change in diabetes medication
In case of any findings, these must be captured in the eCRF.
Follow-up contact after premature discontinuation of trial product:
Subjects that prematurely discontinue trial product will be asked to attend an End of Treatment visit 
(Visit 40A) and follow-up visit 1 (FU1) 7-12 days after visit 40A and follow-up visit 2 (FU2) 30-35
days after V40A.
In the following situations where two visits are close to each other, only one visit should take place:
!
If V40A is more than 10 weeks after randomisation and before the planned V26, only V40A 
should be performed
!
If V26 and FU2 visit windows overlap according to visit schedule, only V26 should be 
performed
!
If V40 and FU1 visit windows overlap according to visit schedule, only V40 should be 
performed
!
If V40 and FU2 visit windows overlap according to visit schedule, only V40 should be 
performed
Diary records after premature discontinuation of trial product:
The Subject will be handed out premature discontinuation diaries to fill in:
!
Date, actual clock time and value of the SMPG measurements performed as part of the 8-
point profiles on the two consecutive days just before Visit 26 and Visit 40
!
Hypoglycaemic episodes. The following information should be recorded:
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Date:
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Version:
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!
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)
A hypoglycaemic episode starting without symptoms should be updated to symptomatic 
if the Subject experience symptoms later during the episode.
!
Was the hypoglycaemic episode associated with severe neuroglycopenia, usually 
resulting in coma or seizure and requiring parenteral therapy (glucagon or intravenous 
glucose)34? (Layman language used in the Subject diaries: Was the low blood glucose 
episode associated with symptoms severe enough to result in unconsciousness or a 
seizure and was glucagon (an injection) or IV glucose/sugar (drip) needed for your child 
to recover?)
!
Hyperglycaemic episodes (see section 8.5.1.2)
Hypoglycaemic and/or hyperglycaemic episode must be reported in the diary until Visit 40 has been 
completed.
8.3
Withdrawal from trial 
If a Subject withdraws consent after randomisation (Visit 14), the Investigator should ensure every 
possible effort is made to undertake procedures similar to those for Visit 40, including the meal test 
for the Subjects included in the CGM and meal test subgroup, as soon as possible. The Subject must
also complete the follow-up visits (Visit 41 and Phone Contact 42). 
The End-of-Treatment/Trial form must be completed in the eCRF and final drug accountability 
must be performed even if the Subject is not able to come to the site. A “Treatment 
Discontinuation” session must be made in IV/WRS and reason for withdrawal must be specified on 
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 should make every effort to ascertain the reason(s), while fully respecting the Subject's 
rights. Where the reasons are obtained, the primary reason for discontinuing trial product and not 
completing the trial must be specified on the End-of-Treatment/trial form in the eCRF. 
In case a premature discontinuation Subject choose to withdraw after completing Visit 40A, FU1 
and FU2, the Visit 40 should be performed but FU1 and FU2 visit is not to be completed again.
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Date:
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Version:
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8.4
Subject related information
8.4.1
Demography
The following demographic data will be obtained by the Investigator and recorded: 
!
Date of birth (if not permitted according to local laws the year of birth will be collected)
!
Age at screening
!
Age at randomisation 
!
Ethnicity (if permitted according to local laws) 
!
Race (if permitted according to local laws) 
!
Sex
The Investigator must document whether females are of non-childbearing potential in the Subject 
medical record and eCRF.
8.4.2
Diagnosis of type 1 diabetes mellitus 
Date of diagnosis of diabetes will be obtained and recorded in the Diabetes History in the eCRF.
8.4.3
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 the 
screening visit) or found as a result of the screening procedures. Any abnormal and clinically 
significant findings at Visit 1 must be recorded on the medical history/concomitant illness form in 
the eCRF. Information about diabetes complications must also be recorded if present.
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 in the eCRF.
The information collected as concomitant illness and medical history should include diagnosis, date 
of onset and date of resolution or continuation, as applicable.
For female Subjects, it must be documented in the Subject’s medical record if they are 
premenarcheal. 
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE as described in section 12.
8.4.4
Concomitant medication
A concomitant medication is any medication, other than trial product(s) and diabetes medication 
which should be reported in accordance with section 8.4.5, which is taken during the trial, including
in the screening, run-in and the follow-up periods.
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Details of any concomitant medication must be recorded in the eCRF at the first visit (Visit 1). 
Changes in concomitant medication must be recorded at each visit as they occur.
The information collected for each concomitant medication includes (as a minimum) trade name or 
generic name, indication, start date and stop date or continuation. 
If a change is due to an AE then this must be 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.
8.4.5
Diabetes treatment history
Any diabetes medication taken at screening, after end of treatment, or during any unplanned events, 
e.g. hospitalisation must be recorded as concomitant diabetes medication in the eCRF including the 
trade name or generic name, total daily dose, start date, stop date or continuation. At the run-in visit 
(Visit 2) all diabetes medication should be discontinued and a stop date recorded. 
8.5
Clinical Assessments
8.5.1
Adverse events requiring special forms in the eCRF
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
!
Hyperglycamic episodes
!
Injection site reactions
!
Medication error (described in section 12.1.4)
8.5.1.1
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All plasma glucose values:
!
≤3.9 mmol/L (70 mg/dL) or 
!
>3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms 
should be reported in the diary according to the instructions below throughout the trial from Visit 2 
to Visit 41. Upon onset of a hypoglycaemic episode the Subject is recommended to measure plasma
glucose every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) or symptoms have been 
resolved in accordance to current guidelines35.
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Version:
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A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the Subject. Repeated SMPG measurements 
and/or symptoms 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.
The record should include the following information:
!
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.
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data.
!
Whether the episode was symptomatic (Yes/No)
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if 
the Subject experience symptoms later during the episode.
!
Was the hypoglycaemic episode associated with severe neuroglycopenia, usually resulting 
in coma or seizure and requiring parenteral therapy (glucagon or intravenous glucose)34?
(Layman language used in the Subject diaries: Was the low blood glucose episode 
associated with symptoms severe enough to result in unconsciousness or a seizure and was 
glucagon (an injection) or IV glucose/sugar (drip) needed for your child to recover?)
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode 
should be reported reflecting the most severe degree of hypoglycaemia.
!
Date, time and dose of last basal insulin dose prior to episode 
!
Date, time and dose of last bolus insulin dose prior to episode
!
Date and time of last meal prior to episode
!
Whether the episode occurred in relation to physical activity
!
Any sign of fever or other intercurrent disease (e.g. gastrointestinal infections)
!
Whether the Subject was asleep when the episode occurred
If yes: Whether the symptoms of the episode woke up the Subject
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Version:
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If the question "Was the hypoglycaemic episode associated with severe neuroglycopenia, usually 
resulting in coma or seizure and requiring parenteral therapy (glucagon or intravenous glucose)?" is 
answered "YES" the hypoglycaemic episode is classified as “severe”34, and the following additional 
information should be recorded:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-
medical person)
!
Where the treatment was administered (in clinic/emergency room/ hospital or other. If the 
Subject was treated in clinic/emergency room/hospital whether they were transported in an 
ambulance or not)
!
Type of treatment provided by other person (i.e. oral carbohydrates, glucagon, IV glucose or 
other)
!
Were symptoms alleviated by the administration of treatment?
!
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)
!
Did the Subject experience seizure?34
!
Did the Subject experience loss of consciousness?34
!
Did the Subject experience any of the following symptoms (modified from table 134)
(layman term used in the diary is specified in brackets if different from the protocol term)?
!
Autonomic: Shakiness, sweatiness, trembling, palpitations (Rapid and irregular heart 
beat) and pallor (extreme paleness)
!
Neuroglycopenic: Poor concentration, blurred or double vision, disturbed colour
vision, difficulty hearing, slurred speech, poor judgment and confusion, problems 
with short-term memory, dizziness and unsteady gait
!
Behavioural signs and symptoms: Irritability, erratic behaviour, agitation
(restlessness associated with irritability and tension), nightmares, inconsolable crying
!
Non-specific symptoms: Hunger, headache, nausea, tiredness
!
Did the Subject experience other symptoms?
Oral carbohydrates should not be given if the Subject is unconscious.
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. 
The Investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes at each contact. The Subject must be questioned whether any of the low values were 
severe i.e. whether the hypoglycaemic episode was associated with severe neuroglycopenia . If the 
hypoglycaemic episode was associated with severe neuroglycopenia it has to be reported as a severe 
hypoglycaemic episode on a hypoglycaemic episode form.
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Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Due to decreased validity of 
such data Novo Nordisk will not query for additional data except for the date, SMPG value and 
whether the hypoglycaemic episode was associated with severe neuroglycopenia36,37.
The Subject must be re-trained in how to report hypoglycaemic episodes if the Investigator 
identifies low SMPG values not reported as hypoglycaemic episodes.  
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in, as described in section 12.
8.5.1.2
Hyperglycaemic episodes
The Subject should be instructed to always perform an SMPG measurement when there is suspicion 
of a hyperglycaemic episode. If the SMPG value is > 14.0 mmol/L (250 mg/dL) and the Subject 
looks/feels ill, the Subject should be instructed to do the following:
!
Measure blood ketones using a BG meter or
!
Measure urine ketones using a urine stick 
If the Subject experiences a hyperglycaemic episode where the Subject looks/feels ill and with 
either a SMPG > 14.0 mmol/L (250 mg/dL) and blood ketones > 1.5 mmol/L or SMPG >14.0 
mmol/L (250 mg/dL) and urine ketones above “moderate”, the Subject should record this in the 
diary as a hyperglycaemic episode and should be instructed to contact the site staff as soon as 
possible for further guidance on titration. Symptoms should be treated in accordance with 
instructions from the Investigator.
Multiple (>1) hyperglycaemic values of an SMPG >14mmol/L (250mg/dL) are considered as one 
hyperglycaemic episode until the SMPG is <14mmol/L (250 mg/dL). One episode is set to a 
maximum of 24 hours from the first SMPG >14 mmol/L (250 mg/dL). If new high SMPG values 
and blood or urine ketones are measured more than 24 hours after the first reported high values it is 
considered as a new hyperglycaemic episode and a new hyperglycaemic episode form is to be filled 
in.
In case of several high SMPG and ketone values within the 24 hours interval, the highest value for 
SMPG and ketone respectively is the one that will be reported as the SMPG and ketone value for 
the hyperglycaemic episode; but the start time of the episode will remain as the time for the first 
high SMPG value
Information on  hyperglycaemic episodes will be collected throughout the trial from Visit 2 to Visit 
41. The following must be reported in the hyperglycaemic episode form in the diary and eCRF:
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!
Start date and time of the hyperglycaemic episode
!
Whether the Subject looked/felt ill prior to the episode
!
The SMPG value before treating the episode and any follow-up measurements
!
The highest value measured during the hyperglycaemic episode will be reported as 
the plasma glucose value for the episode, the remaining values will be kept as 
source data  
!
Result from urine ketone test  or blood ketone test , preferably before treating the episode 
and any follow-up measurements
!
The highest value measured during the hyperglycaemic episode will be reported as 
the ketone value for the episode, the remaining values will be kept as source data. 
!
Any factors contributing to the episode:
!
Physical activity
!
Diet change 
!
Medication error (i.e. too low dose, mix-up between products)
!
Miscalculation of dose of antidiabetic medication
!
Change in any concomitant illness  
!
Any signs of fever or other acute disease 
!
Missed or change in dose of concomitant medication
!
Other 
!
Unknown
The Investigator must review the diary data at each contact for correct reporting of hyperglycaemic 
episodes. High SMPG values and/or ketones not having a hyperglycaemic episode form completed 
within 7 days since the SMPG and/or ketone measurement should be reported on a hyperglycaemic 
episode form with as much information as possible (as a minimum the date and SMPG value); 
hyperglycaemic episodes will not be queried for additional information retrospectively due to 
decreased validity of such data 36,37. 
The subject must be re-trained in how to report hyperglycaemic episodes if the Investigator 
identifies high SMPG and/or ketone values not reported as part of a hyperglycaemic episode.  
If the hyperglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must be filled in, as described in section 12.
8.5.1.3
Injection site reactions
If suspicion of an injection site reaction occurs the Subject should be instructed to call the site staff 
as soon as possible for further guidance.
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Possible injection site reactions related both to the bolus and/or basal insulin must be recorded as an 
AE on an AE form and on a specific injection site reaction form in the eCRF. The following 
information should be obtained:
!
Type of reaction – local or generalised
!
Symptoms associated to the event
!
Treatment given for the event
!
Association with the trial product(s)
!
Risk factors associated to the event
The injection site reaction form should only be used for events with an onset date between Visit 2 
and Visit 41. The Investigator has to evaluate whether further actions are needed (e.g. extra visits, 
supervised injection, discontinuation of trial product, dermatologist consultation).
8.5.2
Body measurements
Height (without shoes) will be measured at site in centimetres (cm) or inches (in) and rounded to
one decimal place.
Body weight should be measured in kilograms (kg) or pounds (lb) without overcoat and shoes, and 
wearing only light clothing. Body weight will be rounded to one decimal place. 
The body weight should be assessed on the same weighing scale equipment throughout the trial, if 
possible. 
Body Mass Index (BMI) will automatically be calculated by the eCRF.
Body measurements will be assessed as described in the flowchart in section 2. All values of the 
body measurements will be recorded in the eCRF.
8.5.3
Continuous glucose monitoring (CGM) and meal test in a subgroup
At selected sites a number of the Subjects will undergo an assessment of their IG levels by wearing 
a blinded CGM device for at least 11 days and up to 13 days in connection to Visit 14 and Visit 40. 
At Visit 14 and Visit 40 the Subjects will undergo a standardised liquid meal test in connection to 
wearing the CGM. Both assessments will be mandatory for an agreed number of Subjects at the 
selected sites. 
A detailed description of the assessments is described in the CGM and meal test protocol 
Appendix B.
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8.5.4
Insulin dose
During the trial, starting at the run-in visit (Visit 2), the Subject should be instructed to record the 
date and doses (units) of the breakfast, lunch, and main evening meal bolus insulin on the three days 
prior to a site visit/phone contact in the diary. In addition, for extra insulin boluses, date, actual 
clock time, dose (units), time of the previous meal, and reason for the extra bolus should be 
recorded.
The Subjects should also be instructed to report the date and the dose (units) of the basal insulin in 
the diary on the three days prior to the scheduled site visits/phone contact. 
The recommended insulin doses will be individually calculated in the eCRF based on the SMPG 
values and the doses taken in accordance with the titration guideline, described in Appendix A. If
the Subject is using the principles of flexible bolus dosing based on the carbohydrate content of the 
meal to adjust the bolus dose, only the basal insulin dose will be calculated in the eCRF as
described in Appendix A. 
Doses of trial products must be recorded in the eCRF.
8.5.5
Physical examination
Physical examination will be assessed as described in the flowchart in section 2 and 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
!
General appearance
Any abnormal, clinically significant findings at the screening visit (Visit 1) must be recorded as a 
concomitant illness (see section 8.4.3) and the Investigator must add a comment in the Subject’s 
medical record.
Any clinically and significant worsening from screening, as well as any new abnormal and 
clinically significant findings, must be reported as an AE in accordance with section 12.2.
8.5.5.1
Pubertal status (Tanner staging)
Pubertal status will be assessed as described in the flowchart in section 2 by Tanner staging in 
accordance with stages I-V38 and will be recorded in the eCRF.
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Version:
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8.5.6
Self-measured plasma glucose 
At the run-in visit (Visit 2), the Subject will be supplied with a BG meter, and ancillaries for the BG 
meter. The Subject will be instructed in how to use the device according to the manufacturer’s 
instructions. The Subject will also be provided with written instructions. Sites will, as necessary, 
review the instructions for use with the Subject during site visits. Throughout the trial, only the BG 
meter provided by Novo Nordisk must be used to measure the PG values to be recorded in the 
diary, and for calibrating the CGM device used in the CGM and meal test subgroup.
The BG meter use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown in the display. These are the values to be used for dose adjustment.
The Subject should be instructed in how to record the results of the SMPGs in the diaries. The 
record of each SMPG should include date and value. All data from the diary must be transcribed 
into the eCRF during or following the contact. If obtained via phone and a discrepancy is later 
detected, the values in the eCRF should be corrected.
Additional SMPG values recorded by the Subject in the diary should not be transcribed to the eCRF
except the following SMPG values which should be recorded as hypoglycaemic or hyperglycaemic
episodes:
!
SMPG values ≤ 3.9 mmol/L (70 mg/dL) 
!
SMPG values > 3.9 mmol/L (70 mg/dL) when they occur in conjunction with 
hypoglycaemic symptoms
!
SMPG values > 14.0 mmol/L (250 mg/dL) if the criteria described in section 8.5.1.2 was 
fulfilled
The Investigator must check if the Subject has recorded all hypoglycaemic and hyperglycaemic
episodes in the hypoglycaemia and hyperglycaemia sections of the diary. If not done the missing 
information should be provided by the Subject, if possible.
8.5.6.1
4-point profile 
The Subjects will be instructed to record 4-point profiles in the diary on the three days prior to a
scheduled site visit/phone contact every week throughout the trial for insulin titration purposes, 
starting at run-in (Visit 2). The record of each SMPG should include date and PG value. The SMPG
values for the 4-point profile should be recorded at the following time points:
!
Before breakfast
!
Before lunch
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!
Before main evening meal
!
At bedtime
SMPG measurements before breakfast should be performed in a fasting condition and before any 
insulin injection. SMPG measurements before lunch, before main evening meal and at bedtime 
should be performed before any insulin injection. 
The 4-point profile can be part of the 8-point profiles if actual clock times of the SMPG 
measurements are recorded.
8.5.6.2
8-point profile 
The Subject will be instructed to perform an 8-point profiles prior to selected visits as described in 
the flowchart in section 2 and record these in the diary, as outlined in the flowchart in section 2. The 
8-point profiles will be used for effect analysis as part of the trial.
Measurement of the 8-point profile should be performed on the 2 consecutive days just before the 
visit as outlined in Table 8–1.
Table 8–1
8-point SMPG profile (8-point profile)
Time point
Day -2
Day -1
Day of visit
Before breakfast
√
√a
√
60 minutes after start of breakfast
√
√
Before lunch
√
√
60 minutes after start of lunch
√
√
Before main evening meal
√
√
60 minutes after start of evening meal
√
√
At bedtime
√
√
aThe last SMPG value of the first 8-point profile will be the first SMPG value of the last 8-point profile.
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Date:
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For each measurement, the SMPG value, actual clock time and date should be recorded in the diary.
The measurements before breakfast should be performed in a fasting condition and before any 
insulin injection. The measurements before lunch, before main evening meal and at bedtime should 
be performed before any insulin injection. 
If the Subject does not fulfil the randomisation criteria of an HbA1c ≤ 9.5 mmol/l (80 mmol/L) 
measured at Visit 12 (analysed by the central laboratory) the 8-point profile should not be 
performed. 
8.5.7
Vital signs
Diastolic blood pressure, systolic blood pressure and pulse should preferable be assessed while the 
Subject is in a sitting position after 5 minutes of rest. Vital signs will be assessed as described in the 
flowchart in section 2 .
Any abnormal and clinically significant findings at Visit 1 must be recorded on the medical 
history/concomitant illness form in the eCRF as described in section 8.4.3.
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.
8.6
Laboratory assessments
Except for urine pregnancy testing which will be performed locally at site and ketone measurements 
(blood and urine in case of hyperglycaemic episodes) which will be performed by the Subjects, 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 arrange transportation of 
all blood samples taken during the trial. The central laboratory may utilise subcontractors.
A detailed description of assay methods, reference ranges, and procedures for obtaining 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. 
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 stated in the flowchart in section 2. 
Samples will be coded in order to keep Subject’s identity anonymous.
Laboratory results will be made available by the central laboratory. Laboratory reports must be 
reviewed, dated and signed by the Investigator on the day of evaluation. It must be specified by the 
Investigator if out of range results are clinically significant.
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If laboratory samples need to be retaken due to missing result(s) (e.g. haemolysed, sample leaked 
during transit, sample not being conclusive, lost in transit etc.), the Subject should be called in for 
resampling. See the laboratory manual for further guidance. To minimise the volume of blood 
collected from the Subject only the affected sample(s) should be retaken. Before repeating any 
blood sampling the Investigator must ensure that the total volume of blood collected from the 
Subject is in accordance with the guideline as described in section 8.6.1.
Only laboratory samples specified in the protocol should be send 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.
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.
If any clinically significant abnormalities occur at screening (Visit 1) or as a result of the screening 
procedures then these must be recorded on the medical history/concomitant illness form in the 
eCRF, as described in section 8.4.3. Any clinically significant deterioration of a pre-existing 
condition as well as any new clinically significant signs or symptoms occurring hereafter should be 
reported as an AE in accordance with section 12.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values must be reported to the Investigator. 
The Investigator must review all laboratory results for concomitant illnesses and AEs and report 
these according to this protocol. The Investigator will not be able to review the antibody results for 
AEs as the antibody samples will be analysed after LSLV.
Laboratory samples will be destroyed on an ongoing basis except antibody samples as described in 
section 24.2.  
8.6.1
Blood volumes for blood sampling
The volume of blood to be collected for trial blood sampling will be minimised, in accordance with 
the EMA and FDA guidelines39,40. Table 8–2 lists the blood volume required to be collected for the 
scheduled trial blood samples. The blood volume to be collected at each blood sampling visit will 
not exceed 1% of the Subject’s total blood volume and the blood volume to be collected over a 
period of four weeks will not exceed 3% of the Subject’s total blood volume41.
The volume of the FPG capillary blood samples is insignificant and will not be considered.
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Table 8–2
Approximate blood volumes collected during the trial  
2 < Age
(mL)
2 ≤ Age < 6 years
(mL)
6 ≤ Age < 18
(mL) 
Age ≥ 8 and in CGM 
and meal test 
subgroup
(mL)
Visit 1
3.0
5.0
6.5a
6.5a
Visit 12
0.5
1.2
2.0
2.0
Visit 14
5.8
8.4
10.0a
10.0a/b
Visit 26
5.8
8.4
10.0
10.0
Visit 40c
5.8
8.4
10.0a
10.0a/b
Total blood volume 
collected
20.9
31.4
38.5
38.5
a Including blood volume for performing hCG pregnancy test for females of childbearing potential only (females having 
had menarche). 
b including four PG blood samples collected during the meal test
c Same blood volume applicable for Visit 40A
It is the responsibility of the Investigator to ensure that the blood volume limits are respected based 
on the age and weight of the Subject42.
In case of re-sampling only the affected blood sample(s) should be collected and the Investigator 
must ensure that no more than 3% of the Subject’s total blood volume is collected over a period of 
four weeks42.
If the Subject’s weight is less than 20.0 kg (44.0 lbs) at screening (Visit 1) the Subject is not eligible 
for the CGM and meal test subgroup.
8.6.2
1,5-anhydroglucitol
Blood samples will be drawn as described in the flowchart in section 2 to determine the level of 1,5-
anhydroglucitol in order to evaluate postprandial glycaemic fluctuations. 
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8.6.3
Biochemistry
Blood samples for biochemistry will be collected as described in the flowchart in section 2 and
analysed to determine:
!
Alanine aminotransferase (ALT)
!
Albumin
!
Alkaline phosphatase
!
Aspartate aminotransferase (AST)
!
Creatinine
!
Potassium
!
Sodium
!
Total bilirubin
8.6.4
Fasting plasma glucose
FPG will be measured in order to evaluate metabolic control. 
Capillary blood samples for FPG will be taken at home using a home blood sampling kit in the 
morning on the day of the visits, as described in the flowchart in section 2. 
The Subject will receive a home blood sampling kit and instruction on how to use it. The Subject 
will bring the blood sample to the site visit and the sample will be handled by the site staff in 
accordance with the instructions described in the laboratory manual. If preferred, the FPG blood 
sampling can be performed at the site provided that the Subject is fasting for the site visit.
The FPG capillary blood sample must be taken while the Subject is fasting, in accordance with the 
fasting definition described in section 8.1.7 and before administration of insulin on that day. If these 
conditions cannot be met, collection of the FPG sample should be rescheduled within the permitted 
visit window, except for the capillary FPG sample to be collected at the randomisation visit (Visit 
14). If no FPG sample is available at the randomisation visit the randomisation visit should be 
rescheduled within the visit window.
FPG results ≤ 3.9 mmol/L (70 mg/dL) should not be reported as hypoglycaemic episodes in the 
eCRF but as an AE related to the procedure (e.g. if the FPG result is 2.9 mmol/L (52 mg/dL), please 
report as ‘low plasma glucose of 2.9 mmol/L (52 mg/dL)’).
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8.6.5
Haematology
Blood samples for haematology will be collected as described in the flowchart in section 2 and 
analysed to determine:
!
Erythrocytes
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Thrombocytes 
8.6.6
HbA1c
Blood samples will be collected as described in the flowchart in section 2 to determine HbA1c level 
in order to evaluate metabolic control. The HbA1c blood sample collected at Visit 1 will be used to 
determine if the Subject is eligible to enter the trial (the run-in period) and the HbA1c blood sample 
collected at Visit 12 will be used to determine if the Subject is eligible for randomisation i.e. fulfils 
the randomisation criterion.
8.6.7
Insulin antibodies
On the day of insulin antibody sampling as described in the flowchart in section 2 the Subject need 
not to be fasting but must attend the visit without having taken any kind of insulin for at least 8 
hours before insulin antibody blood sampling. The Subject should bring the trial product to the site 
visit and the insulin can be administered after the blood sampling has been performed.
If the Subject has taken insulin less than 8 hours before insulin antibody blood sampling, the insulin 
antibody blood sampling must be rescheduled within the visit window.
Anti-insulin aspart antibodies (specific and cross-reacting with human insulin and total of these)
will be measured. Antibody samples may be retained until drug approval by U.S. Food and Drug 
Administration (FDA) and/or European Medicins Agency (EMA). The retained antibody samples 
may be used for further charcterisation for antibody response towards drug if required by health 
authorities or for safety reasons, see section 24.2
8.6.8
Lipids
Blood samples for lipids will be collected as described in the flowchart in section 2 and analysed to 
determine:
!
Total cholesterol
!
High density lipoproteins (HDL) cholesterol
!
Low density lipoproteins (LDL) cholesterol
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8.6.9
Pregnancy testing
For females of childbearing potential (females having had menarche), a blood Human Chorionic
Gonadotropin (hCG) pregnancy test will be performed as described in the flowchart in section 2. In 
addition, urine pregnancy tests will be performed locally, at site, during the trial if a menstrual 
period is missed, if menarche occurs or if deemed necessary by the Investigator or required by local 
law. A positive urine test should be followed by a confirmatory serum-hCG (central laboratory).
The central laboratory will provide the pregnancy kits for urine testing performed locally at the site.
8.7
Other assessments and procedures
8.7.1
Diary
At each site visit, starting at the run-in visit (Visit 2), the Subjects will be provided with a new 
diary. The diary should be collected at the next site visit, and retained at the site as source data in 
accordance with section 14. No diary will be handed out for the 30-day follow-up visit (between 
FU1 and FU2) and consequently source data will be the notes written in Subject’s medical record 
for FU2.
The Investigator must carefully instruct the Subject in how to fill in 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 is considered as source data and must be transcribed into the eCRF by the site personnel. In 
case some information is missing in the diary and is available in the medical records, this 
information can be used. 
The Subjects should be instructed to record the following in the diary:
!
Date, time point and value of the SMPG measurements performed on the three days prior to 
each site visit/phone contact (4-point profiles)
!
Date, actual clock time and value of the SMPG measurements performed as part of the 8-
point profiles on the two consecutive days just before Visit 14, Visit 26 and Visit 40
!
Date, time point and doses (units) of bolus insulin on the three days prior to each site 
visit/phone contact throughout the trial 
!
Date and dose (units) of basal insulin on the three days prior to each site visit/phone contact
throughout the trial
!
For extra insulin boluses: Date, actual clock time, dose (units), time and type of previous 
meal and reason for the extra bolus
!
Carbohydrate content per meal on the three days prior to each site visit/phone contact
throughout the trial, if the Subject is using principles of flexible dosing.
!
Prescribed doses of trial products during the phone contacts
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!
I:Carb ratio and insulin correction factor (sensitivity factor) per type of meal (breakfast, 
lunch and main evening meal), at each phone contact (applicable for flexible dosing 
Subjects).
!
Date for first dose of trial products. 
!
Date of last dose of bolus insulin in run-in period
!
Hypoglycaemic episodes (see section 8.5.1.1)
!
Hyperglycaemic episodes (see section 8.5.1.2)
!
A comment for the reason for deviating from the titration algorithm, if applicable
The Investigator should record the following in the diary:
!
Prescribed doses of trial products during the site visits
!
I:Carb ratio and insulin correction factor (sensitivity factor) per type of meal (breakfast, 
lunch and main evening meal), at each site visit (applicable for flexible dosing Subjects).
!
Time and date of next visit and/or phone contact
!
Subject number
!
Site contact details
The temporary transferral of data between the Subject and the Investigator for titration purposes can 
be performed electronically e.g. by sending a picture file or a scanned copy of the relevant diary 
pages by email in addition to the scheduled phone contacts. The diary will act as source at any time.  
When the Subject comes in for the following site visit, and if there is a discrepancy between the 
data in the diary and the transferred data, then the diary will be considered source data. The eCRF 
should be updated accordingly, and a comment explaining that the titration was based on wrong 
values should be entered into the eCRF.
Review of the diaries must be documented either on the front page of the documents and/or in the 
Subject’s medical record.
If clarification of entries in the diary is needed then the Subject should be questioned and a 
conclusion made in the medical record. Care should be taken not to bias the Subject.
8.7.2
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 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 oral carbohydrates
!
Ability to sum up the carbohydrate content of a meal  
8.7.3
Training in trial product and pen handling
The Subjects should be trained in how to handle the insulin pen system when handed out the first 
time. The Subjects must demonstrate for the Investigator at the following visit after NovoPen Echo®
and the pre-filled PDS290 pen-injector (FlexTouch®) has been handed out, that the Subject can use 
the pen correctly. Training should be repeated during the trial if necessary. It is important to 
emphasise that the Subject should remember the following:
!
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
!
Priming to ensure the insulin flow 
!
The needle should be kept in the skin while counting slowly to 6 after the dose counter has 
returned to zero after injection. If the needle is removed too early then the full dose may not 
have been delivered
Important:
The Subjects should be thoroughly trained in distinguishing between the basal insulin and the bolus 
insulin. The pens will come in different colours and types, so they can be differentiated. The bolus 
insulins are to be injected with a durable pen (NovoPen Echo®) and should be loaded with a 
Penfill® before use. The basal insulin is to be injected with a pre-filled PDS290 pen-injector
(FlexTouch®). The Subjects must be instructed to always check the name on the label before 
administering the insulin.
8.7.4
Safety precautions
The Investigator must instruct the Subjects always to carry the following supplies in case of 
hypoglycaemic episodes and need for ketone measurement (as described in section 8.5.1.1 and 
8.5.1.2): 
!
Glucagon for injection, according to local practice
!
A fast-acting glucose preparation (e.g. tablets or powder)
!
Urine sticks for ketone monitoring 
The Subject must be trained in how and when to use the supplies. 
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8.8
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 glycaemic control, adherence to the visit schedule and completion of the Subject’s 
diary including the SMPG profiles. If a Subject is being non-compliant with the treatment the 
Investigator must discuss this with the Subject and emphasise the importance of being in 
compliance.
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Date:
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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. 
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. 
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Date:
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Version:
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9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S:
Table 9–1
Trial Products
Trial product
Strength
Dosage form
Route of 
administration
Faster aspart (blinded for the 
meal-time arm)a
(IMP)b
100 U/mL 
Penfill® 3 mL 
s.c.
Faster aspart (open-label for 
the post-meal arm)a
(IMP)b
100 U/mL 
Penfill® 3 mL 
s.c.
Insulin aspart (NovoRapid®)
(blinded for the treatment 
period)
(IMP)b
100 U/mL 
Penfill® 3 mL 
s.c.
Insulin aspart (NovoRapid®) 
(open- label for the run-in 
period)
100 U/mL 
Penfill® 3 mL 
s.c.
Insulin degludec (open-label)
(IMP)b
100 U/mL
Pre-filled 
PDS290 pen-
injector 3 mL
s.c.
a Faster aspart is the short name for faster-acting insulin aspart and will be used as text on the labels. 
b Investigational medical product
All bolus insulins will be administered with NovoPen Echo®. Penfill® is the cartridge used for durable Novo Nordisk 
pens. Basal insulin will be administrated with a pre-filled PDS290 pen-injector (FlexTouch®).
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Version:
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9.2
Labelling
Labelling of the trial products will be in accordance with Annex 1343, local regulations and trial 
requirements.
Labelling will include the product related requirements and precautions. 
Each Investigator 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. 
The Investigator must document that direction for use is given to the Subject orally and in writing at 
each dispensing visit. Direction for use must as a minimum be provided to the Subject in writing at 
the first dispensing visit (Visit 2).
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9.3
Storage
Table 9–2
Storage of trial products
Trial product
Storage 
conditions
(not-in-use)
In-use 
conditionsa
In-use timea
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®)
Insulin degludec
Store in 
refrigerator 
(2°C – 8°C)
Do not freeze
Protect from light
Do not store 
above 30°C
Can be stored in 
refrigerator (2°C 
– 8°C)
Do not freeze
Protect from light
Use within 8 
weeks
a In-use time starts when first dose is taken.
The Investigator must ensure the availability of proper storage conditions, and record and evaluate 
the temperature. The Investigator must inform Novo Nordisk immediately if any trial product has 
been stored outside specified conditions (e.g. outside temperature range).
For Japan only: The head of the trial site or the trial product storage manager if assigned by the 
head of the trial site must ensure the availability of proper storage conditions, record and evaluate 
the temperature.  
Trial product that has been stored improperly must not be dispensed to any Subject and should be 
made temporarily unavailable in the IV/WRS and stored separately (quarantined) within the correct 
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temperature range until it has been evaluated and approved for further use by Novo Nordisk. The 
Investigator must take appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability 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. See flowchart in section 2 for timing of the dispensing visits.
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 IV/WRS Drug Accountability module.
The Monitor is responsible for ensuring that there is a process for the destruction of used and 
unused trial products. The destruction of trial products will be recorded on a Destruction Form, 
which will be signed by the person responsible for destruction. Destruction of products must be 
documented.
9.5
Auxiliary supplies
9.5.1
Auxiliaries supplied by Novo Nordisk A/S
The following auxiliaries will be supplied by Novo Nordisk A/S:
!
NovoPen Echo®
!
Direction for use
!
BG meters, and ancillary for BG meters
!
Needles, the size of the needle will be a maximum of 8 mm
!
Standardised liquid meal (for the subgroup only)
!
CGM supplies as described in Appendix B (for the subgroup only)
!
Strips for ketone measurement
!
A fast-acting glucose preparation (e.g. tablets or powder)
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Version:
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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 failure
!
Run-in failure
!
Randomisation
!
Medication arrival
!
Run-in dispensing
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
As the trial is blinded with regards to faster-acting insulin aspart and NovoRapid® it is important 
that, at all times during the trial, only DUNs allocated by the IV/WRS are dispensed to the Subject.
If a Subject requires additional trial product between dispensing visits, the site must perform an 
additional dispensing session in IV/WRS.
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 14) the Subject will be randomised to either faster-acting insulin aspart or 
NovoRapid®, both in combination with insulin degludec. 
The randomisation will be carried out in a 1:1:1 manner to the three different treatment arms 
described below using the IV/WRS:
!
Meal-time faster-acting insulin aspart and insulin degludec
!
Meal-time NovoRapid® and insulin degludec
!
Post-meal faster-acting insulin aspart and insulin degludec
The randomisation will be stratified according to age at randomisation (Visit 14):
!
1 ≤ age < 3
!
3 ≤age <  6
!
6 ≤ age < 12
!
12 ≤ age < 18
The Investigators must strive to include Subjects in the youngest age groups (age < 6), to enable 
investigation of the efficacy and safety of faster-acting insulin aspart in these age groups. It will be 
attempted to include at least 20 Subjects below 6 years of age in each treatment arm.
The bolus insulin treatment is double blinded, except for the post-meal faster-acting insulin aspart
treatment arm.
11.1
Breaking of blinded codes
The IV/WRS will notify Novo Nordisk (monitor and the Global Safety department) immediately 
after the code is broken.
The code for a particular Subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the Subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IV/WRS, 
record the reason, and sign and date the document.
When the code is broken, the treatment allocation will be accessible to the Investigator and the 
Novo Nordisk Global Safety department. If IV/WRS is not accessible at the time of code break the 
IV/WRS vendor helpdesk should be contacted. The IV/WRS vendor helpdesk is available at all 
hours. Contact details are listed in Attachment I.
If the code has been broken the Subject must discontinue trial product and a discontinuation of trial 
product session must be completed in IV/WRS.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a Subject administered a 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. 
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An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event: a clinical laboratory abnormality which is clinically 
significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a severity 
that requires active management. Active management includes active treatment or further 
investigations, for example change of medicine dose or more frequent follow-up due to the 
abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the Subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see section 8.5.1.1.
!
Non-serious hyperglycaemia is an AE, but is reported on a hyperglycaemic episode form 
instead of on an AE form, see section 8.5.1.2
The following three definitions are used when assessing an AE:
!
Severity assessment
!
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 assessment
The following terms are used when assessing the relationship between an AE and the relevant 
trial product(s): 
!
Probable - Good reason and sufficient documentation to assume a causal 
relationship.
!
Possible - A causal relationship is conceivable and cannot be dismissed.
!
Unlikely - The event is most likely related to aetiology other than the trial product.
!
Final outcome of an AE
!
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.
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!
Recovering/resolving - The condition is improving and the Subject is expected to 
recover from the event. This term is only applicable if the Subject has completed the 
trial or has died from another AE.
!
Recovered/resolved with sequelae - The Subject has recovered from the condition, 
but with lasting effect due to a disease, injury, treatment or procedure. If a sequela 
meets an SAE criterion, the AE must be reported as an SAE.
!
Not recovered/not resolved - The condition of the Subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
!
Fatal - This term is only applicable if the Subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a Subject before he/she died should 
be assessed as "recovered/resolved", "recovering/resolving", "recovered/resolved 
with sequelae" or "not recovered/not resolved". An AE with fatal outcome must be 
reported as an SAE.
!
Unknown - This term is only applicable if the Subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) is an experience that at any dose results in any of the following:
!
Death.
!
A life-threateninga experience.
!
In-patient hospitalisationb or prolongation of existing hospitalisation.
!
A persistent or significant disability or incapacityc.
!
A congenital anomaly or birth defect.
!
Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement -
they may jeopardise the Subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of SAEd. 
a.
The term "life threatening" in the definition of SAE refers to an event in which the Subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it was more severe.
b. The term "hospitalisation" is used when a Subject: 
-
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
-
Stays at the hospital for treatment or observation for more than 24 hours
–
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.
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c.
A substantial disruption of a Subject's ability to conduct normal life functions (e.g. following the 
event or clinical investigation the Subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d.
For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following event must always be reported as a SAE using the important medical event criteria if 
no other seriousness criteria are applicable:
!
Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's 
law)
!
Suspicion of transmission of infectious agents via the trial product must always be 
considered an SAE. 
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medical event 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 criterion.
Medication errors concerning trial products:
!
Administration of wrong drug.
!
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).
!
Accidental administration of a lower or higher dose than intended. That is a dose that 
deviates from the intended dose to an extent 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.
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Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
The packaging material (e.g. leakage, cracks, rubber membrane issues or errors in labelling 
text)
!
Problems related to devices and/or needles (e.g. to the injection mechanism, dose setting 
mechanism, push button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the Subject has signed the informed consent until the end of 
the post-treatment follow-up period. The events must be recorded in the applicable CRF forms in a 
timely manner, see timelines below and Figure 12–1. 
During each contact with the trial site staff, the Subject must be asked about AEs and technical 
complaints, for example by asking: "Have you experienced any problems since the last contact?"
All AEs, either observed by the Investigator or Subject, must be reported by the Investigator and 
evaluated. Novo Nordisk assessment of expectedness is performed according to the following 
reference documents: 
!
Faster-acting insulin aspart: IB. Current version and any updates hereof 17
!
NovoRapid®: Company Core Data Sheet. Current version and any updates hereof
!
Insulin degludec: Insulin degludec IB. Current version and any updates hereof 22
All AEs must be recorded by the Investigator on an AE form. The Investigator should report the 
diagnosis, if available. If no diagnosis is available, the Investigator should record each sign and 
symptom as individual AEs using separate AE forms.  
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
MESIs, regardless of seriousness, must be reported using the AE form, the safety information form 
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 should be signed when the event is resolved or at the end of the 
trial.
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12.2.1
Timelines for initial reporting of AEs:
The Investigator must complete the following forms in the eCRF within the specified timelines:
!
SAEs: The AE form within 24 hours and the safety information form within 5 calendar days 
of the Investigator's first knowledge of the SAE.
Both forms must be signed within 7 calendar days from the date the information was entered in 
the eCRF. 
!
SAEs fulfilling the MESI criteria: In addition to above, the 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, safety information form 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 (AE and 
SIFs) 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 re-enter the information on the 
appropriate forms in the eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the Investigators trial file. 
An AE is 
observed and 
reported 
It is an SAE
complete:
!
AE form ≤ 24 hours
!
SIF ≤ 5 calendars days
It is a non-serious AE
complete:
!
AE form
Fulfilling 
seriousness 
criteria?
Fulfilling 
MESI 
criteria?
Fulfilling 
MESI 
criteria?
Complete ≤ 14 calendar 
days:
!
MESI form 
No additional forms to 
be completed
Complete ≤ 14 calendar 
days: 
!
AE form 
!
SIF 
!
MESI form 
No additional forms to 
be completed
Yes
No
Yes
No
Yes
No
SIF: safety information form
All timelines are from the investigator’s first knowledge of the event
Figure 12–1
Initial reporting of AEs 
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12.2.2
Reporting of trial product-related SUSARs by the sponsor:
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 (IRBs)/independent ethics committees (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 an SAE and/or MESI is considered to have a causal relationship with a Novo Nordisk marketed 
product used as concomitant medication in the trial, it is important that the suspected relationship is 
reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. 
Novo Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
The Investigator must record follow-up information by updating the forms in the eCRF. 
Follow up information must be reported to Novo Nordisk according to the following:
!
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 (eg 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 
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"recovering/resolving" or "not recovered/not resolved". Cases can be closed with the outcome 
of "recovering/resolving" when the Subject has completed the follow-up period and is expected 
by the Investigator to recover.
!
Non-serious AE fulfilling the MESI criteria: Non-serious 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 products: 
!
Faster-acting insulin aspart (insulin aspart), 100 U/mL Penfill® 3 mL
!
Insulin aspart (NovoRapid®), 100 U/mL Penfill® 3 mL
!
Insulin degludec, 100 U/mL, pre-filled PDS290 pen-injector 3 mL
!
NovoPen Echo®
!
Novo Nordisk needles
which occur from time of delivery of the product until the time of the last usage of the product, 
must be collected and sent to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The Investigator must assess whether the technical complaint is related to any AEs, SAEs, and/or
MESI’s.
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 and/or lot number or 
more than one DUN, a technical complaint form for each batch, code and/or lot number or for each 
DUN must be completed.
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The Investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
!
Technical complaint assessed as related to an SAE within 24 hours 
!
All other technical complaints within 5 calendar days
If the eCRF is unavailable or when reporting a technical complaint that is not Subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available, the Investigator must enter the information on the technical complaint form in the eCRF.
12.4.2
Collection, storage and shipment of technical complaint samples
The Investigator must collect the technical complaint sample and notify the Monitor within 5 
calendar days of obtaining the sample at trial site. The Monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A print or copy of the technical complaint form from the 
eCRF must be sent with the sample.
The Investigator must ensure that the technical complaint sample contains the batch, code and/or lot 
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 (see section 9.3). 
12.5
Pregnancies
12.5.1
Pregnancies in female Subjects
Female Subjects must be instructed to notify the Investigator immediately if they become pregnant 
during the trial. The Investigator must report any pregnancy in Subjects who have received trial 
product(s).
The Investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The Investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
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The following must be collected and reported by the Investigator to Novo Nordisk electronically (eg 
in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (ie congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female Subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
Investigator's first knowledge of initial or follow-up information. 
2. Reporting of AE information
The Investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
Paper AE form* within 14 calendar days of the Investigator's first knowledge of the initial 
or follow-up information to the non-serious AE.
SAEs: 
!
Paper AE form* within 24 hours of the Investigator's first knowledge of the SAE.
!
Paper safety information form within 5 calendar days of the Investigator's first knowledge 
of the SAE.
!
SAE follow-up information to the AE form and/or safety information form within 24 
hours of the Investigator's first knowledge of the follow-up information.
*
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in the 
Subject, foetus or newborn infant.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the Investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
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12.6
Precautions and/or overdose
During treatment with insulin, there is a risk of hypoglycaemia (see section 8.5.1.1). Symptoms of 
hypoglycaemia usually occur suddenly and may include cold sweat, tremor, unusual tiredness, 
confusion, difficulty in concentration, excessive hunger, temporary vision changes, headache, 
nausea and palpitation. Prolonged or severe hypoglycaemia can lead to spasms, and/or 
unconsciousness and, in extreme cases, death. In small children symptoms of hypoglycaemia can in 
addition to the above be erratic behaviour, nightmares, inconsolable crying, trembling, pounding 
heart, difficulty hearing, slurred speech and seizure34.
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.
See the current version of the faster-acting insulin aspart IB17. For NovoRapid® see the current 
versions of the SmPC15 or local labelling. For insulin degludec see the Tresiba® EU SmPC, current 
version20 and if not approved in the country of interest see the insulin degludec IB22.
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
No external data monitoring committee is planned.
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13 Case report forms 
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be supplied by an external supplier
The Investigator must ensure that all relevant questions are answered, and that no empty data field 
exists. If a test or an assessment has not been done and will not be available, or if the question is 
irrelevant (eg is not applicable), indicate this according to the data entry instructions. 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.
The following will be provided as paper CRF:
!
Pregnancy forms
!
AE forms
!
Safety information forms
!
Technical complaint forms
The paper AE forms, safety information forms and technical complaint forms must be used when 
access to the eCRF is revoked or if the eCRF is unavailable.
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing "ND" (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (eg is not applicable) 
indicate this by writing "NA" (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The Investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the Investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the CRF data may be made by the Investigator or the Investigator's delegated staff. 
An audit trail will be maintained in the CRF 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 authorised 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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Corrections to the data in paper 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 by the Investigator or the 
Investigator's authorised staff).
Corrections necessary after the CRFs have been removed from the trial site must be documented on 
a data clarification form (DCF) or a monitor-initiated discrepancy form (MIDF). 
13.2
Case report form flow
The Investigator must ensure that data is recorded in the eCRF/paper CRFs as soon as possible after 
the visits and phone contacts, preferably within 5 days. At the end of the trial at the site all data 
should be recorded no later than 24 hours after the last Subject’s last visit. Once data has been 
entered, it will be available to Novo Nordisk for data verification and validation purposes.
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14 Monitoring procedures 
During the course of the trial, the Monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after FSFV at 
the trial site and no later than 4 weeks after. The monitoring visit intervals will depend on the 
outcome of the remote monitoring of the CRFs, the trial site's recruitment rate and the compliance 
of the trial site to the protocol and GCP, 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).
All data must be verifiable in source documentation other than the CRF.
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.
Data recorded in the Subject’s diary is considered source data with respect to:
!
SMPG values and corresponding dates and time points for the 4-point profiles
!
SMPG values and corresponding dates and actual clock times for the 8-point profiles
!
Date, time point and doses of bolus injections
!
Date and doses of basal injections
!
Hypoglycaemic episodes
!
Hyperglycaemic episodes
!
Carbohydrate content of the meal, if applicable 
!
I:Carb ratio and sensitivity (correction) factor, if applicable
For the CGM and meal test subgroup additional data is considered source data as described in 
Appendix B.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
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Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The Monitor will verify that the eCRFs are completed and that paper CRFs are collected, if 
applicable.
Monitors must review the Subject's medical records and other source data (Subject diary data) 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 action to be taken.
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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 contract 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. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The Subject and any biological material obtained from the Subject will be identified by Subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of Subjects in all presentations and publications as required by 
local, regional and national requirements.
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16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data. 
Novo Nordisk will collect information on the practical use of these systems within the conduct of 
this clinical trial. 
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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 the randomisation visit (Visit 14). In case a 
measurement is not available at the randomisation visit, the most recent measurement prior to the 
randomisation visit will be used as baseline. Two observation periods are defined, “in trial” and “on 
treatment”, and will be specified for each statistical analysis. 
!
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 treatment 
discontinuation.
!
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 
NovoRapid®/faster-acting insulin aspart. The on treatment observation period includes data 
collected up to and including 7 days after treatment discontinuation.
The primary objective, confirming the effect of treatment with meal-time faster-acting insulin aspart
in children and adolescents with type 1 diabetes will be assessed using a non-inferiority approach 
comparing the change from baseline HbA1c to meal-time NovoRapid®, where both treatments are 
combined with insulin degludec . More specifically the upper limit of the 95% confidence interval 
should be compared to a non-inferiority margin of 0.4. If it is below 0.4 non-inferiority will be 
considered established and the effect demonstrated. 
The trial also aims to confirm the effect of treatment with post-meal faster-acting insulin aspart and 
to confirm superiority of meal-time faster-acting insulin aspart both in combination with insulin 
degludec in children and adolescents with type 1 diabetes. In order to control the family-wise type I 
error rate in the strong sense a hierarchical (fixed sequence) testing procedure will be deployed. 
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 the null hypothesis only will be confirmed for analyses where all previous null-
hypotheses have been rejected in favour of faster-acting insulin aspart. This is done using a 
hierarchical testing procedure with three steps:
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Step 1:  HbA1c non-inferiority of meal-time faster-acting insulin aspart versus meal-time 
NovoRapid® both in combination with insulin degludec
Step 2: HbA1c non-inferiority of post-meal faster-acting insulin aspart versus meal-time 
NovoRapid® both in combination with insulin degludec
Step 3: HbA1c superiority of meal-time faster-acting insulin aspart versus meal-time NovoRapid®
both in combination with insulin degludec
Primary estimand
The primary estimand is defined as the treatment difference between Subjects randomised to faster-
acting insulin aspart and NovoRapid® both in combination with insulin degludec, in children and 
adolescents with type 1 diabetes assessed by change from baseline HbA1c 26 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 glycaemic benefit a Subject can achieve if prescribed 
to faster-acting insulin aspart as compared to NovoRapid® both in combination with insulin 
degludec in children and adolescents with type 1 diabetes. By not putting any restrictions on the 
treatment adherence, this estimand aims at a difference as close as possible to the one that can be 
expected in real-world clinical practice. Thereby the primary estimand provides a clinically relevant 
treatment difference for clinicians concerning the glycaemic effect of faster-acting insulin aspart 
compared to NovoRapid® in the day to day life in individual children and adolescents with type 1 
diabetes, where both treatments are combined with insulin degludec.
Secondary estimand
As an alternative to the primary estimand, a secondary estimand is defined as the treatment 
difference in change from baseline HbA1c 26 weeks after randomisation between faster-acting 
insulin aspart and NovoRapid® both in combination with insulin degludec in children and 
adolescents with type 1 diabetes aged 1 to less than 18 years if Subjects continue on treatment until 
26 weeks. This estimand is a de jure estimand, addressing efficacy. 
The de-jure treatment difference is the difference if all Subjects adhered and did not use ancillary 
medication. This estimand provides a more hypothetical treatment difference, but may also be the 
most sensitive for a non-inferiority comparison, since the intake of ancillary medication may 
equalize the treatment effect resulting in a difficult assessment if a difference is seen with respect to 
ancillary medication. Hence the analyses associated with this estimand will serve as sensitivity 
analyses for the non-inferiority analyses.
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All primary and secondary 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 (SAS) 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 intervals 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 will only be summarised descriptively.
Selected tables and figures will also be presented by strata (age).
17.1
Sample size calculation
The primary objective of the trial is to confirm the effect of treatment with meal-time faster-acting 
insulin aspart in terms of glycaemic control measured by change from baseline in HbA1c 26 weeks 
after randomisation by comparing it to treatment with meal-time NovoRapid®, both in combination 
with insulin degludec, using a non-inferiority approach in children and adolescents with type 1 
diabetes. The sample size is determined using a non-inferiority limit of 0.4%.
The trial also aims to confirm the effect of treatment with post-meal faster-acting insulin aspart and 
to confirm superiority of meal-time faster-acting insulin aspart, both in combination with insulin 
degludec in children and adolescents with type 1 diabetes. This is done using a hierarchical testing 
procedure with three steps:
Step 1:  HbA1c non-inferiority of meal-time faster-acting insulin aspart versus meal-time 
NovoRapid® both in combination with insulin degludec
Step 2: HbA1c non-inferiority of post-meal faster-acting insulin aspart versus meal-time 
NovoRapid® both in combination with insulin degludec
Step 3: HbA1c superiority of meal-time faster-acting insulin aspart versus meal-time NovoRapid®, 
both in combination with insulin degludec
The sample size is determined to ensure a sufficient power for the first step and the second step in 
the hierarchical testing procedure.
Power for the non-inferiority steps are based on a t-statistic under the assumption of a one-sided test 
of size 2.5%. A zero mean treatment difference for the comparison between meal-time faster-acting 
insulin aspart and meal-time NovoRapid® is expected, and for the comparison of post-meal faster-
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acting insulin aspart and meal-time NovoRapid® a mean difference of 0.05% in favour of meal-time 
NovoRapid® is expected. 
Based on experience from previous trials, and taking into account that the in trial observation period
includes data collected after treatment discontinuation, the standard deviation for change in HbA1c
is assumed to be 1.3%. With this standard deviation, a sample size of 250 Subjects per group (750 
in total) will ensure more than 93% power to show non-inferiority, given that the actual treatment 
difference is 0%. This sample size will ensure a power of 85% to show non-inferiority of post-meal 
faster-acting insulin aspart compared to meal-time NovoRapid®.
The number of subjects to prematurely discontinue trial product is expected to be less than 10% 
based on previous trials. The number of subject to withdraw from trial is expected to be less than 
5%.
17.1.1
Sample size calculation for the CGM and meal test subgroup
The CGM and meal test subgroup is included in the trial in order to compare additional assessments 
for evaluation of postprandial and overall glucose regulation between the treatment arms. As this 
additional assessment is exploratory in nature, this subgroup is not strictly powered to demonstrate 
a statistical significant difference between treatment arms in any particular endpoint. Fifty (50) 
Subjects per treatment arm have been chosen as this number is considered enough to provide 
sufficient information for evaluation in this exploratory analysis, and as this is a similar number to 
what have been included in previous trials using CGM subgroups.
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance:
!
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 that comply with 
inclusion and exclusion criteria. Subjects in the PP set will contribute to the evaluation “as 
treated”
!
SAS includes all Subjects receiving at least one dose of the investigational product or its 
comparator. Subjects in the safety set will contribute to the evaluation “as treated”. 
Randomised Subjects who are lost to follow up, and where no exposure information of the 
investigational product or its comparator is available after randomisation, will be handled as 
unexposed.
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Before data are released for statistical review after 26 weeks, a blinded review of all data will take 
place to identify protocol deviations 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-E944. 
The Subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before database lock. The Subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
17.3
Primary endpoint
The primary endpoint to address all three confirmatory objectives is:
!
Change from baseline in HbA1c 26 weeks after randomisation
Primary analysis:
1) The primary estimand will be addressed by the below primary analysis on all Subjects
included in 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, actual 
missing data will occur. The primary analysis will be implemented as a statistical model 
using multiple imputation 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.  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 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 region and strata as factors and baseline HbA1c as covariate is fitted to the 
change in HbA1c from baseline to week 12 for each treatment group separately. The 
estimated parameters, and their variances, from these models are used to impute missing 
values at week 12 for Subjects in each treatment group, based on region, strata, and 
baseline HbA1c.
!
In the third step, for each of the 100 copies of the dataset, missing values at week 26 are 
imputed in the same way as for week 12. The imputations are based on an analysis of 
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variance model with region and strata as factors and baseline HbA1c and HbA1c at week 
12 as covariates.
!
For each of the complete data sets, the change from baseline to week 26 is analysed using 
an analysis of variance model with treatment, region and strata as factors, and baseline 
HbA1c as a covariate. 
!
The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s formula:
m =
1
100 
 m,   


SD =  1
100 
 SD



+ 1 + 1
100 
1
100 −1 
(m −m)


, 
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. 
All 3 objectives will be addressed by treatment differences and associated 95% confidence interval
obtained from the same primary statistical model described above. 
Non-inferiority of meal-time faster-acting insulin aspart will be considered confirmed if the upper 
boundary of the two-sided 95% confidence interval 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 (meal-time faster-acting 
insulin aspart minus meal-time NovoRapid®). 
If the primary objective is confirmed the effect of treatment with post-meal faster-acting insulin 
aspart in terms of glycaemic control is to be investigated by showing that post-meal faster-acting 
insulin aspart is non-inferior to NovoRapid® both in combination with insulin degludec in terms of 
glucose lowering effect as assessed by change from baseline in HbA1c 26 weeks after 
randomisation. This will be determined in the same way as above where treatment difference is set 
to (post-meal faster-acting insulin aspart minus meal-time NovoRapid®). 
Finally, if both the primary and the first secondary confirmatory objective are fulfilled, the 
superiority of the meal-time faster-acting insulin aspart as compared to meal-time NovoRapid® will 
be tested in terms of glycaemic control. This will be assessed by comparing the upper limit of the 
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95% CI from the primary analysis to 0. If the upper 95% CI is below 0 then superiority will be 
confirmed.
Sensitivity analyses for the primary estimand:
2) The internal validity of the primary estimand will first be evaluated by repeating the primary 
analysis in 1), but excluding all factors and covariates except from treatment in the model. 
This analysis will explore the influence of the different factors and covariates. The analysis 
will use the in trial observation period.
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 or at the discretion of the Investigator. Therefore the statistical model using 
multiple imputation will be repeated with the following alterations:
a.
Imputation will be done from the treatment arm that the Subject was randomised to 
and a value of 0.4% (the non-inferiority limit) is added to the change in HbA1c at 26 
weeks for Subjects, on either of the faster-acting insulin aspart arms, withdrawing 
from the trial45. This will serve as a sensitivity analyses for the non-inferiority 
analyses. The analysis will use the in trial observation period.
b. Imputation 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 that withdraw the trial in the faster-acting 
insulin aspart arms shift to NovoRapid®. The imputation will be done such that the 
treatment effect diminishes gradually after trial discontinuation (copy reference). The 
analysis will use the in trial observation period.
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 shift to NovoRapid®. The imputation will be done such that 
the treatment effect diminishes immediately after trial discontinuation (jump to 
reference). The analysis will use the in trial observation period. 
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Analyses for the secondary estimand
4) The secondary estimand will be analysed using the same statistical model using multiple 
imputation as the primary analysis in 1) except using the on treatment observation period. 
The analysis will use the FAS.
5) A tipping point analysis will be implemented based on a statistical model using multiple 
imputation, using the FAS and the on treatment observation period. In this analysis Subjects 
that discontinued treatment are imputed based on the treatment arm they were randomised to 
and Subjects discontinuing treatment in the faster-acting insulin aspart groups 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 groups. Second, the imputed values for week 26 in the faster-acting insulin aspart 
groups will be added a penalty. This is done repeatedly gradually increasing the penalty until 
the conclusion from the primary analysis no longer holds. The specific value of the penalty 
that changes the conclusion will be used to evaluate the robustness of the conclusion of the 
primary analysis.
6) A tipping point analysis will be implemented 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 trial product prematurely due to criteria 1, 2, 3, and 
4) in the faster-acting insulin aspart groups will have their imputations based on parameters 
estimated from the faster-acting insulin aspart groups (and not the NovoRapid® group). 
These analyses are motivated by the fact that data from Subjects prematurely discontinuing 
trial product due to non-eligibility can reasonably be assumed to be missing completely at 
random. The analysis will use the on treatment observation period.
7) The same statistical model using multiple imputation as the primary 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 deviate from the ideal treatment during the on 
treatment observation period and will serve as sensitivity analysis for the non-inferiority 
analysis.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
For all supportive secondary endpoints, meal-time faster-acting insulin aspart will be compared to 
meal-time NovoRapid®, and post-meal faster-acting insulin aspart will be compared to meal-time 
NovoRapid®.
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17.4.1.1
Change from baseline refers to the change from randomisation to 26 weeks after 
randomisation.Efficacy endpoints
All endpoints except insulin dose 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 will only be 
presented using the on treatment observation period.
The following endpoints will be assessed 26 weeks after randomisation:
Change from baseline in 8-point profiles. 
PPG increments based on the 8-point 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. PPG will be recorded by the Subject as 
part of two 8-point profiles prior to the visits. PPG increment for each meal (breakfast, 
lunch, main evening meal) will be derived from the 8-point 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 PPG increment over all 
meals will be derived as the mean of all corresponding mean meal increments.
!
Change from baseline in mean PPG and PPG increment over all three meals
Mean PPG and PPG increment 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 and PPG increment from 8-point profile
PPG and PPG increment endpoints for the individual meals (breakfast, lunch, main 
evening meal) will be analysed separately using a model similar to 1) except with the 
corresponding baseline value as covariate.
!
Change from baseline in mean of the 8-point profile
The mean of the 8-point profile is defined as the area under the profile divided by the 
measurement time, and is calculated using the trapezoidal method. Mean of the 8-point 
profile will be analysed using a model similar to 1) except with the corresponding
baseline value as covariate.
!
Change from baseline in fluctuation in 8-point profile
The fluctuation in the 8-point profile is defined as 
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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. Fluctuation in the 8-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 values 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 from baseline in FPG
Change from baseline in FPG will be analysed using a model similar to 1) except with 
baseline FPG as covariate.
!
Change from baseline in 1,5-anhydroglucitol
Change from baseline in 1,5-anhydroglucitol will be using a model similar to 1) except with 
baseline 1,5-anhydroglucitol as covariate.
!
Percentage of Subjects reaching HbA1c target (HbA1c <7.5%) according to ISPAD 
guidelines7
This dichotome (responder/non-responder) endpoint will be defined based on whether a 
Subject has met the ISPAD HbA1c target (HbA1c < 7.5%) 26 weeks after randomisation.  
This responder endpoint will be analysed based on a logistic regression model using 
treatment, region and strata as factors, and baseline HbA1c as covariate. In the in trial 
observation period analysis subjects withdrawn from trial is included as non-responders. In 
the on treatment observation period analysis both subjects who prematurely discontinue 
faster-acting insulin aspart/NovoRapid® or withdraw from trial are included as non-
responders. Subjects without HbA1c at week 26 will be treated as non-responders.
!
Percentage of Subjects reaching HbA1c target (HbA1c <7.5%) according to ISPAD 
guidelines, without severe hypoglycaemia7.
This dichotome (responder/non-responder) endpoint will be defined based on whether a 
Subject has met the ISPAD HbA1c target (HbA1c < 7.5%)  26 weeks after randomisation 
without treatment emergent severe hypoglycaemic episodes7.
This responder endpoint will be analysed based on a logistic regression model using 
treatment, region and strata as factors, and baseline HbA1c as covariate. In the in trial 
observation period analysis subjects withdrawn from trial is included as non-responders. In 
the on treatment observation period analysis both subjects who prematurely discontinue 
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faster-acting insulin aspart/NovoRapid® or withdraw from trial are included as non-
responders. Subjects without HbA1c at week 26, will be treated as non-responders.
!
Insulin dose (total basal, total bolus and individual meals insulin dose). 
Bolus insulin doses will be recorded together with time of administration. 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). Insulin doses will be summarised using the on treatment observation period and 
using the SAS.
Supportive secondary CGM related efficacy endpoints
The following endpoints will be assessed 26 weeks after randomisation:
!
Change from baseline of time spent in low IG (IG ≤ 3.9 mmol/L [70 mg/dL])
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 from the first valid sensor value divided by the actual 
duration of the entire profile. To report the endpoint in minutes per 24 hours the ratio is multiplied 
by 1440. The endpoint will be analysed using an analysis of variance model including treatment, 
region and strata as factors and the baseline value of time in low IG as covariate.
!
Incidence of episodes and percentage of time spent with IG ≤2.5, 3.0, 3.9 mmol/l [45, 54, 70 
mg/dL]) and IG >10.0, 12.0 mmol/l [180, 216 mg/dL]) 
!
Percentage of time spent within IG target range 4.0-10.0 mmol/L (71-180 mg/dL)
IG measurements during meal test will be excluded. 
All CGM endpoints will be summarised descriptively by treatment.
Supportive secondary CGM and meal-characteristics efficacy endpoints 
The following endpoints will be assessed 26 weeks after randomisation:
Change from baseline in meal characteristics of IG profile (4 hours after start of each meal), 
measured as:
!
Change from baseline in mean IG increment (0-1 hours and 0-2 hours after start of the meal)
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The mean IG (meal) increment will be defined as the mean across main meals of the prandial 
increments, i.e. the difference between IG 1 hours (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. The endpoints will be analysed 
separately, using an analysis of variance model including treatment, region and strata as factors and 
the corresponding baseline value as covariate.
All CGM endpoints will be summarised descriptively by treatment.
Supportive secondary meal test related efficacy endpoints
The following endpoints will be assessed 26 weeks after randomisation:
!
Change from baseline in 30-min PPG and PPG increment
!
Change from baseline in 1-hour PPG and PPG increment
!
Change from baseline in 2-hour PPG and PPG increment
Laboratory measured plasma glucose from the meal test will be analysed for 30-min, 1-hour and 2-
hour PPG separately. The corresponding PPG increments will be derived separately using each PPG 
measurement minus the pre-prandial PG.
Change from baseline 26 weeks after randomisation in PPG and PPG increment endpoints will be 
analysed separately using an analysis of variance model including treatment, region and strata as 
factors and the corresponding baseline value as covariate.
All PPG endpoints will be summarised descriptively by treatment.
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Supportive secondary CGM and meal test related efficacy endpoints
Endpoints listed below will be assessed during meal test and based on CGM measurements.
The following endpoints will be assessed 26 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 area 
under the IG curve using the trapezoidal method. Each endpoint will be analysed using an analysis 
of variance model including treatment, region and strata as factors and the corresponding baseline 
value as covariate. 
IG peak and time to IG peak 26 weeks after randomisation will be compared separately between 
treatments using an analysis of variance model including treatment, region and strata as factors and 
with the corresponding baseline value as covariate. An additive model will be used to estimate the 
treatment means and treatment differences with a 95% confidence interval.
All CGM endpoints will be summarised descriptively by treatment.
17.4.1.2
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. 
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 treatment with IMP after randomisation, and no later 
than 1 day after the last day on IMP.
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Nocturnal hypoglycaemic episodes: are episodes occurring between 23:00 and 07.00 both inclusive.
Hypoglycaemic episodes are classified according to ISPAD’s definition of severe hypoglycaemia34, 
as well as Novo Nordisk classification of hypoglycaemia (see Figure 17–1) and the ADA 
classification of hypoglycaemia35 (see Figure 17–2).
Novo Nordisk classification of hypoglycaemia in paediatrics
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L (56 
mg/dL)46. 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 ISPAD classification34: Was the hypoglycaemic 
episode associated with severe neuroglycopenia, usually resulting in coma or seizure and 
requiring parenteral therapy (glucagon or intravenous glucose)?
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
< 3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ISPAD classification34 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia. 
!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a PG value < 3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ISPAD
classification34 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with or without
symptoms consistent with hypoglycaemia. 
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Hypo-
glycaemic
episode
SMBG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
No
Yes
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Severe 
hypoglycaemia
(ISPAD 2014)
Was the 
hypoglycaemic 
episode 
associated with 
severe 
neuroglyco-
penia, usually 
resulting in 
coma or seizure 
and requiring 
parenteral 
therapy 
(glucagon or 
intravenous 
glucose)?
Figure 17–1
Novo Nordisk classification of hypoglycaemia in paediatrics
ADA35/ISPAD classification of hypoglycaemia in paediatrics
!
Severe hypoglycaemia according to the ISPAD classification34: Was the hypoglycaemic 
episode associated with severe neuroglycopenia, usually resulting in coma or seizure and 
requiring parenteral therapy (glucagon or intravenous glucose)?
!
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).
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Hypo-
glycaemic 
episode 
SMBG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
Yes
No
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Was the 
hypoglycaemic 
episode 
associated with 
severe 
neuroglyco-
penia, usually 
resulting in 
coma or seizure 
and requiring 
parenteral 
therapy 
(glucagon or 
intravenous 
glucose)?
Severe 
hypoglycaemia
(ISPAD 2014)
Figure 17–2
ADA/ISPAD classification of hypoglycaemia in paediatrics
The following safety endpoints will be assessed:
!
Number of treatment emergent hypoglycaemic episodes
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
!
Number of treatment emergent hypoglycaemic episodes subdivided into daytime and 
nocturnal (23:00-7:00, both included) 
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
!
Number of treatment emergent meal related (from start of meal until 1, 2, and 4 hours after 
start of meal and from 2-4 hours after start of meal, respectively) hypoglycaemic episodes 
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
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 
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number of events (E) and the event rate per 100 years of exposure (R). Separate summaries are 
made by severity (the ISPAD criterion for severe hypoglycaemia34) considering all episodes, 
nocturnal and daytime episodes using Novo Nordisk and ADA classified episodes. Episodes will 
also be summarised overall and by category in relation to time since start of meal, as occurring 
during first 1, 2, and 4 hours after start of meal and from 2-4 hours after start of meal. Non-
treatment emergent hypoglycaemic episodes will be listed.
The number of treatment emergent hypoglycaemic episodes (all, daytime, nocturnal) will be 
analysed using a negative binomial regression model with a log-link function and the logarithm of 
the time period for which a hypoglycaemic episode is considered treatment emergent as offset. The 
model will include treatment, region and strata as factors, and will be based on the FAS. To the 
extent where data allow, separate analyses will be performed for severe episodes (all).
!
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 7 days after the last day of 
randomised treatment. 
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 Subjects years of 
exposure. These summaries are done by seriousness, severity, relation to insulin treatment, relation 
to device, withdrawal due to AEs and outcome.
Furthermore summary tables based on system organ class and preferred term 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 summarised and listed.
AEs occurring during the run-in period are considered non treatment emergent and will be 
summarised separately.
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!
Number of treatment emergent injection site reactions 
Injection site reactions occurring during the trial, related to either basal and/or bolus insulin will be 
summarised and listed. No formal statistical analysis will be made.
!
Change from baseline in clinical evaluations
!
Physical examination (head, ears, eyes, nose, throat, neck, respiratory system, 
cardiovascular system, gastrointestinal system incl. mouth, musculoskeletal system, 
central and peripheral nervous system, skin, Tanner stage) 
The physical examination parameters, and their change from baseline, will be 
summarised descriptively in shift tables. All findings will be listed. 
!
Vital signs (blood pressure, pulse)
Vital signs include diastolic blood pressure, systolic blood pressure and pulse. The 
measurements and their change from baseline will be summarised descriptively. 
!
Change from baseline in body weight, height, body mass index (BMI) and SD-score of body 
weight and BMI (z-score)
SD-scores are defined to be able to normalise the body weight in the various age groups. To 
estimate the growth of children, standardised weight is calculated for each year of age and 
for each sex. Thus, a child with a weight equal to the mean value for its age and sex has an 
SD score of 0, while a child with a weight 2 SDs above the mean value for its age and sex 
has an SD score of +2. The SD scores are derived from the age and sex of the Subjects and 
the body weight together with growth curves defined for reference population of each 
country. SD scores for BMI will be determined in a similar way as SD scores for weight 
based on reference populations for each country, based on age and sex. For countries with 
no accessible reference values, the reference values for the US will be used.
The measurements and their change from baseline will be summarised descriptively. In 
addition, the endpoints will be analysed separately using a statistical model using multiple 
imputation similar to 1) including treatment, region and strata as factors and the 
corresponding baseline measurement as covariate.
!
Change from baseline in laboratory assessments 
!
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, and 
leucocytes)
!
Biochemistry (creatinine, ALT, AST, AP, sodium, potassium, albumin, and total 
bilirubin)
!
Lipid profile (total cholesterol, HDL, low density lipoproteins LDL)
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 
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be summarised descriptively. Change from baseline will be summarised descriptively using both the 
actual values and the low/normal/high categorisation in shift tables.
Lipid endpoints (LDL, HDL, and total cholesterol) will be log-transformed and analysed separately 
using a statistical model using multiple imputation similar to 1) including treatment, region and 
strata as factors and the corresponding log-transformed baseline measurement as 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. NovoRapid® will be used as 
reference.
!
Change from baseline in anti-insulin aspart (specific and cross-reacting with human insulin)
antibody development
The measurements and their change from baseline will be summarised descriptively. The 
correlation to other relevant variables such as insulin dose and HbA1c are illustrated using graphs.
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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.
18.1
Clinical benefits and risk assessments
All Subjects included in the trial will be treated with insulin degludec as basal insulin in addition to 
either NovoRapid® or faster-acting insulin aspart. Insulin degludec will be titrated weekly by the 
Investigator during the initial 12-week run-in period. The bolus insulin will be adjusted daily or 
weekly during the treatment period of the trial depending on the methods used by the Subject to 
adjust their bolus dose.
The most common side effect of all available insulin preparations is hypoglycaemia. The 
Investigator will explain to the Subject how they should check their blood sugar 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 received at the time they entered the trial. However, 
Subjects will have to use extra time, as additional visits to the clinic are required and some of the 
assessments performed during the trial are done outside normal practice. 
When treatment with trial products ends, 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 or insulin degludec trial products.
Summary of clinical pharmacology 
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 effect17. 
Results from a clinical pharmacology trial comparing the pharmacokinetic and pharmacodynamic 
properties of faster-acting insulin aspart and NovoRapid® during a meal test in children (6-11 
years), adolescents (12-17 years) and adults (18-64 years) with T1DM have shown that faster-acting 
insulin aspart elicited an earlier onset of exposure and a higher early insulin exposure whilst 
maintaining a similar total exposure and maximum concentration compared to NovoRapid® across 
all age groups. Faster-acting insulin aspart had a larger glucose-lowering effect compared to 
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NovoRapid® during the meal-test in children. In adolescents, a larger glucose-lowering effect for 
faster-acting insulin aspart was not demonstrated during the meal-test, despite a greater early insulin 
exposure. In adults, the glucose-lowering effect tended to be larger for faster-acting insulin aspart 
than for NovoRapid® during a meal-test. Overall, the glucose-lowering effect was comparable 
between age groups17.
No safety concerns were raised during any of the trials17.
Clinical benefits and risk considerations for the trial
The current trial will compare the efficacy and safety of meal-time and post-meal faster-acting 
insulin aspart as meal-time insulin as well as post-meal injected insulin versus NovoRapid® in a 
basal-bolus regimen in combination with insulin degludec in children and adolescents. 
In a recent study in a population aged 1 to less than 18 years, insulin degludec was shown to be safe 
and to effectively improve long-term glycaemic control in all Subjects19. At the time of this protocol 
issuance, insulin degludec is approved in more than 60 countries, including USA, all of the EU
countries, and marketed in 26 countries. Insulin degludec was recently approved for use in children 
and adolescents aged 1 to less than 18 years old in the EU.
For the individual Subjects the personal health-related benefits are related to the medical 
examination and the benefit from an intensified 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 insulin sensitivity and I:Carb 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 diabetes training 
including carbohydrate counting. 
In a subgroup, the trial will also assess glucose excursions during blinded CGM, further 
contributing to obtaining improved HbA1c results, as these excursions are revealed to the 
Investigator when the data is uploaded.
For the individual Subjects, the anticipated risks include hypoglycaemia, hyperglycaemia, systemic 
allergic reactions, injection site reactions and antibody development. The risks will be mitigated by 
the close supervision of the Subjects and the frequent measurements of BG levels.
Injection site reactions can occur. The nature of the injection site reactions is expected to be mild, 
transient and more of a visual character and is not expected to be of concern to the Subject’s safety. 
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In the periods where a blinded CGM is being worn by the subgroup, inconvenience from the CGM 
sensor due to local skin irritation or pain from the attached small transmitter might occur, but is 
considered to be transient and not to be of any safety concern to the Subject. 
The three blood samples during meal tests might be inconvenient to the Subjects, but is not of any 
safety concern. 
Subjects in this trial will be using bolus and basal insulin administered via two differently coloured 
durable pens. This colour difference will help the Subject to distinguish between the pens and 
thereby minimise the risk of medication errors with regard to mixing up the pens used for basal and 
bolus injection. Special attention is required when changing the insulin cartridges and the Subject 
will be trained in handling the devices safely. It is expected that the risk of mixing up basal and 
bolus insulin in this trial is similar to in normal clinical practice. 
No maximum dose of insulin is specified as doses are titrated individually. All Subjects will record
4-point profiles on the three days prior to a scheduled site visit/phone contact every week 
throughout the trial for safety purposes and for the purpose of insulin titration. 
Insulin aspart is marketed as NovoRapid® (marketed as NovoLog® in the US) and approved in 
children down to 2 years. No studies have been performed in children below the age of 2 years. In 
line with current praxis NovoRapid® will only be used in this age group under careful medical 
supervision. See the local labelling for a description of risks and benefits15,16. 
All treatments are contraindicated in case of hypersensitivity to the active substances or any of the 
excipients.
Conclusion
Subjects in this trial will benefit from an intensified insulin treatment in a basal-bolus 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 this 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 this 
trial.
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18.2
Informed consent 
In seeking and documenting informed consent, the Investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 and the requirements in the Declaration of 
Helsinki2.
Before any trial-related activity, the Investigator must give the Subject and LAR(s) verbal and 
written information about the trial and the procedures involved in a form that the Subject and
LAR(s) can read and understand. 
The Subject and LAR(s) must be fully informed of their rights and responsibilities while 
participating in the trial as well as possible disadvantages of being treated with the trial products.
The Investigator must ensure the Subject and LAR(s) ample time to come to a decision whether or 
not to participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the Subject and 
LAR(s) before any trial-related activity commence.  
If the minor reaches legal age during the conduct of the trial, the Subject has to re-consents to the 
standard (adult) SI/IC. This is done by using the SI/IC signature sheet for Subject turning legal age 
included in the standard (adult) SI/IC form. 
The responsibility for seeking informed consent must remain with the Investigator, but the task may 
be delegated by the Investigator to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the Subject's willingness to continue 
participating in the trial, the Investigator must inform the Subject and LAR(s) in a timely manner, 
and revised written Subject information must be provided and a new informed consent must be 
obtained.
18.2.1
Child Assent Form
A minor’s choice to participate in a clinical trial is called “assent” as a child is not legally capable 
of giving consent. An assent means a child’s affirmative agreement to participate in research. The 
form that documents this agreement is called an “assent form”.
If required by local requirements, assent from the child (17 years of age and below) must be 
obtained in addition to parental consent/consent from the LAR(s). A Child Assent Form must be 
used to document the child’s affirmative agreement.
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18.3
Data handling
If the Subject is withdrawn from the trial or lost to follow up, then the Subject's data will be handled 
as follows:
!
Data already collected and data collected at the end-of-trial visit will be retained by Novo 
Nordisk, entered into the database and used for the trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to Subject during trial
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 to the Subjects will be submitted to the health authorities and IRBs/IECs for 
approval/favourable opinion and to the regulatory authorities for approval or notification according 
to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the Investigator, the IRBs/IECs or a regulatory authority may decide to stop the trial, 
part of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained.
If a trial is suspended or prematurely terminated, the Investigator must inform the Subjects 
promptly and ensure appropriate therapy and follow-up. The Investigator and/or Novo Nordisk 
must also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 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 deviations
Deviations from the protocol should be avoided.
If deviations do occur, the Investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the clinical 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 a potential source of bias when analysing data in 
clinical trials leading to a risk of misinterpretation of the trial results. Missing data may affect both 
estimation of treatment effect and the confidence interval that surrounds it as well as the 
representativeness of the sample size in relation to the target population.  
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 
withdrawal 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 withdrawals 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.
The importance of subject retention will be addresses by Novo Nordisk in the communication with
the trial sites. The subjects will be carefully informed about the trial procedures before signing
informed consent so they know the implication by participating in the trial.
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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, Subject information/informed consent form, 
any other written information to be provided to the Subject and Subject recruitment 
materials
!
List of IRB/IEC members and/or constitution
!
Curricula vitae of Investigator and Sub-Investigator(s) (current, dated and signed - must 
include documented GCP training or a certificate)
!
Signed receipt of IB and SmPC as appropriate
!
Signed and dated agreement on the final protocol
!
Signed and dated agreement on protocol amendment, if applicable
!
Financial agreement(s)
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Signed and dated Investigator Agreement
!
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 each Investigator
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US Investigators, as described above,  will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All Investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together.
By signing the protocol, each Investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2. 
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By signing the protocol, each Investigator also agrees to allow Novo Nordisk making 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 involved in the trial (Novo Nordisk, site, laboratory, CRO etc.) will conduct the trial in 
compliance with ICH GCP1, applicable regulatory requirements and the Declaration of Helsinki2.
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 should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The Subject identification code list must be 
kept securely and separate from the personal data.
The Investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The Investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The Investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the Investigator must delegate responsibility for medical care 
of Subjects to a specific qualified physician who will be readily available to Subjects during that 
time.
If the Investigator is no longer able to fulfil the role as Investigator (e.g., if he/she moves or retires), 
a new Investigator will be appointed in consultation with Novo Nordisk. 
The Investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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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 Principal Investigator will be appointed to review and sign the clinical trial report (signatory 
Investigator) on behalf of all participating Investigators. The signatory Investigator will be 
appointed based upon the criteria defined by the ICMJE for research publications47.
23.1
Communication of results
No permission to publish shall be granted to any clinical research organisation involved in the trial. 
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 clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
Investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the Investigators' and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the principal Investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any Investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication. 
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors 47 (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 publications by Investigators
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. 
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Individual Investigators will have their own research Subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biospecimens
24.1
Retention of clinical trial documentation
Subject's medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The Investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The Investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the Investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the Investigator to an independent archive provider that has a system in place to allow 
only the Investigator to access the files.
The Investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other Subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the Investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
Novo Nordisk 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.  
24.2
Retention of human biospecimens
Blood samples will be collected to measure insulin antibodies. The total volume of blood that will 
be obtained from a Subject during the trial for antibody analysis is approximately 4.5 mL. The
blood samples will be stored at a central archive for later analysis and will be destroyed after 
marketing approval. 
Antibody samples may be retained until drug approval by U.S. Food and Drug Administration 
(FDA) and/or European Medicines Agency (EMA). The retained antibody samples may be used for 
further characterisation for antibody responses towards drug if required by health authorities or for 
safety reasons.
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Protocol
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Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170 
Status:
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the Investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to the 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 risk/benefit analysis in case it will have an impact on the planned follow-up of 
the Subjects), annually written summaries of the trial status, and other documents as required by the 
local IRB/IEC.
The Investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the Subjects.
The Investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the Investigator's trial file and copies must be sent to Novo 
Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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Protocol
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170 
Status:
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
Investigators conducting the trial, or by persons for whom the said site or Investigator are 
responsible.
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Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170 
Status:
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27 References
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3 The effect of intensive treatment of diabetes on the development and progression of long-term 
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4 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
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6 Brange J, Owens DR, Kang S, Vølund A. Monomeric insulins and their experimental and 
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10 Home PD, Lindholm A, Riis A. Insulin aspart vs. human insulin in the management of long-
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Med 2000; 17(11):762-770.
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Date:
10 November 2015
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Version:
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UTN: U1111-1158-1170 
Status:
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11 Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Use of insulin aspart, a fast-acting 
insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. 
Diabetes Care 2000; 23(5):583-588.
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 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.
15 NovoRapid® Summary of Product Characteristics - current version (EU) 16-Jan-2015.  
16 NovoLog® US Label Information - current version (US) 17-Apr-2015.  
17 Novo Nordisk A/S. Investigator's Brochure, Faster-acting insulin aspart (8th Edition) and any 
updates hereof. 08-Jun-2015.  
18 Biester T, Blaesig S, Remus K, Aschemeier B, Kordonouri O, Granhall C et al. Insulin 
degludec's ultra-long pharmacokinetic properties observed in adults are retained in children 
and adolescents with type 1 diabetes. Pediatr Diabetes 2014; 15(1):27-33.
19 Thalange N, Deeb L, Iotova V, Kawamura T, Klingensmith G, Philotheou A et al. Insulin 
degludec in combination with bolus insulin aspart is safe and effective in children and 
adolescents with type 1 diabetes. Pediatr Diabetes 2015; 16(3):164-176.
20 Tresiba® Summary of Product Characteristics - current version (EU) 21-Jul-2015.  
21 U.S. Tresiba® Label information - current version 25-Sep-2015.  
22 Novo Nordisk A/S. Investigator's Brochure, Insulin degludec (10th Edition) and any updates 
hereof. 16-Dec-2014.  
23 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. 
24 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.  2008. 
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Protocol
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170 
Status:
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25 International Conference on Harmonisation. Clinical Investigation of Medicinal Products in 
the Pediatric Population (ICH Topic 11), July 2000. ICH Harmonised Tripartite Guideline.  20 
Jul 2000. 
26 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. 
27 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.
28 http://novonordisk-trials.com/website/content/how-we-disclose-trial-information.aspx.  2013. 
29 De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. New 
Engl J Med 2004; 351(12):1250-1251.
30 Food and Drug Administration Amendments Act (FDAAA). 2007.
31 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. 
32 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. 
33 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.  
34 ISPAD Clinical Practice Consensus Guidelines 2014 Compendium. Assessment and 
management of hypoglycemia in children and adolescents with diabetes. Pediatr.Diabetes 
2014[15 (Suppl. 20)], 180-192. 2014. 
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10 November 2015
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Version:
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UTN: U1111-1158-1170 
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35 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.
36 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.
37 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. 
38 Tanner JM. Normal growth and techniques of growth assessment. Clinics in endocrinology 
and metabolism 1986; 15(3):411-451.
39 European Medicines Agency. Clinical Investigation of Medicinal Products in the Paediatric 
Population - ICH Topic E 11, January 2001. [CPMP/ICH/2711/99]. 
40 U.S.Department of Health and Human Services FaDA. Guidance for Industry - E11 Clinical 
Investigation of Medicinal Products in the Pediatric Population.  2014. ICH December 2000. 
41 Ethical considerations for clinical trials on medicinal products conducted with the paediatric 
population - Recommendations of the adhoc group for the development of implementing 
guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of 
clinical trials on medicinal products for human use.  2014.  European Commission, ad hoc 
group for the development of implementing guidelines for Directive 2001/20/EC. 
42 Diem K, Lentner C. Documenta Geigy Scientific tables. 7th ed. Basle Geigy, 1970.
43 European Union. The rules govering medicinal products in the European Union, volume 4, 
Annex 13, Manufacture of Investigational Medicial Products.  Feb 2010. 
44 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Statistical 
principles for clinical trials E9. International Conference on Harmonisation E9 Expert 
Working Group.  5 Feb 1998. 
45 Koch G. Comments on 'Current issues in non-inferiority trials'. Statistics in Medicine 2008; 
27(3):333-342.
46 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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Date:
10 November 2015
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Version:
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Status:
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47 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


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
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EudraCT No.: 2014-002568-33 
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1 of 13
Appendix A
Faster-acting insulin aspart titration guideline
Trial ID: NN1218-4101 
Efficacy and Safety of Faster-acting Insulin Aspart compared 
to NovoRapid® both in Combination with Insulin Degludec in 
Children and Adolescents with Type 1 Diabetes 
onset®7
Trial Phase: 3b
Author
 Insulin & Diabetes Outcomes
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
2 of 13
Table of Contents
Page
Table of Contents..............................................................................................................................................2
List of in-text tables..........................................................................................................................................2
1
Introduction...............................................................................................................................................3
2
Treatment regimens..................................................................................................................................4
2.1
Injection area..................................................................................................................................4
2.2
Time of injection............................................................................................................................4
3
Initiation and titration of insulin degludec, faster-acting insulin aspart and NovoRapid®................5
3.1
Initiation of insulin degludec .........................................................................................................5
3.2
Titration of insulin degludec (during run-in).................................................................................6
3.3
Initiation of NovoRapid® ...............................................................................................................6
3.4
Titration of bolus insulin from randomisation...............................................................................6
3.4.1
Bolus dosing according to the algorithm .....................................................................7
3.4.1.1
Pre-breakfast and pre-lunch bolus insulin titration................................7
3.4.1.2
Pre-dinner bolus insulin titration...........................................................7
3.4.2
Subjects following principles of flexible bolus insulin dosing....................................8
3.5
Deviations from the algorithm.......................................................................................................9
4
Data collection .........................................................................................................................................10
5
Review procedure....................................................................................................................................11
6
References ................................................................................................................................................12
Table of tables
Page
Table 3-1
Start doses of total basal and bolus insulin ....................................................................................5
Table 3-2
Titration of insulin degludec..........................................................................................................6
Table 3-3
Titration of pre-breakfast and pre-lunch faster-acting insulin aspart/NovoRapid® .......................7
Table 3-4
Titration of pre-dinner faster-acting insulin aspart/NovoRapid®...................................................7
Table 5
Plasma glucose correction factors and I:Carb ratios......................................................................9
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
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1
Introduction
The goal of insulin therapy is to achieve near normoglycaemia, i.e. to reach a pre-defined HbA1c
level with a low rate of hypoglycaemic episodes and as little weight gain as possible. Several trials 
have shown that this is difficult to achieve, unless plasma glucose (PG) values are intensively 
monitored and the insulindose(s) frequently adjusted 1-10.
To ensure treatment uniformity between the sites, as well as to ensure that Subjects receive an 
optimal treatment, titration algorithms have been developed specifying recommendeddose 
adjustments at different PG levels.
It is recognised that treatments differ between different regions and countries. Likewise, specific 
titration guidelines may not be applicable in certain clinical situations. It is important that other 
information,such as symptoms of hypo/hyperglycaemia, previous response to dose adjustments, 
other glucose measurements and other indicators of the Subject’s level of glycaemic control, is 
taken into consideration when decisions on dosing are made. The Investigatorshould always use his 
clinical judgement to avoid safety hazards. The Investigatoris responsible for the treatment of the 
Subjectsand can therefore overrule the guideline.
To optimise and maintain glycaemic control, the Investigator should,throughout the trial be at least 
in weeklycontact with the Subjectsand/or the Subjects’ legally acceptable representative(s) 
(LAR(s))to assist the Subjects in adjusting insulin doses and to ensure the Subject’swelfare.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
Final
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2
Treatment regimens
All Subjects will be treated with insulin degludec once daily (OD) and NovoRapid® / faster-acting 
insulin aspart in a basal-bolus regimen in connection with meal.
At the run-in (Visit 2), eligible Subjects will be transferred from their previous basal insulin to 
insulin degludec OD (section 3.1). During the following 12 weeks the basal insulin will be titrated 
by the Investigator on a weekly basis to the pre-breakfast glycaemic target (section 3.2). In addition, 
the Subjects will be transferred to NovoRapid® as bolus insulin at the run-in (Visit 2). NovoRapid®
will not be titrated during the run-in period unless the Investigator finds it necessary for safety 
reasons.
At randomisation (Visit 14), Subjects will be randomised to continue using meal time NovoRapid®
or to receive meal time/post-meal faster-acting insulin aspart.
In the 26-week treatment period, the Investigator should focus on optimising bolus insulin on a 
weekly basis to the pre-meal targets. Adjustment of basal insulin dose should be minimized during 
the treatment phase. However, if necessary, basal insulin dose may be adjusted at the Investigator’s 
discretion. (section 3.4). 
No maximum or minimum insulin dose is specified.
2.1
Injection area
Insulin degludec should be injected subcutaneously into the thigh, or upper arm (deltoid area). 
Faster-acting insulin aspart and NovoRapid® should be injected subcutaneously into the abdominal 
wall.
Rotation of injection sites within a given region is recommended.
2.2
Time of injection
Insulin degludec should be administered once daily at any time of the day, preferably at the same 
time every day.
Meal time faster-acting insulin aspart or NovoRapid® should be given 0-2 minutes before meals. 
Post-meal dosing is defined as injecting 20 minutes after the start of the meal. 
Main meals are defined as breakfast, lunch and main evening meal. Extra bolus dosing is allowed at
the Investigator’s recommendation.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
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3
Initiation and titration of insulin degludec, faster-acting insulin 
aspart and NovoRapid® 
3.1
Initiation of insulin degludec
When changing basal insulin to insulin degludec, dose reduction of basal and bolus insulin needs to 
be considered on an individual basis in order to minimise the risk of hypoglycaemia. 
At the beginning of run-in (Visit 2), the Investigator should aim at adjusting the basal-bolus ratio to 
be between 50:50 to 30:70. The desired total daily bolus and basal doses can be found in Table 3-1. 
When Subjects switch from their previous insulin regimen to the trial insulin regimen at Visit 2, the 
total daily dosage should be calculated, and the dose of insulin degludec will be estimated according 
to Table 3-1. e.g. if the total daily insulin dose is 28U, the Subject should receive a total of 8U of 
insulin degludec at the ratio of 30:70, or a total of 14U of insulin degludec at the ratio of 50:50. 
Table 3-1 Start doses of total basal and bolus insulin
Total
daily
insulin
dose (U)
Basal: bolus ratio
50:50
Basal: bolus ratio
30:70
Total
daily
insulin
dose (U)
Basal: bolus ratio
50:50
Basal: bolus ratio
30:70
Total
Basal (U)
Total
Bolus (U)
Total
Basal (U)
Total
Bolus (U)
Total
Basal (U)
Total
Bolus (U)
Total
Basal (U)
Total
Bolus (U)
4
2
2
1
3
46
23
23
14
32
6
3
3
2
4
48
24
24
14
34
8
4
4
2
6
50
25
25
15
35
10
5
5
3
7
52
26
26
16
36
12
6
6
4
8
54
27
27
16
38
14
7
7
4
10
56
28
28
17
39
16
8
8
5
11
58
29
29
17
41
18
9
9
5
13
60
30
30
18
42
20
10
10
6
14
62
31
31
19
43
22
11
11
7
15
64
32
32
19
45
24
12
12
7
17
66
33
33
20
46
26
13
13
8
18
68
34
34
20
48
28
14
14
8
20
70
35
35
21
49
30
15
15
9
21
72
36
36
22
50
32
16
16
10
22
74
37
37
22
52
34
17
17
10
24
76
38
38
23
53
36
18
18
11
25
78
39
39
23
55
38
19
19
11
27
80
40
40
24
56
40
20
20
12
28
82
41
41
25
57
42
21
21
13
29
84
42
42
25
59
44
22
22
13
31
86
43
43
26
60
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
6 of 13
3.2
Titration of insulin degludec during run-in
The dose of insulin degludec will be adjusted weekly by the Investigator in the run-in period in
connection with the scheduled visit/phone contacts.
Insulin degludec should be titrated based on the lowest of three pre-breakfast SMPG values 
measured on the three days prior to the contact in accordance with Table 3-2. The fasting SMPG
will be targeted at 4.0 – 8.0 mmol/L (71 – 145 mg/dL). 
Table 3-2 Titration of insulin degludec
Current dose
≤ 15U
>15U
Lowest of three pre-breakfast SMPGs 
Adjustment
mmol/L
mg/dL
≤ 3.9
≤ 70
-1
-2
4.0 – 8.0  
71 - 145
0
0
8.1 – 10.0
146 - 180
+1
+2
10.1 – 15.0
181 – 270
+2
+4
> 15.1
> 270
+3
+6
3.3
Initiation of NovoRapid®
At the beginning of run-in (Visit 2), the Investigator should aim at adjusting the basal-bolus ratio to 
be between 50:50 to 30:70. The desired total daily bolus and basal doses can be found in Table 3-1.
When Subjects switch from their previous insulin regimen to the trial insulin regimen at Visit 2, the 
total daily insulin dosage will be calculated, and the dose of NovoRapid® will be estimated 
according to Table 3-1 e.g. if the total daily insulin dose is 28U, the Subject should receive a total of 
20U of NovoRapid® at the ratio of 30:70, or a total of 14U of NovoRapid® at the ratio of 50:50. 
3.4
Titration of bolus insulin from randomisation
Titration of bolus insulin will be performed from randomisation (Visit 14) and onwards while the 
adjustments of basal insulin dose(s) can be performed according to the Investigators’ discretion.  
For the purpose of insulin titration the Subjects will be instructed to perform 4-point profiles on the 
three days prior to a scheduled site visit/phone contact every week during the conduct of the trial.
Faster-acting insulin aspart/NovoRapid® titration will be done once weekly based on the lowest pre-
meal and bedtime SMPG measured on the three days prior to the scheduled site visit/phone contact 
in accordance with Table 3-3 and Table 3-4 respectively, or using principles of flexible bolus 
CONFIDENTIAL


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Date:
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dosing based on the carbohydrate content of a meal 3.4.2. It is recommended that the Subjects use 
the method that they are most familiar with.
3.4.1
Bolus dosing according to the algorithm
The pre-meal SMPG will be targeted at 4.0 – 8.0 mmol/L (71 – 145 mg/dL), while the bed-time 
SMPG will be targeted at 6.7–10 mmol/L (120–180 mg/dL)10.
3.4.1.1
Pre-breakfast and pre-lunch bolus insulin titration
! Pre-breakfast faster-acting insulin aspart/NovoRapid® will be adjusted according to the lowest 
pre-lunch SMPG value measured on the three days prior to the site visit/phone contact Table 3-3
! Pre-lunch faster-acting insulin aspart/NovoRapid® will be adjusted according to the lowest pre-
main evening meal SMPG value measured on the three days prior to the site visit/phone contact
Table 3-3
Table 3-3 Titration of pre-breakfast and pre-lunch faster-acting insulin aspart/NovoRapid®
Current dose
< 5U
∀5U
Lowest pre-meal SMPG value measured 
on the three days prior to the site 
visit/phone contact
Adjustment
mmol/L
mg/dL
≤3.9 
≤70
-1
-2
4.0 – 8.0
71 – 145
0
0
≥8.1a
≥146
+½ 
+1
a. It is at the Investigator’s discretion to use a higher dose increment. 
3.4.1.2
Pre-dinner bolus insulin titration
! Before main evening meal faster-acting insulin aspart/NovoRapid® will be adjusted according to 
the lowest bedtime SMPG value measured on the three days prior to the site visit/phone contact
Table 3-4
Table 3-4 Titration of pre-dinner faster-acting insulin aspart/NovoRapid®
Current dose
< 5U
∀5U
Lowest bed-time SMPG value measured 
on the three days prior to the site 
visit/phone contact 
Adjustment
mmol/L
mg/dL
≤ 6.7 
≤ 120
-1
-2
6.7 – 10.0  
120 – 180 
0
0
≥ 10.0 a
≥ 180 
+½ 
+1
a. It is at the Investigator’s discretion to use a higher dose increment. 
CONFIDENTIAL


Protocol - Appendix A
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Date:
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3.4.2
Subjects following principles of flexible bolus insulin dosing
NovoRapid® and faster-acting insulin aspart may be titrated in accordance with principles of 
flexible bolus dosing whereby the meal carbohydrate content and pre-prandial plasma glucose value 
are used to determine the bolus insulin dose. This method is applicable to Subjects and/or LAR(s)
who have demonstrated prior hands-on experience with using this method of determining bolus 
insulin doses. At visit 2, it is the responsibility of the Investigator to ensure that the Subject and/or 
LAR(s) are adequately trained and comfortable using this method. If more training is needed this 
should be carried out according to local practise. 
Using this method, bolus insulin dose adjustment is conducted several times daily in accordance 
with the Insulin:Carbohydrate (I:Carb) ratio and the plasma glucose correction factor (sensitivity 
factor). Bolus insulin dose consists of meal bolus to cover for carbohydrates consumed in the meal 
and, if required, a correction dose (to supplement or reduce the dose based on the difference 
between the SMPG and the target). 
The I:Carb ratio expresses the amount of carbohydrate (in grams) for which 1U of bolus insulin 
would effectively minimise postprandial plasma glucose excursions. The plasma glucose correction 
factor (sensitivity factor) expresses the expected reduction in plasma glucose per 1U of bolus 
insulin. The I:Carb ratio and the correction factor (sensitivity factor) per type of meal should be 
recorded at Visit 2 and should, if needed, be adjusted at the discretion of the Investigator during the 
weekly contacts based on the reviewed SMPGs. 
The target pre-prandial plasma glucose ranges are 4.0 – 8.0 mmol/L (71 – 145 mg/dL) for breakfast 
and lunch and 6.7 – 10.0 mmol/L (120-180 mg/dL) for bedtime.
In the following, an example on how to cover a Subject’s prandial insulin dose is provided. In case 
of hypoglycaemic episodes, the dose will be reduced at the Investigator’s discretion. 
Example 1 – Carbohydrate coverage of a meal and plasma glucose correction dose:
At lunchtime, a Subject has pre-prandial plasma glucose of 10.0 mmol/L (180 mg/dL) and intends 
to eat a meal containing 60 g of carbohydrates. The I:Carb ratio has been estimated to 1U:10g. 
The meal coverage dose is calculated as follows: 
Total carbohydrate in meal * I:Carb ratio = 60 g * (1U/10g) = 6U. 
The plasma glucose correction factor (sensitivity factor) has been estimated to be 2 mmol/L (36 
mg/dL) per 1U. The pre-prandial plasma glucose target range is 4.0 – 8.0 mmol/L (71 – 145 mg/dL)
for breakfast and lunch. The Subject was advised to correct to the target plasma glucose of 
8.0 mmol/L (145 mg/dL) at this meal.
CONFIDENTIAL


Protocol - Appendix A
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Date:
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170 
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The correction dose can be calculated as follows: (Pre-prandial plasma glucose – target plasma 
glucose) ÷ plasma glucose correction factor = bolus insulin unit
(10.0 mmol/L – 8.0 mmol/L) ÷ 2.0 mmol/L/U  = 1U  or  
(180 mg/dL – 145 mg/dL) ÷ 36 mg/dL/U = 1U 
Thus this Subject needs 7U of bolus insulin to cover for the meal and correct for hyperglycaemia 
before the meal.
Examples for initial plasma glucose correction factors and I:Carb ratios according to age group are 
presented in Table 5.
Table 5
Plasma glucose correction factors and I:Carb ratios
Age group 
Plasma glucose correction
Factor
I:Carb ratio
Infant/Toddler 
1U:15 mmol/L (270 mg/dL) 
1U:60g
Pre-Pubertal 
1U:10 mmol/L (180 mg/dL) 
1U:45g
Early Puberty 
1U:5 mmol/L (90 mg/dL) 
1U:15 g
Older Adolescent 
1U:2.5 mmol/L (45 mg/dL) 
1U:10g
3.5
Deviations from the algorithm
It is recommended that the algorithms described in the present guideline will be followed. However, 
it is also important that the decision to adjust the insulin doses are based on all relevant information 
as described in section 1. A reason for deviating from the algorithm should be entered into the
eCRF.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
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EudraCT No.: 2014-002568-33 
Page:
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4
Data collection
In this trial the Subjects will be provided with a diary where the Subjects should record the 4-point 
profiles and insulin doses on the three days prior to a site visit/phone contact and all hypoglycaemic 
episodes. The data used for titration (4-point profiles and insulin doses) should be transcribed into 
the eCRF by the Investigator within 24 hours on work days after each site visit/phone contact.
CONFIDENTIAL


Protocol - Appendix A
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Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170 
Status:
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EudraCT No.: 2014-002568-33 
Page:
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5
Review procedure
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased manner. It 
is important that data regarding dose titration is entered into the eCRF within 24 hours (on 
weekdays). If delays occur, action cannot be taken in due time before the Subject’s next site 
visit/phone contact. The aim is to reduce the time periods in which a Subject may receive 
suboptimal treatment.
The titration data will be reviewed by Novo Nordisk within 24 hours (on weekdays). The reviewer 
may contact the Investigator to get clarification regarding the reason for deviation or to request 
entry of missing data.
When the Investigator receives an inquiry, a response should be received at Novo Nordisk within 24 
hours (on weekdays). 
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the 
glycaemic control. Novo Nordisk may be in contact with sites (visit or phone contact) to discuss 
progress in glycaemic control and titration of individual Subjects based on SMPGs and HbA1c. This 
will be done in an unbiased and whenever possible in a blinded manner.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170 
Status:
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EudraCT No.: 2014-002568-33 
Page:
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6
References
1 Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-
week, treat-to-target trial comparing insulin detemir with insulin glargine when administered 
as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 
2008; 51(3):408-416.
2 Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P. A 26-week, 
randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-
on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. 
Diabetes Care 2006; 29(6):1269-1274.
3 Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. 
Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral 
antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006; 28(10):1569-1581.
4 Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine 
or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 
26(11):3080-3086.
5 Garber AJ, King AB, Del PS, Sreenan S, Balci MK, Munoz-Torres M et al. Insulin degludec, 
an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with 
mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, 
randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012; 379(9825):1498-
1507.
6 Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L et al. Insulin degludec, an ultra-
longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin 
aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, 
treat-to-target non-inferiority trial. Lancet 2012; 379(9825):1489-1497.
7 Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Insulin analogues in children with 
Type 1 diabetes: a 52-week randomized clinical trial. Diabet Med 2013; 30(2):216-225.
8 Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Treatment with insulin detemir or 
NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus. Pediatr Diabetes 2011; 
12(7):632-641.
9 Thalange N, Deeb L, Iotova V, Kawamura T, Klingensmith G, Philotheou A et al. Insulin 
degludec in combination with bolus insulin aspart is safe and effective in children and 
adolescents with type 1 diabetes. Pediatr Diabetes 2015; 16(3):164-176.
CONFIDENTIAL


Protocol - Appendix A
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170 
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
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10 Rewers MJ, Pillay K, de BC, Craig ME, Hanas R, Acerini CL et al. ISPAD Clinical Practice 
Consensus Guidelines 2014. Assessment and monitoring of glycemic control in children and 
adolescents with diabetes. Pediatr Diabetes 2014; 15 Suppl 20:102-114.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
1 of 23
Appendix B
Continuous Glucose Monitoring (CGM) and Meal Test
Trial ID: NN1218-4101
Efficacy and Safety of Faster-acting Insulin Aspart compared 
to NovoRapid® both in Combination with Insulin Degludec in 
Children and Adolescents with Type 1 Diabetes 
onset®7
Trial phase: 3b
Author
 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
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
2 of 23
Table of Contents
Page
Table of Contents..............................................................................................................................................2
Table of Tables..................................................................................................................................................3
1
List of abbreviations..................................................................................................................................4
2
Investigators to whom this protocol appendix applies...........................................................................5
2.1
Rationale for protocol appendix.....................................................................................................5
3
Flow chart ..................................................................................................................................................6
4
Rationale for the CGM and meal test assessment..................................................................................7
4.1
Rationale for the CGM assessment................................................................................................7
4.2
Rationale for the meal test assessment...........................................................................................7
4.3
CGM and meal test subgroup population ......................................................................................7
5
Continuous glucose monitoring................................................................................................................8
5.1
CGM receiver setting and test upload............................................................................................8
5.2
Eligibility for baseline CGM and meal test subgroup....................................................................8
5.3
Fitting and removal of the CGM device ........................................................................................9
5.4
Wearing and calibration of the CGM device ...............................................................................11
5.5
Uploading of CGM data...............................................................................................................12
5.5.1
CGM reports ..............................................................................................................13
5.5.1.1
CGM data capture report.....................................................................13
5.5.1.2
Unblinded CGM trend reports.............................................................13
5.6
CGM data.....................................................................................................................................13
6
Meal test ...................................................................................................................................................14
6.1
Meal test procedure......................................................................................................................14
6.1.1
Handling of blood samples ........................................................................................17
6.2
Data collection and data management .........................................................................................17
7
Premature discontinuation of trial product..........................................................................................18
8
Withdrawal from trial ............................................................................................................................19
9
Interactive voice/web response system ..................................................................................................20
9.1
IV/WRS data change session.......................................................................................................20
10 Trial Supplies...........................................................................................................................................21
10.1
CGM supplies ..............................................................................................................................21
10.1.1
Site PC .......................................................................................................................21
10.1.2
Storage of CGM sensors............................................................................................21
10.2
Meal test supplies.........................................................................................................................21
11 Monitoring procedures ...........................................................................................................................22
11.1
CGM procedures..........................................................................................................................22
11.1.1
CGM Source data verification ...................................................................................22
11.2
Meal test procedures ....................................................................................................................23
11.2.1
Meal test source data verification ..............................................................................23
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
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Table of Tables
Page
Table 1
Flow chart – CGM and meal test procedures............................................................................6
Table 2
Overview of scheduled CGM sensor fitting and removal days relative to meal test at 
either Visit 14 or Visit 40 .........................................................................................................9
Table 3
Meal test schedule...................................................................................................................16
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33 
Page:
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1
List of abbreviations
CGM
continuous glucose monitoring
eCRF
electronic case report form
i.v.
intravenous
I:carb
insulin:carbohydrate ratio
IG
interstitial glucose
IV/WRS
interactive voice/web response system
LAR
legally acceptable representative
PG
plasma glucose
PPG
postprandial glucose
SMPG
self-measured plasma glucose
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33 
Page:
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2
Investigators to whom this protocol appendix applies
This protocol appendix only applies to Investigators at selected sites providing trial Subjects to the 
Continuous Glucose Monitoring (CGM) and meal test subgroup as part of the NN1218-4101 trial.
The sites that will participate in the CGM and meal test subgroup will be selected by Novo Nordisk 
based on their qualifications and experience with performing CGM and standardised meal tests. The
site selection will also be based on the country specific approval status of the CGM device. 
Once the required number of 150 randomised Subjects (approximately 50 Subjects in each 
treatment arm) is met in the CGM and meal test subgroup globally, no more Subjects will be asked 
to participate in the CGM and meal test assessment.
2.1
Rationale for protocol appendix
As only selected countries and sites will participate in the CGM and meal test assessment, this 
appendix has been prepared for these selected sites. The appendix will be available to all 
Investigators, Regulatory Authorities and Institutional Review Boards/Independent Ethics 
Committees. 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33 
Page:
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3
Flow chart
In addition to the trial design and flow chart described in the NN1218-4101 protocol section 2, the 
below flow chart describes the procedures which should be carried out for Subjects participating in
the CGM and meal test assessment.
Table 1
Flow chart – CGM and meal test procedures
Trial NN1218-4101
Appendix 
section
Screening
Run-in
Randomisa
tion
Treatment 
periodd
Premature 
Discontinu
ation
Visit (V) / Phone contact(P)
V1
V12
P13
V14
V38
P39
V40
V40A
Time of visit (weeks)a
-14
-2
-1
0
24
25
26
Visit window (days)
±3
±3
±3
±3
±3
CGM Assessment
CGM 
Fitting
CGM 
Fitting
CGM 
Removal 
CGM 
Fitting
CGM 
Fitting
CGM 
Removal
CGM 
Fitting
CGM 
Removal
Meal test Assessment
Meal test
Meal test
Meal test
Subgroup informed consent
4.3
x
Fitting & supply of the CGM devicesb
5.2
&
5.3
x
x
x
x
x
Instruct Subjects in CGM calibration 
procedure 
(beginning 2 hours after the device is 
fitted and every 12 hours during the 
CGM period)
5.4
x
x
x
x
x
Instruct Subjects in CGM procedures in 
general
5.4
x
x
x
x
x
Meal testc
6
x
x
x
Attend visit fasting
6.1
x
x
x
Removal of CGM device
5.3
x
x
x
x
x
Upload of CGM data
5.5
x
x
x
x
x
Weight & age check
4.3
x
                                                
a The time of the visit is defined from the randomisation visit (V14)
b The fitting of the CGM devices must be scheduled to ensure the meal test is not performed on the 1st or 7th day when 
Subject is wearing a CGM sensor. In case of premature discontinuation of trial product or withdrawal from trial please 
see section 7 and 8
c The meal test must be performed after a minimum of 11 days of wearing a CGM sensor
d The assessments is not applicable for premature discontinued Subjects, see section 7
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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EudraCT No.: 2014-002568-33 
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4
Rationale for the CGM and meal test assessment
4.1
Rationale for the CGM assessment
The rationale for the CGM assessment is to get a thorough evaluation of the glycaemic control 
achieved with the different treatments in this trial. The glucose profiles will be recorded by the 
CGM device during 11 to 13 consecutive days also covering the meal test.
The CGM assessment will be performed in two periods during the trial:
!
At baseline: 11 to 13 consecutive days before randomisation and before randomised 
treatment 
!
During treatment: 11 to 13 consecutive days before the end of the 26-week treatment period
4.2
Rationale for the meal test assessment
The rationale for the meal test is to evaluate postprandial glucose (PPG) excursions after a 
standardised liquid meal when injecting faster-acting insulin aspart compared to NovoRapid®.
4.3
CGM and meal test subgroup population
A total of 150 randomised Subjects are planned to enter the CGM and meal test subgroup. To 
ensure capability of the Subjects to comply with the CGM and meal test procedures only Subjects ≥ 
8 years of age and with a weight of ≥ 20.0 kg (44.0 lbs) at screening (due to blood sampling volume
restrictions) are allowed to participate in the CGM and meal test subgroup. Subjects participating in 
the subgroup will be selected by the Investigator based on the Subject’s interest in participating and 
the Investigator’s judgement of the Subject’s capability of fulfilling the requirements for the CGM 
and meal test assessment. The Subjects must not wear their own real time CGM during the run-in 
and treatment periods.
For the Subjects who wish to take part in the CGM and meal test subgroup an additional Informed 
Consent Form and Child Assent Form must be signed according to local requirements before any 
trial-related procedures commence. See protocol section 18.2 and 18.2.1 for detailed information.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33 
Page:
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5
Continuous glucose monitoring
As indicated in the flow chart (section 3) and described in section 4.1, Subjects will have CGM 
profiles generated for a period of 11 to 13 consecutive days, twice during this trial. The profiles will 
be generated by a Food and Drug Administration approved and European Union 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 site staff should review the CGM data capture and CGM trends
and document this according to section 5.5.1. The unblinded CGM trend reports must remain 
blinded to the Subject and the legally acceptable representatives(s) (LAR(s)) prior to End of 
Treatment visit (Visit 40).
The unblinded CGM trend reports generated must not be used for insulin dose titration or for 
hypoglycaemic episodes reporting; only when supported by self-measured plasma glucose (SMPG)
measurements.
Please refer to the CGM manufacturer’s user guide for how to use the CGM device.
5.1
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 
upload must be performed to verify correct installation of CGM software and correct set up of the 
CGM receiver.
Upon 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 and filed as source 
document. 
5.2
Eligibility for baseline CGM and meal test subgroup
At the fitting visit the Investigator must ensure that Subjects are eligible to continue in the trial, i.e. 
assess the withdrawal criteria for the trial before the CGM device is fitted. If the Subject is not 
eligible to be randomised based on the randomisation criteria listed in protocol section 6.5 and 
6.5.1, a site visit must be scheduled in order to stop the CGM sensor measurement and have the 
CGM device removed and the Subject is considered a run-in failure.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33 
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5.3
Fitting and removal of the CGM device
During the fitting visit the Investigator will insert a glucose sensor under the Subject’s skin in the 
belly or the upper buttocks, measuring the concentration of glucose in the interstitial fluid every 5 
minutes. The sensor is attached to a transmitter and both are worn by the Subject. The transmitter 
transfers the interstitial glucose (IG) data wirelessly to the receiver where data is stored.
The CGM sensor has an in-use period of 7 days (168 hours). 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 before or when reaching the 168 hours after first insertion 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 (264 hours) by each Subject in each of the two 
CGM periods. 
The CGM device should be fitted to the Subject at the site as indicated in the flowchart (see section 
3).
The first fitting visit in the first CGM period (during the run-in period) 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 14. The first fitting visit in the second CGM period (during treatment) has to be 
planned from 11 to 13 days prior to Visit 40 in order to register treatment CGM data while the meal 
test is performed at Visit 40.
An overview of the scheduled CGM sensor fitting and removal days relative to the meal test is 
outlined in Table 2.
Table 2
Overview of scheduled CGM sensor fitting and removal days relative to meal 
test at either Visit 14 or Visit 40
Visit(V) /
Phone 
contact(P)
V12/V38 (±3 days)
P13/P39 (±3 days)a
V14/V40
Days prior to
V14/V40
-17
-16
-15
-14
-13
-12
-11
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
CGM based 
on two 
sensor 
periods
Schedule
Fitting 1
Schedule 
Removal 1 
and Fitting 2
Meal
test
and
Removal 2
a Removal of the first sensor and fitting of the second sensor can be performed at home by the Subject and LAR(s), if 
the Subject and LAR(s) have been trained and are able to perform it correctly, according to the Investigator’s 
judgement. Otherwise Phone Contact 13 and Phone Contact 39 can be changed to a site visit.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
10 of 23
Additional fitting of sensors can be planned if the meal test assessment has to be rescheduled more 
than 7 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 visit windows must be accommodated 
additional fitting of sensors can be planned as well. In case the sensor dislodges, the Subject and 
LAR(s) must contact site in order to schedule a new fitting at site or if capable at home according to 
the Investigator’s judgement.
The meal test must not be scheduled on the 1st or 7th 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. The rationale for this is firstly; the sensor will not start measuring IG until after 
the 2 hour start-up calibration on the 1st day, and the Subject will have to wait 2 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 the recording of data 
exact 7 days after sensor insertion.
Removal of the first sensor and fitting of the second sensor can be performed at home by the 
Subject and LAR(s), if they have been trained and are able to perform it correctly, according to the 
Investigator’s judgement.
In order to ensure that the CGM device is measuring correctly the insulin injection site must be in a 
distance of at least 7.6 cm (3 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. 
Inserting the sensor and wearing the adhesive patch might cause infection, bleeding, pain or skin 
irritations (redness, swelling, bruising, itching, scarring or skin discoloration). 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.
The Subject should be instructed to remove the CGM device prior to any x-ray, computerised 
tomography (CT) scan or magnetic resonance imaging (MRI).
The second sensor should not be removed until after the meal test has been completed (after 240 
minutes) at Visit 14 and Visit 40 respectively.
It is not considered an unscheduled visit, if the Subjects attend the site for a CGM fitting between 
visits. Instead this needs to be documented in the Subject’s medical record.
For further information on preparing, fitting and removal of the CGM device please refer to the 
CGM manufacturer’s user guide.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
11 of 23
5.4
Wearing and calibration of the CGM 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 System (false high CGM 
readings))
The accuracy of the CGM system is dependent on calibration values from the Subject. It is therefore 
essential that the Subject, the LAR(s) and site staff are fully trained in the use of the CGM device 
according to the CGM manufacturer’s user guide and quick user guide. 
!
Start-up calibration should be performed 2 hours after fitting the device; two SMPG 
measurements are needed for start-up calibration.
!
While wearing the device the Subjects will continue to enter at least two SMPG values into 
the CGM receiver per day for calibration purposes according to the CGM manufacturer’s 
user guide. 
!
The SMPG value for calibration should be entered directly into the CGM receiver within 5 
minutes from performing the SMPG measurement.
!
One calibration must be entered every 12 hour. The device will give an alert if calibration 
values are missing after 12 hours. 
!
Two SMPG values from the 4-point profile can be used for the calibration. 
!
Any SMPG values ≤ 3.9 mmol/L (70 mg/dL) used for calibrations must also be recorded as 
a hypoglycaemic episodes by the Subject, according to the protocol section 8.5.1.1.
!
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 mmol/L to 22.2 mmol/L [40 
mg/dL to 400 mg/dL].
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
(2 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)
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
12 of 23
The following data should be recorded in the diary when wearing the CGM device: 
!
Date, actual clock time and carb content of meals (breakfast, lunch, main evening meal and
other meals)
!
Date, actual clock time and dose of bolus and basal injections
!
For extra insulin boluses: Date, actual clock time, dose (units), time and type of previous
meal and reason for the extra bolus
The receiver battery will need to be charged by the Subject during the 11 to 13 days, this should be 
done taking into account the transmission range of 6 meters (20 feet) from the transmitter to the 
receiver.
For further information on wearing and calibrating the CGM device please refer to the CGM 
manufacturer’s user guide.
5.5
Uploading of CGM 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 no later than 3 days after Visit 14 and 
Visit 40, respectively.
A CGM Software program will be provided by the CGM manufacturer to allow upload of the CGM 
data. Following information must be entered in the CGM Software program when uploading CGM 
data:
!
Trial ID
!
Subject ID
!
Visit ID
The following information must also be recorded and transferred into the trial database:
!
Confirmation of CGM assessment
!
Serial number of the CGM receiver
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
13 of 23
5.5.1
CGM reports
Upon each data upload the CGM data capture report and the unblinded CGM trend reports will be 
available in the CGM Software system. Both the CGM data capture report and the unblinded CGM 
trend reports should be printed out, dated and signed and filed as source documents.
5.5.1.1
CGM data capture report
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 6 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
5.5.1.2
Unblinded CGM trend reports
The unblinded CGM trend reports show the CGM profiles generated by the CGM device during 
each CGM period.
!
The CGM profiles show trends or patterns which could lead to consideration whether
additional plasma glucose measurements may be needed 
The unblinded CGM trend reports must not be shared with the Subject and the LAR(s) prior to End 
of Treatment visit (Visit 40).
5.6
CGM 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 at the trial 
site. 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 capture and CGM trends upon data upload at site but the 
unblinded CGM trend reports must remain blinded to the Subject and the LAR(s) prior to End of 
Treatment visit (Visit 40). After finalisation of the trial, the CGM source data for each Subject will 
be provided to the Investigator. The CGM source data is then stored and archived on site.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
14 of 23
6
Meal test
The Subjects will have two standardised meal tests performed; one at Visit 14 and one at Visit 40, 
as outlined in Table 1.
The meal test has to be performed in the morning as the Subject needs to be fasting on the day of 
the visit.
The CGM sensor used at Visit 14 and Visit 40 must not be removed until after the meal test has 
been completed (after 240 minutes).
The total duration of the meal test is expected to be approximately 5 hours and will include 
consumption of a standardised liquid meal, i.v. cannulation, and four blood samples obtained in 
total during 120 minutes. One blood sample will be obtained prior to consumption of the liquid 
meal and three blood samples will be obtained after consumption of the liquid meal according to the 
schedule in Table 3.
6.1
Meal test procedure
The Subject should achieve an SMPG value within a range of 4.0-8.8 mmol/L [71-160 mg/dL] 
before beginning the meal test. The time and value of this SMPG measurement should be recorded 
in the diary before starting the meal test. If the Subject does not attend the meal test visit fasting 
and/or the SMPG value is outside the range, then the entire visit should be rescheduled within the 
visit window.
The Subject should be instructed to:
!
Follow normal routine regarding eating and exercise habits 24 hours prior to the meal test
!
Bring their trial bolus insulin to the meal test visits
!
Attend the meal test visits in a fasting condition. For definition of fasting please refer to 
protocol section 8.1.7
!
Withhold Insulin injections (including basal insulin if this is usually taken in the morning) 
and medication which should be taken during or after a meal until the meal test has been 
performed 
The Subject’s body weight must be measured and a blood sample for assessment of plasma glucose 
(PG) must be drawn 2 minutes before intake of the standardised liquid meal.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
15 of 23
Meal test at Visit 14:
!
The Subjects should consume 1.5 g of carbohydrates per kg body weight, but no more than 
80 g of carbohydrates in total.
The volume of the standardised liquid meal to be consumed should be measured out by the 
Investigator.
The carbohydrate content of the standardised liquid meal may differ from country to 
country.
!
The bolus insulin dose for the meal test should be calculated by the Investigator by dividing 
the carbohydrate content of the standardised liquid meal by the Subject’s current I:carb ratio.
The calculated dose should be rounded to the nearest half unit.
!
The bolus insulin should be injected 0-2 minutes before the start of consuming the liquid 
meal. The bolus insulin injection should be injected subcutaneously in the abdomen.
Meal test at Visit 40:
!
The Subjects must consume same amount of carbohydrates and use same bolus insulin dose 
as they did for Visit 14, i.e. calculations of the volume of the liquid meal and the bolus dose 
should not be repeated.
!
The bolus insulin injection should be injected subcutaneously in the abdomen depending on 
the Subject’s randomisation, as described below:
o
Meal-time dosing: Injecting 0 - 2 minutes before the start of consuming the 
standardised liquid meal 
o
Post-meal dosing: Injecting 20 minutes after the start of consuming the standardised 
liquid meal
The Subject must consume the standardised liquid meal as quickly as possible and preferably within 
12 minutes. The Investigator should confirm that the Subject consumed the required volume of the 
standardised liquid meal in the electronic case report form (eCRF). Please refer to section 10.2 for 
details regarding supply of the standardised liquid meal.
Time point 0 is defined as the time when the Subject starts the consumption of the standardised 
liquid meal. Blood samples should be taken at -2, 30, 60 and 120 minutes after the start of the meal 
test as outlined in Table 3.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
16 of 23
Table 3
Meal test schedule
Time point
(minutes)
Blood 
sample 
(PG)
SMPG 
measurement
Standardised 
liquid meal
Visit 14
Bolus insulin injection
Visit 40
Bolus insulin injection
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
X
Bolus insulin injection 
0 – 2 minutes before the 
start of the standardised 
liquid meal
X
Meal-time dosing:
Bolus insulin injection 
0 – 2 minutes before the 
start of the standardised 
liquid meal 
20
X
Post-meal dosing:
Bolus insulin injection
20 minutes after the start 
of the standardised liquid 
meal
30
X
60
X
120
X
240
End of meal 
test
X 
(for Subject’s 
safety)
The Subject should stay at the clinic during the meal test to have the blood samples drawn after 30, 
60 and 120 minutes from the start of the standardised liquid meal, as indicated in Table 3.
For the meal test at Visit 14 at time point 0 the Subjects must receive the trial product that was also 
used in the run-in period. 
For the meal test at visit 40 the Subjects should receive the trial product they are randomised to and
have used throughout the treatment period. Depending on the randomisation to either meal-time or
post-meal dosing, the Subjects must be dosed at time point 0 or at time point 20 accordingly.
During the meal test the Subject should be resting in a chair. Water consumption should, to the 
extent possible, be avoided during the first two hours of the meal test. Food intake should not take 
place until at least 4 hours after meal test bolus insulin injection, as the Subject’s glucose values 
will be measured by the CGM device until end of the meal test.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
17 of 23
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 hypoglycaemia must be reported according to protocol section 8.5.1.1. 
After the end of the meal test the Investigator should confirm that the Subject is safe to leave the 
site by performing an additional SMPG measurement. The Subject needs to stay at the site for at 
least 4 hours after the bolus insulin injection time due to safety concerns.
6.1.1
Handling of blood samples 
For convenience and for safety reasons, the Subjects may have i.v. catheters inserted for the 
collection of blood samples during the meal test according to Table 3 and in the event of 
hypoglycaemic episodes requiring immediate i.v. glucose administration.
All blood samples must be sent to the central laboratory for analysis.
6.2
Data collection and data management
The following must be recorded in relation to the meal test: 
!
Fasting status
!
Body weight
!
Time and value of SMPG measurement prior to the meal test confirming that the Subject is 
within the target of 4.0-8.8 mmol/L (71-160 mg/dL) 
!
Time of blood samples
!
Time and dose of insulin injection
!
I:carb ratio used for bolus dose calculation (to be recorded at Visit 14 only)
!
Start and end-time of standardised liquid meal
!
Volume and carb content of standardised liquid meal calculated for consumption (calculated 
amounts for Visit 14 must also be used at Visit 40)
!
Confirmation that the Subject consumed the required volume of the standardised liquid meal
!
Volume of standardised liquid meal consumed
!
Batch no. of standardised liquid meal consumed
!
Hypoglycaemic episode number, time of intervention and amount of glucose rescue 
treatment if relevant 
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 end of trial.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
18 of 23
7
Premature discontinuation of trial product 
If a Subject is prematurely discontinued from trial product after randomisation (Visit 14), the 
Investigator must ensure every possible effort is made to undertake the CGM and meal test 
procedures at Visit 40A, similar to the CGM and meal test procedures for Visit 38, Phone contact 
39 and Visit 40, as soon as possible after decision of ending treatment.
The CGM and meal test procedure at the premature discontinuation Visit 40A must be performed 
with the exception that the CGM period can be less than 11 days. The meal test must not be 
scheduled on the 1st or 7th day after having fitted the sensor. The meal test at Visit 40A should be 
performed with trial product according to randomisation unless this is not feasible for safety reasons
as judged by the Investigator. Confirmation that the meal test was taken with trial product will be 
recorded in the eCRF. 
The CGM and meal test procedure should not be repeated at Visit 40.
Please refer to protocol section 8.2 for further procedures related to premature discontinuation of 
trial product.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
19 of 23
8
Withdrawal from trial 
If a Subject withdraws consent from the trial after randomisation (Visit 14), the Investigator must 
ensure every possible effort is made to undertake procedures similar to those for Visit 40, including 
the CGM and meal test procedures 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.
Please refer to protocol section 8.3 for further procedures related to withdrawal from trial.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
20 of 23
9
Interactive voice/web response system
The Interactive voice/web response system (IV/WRS) will be used to register that a Subject will 
take part in the CGM and meal test subgroup and to ensure the required number of Subjects in the 
CGM and meal test subgroup has been met.
During the Screening Visit the Subject will be registered as a CGM and meal test Subject. At Visit 
14 the Subject will be asked to confirm that he/she has performed the subgroup assessment. This 
confirmation is used for tracking the recruitment of the subgroup.
9.1
IV/WRS data change session
If a CGM and meal test Subject changes his/her mind with regards to consenting/participate in the 
CGM and meal test subgroup an IV/WRS data change session must be performed prior to 
randomisation (Visit 14). If a Subject who has not consented to the CGM and meal test subgroup 
would like to participate, the data change session must be performed prior to Visit 12 in order to 
have the CGM device fitted in due time. 
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
21 of 23
10 Trial Supplies
10.1
CGM supplies
Novo Nordisk will provide the following:
!
CGM devices (receiver and transmitter)
!
CGM user manual and quick guides (for site use) 
!
Instructions for Subjects and the LAR(s)
CGM devices should be returned to Novo Nordisk at end of trial. 
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)
10.1.1
Site PC
Please ensure that a PC with internet connection is available at site (same PC as used for electronic 
data capture can be utilised). For further instruction and requirements please see CGM 
manufacturer’s user guide.
10.1.2
Storage of CGM sensors
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’s instructions and must be temperature 
monitored due 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.
10.2
Meal test supplies
The meal test will be provided by Novo Nordisk. More details on composition and ordering of the 
product are described in the laboratory flowchart.
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
22 of 23
11 Monitoring procedures
11.1
CGM procedures
During the course of the trial, the monitor will verify that the CGM procedures described in this 
appendix have been adhered to, that all issues have been recorded and that monitoring and source 
data verification 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
11.1.1
CGM Source data verification
In addition to protocol section 14 and 14.1 the following should be monitored from the diary data:
!
Date, actual clock time and carb content of meals (breakfast, lunch, main evening meal and 
other meals)
!
Date, actual clock time and dose of bolus and basal injections
!
For extra insulin boluses: Date, actual clock time, dose (units), time and type of previous 
meal and reason for the extra bolus
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
CONFIDENTIAL


Protocol - Appendix B
CONFIDENTIAL
Date:
10 November 2015
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
2.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33 
Page:
23 of 23
11.2
Meal test procedures
During the course of the trial, the Monitor will verify that the meal test procedures described in this 
appendix have been adhered to, that all issues have been recorded and that monitoring and source 
data verification have taken place. 
The Monitor will have to verify that:
!
Meal test procedures have been followed
!
Blood samples have been drawn and recorded in accordance with the time schedule 
!
All blood samples have been sent to the central laboratory
11.2.1
Meal test source data verification
In addition to protocol section 14 and 14.1 the following should be source data verifiable: 
!
Fasting status
!
Body weight
!
Time and value of SMPG measurement prior to meal test confirming that the Subject is 
within the target of 4.0-8.8 mmol/L (71-160 mg/dL) 
!
Time of blood samples
!
Time and dose of insulin injection
!
I:carb ratio used for bolus dose calculation (to be recorded at Visit 14 only)
!
Start and end-time of standardised liquid meal
!
Volume and carb content of standardised liquid meal calculated for consumption (calculated 
amounts for Visit 14 must also be used at Visit 40)
!
Confirmation that the Subject consumed the required volume of the standardised liquid meal
!
Volume of standardised liquid meal consumed
!
Batch no. of standardised liquid meal consumed
!
Hypoglycaemic episode number, time of intervention and amount of glucose rescue 
treatment if relevant 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 February 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
1 of 3
Protocol Amendment
no 1
to Protocol, final version 2.0
dated 10 November 2015
Trial ID: NN1218-4101
Efficacy and Safety of Faster-acting Insulin Aspart compared to NovoRapid® both in 
Combination with Insulin Degludec in Children and Adolescents with Type 1 Diabetes
onset®7
Trial phase: 3b
Applicable to all countries
Amendment originator:
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
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:
16 February 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
2 of 3
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 February 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
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UTN:U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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1
Introduction including rationale for the protocol amendment
A minor discrepancy have been identified in the presentation of the non-inferiority concept in the 
statistical section “General considerations” compared to what is presented in detail in the section 
“Primary analysis”. The primary analysis remains unchanged.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
17 Statistical considerations
General considerations
The primary objective, confirming the effect of treatment with meal-time faster-acting insulin aspart 
in children and adolescents with type 1 diabetes will be assessed using a non-inferiority approach 
comparing the change from baseline HbA1c to meal-time NovoRapid®, where both treatments are 
combined with insulin degludec. More specifically the upper limit of the 95% confidence interval 
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 the effect demonstrated. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
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Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
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Protocol Amendment
no 2
to Protocol, final version 3.0
dated 16 February 2016
Trial ID:NN1218-4101
Efficacy and Safety of Faster-acting Insulin Aspart compared to NovoRapid® both in 
Combination with Insulin Degludec in Children and Adolescents with Type 1 Diabetes
Trial phase: 3b
Applicable to all countries
Amendment originator:
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
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:
30 March 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
2 of 10
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Tables..................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes to the protocol ............................................................................................................................4
2.1
Table of Contents...........................................................................................................................4
2.2
List of abbreviations ......................................................................................................................4
2.3
Section 2 Flow chart ......................................................................................................................4
2.4
Section 5.2.2 Rationale for choice of non-inferiority margin........................................................4
2.5
Section 6.2.1 Additional inclusion criteria for the CGM and meal test subgroup.........................5
2.6
Section 6.3 Exclusion criteria ........................................................................................................5
2.7
Section 8.2 Premature discontinuation of trial product..................................................................5
2.8
Section 8.5.1.1 Hypoglycaemic episodes ......................................................................................5
2.9
Section 8.5.1.2 Hyperglycaemic episodes .....................................................................................6
2.10
Section 8.6.1 Blood volumes for blood sampling..........................................................................6
2.11
Section 8.6.4 Fasting plasma glucose ............................................................................................7
2.12
Section 9.2 Labelling.....................................................................................................................7
2.13
Section 12.1.1 Adverse event.........................................................................................................7
2.14
Section 17.4.1 Supportive secondary endpoints ............................................................................7
2.15
Section 17.4.1.1 Change from baseline refers to the change from randomisation to 26 
weeks after randomisation.Efficacy endpoints ..............................................................................7
3
Changes to Appendix A ............................................................................................................................8
3.1
Section 3.2 Titration of insulin degludec during run-in.................................................................8
3.2
Section 3.4.1.2 Pre-dinner bolus insulin titration...........................................................................8
4
Changes to Appendix B ............................................................................................................................9
4.1
Section 3 Flow chart ......................................................................................................................9
4.2
Section 4.3 CGM and meal test subgroup population .................................................................10
Table of Tables   
Page
Table 2–1
Table 8-2 Approximate blood volumes collected during the trial ............................................6
Table 3–1
Table 3-2 Titration of insulin degludec ....................................................................................8
Table 3–2
Table 3-4 Titration of pre-dinner faster-acting insulin aspart/NovoRapid®............................8
Table 4–1
Table 1 Flow chart – CGM and meal test procedures ..............................................................9
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
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1
Introduction including rationale for the protocol amendment
The main reason for preparing this protocol amendment is to address a mistake identified in the
blood sampling volume at visit 14 and visit 40 for the subjects participating in the CGM and meal 
test subgroup. Consequently the required minimum weight for participation in the CGM and meal 
test subgroup has increased to ensure the  blood volume collected at visit 14 and visit 40 does not 
exceed 1% of the subjects total blood volume.
Additional changes are described below:
Exclusion criterion #3 has been updated to clarify adequate contraceptive measures for Bulgaria, 
Czech Republic, Lithuania, Latvia, Poland, Estonia and Finland.
The requirements for reporting of hyperglycaemic episodes have been updated to reflect that 
subjects have to have high SMPG values, feeling/looking ill and have elevated ketones before 
reporting the hyperglycaemic episode in the eCRF. 
It has been clarified that fasting plasma glucose results measured at central laboratory ≤3.9 mmol/L 
(70 mg/dL) has to be reported as a clinical laboratory adverse event instead of an adverse event. 
The tables for titration of insulin degludec and pre-dinner bolus insulin in appendix A have been 
corrected so there is no overlap between the SMPG values used for titration. 
Minor mistakes and inconsistencies have been corrected. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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2
Changes to the protocol
2.1
Table of Contents
17 Statistical considerations...........................................................................................................88
17.1
Sample size calculation ...................................................................................................90
17.1.1
Sample size calculation for the CGM and meal test subgroup.......................91
17.2
Definition of analysis sets ...............................................................................................91
17.3
Primary endpoint .............................................................................................................92
17.4
Secondary endpoints........................................................................................................95
17.4.1
Supportive secondary endpoints .....................................................................95
17.4.1.1
Change from baseline refers to the change from 
randomisation to 26 weeks after randomisation.Efficacy 
endpoints ....................................................................................96
17.4.1.2         Safety endpoints……………………………………………...100
2.2
List of abbreviations
CLAE 
clinical laboratory adverse event
EU
European Union
2.3
Section 2 Flow chart
For ‘Informed consent’ the following footnote is added:
n Informed consent for participation in the CGM and meal test subgroup can be obtained up to visit 
12 (including visit 12)
Footnote b:
b) Visit 2 can take place as soon as the Subject has been found eligible and must take place no later 
than 137 days after the screening visit (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
For both ‘Hypoglycaemic episodes’ and for ‘Hyperglycaemic episodes’ the ‘x’ at V2 is deleted.
2.4
Section 5.2.2 Rationale for choice of non-inferiority margin
….
In a similar phase 4 trial2726 investigating the stepwise addition of insulin aspart to a full basal bolus 
regimen in bolus naïve T2DM adults the observed reduction in HbA1c after 21 weeks of treatment 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
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Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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was 1.15% (data on file) with 3 times daily insulin aspart added to basal insulin. This gives some 
indication that the effect of NovoRapid® versus placebo would be close to the 0.94% observed in 
trial NN1218-4049. Using a non-inferiority margin of 0.4, one of the suggested margins in the FDA 
guidance2627, an improvement of approximately 0.54% would have been preserved using the 0.4% 
non-inferiority margin. 
2.5
Section 6.2.1 Additional inclusion criteria for the CGM and meal test subgroup
….
11. Weight ≥ 20.0 22.5 kg (44.0 49.5 lbs) measured at the time of screening (Visit 1)
2.6
Section 6.3 Exclusion criteria
….
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 EU only: Adequate contraceptive measures are implants, injectable, combined oral 
contraceptives, hormonal IUD, sexual abstinence or vasectomised partner.
For Bulgaria, Czech Republic, Lithuania, Latvia, Poland, Estonia and Finland only: Adequate
contraceptive measures also include double barrier method (condom or diaphragm with 
spermicide) in addition to the measures listed under EU.
2.7
Section 8.2 Premature discontinuation of trial product
….
In addition, Subjects prematurely discontinued from trial product should continue with the per 
protocol planned visits after 12 weeks (Visit 26) and 26 weeks (Visit 40) from randomisation 
depending on when the Subject discontinues trial product. The following assessments are not 
applicable for prematurely discontinued Subjects at V26 and V40: 4-point profile, technical 
complaints, CGM and meal test, IV/WRS call., drug accountability and training in trial product 
and pen handling.
2.8
Section 8.5.1.1 Hypoglycaemic episodes
….
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in, as described in section 1.. One AE form and safety 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
6 of 10
information form can cover several hypoglycaemic episode forms if the subject has not recovered 
between the episodes.
2.9
Section 8.5.1.2 Hyperglycaemic episodes
....
The Investigator must review the diary data at each contact for correct reporting of hyperglycaemic 
episodes. High SMPG values and/or ketones not having a hyperglycaemic episode form completed 
within 7 days since the SMPG and/or ketone measurement should be reported on a hyperglycaemic 
episode form with as much information as possible (as a minimum the date and SMPG value); 
hyperglycaemic episodes will not be queried for additional information retrospectively due to 
decreased validity of such data High SMPG values where subject looked/felt ill, and had elevated 
ketones but not having a hyperglycaemic episode form completed in the eCRF within 7 days since 
the SMPG measurement should be reported on a hyperglycaemic episode form in the eCRF with as 
much information as possible. Novo Nordisk will not query for additional data except for the date, 
SMPG value, ketone value and looking/feeling ill due to decreased validity of such data 36,37. 
2.10
Section 8.6.1 Blood volumes for blood sampling
Table 2–1
Table 8-2 Approximate blood volumes collected during the trial  
Age 2 < Age 2
(mL)
2 ≤ Age < ≤ 6 years
(mL)
6 ≤ < Age < 18
(mL) 
Age ≥ 8 and in CGM 
and meal test 
subgroup
(mL)
Visit 1
3.0
5.0
6.5a
6.5a
Visit 12
0.5
1.2
2.0
2.0
Visit 14
5.8
8.4
10.0a
18.010.0a/b
Visit 26
5.8
8.4
10.0
10.0
Visit 40c
5.8
8.4
10.0a
18.010.0a/b
Total blood volume 
collected
20.9
31.4
38.5
54.538.5
a Including blood volume for performing hCG pregnancy test for females of childbearing potential only (females having 
had menarche). 
b including four PG blood samples collected during the meal test
c Same blood volume applicable for Visit 40A
….
If the Subject’s weight is less than 20.0 22.5 kg (44.0 49.5 lbs) at screening (Visit 1) the Subject is 
not eligible for the CGM and meal test subgroup.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
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2.11
Section 8.6.4 Fasting plasma glucose
….
FPG results ≤ 3.9 mmol/L (70 mg/dL) should not be reported as hypoglycaemic episodes in the 
eCRF but as an AE related to the procedure (e.g. if the FPG result is 2.9 mmol/L (52 mg/dL), please 
report as ‘low plasma glucose of 2.9 mmol/L (52 mg/dL)’). a clinical laboratory adverse event 
(CLAE) at the discretion of the investigator (see Section 12.1.1).
2.12
Section 9.2 Labelling
….
The Investigator must document that direction for use is given to the Subject orally and in writing at 
each the first dispensing visit (Visit 2). Direction for use must as a minimum be provided to the 
Subject in writing at the first dispensing visit (Visit 2).
2.13
Section 12.1.1 Adverse event
….
An AE includes:
!
A clinically significant worsening of a concomitant illness.
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is 
of a severity that requires active management. 
2.14
Section 17.4.1 Supportive secondary endpoints
For all supportive secondary endpoints, meal-time faster-acting insulin aspart will be compared to 
meal-time NovoRapid®, and post-meal faster-acting insulin aspart will be compared to meal-time 
NovoRapid®. Change from baseline refers to the change from randomisation to 26 weeks after 
randomisation.
2.15
Section 17.4.1.1 Change from baseline refers to the change from randomisation to 26 
weeks after randomisation.Efficacy endpoints
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
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Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
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3
Changes to Appendix A
Appendix A, version 3.0, dated 16 February 2016
3.1
Section 3.2 Titration of insulin degludec during run-in
Table 3–1
Table 3-2 Titration of insulin degludec
Current dose
≤ 15U
>15U
Lowest of three pre-breakfast SMPGs 
Adjustment
mmol/L
mg/dL
≤ 3.9
≤ 70
-1
-2
4.0 – 8.0  
71 - 145
0
0
8.1 – 10.0
146 - 180
+1
+2
10.1 – 15.0
181 – 270
+2
+4
> ≥15.1
> ≥ 2701
+3
+6
3.2
Section 3.4.1.2 Pre-dinner bolus insulin titration
Table 3–2
Table 3-4 Titration of pre-dinner faster-acting insulin aspart/NovoRapid®
Current dose
< 5U
∀5U
Lowest bed-time SMPG value measured 
on the three days prior to the site 
visit/phone contact 
Adjustment
mmol/L
mg/dL
≤ 6.76
≤ 12019
-1
-2
6.7 – 10.0  
120 – 180 
0
0
≥ 10.01 a
≥ 1801
+½ 
+1
a. It is at the Investigator’s discretion to use a higher dose increment. 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
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Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
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4
Changes to Appendix B
Appendix B, version 3.0, dated 16 February 2016
4.1
Section 3 Flow chart
Table 4–1
Table 1 Flow chart – CGM and meal test procedures
Trial NN1218-4101
Appendix 
section
Screening
Run-in
Randomisa
tion
Treatment 
periodd4
Premature 
Discontinu
ation
Visit (V) / Phone contact(P)
V1
V12
P13
V14
V38
P39
V40
V40A
Time of visit (weeks)1
-14
-2
-1
0
24
25
26
Visit window (days)
+10
±3
±3
±3
±3
±3
CGM Assessment
CGM 
Fitting
CGM 
Fitting
CGM 
Removal 
CGM 
Fitting
CGM 
Fitting
CGM 
Removal
CGM 
Fitting
CGM 
Removal
Meal test Assessment
Meal test
Meal test
Meal test
Subgroup informed consent5
4.3
(x)
(x)
Fitting & supply of the CGM devices2
5.2
&
5.3
X
x
x
x
x
Instruct Subjects in CGM calibration 
procedure 
(beginning 2 hours after the device is 
fitted and every 12 hours during the 
CGM period)
5.4
X
x
x
x
x
Instruct Subjects in CGM procedures in 
general
5.4
X
x
x
x
x
Meal test3
6
x
x
x
Attend visit fasting
6.1
x
x
x
Removal of CGM device
5.3
x
x
x
x
x
Upload of CGM data
5.5
x
x
x
x
x
                                                
1 The time of the visit is defined from the randomisation visit (V14)
2 The fitting of the CGM devices must be scheduled to ensure the meal test is not performed on the 1st or 7th day when 
Subject is wearing a CGM sensor. In case of premature discontinuation of trial product or withdrawal from trial please 
see section 7 and 8 
3 The meal test must be performed after a minimum of 11 days of wearing a CGM sensor
d4 The assessments is not applicable for prematurely discontinued Subjects, see section7
5 Informed consent for participation in the CGM and meal test subgroup can be obtained up to visit 12 (including visit 
12)
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
30 March 2016
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
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Trial NN1218-4101
Appendix 
section
Screening
Run-in
Randomisa
tion
Treatment 
periodd4
Premature 
Discontinu
ation
Visit (V) / Phone contact(P)
V1
V12
P13
V14
V38
P39
V40
V40A
Time of visit (weeks)1
-14
-2
-1
0
24
25
26
Visit window (days)
+10
±3
±3
±3
±3
±3
Weight & age check
4.3
x
4.2
Section 4.3 CGM and meal test subgroup population
A total of 150 randomised Subjects are planned to enter the CGM and meal test subgroup. To 
ensure capability of the Subjects to comply with the CGM and meal test procedures only Subjects ≥ 
8 years of age and with a weight of ≥ 20.0 22.5 kg (44.0 49.5 lbs) at screening (due to blood 
sampling volume restrictions) are allowed to participate in the CGM and meal test subgroup. 
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
29 July 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
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Protocol Amendment
no 3
to Protocol, final version 4.0
dated 01 April 2016
Trial ID:NN1218-4101
Efficacy and Safety of Faster-acting Insulin Aspart compared to NovoRapid® both in 
Combination with Insulin Degludec in Children and Adolescents with Type 1 Diabetes
onset®7
Trial phase: 3b
Applicable to Serbia only
Amendment originator:
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 3
CONFIDENTIAL
Date:
29 July 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
2 of 5
Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
Section 1 Summary, Trial design................................................................................................................4
Section 1 Summary, Key inclusion criteria.................................................................................................4
Section 5.1 Type of trial..............................................................................................................................4
Section 6.2 Inclusion criteria.......................................................................................................................4
Section 6.9 Rationale for trial population ...................................................................................................4
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
29 July 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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1
Introduction including rationale for the protocol amendment
The  reason for preparing this protocol amendment is to address the concerns received from Serbian 
Medicines and Medical Devices Agency for initial trial application. The Agency did not issue 
approval to run the trial in Serbia in population of children and adolescents between 1 year old and 
below 18 years old at the time of signing informed consent and below 18 years old at the time of 
randomisation. 
The main rationale for rejecting the trial was lack of approval of comparator (Insulin Aspart –
NovoRapid) and Insulin Degludec (Tresiba) in Serbia for diabetes treatment in children below 2 
years old. Furthermore, the Serbian Medicines and Medical Devices Agency had concerns in 
relation to inability of children below 2 years old to properly recognize and acknowledge 
hypoglycaemia as well as high incidence of hypoglycaemic episodes in this population. Based on 
the above the Serbian Medicines and Medical Devices Agency judged the overall benefit-risk ratio
for the trial subjects as unfavourable.
This protocol amendment changes the inclusion criterion number 2 for Serbia only in order to 
include subjects from 2 years old and below 18 years old at the time of signing informed consent
and below 18 years old at the time of randomisation.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
29 July 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
Page:
4 of 5
2
Changes
Section 1 Summary, Trial design
This is a 26-week randomised, partly double-blind, multicentre, multinational, active controlled, 
treat-to-target, three-armed parallel group trial with a 12-week run-in period comparing the effect 
and safety of meal-time faster-acting insulin aspart vs. meal-time NovoRapid® both in combination 
with insulin degludec once daily in a basal-bolus regimen in type 1 diabetes mellitus Subjects from 
12 years to less than 18 years of age. The trial will also include a 26-week open-label post-meal 
faster-acting insulin aspart dosing arm in combination with insulin degludec.
Section 1 Summary, Key inclusion criteria
!
Male or female, 12 ≤ age < 18 years at the time of signing informed consent and < 18 years 
at the time of randomisation
Section 5.1 Type of trial
This is a 26-week randomised, partly double-blind, multicentre, multinational, active controlled, 
treat-to-target, parallel group trial with a 12-week run-in period comparing the efficacy and safety 
of meal-time faster-acting insulin aspart vs. meal-time NovoRapid® both in combination with 
insulin degludec once daily in a basal-bolus regimen in Subjects with T1DM from 12 years to less 
than 18 years of age. The trial will also include a 26-week open-label post-meal faster-acting insulin 
aspart dosing arm in combination with insulin degludec.
Section 6.2 Inclusion criteria
2. Male or female, 12 ≤ age < 18 years at the time of signing informed consent and < 18 years at the 
time of randomisation
Section 6.9 Rationale for trial population
For children and adolescents diagnosed with T1DM, insulin therapy is indicated, and data from the 
The Diabetes Control and Complications Trial Research Group (DCCT) show that intensive 
treatment is beneficial in terms of the risk of developing long term complications3. As the disease 
usually presents in early childhood and adolescence, the assessment of safety and efficacy of new 
insulins is appropriate in all ages including childhood and adolescence. 
The trial population consist of children and adolescents with T1DM, 12 ≤ age < 18 years with an 
HbA1c ≤ 9.5 % (80 mmol/mol) at screening and at randomisation. Infants below the age of 1 year 
are not eligible for this trial since most cases of diabetes diagnosed at this very young age are cases 
CONFIDENTIAL


Protocol Amendment no 3
CONFIDENTIAL
Date:
29 July 2016
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
5 of 5
of neonatal diabetes. Neonatal diabetes is a distinct form of diabetes requiring specialized diagnosis 
and management beyond the scope of this trial. 
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 9.5% (80 mmol/mol) are 
not included in this trial. The HbA1c limit is also expected to select a population that can achieve 
adequate basal insulin coverage in the 12-week run-in basal insulin titration period where focus is 
not on bolus titration.
During the last 3 months prior to Visit 1 the Subjects must have been on an ongoing daily treatment 
with a basal-bolus insulin regimen using basal insulin analogue or NPH insulin in order to ensure a 
smooth switch from prior treatment to trial treatment, and to ensure that optimal adjustment of basal 
insulin can be done during the 12-week run-in period. 
For safety reasons, Subjects with more than one episode of diabetic ketoacidosis requiring 
hospitalisation within the last 90 days prior to the screening visit are not eligible for this trial.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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Protocol Amendment
no 4.0
to Protocol, final version 4.0
dated 01 April 2016
Trial ID: NN1218-4101
Efficacy and Safety of Faster-acting Insulin Aspart compared to NovoRapid® both in
Combination with Insulin Degludec in Children and Adolescents with Type 1 Diabetes
onset®7
Trial phase: 3b
Applicable to all countries
Amendment originator:
 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:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
2 of 11
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Section 2 Flowchart .......................................................................................................................4
2.2
Section 6.4 Run-in failure criteria..................................................................................................4
2.3
Section 6.7 Withdrawal from trial .................................................................................................4
2.4
Section 7 Milestones......................................................................................................................5
2.5
Section 8.1.7 Fasting visits ............................................................................................................5
2.6
Section 8.2 Premature discontinuation of trial product..................................................................5
2.7
Section 8.3 Withdrawal from trial .................................................................................................5
2.8
Section 8.5.1.1 Hypoglycaemic episodes ......................................................................................6
2.9
Section 8.5.1.3 Injection site reactions ..........................................................................................6
2.10
Section 8.6.4 Fasting plasma glucose ............................................................................................6
2.11
Section 9.5.1 Auxiliaries supplied by Novo Nordisk A/S .............................................................7
2.12
Section 12.1.4 Medical event of special interest............................................................................7
2.13
Section 17.3 Primary endpoint.......................................................................................................7
2.14
Section 17.4.1.1 Efficacy endpoints ..............................................................................................8
2.15
Section 17.4.1.2 Safety endpoints..................................................................................................9
3
Changes to Appendix A ..........................................................................................................................10
3.1
Section 4 Data collection.............................................................................................................10
4
Changes to Appendix B ..........................................................................................................................11
4.1
Section 5.1 CGM receiver setting and test upload.......................................................................11
4.2
Section 6.2 Data collection and data management ......................................................................11
4.3
Section 10.1 CGM supplies .........................................................................................................11
4.4
Section 11.2.1 Meal test source data verification ........................................................................11
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
3 of 11
1
Introduction including rationale for the protocol amendment
The main reason for preparing this protocol amendment is to address an inaccuracy identified in the
layman language for reporting hypoglycaemic episodes. This is to ensure adequate reporting of 
severe hypoglycaemia. The layman language is used in the Subject diaries and in EDC. 
Additional changes are described below:
There was a need to clarify the run-in failure criteria, to provide more guidance on when to report a 
MESI, and that the FPG sample must be collected using the FPG home sampling kit no matter if the 
FPG sample is taken at home or at site. 
The statistical section has been updated to clarify the analyses made for the primary and secondary 
estimand, the supportive secondary CGM and meal test related efficacy endpoints. A clarification 
has also been made to which treatment emergent hypoglycaemic episodes will be included in the 
analyses. 
Appendix B has been updated to reflect the changes that have occurred due to the change in CGM 
supplier shortly before trial initiation. 
Furthermore, minor mistakes and inconsistencies have been corrected.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
4 of 11
2
Changes
2.1
Section 2
Flowchart
Changes to the flowchart:
For “Technical complaint” and for “Dosing” “x” is added at the premature discontinuation visit 
(V40A).
For “Hypoglycaemic episodes” and for “Hyperglycaemic episodes” “x” is added at V2.
For “Hypoglycaemic episodes” and “Hyperglycamic episodes” a foot note reference “o” is added.
Changes to the foot notes:
a) Visit windows before Visit 14 is relative to Visit 2. Visit windows after Visit 14 are relative to 
randomisation visit (Visit 14), except for the follow-up visits which are relative to last day on trial 
product 
o) Serious hypoglycaemic episodes and serious hyperglycaemic episodes must be reported from the 
first trial-related activity after the Subject has signed the informed consent
2.2
Section 6.4
Run-in failure criteria
The Subject may be withdrawn from the trial during the run-in period at the discretion of the 
Investigator due to a safety concern.
….
2.3
Section 6.7
Withdrawal from trial
The Subject may withdraw at will at any time either by the Subject or by the Subject's LAR(s). The 
Subject's request to discontinue withdraw must always be respected.
If the Subject considers withdrawing consent after randomisation, 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 to stay in the trial, procedures similar to those 
described in section 8.2 must be followed.
….
A Subject randomised included in the trial in violation of the inclusion and/or exclusion criteria 
and/or randomised in violation of the randomisation criteria must discontinue treatment with trial 
product, but will not be withdrawn from the trial and will be followed as described in section 8.2
….
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
5 of 11
2.4
Section 7
Milestones
Planned duration of recruitment period (FSFV – LSFV): 5138 weeks
….
2.5
Section 8.1.7
Fasting visits
….
The Subjects included in the CGM and meal test subgroups must attend Visit 14 and Visit 40 fasting. If 
the Subject prematurely discontinues trial product, Visit 40A must also be attended fasting.
….
2.6
Section 8.2
Premature discontinuation of trial product
….
Diary records after premature discontinuation of trial product: 
….
!
Was the hypoglycaemic episode associated with severe neuroglycopenia, usually resulting 
in coma or seizure and requiring parenteral therapy (glucagon or intravenous glucose)34? 
(Layman language used in the Subject diaries: Was the low blood glucose episode
associated with symptoms severe enough to result in unconsciousness or a seizure orand
was glucagon (an injection) or IV glucose/sugar (drip) needed for your child to recover?)
….
2.7
Section 8.3
Withdrawal from trial
The Subject will become a run-in failure if the Subject withdraws consent prior to randomisation.
If a Subject withdraws consent after randomisation (Visit 14), the Investigator should must ensure 
every possible effort is made to undertake procedures similar to those for Visit 40, including the 
meal test for the Subjects included in the CGM and meal test subgroup, as soon as possible. The 
Subject shouldmust also complete the follow-up visits (Visit 41 and Phone Contact 42). 
….
The End-of-Treatment/Trial form must be completed in the eCRF and final drug accountability 
must be performed even if the Subject is not able to come to the site. A “Treatment 
Discontinuation” session must be made in IV/WRS and reason for withdrawal must be specified on 
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.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
6 of 11
….
2.8
Section 8.5.1.1
Hypoglycaemic episodes
….
The record should include the following information: 
….
!
Was the hypoglycaemic episode associated with severe neuroglycopenia, usually resulting 
in coma or seizure and requiring parenteral therapy (glucagon or intravenous glucose)34? 
(Layman language used in the Subject diaries: Was the low blood glucose episode
associated with symptoms severe enough to result in unconsciousness or a seizure orand
was glucagon (an injection) or IV glucose/sugar (drip) needed for your child to recover?)
….
2.9
Section 8.5.1.3
Injection site reactions
….
The injection site reaction form should only be used for events with an onset date starting at 
between Visit 2 and up until Visit 41 (including Visit 41).
…..
2.10
Section 8.6.4
Fasting plasma glucose
….
The Subject will receive a home blood sampling kit and instruction on how to use it. The Subject 
will bring the blood sample to the site visit and the sample will be handled by the site staff in 
accordance with the instructions described in the laboratory manual. If preferred, the FPG blood 
sampling can be performed at the site provided that the Subject is fasting for the site visit. The home 
sampling kit must also be used if the FPG blood sampling is performed at the site. 
The FPG capillary blood sample must be taken while the Subject is fasting, in accordance with the 
fasting definition described in section 8.1.7 and before administration of insulin on that day. If these 
conditions cannot be met, collection of the FPG sample should be rescheduled within the permitted 
visit window, except for the capillary FPG sample to be collected at the randomisation visit (Visit 
14). at Visit 14(randomisation visit), where Iif conditions for no FPG sampleing is not met available 
at the randomisation visit the entire randomisation visit should be rescheduled within the visit 
window.
….
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
7 of 11
2.11
Section 9.5.1
Auxiliaries supplied by Novo Nordisk A/S
The following auxiliaries will be supplied by Novo Nordisk A/S: 
….
2.12
Section 12.1.4
Medical event 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 criterion. 
A medication errors concerning trial products is defined as:
!
Administration of wrong drug.
Note: Use of wrong DUN is not considered a medication error unless it results in a confirmed
administration of wrong drug.
!
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), misuse
or abuse of trial product.
!
Accidental administration of a lower or higher dose than intended. i.e. dose which may lead to
significant health consequences, as judged by the Investigator, irrespective of whether the SAE
criteria are fulfilled or not.That is a dose that deviates from the intended dose to an extent where
clinical consequences for the trial Subject were likely to happen as judged by the Investigator,
although not necessarily did happen.
2.13
Section 17.3
Primary endpoint
….
Sensitivity analyses for the primary estimand:
2)
The internal validity of the primary estimand will first be evaluated by repeating the
primary analysis in 1), but excluding all factors and covariates except from treatment
in the model. This analysis will explore the influence of the different factors and
covariates. The analysis will use the in trial observation period.
….
b. Imputation 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 that withdraw the trial in the faster-acting
insulin aspart arms shift to NovoRapid®. The imputation will be done conditional
on observed information for Subjects that withdraw from the faster-acting insulin
aspart arms such that the treatment effect diminishes gradually after trial
discontinuation (copy reference/conditional imputation). The analysis will use the
in trial observation period.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
8 of 11
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 shift to NovoRapid®. The imputation will be done 
with no regard to observed information for Subjects that withdraw from the faster-
acting insulin aspart arms such that the treatment effect diminishes immediately 
after trial discontinuation (jump to reference/unconditional imputation). The 
analysis will use the in trial observation period. 
….
Analyses for the secondary estimand
….
6)
A tipping point analysis will be implemented 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 trial product prematurely due to criteria 1, 
2, 3, and 4) in the faster-acting insulin aspart groups will not have a penalty added. have 
their imputations based on parameters estimated from the faster-acting insulin aspart 
groups (and not the NovoRapid® group). These analyses are motivated by the fact that 
data from Subjects prematurely discontinuing trial product due to non-eligibility can 
reasonably be assumed to be missing completely at random. The analysis will use the on 
treatment observation period.
7)
The same statistical model using multiple imputation as the primary 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 deviate from the ideal treatment 
during the on treatment observation period and will serve as a sensitivity analysis for the 
non-inferiority analysis.
2.14
Section 17.4.1.1
Efficacy endpoints
….
Supportive secondary CGM and meal test related efficacy endpoints
….
AUCIG,0-15 min, AUCIG,0-30 min, AUCIG,0-1h, AUCIG,0-2h, and AUCIG,0-4h will be calculated as the area 
under the IG curve using the trapezoidal method and weighted by duration. The endpoint will also 
be calculated as increment where an average of the IG concentrations immediately before the meal 
is subtracted from the weighted AUC. Each endpoint will be analysed using an analysis of variance 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
9 of 11
model including treatment, region and strata as factors and the corresponding baseline value as 
covariate.
….
2.15
Section 17.4.1.2
Safety endpoints
….
The number of treatment emergent severe or BG confirmed hypoglycaemic episodes (all, daytime, 
nocturnal) will be analysed using a negative binomial regression model with a log-link function and 
the logarithm of the time period for which a hypoglycaemic episode is considered treatment 
emergent as offset. The model will include treatment, region and strata as factors, and will be based 
on the FAS. To the extent where data allow, separate analyses will be performed for severe episodes 
(all).
….
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
10 of 11
3
Changes to Appendix A
Appendix A, version 4.0, dated 01 April 2016
3.1
Section 4
Data collection
In this trial the Subjects will be provided with a diary where the Subjects should record the 4-point
profiles and insulin doses on the three days prior to a site visit/phone contact, and all 
hypoglycaemic episodes and hyperglycaemic episodes within the definition of this protocol. The 
data used for titration (4-point profiles and insulin doses) should be transcribed into the eCRF by 
the Investigator within 24 hours on work days after each site visit/phone contact.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
13 January 2017
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN:U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
11 of 11
4
Changes to Appendix B
Appendix B, version 4.0, dated 01 April 2016
4.1
Section 5.1
CGM receiver setting and test upload
The CGM receiver must be set up before use has been setup when provided at site. 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 upload must be performed to verify correct installation of 
CGM software and correct set up of the CGM receiver. Upon installation of the CGM Web 
uploader a ‘Test of connectivity’ should be performed to verify the connectivity from the CGM Web 
uploader to the server where CGM data will be uploaded to.
Upon the test upload Upon the first upload for each subject 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, and the clock accuracyand verification that no data exists on the CGM receiver prior 
to use.
The CGM device status report should be printed out, dated and signed and filed as source 
document.
4.2
Section 6.2
Data collection and data management
….
!
LotBatch no. of standardised liquid meal consumed ….
4.3
Section 10.1
CGM supplies
Novo Nordisk will provide the following:
….
!
CGM Training (eLearning)
CGM devices should be returned to Novo Nordisk at end of trial. 
The CGM manufacturer will provide the following:
!
CGM Installation link to CGM software
!
CGM sensors (customs clearance must may be expected)
!
CGM Training (webinar or on-site)
4.4
Section 11.2.1
Meal test source data verification
….
!
LotBatch no. of standardised liquid meal consumed ….
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
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CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical analysis plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02670915 
Sponsor trial ID: 
NN1218-4101 
Official title of study: 
Efficacy and Safety of Faster-acting Insulin Aspart compared 
to NovoRapid® both in Combination with Insulin Degludec in 
Children and Adolescents with Type 1 Diabetes 
Document date: 
17 August 2018 
 


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CONFIDENTIAL
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Includes redaction of personal identifiable information only. 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
1 of 27
Statistical Analysis Plan
Trial ID: NN1218-4101
Efficacy and Safety of Faster-acting insulin aspart compared 
to NovoRapid® both in Combination with Insulin Degludec in 
Children and Adolescents with Type 1 Diabetes 
Onset® 7
Author:
Name: 
Department: 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
2 of 27
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 .....................................................................................................................6
2.1
Sample size calculation .............................................................................................................8
2.1.1
Sample size calculation for the CGM and meal test subgroup...................................9
2.2
Definition of analysis sets..........................................................................................................9
2.3
Primary endpoint.....................................................................................................................10
2.4
Secondary endpoints ...............................................................................................................14
2.4.1
Supportive secondary endpoints.............................................................................14
2.4.1.1
Efficacy endpoints............................................................................14
2.4.1.2
Safety endpoints...............................................................................19
3
Changes to the statistical analyses planned in the protocol..............................................................25
4
References ..........................................................................................................................................27
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
3 of 27
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
CTR
clinical trial report
FAS
full analysis set
FPG
fasting plasma glucose
HDL
high density lipoprotein
ICH
international council on harmonisation
IG
interstitial glucose
IMP
investigational medicinal product
ISPAD
International Society for Paediatric and Adolescent Diabetes 
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
TEAE
treatment emergent adverse event
WHO
World Health Organization
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
4 of 27
1
Introduction
1.1
Trial information
This is a 26-week randomised, partly double-blind, multicentre, multinational, active controlled, 
treat-to-target, three-armed parallel group trial with a 12-week run-in period comparing the effect 
and safety of meal-time fast-acting insulin aspart1 vs. meal-time NovoRapid® both in combination 
with insulin degludec once daily in a basal-bolus regimen in type 1 diabetes mellitus Subjects from 
1 year to less than 18 years of age (For Serbia only: 2 years to less than 18 years of age). The trial 
will also include a 26-week open-label post-meal fast-acting insulin aspart dosing arm in 
combination with insulin degludec.
For each Subject, the total trial duration is approximately 45 weeks consisting of the following 
periods (see Figure 1–1):
!
Up to 2 weeks for screening
!
A 12-week run-in period primarily with the aim of optimising the insulin degludec dose
!
A 26-week treatment period 
!
A 7-day and a 30-day follow-up period
A subgroup of Subjects, age ≥ 8 years old at screening (Visit 1), will have blinded continuous 
glucose monitoring (CGM) and a standardised meal test at two occasions during the trial leading up 
to Visit 14 and Visit 40. The Subjects will have the blinded CGM for at least 11 days and up to 13 
days before randomisation and up to 13 days before the end of the 26-week treatment period. The 
standardised meal test will be performed at baseline (Visit 14) and at the End of Treatment. The 
CGM and meal test subgroup and procedures are described in the CGM and meal test protocol 
Appendix B. 
The trial includes a screening visit to assess the Subject’s eligibility. At Visit 2, the eligible Subjects 
will be enrolled in a 12-week run-in period where all Subjects will be switched from their previous 
insulin treatment to insulin degludec once daily and meal-time NovoRapid®. During the 12-week 
run-in period the Investigator will focus on optimisation of the basal insulin on a weekly basis to 
individual fasting plasma glucose (FPG) targets. After the run-in period, Subjects with HbA1c ≤ 
9.5% (80 mmol/mol) who based on the Investigator’s judgement have shown ability and willingness 
to adhere to the trial protocol will be randomised (1:1:1) to receive meal-time fast-acting insulin
aspart, post-meal fast-acting insulin aspart or meal-time NovoRapid®, all in combination with 
insulin degludec. Here, Meal-time dosing is defined as injecting 0 - 2 minutes before the meal, and 
Post-meal dosing, is defined as injecting 20 minutes after the start of the meal.
                                               
1 In the protocol fast-acting insulin aspart was referred to as faster-acting insulin aspart.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
5 of 27
Figure 1–1
Trial design
In order to ensure a comparable number of Subjects of similar age in each treatment group the 
randomisation is stratified by age at randomisation according to the following categorisation: 1 ≤ 
age < 3 years, 3 ≤ age < 6 years, 6 ≤ age < 12 years and 12 ≤ age < 18 years. This categorisation of 
age will henceforth be referred to as strata.
Subjects prematurely discontinued from trial product should continue with the per protocol planned 
visits after 12 weeks (Visit 26) and 26 weeks (Visit 40) from randomisation depending on when the 
Subject discontinues trial product. 
For further details on handling of Subjects that prematurely discontinue from trial product and the 
trial in general, please see the trial protocol.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol Efficacy and Safety of Faster-acting 
insulin aspart compared to NovoRapid® both in Combination with Insulin Degludec in Children 
and Adolescents with Type 1 Diabetes, version 5.0 (dated 16 January 2017). The statistical analyses 
and derivations of endpoints presented in this SAP are almost identical to those described in the 
protocol. It contains minor clarifications for derivations, calculation of endpoints and analyses as 
well as a few additions.
The changes to the statistical considerations proposed in this SAP and the reasons for the changes 
are described in section 3 and will be reported in the clinical trial report (CTR).
Screening
Randomisation
Meal-time fast-acting insulin aspart and 
insulin degludec
Meal-time NovoRapid
® and insulin 
degludec
Week  -14       -12    
0
                                                                                             26   27          30
Note: Prior to run-in and after End of Treatment Subjects are on marketed products
FU1
12-week run-in period
Meal-time 
NovoRapid
® and 
insulin degludec
26-week treatment period
FU2
Post-meal fast-acting insulin aspart 
and insulin degludec
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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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 the randomisation visit (Visit 14). In case a 
measurement is not available at the randomisation visit, the most recent measurement prior to the 
randomisation visit 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 treatment 
discontinuation.
!
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 
NovoRapid®/fast-acting insulin aspart. The on treatment observation period includes data 
collected up to and including 7 days after treatment discontinuation.
All primary and secondary 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 (SAS) and analysed using the FAS, unless otherwise stated.
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 intervals 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 14) will only be summarised descriptively.
Selected tables and figures will also be presented by age group, where age group refers to the 
following categorisation of age: 1 ≤ age < 6 years, 6 ≤ age < 12 years and 12 ≤ age < 18 years.
Testing strategy and estimands
The primary objective, confirming the effect of treatment with meal-time fast-acting insulin aspart 
in children and adolescents with type 1 diabetes will be assessed using a non-inferiority approach 
comparing the change from baseline HbA1c to meal-time NovoRapid®, where both treatments are 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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combined with insulin degludec . More specifically the upper limit of the 95% confidence interval 
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 the effect demonstrated. 
The trial also aims to confirm the effect of treatment with post-meal fast-acting insulin aspart and to 
confirm superiority of meal-time fast-acting insulin aspart both in combination with insulin 
degludec in children and adolescents with type 1 diabetes. In order to control the family-wise type I 
error rate in the strong sense, a hierarchical (fixed sequence) testing procedure will be deployed. 
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 the null hypothesis will only be confirmed for analyses where all previous null-
hypotheses have been rejected in favour of fast-acting insulin aspart. This is done using a 
hierarchical testing procedure with three steps:
Step 1: HbA1c non-inferiority of meal-time fast-acting insulin aspart versus meal-time NovoRapid®
both in combination with insulin degludec
Step 2: HbA1c non-inferiority of post-meal fast-acting insulin aspart versus meal-time NovoRapid®
both in combination with insulin degludec
Step 3: HbA1c superiority of meal-time fast-acting insulin aspart versus meal-time NovoRapid®
both in combination with insulin degludec
Primary estimand
The primary estimand is defined as the treatment difference between Subjects randomised to fast-
acting insulin aspart and NovoRapid® both in combination with insulin degludec, in children and 
adolescents with type 1 diabetes assessed by change from baseline HbA 1c 26 weeks after 
randomisation for all randomised Subjects regardless of treatment discontinuation or use of 
ancillary therapies. 
The primary estimand assesses the expected difference in glycaemic benefit for a subject if 
prescribed to fast-acting insulin aspart as compared to NovoRapid® both in combination with 
insulin degludec in children and adolescents with type 1 diabetes. By not putting any restrictions on 
the treatment adherence, this estimand aims at a difference as close as possible to the one that can 
be expected in real-world clinical practice. Thereby the primary estimand provides a clinically 
relevant treatment difference for clinicians concerning the glycaemic effect of fast-acting insulin 
aspart compared to NovoRapid® in the day to day life in individual children and adolescents with 
type 1 diabetes, where both treatments are combined with insulin degludec.
The confirmatory analyses are made under the framework of the primary estimand.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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Secondary estimand
As an alternative to the primary estimand, a secondary estimand is defined as the treatment 
difference in change from baseline HbA1c 26 weeks after randomisation between fast-acting insulin 
aspart and NovoRapid® both in combination with insulin degludec in children and adolescents with 
type 1 diabetes aged 1 to less than 18 years if Subjects continue on treatment until 26 weeks. 
The secondary estimand assesses the expected difference in glycaemic benefit for a Subject if 
prescribed to fast-acting insulin aspart as compared to NovoRapid® both in combination with 
insulin degludec in children and adolescents with type 1 diabetes if all Subjects adhered. This 
estimand provides a more hypothetical treatment difference, but may also be more sensitive for a 
non-inferiority comparison, since the marketed product that Subjects discontinuing from 
randomised treatment are switched to may equalize the treatment effect. 
Visit reallocation
Subjects that prematurely discontinue from treatment or withdraw from trial will attend end of 
treatment visit called Visit 40A. Data collected at this visit 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.
2.1
Sample size calculation
The primary objective of the trial is to confirm the effect of treatment with meal-time fast-acting 
insulin aspart in terms of glycaemic control measured by change from baseline in HbA1c 26 weeks 
after randomisation by comparing it to treatment with meal -time NovoRapid®, both in combination 
with insulin degludec, using a non-inferiority approach in children and adolescents with type 1 
diabetes. The sample size is determined using a non-inferiority limit of 0.4%.
The trial also aims to confirm the effect of treatment with post-meal fast-acting insulin aspart and to 
confirm superiority of meal-time fast-acting insulin aspart, both in combination with insulin 
degludec in children and adolescents with type 1 diabetes. This is done using a hierarchical testing 
procedure with three steps:
Step 1: HbA1c non-inferiority of meal-time fast-acting insulin aspart versus meal-time NovoRapid®
both in combination with insulin degludec
Step 2: HbA1c non-inferiority of post-meal fast-acting insulin aspart versus meal-time NovoRapid®
both in combination with insulin degludec
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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Step 3: HbA1c superiority of meal-time fast-acting insulin aspart versus meal-time NovoRapid®, 
both in combination with insulin degludec
The sample size is determined to ensure sufficient power for the first step and the second step in the 
hierarchical testing procedure.
Power for the non-inferiority steps are based on a t-statistic under the assumption of a one-sided test 
of size 2.5%. A zero mean treatment difference for the comparison between meal-time fast-acting 
insulin aspart and meal-time NovoRapid® is expected, and for the comparison of post-meal fast-
acting insulin aspart and meal-time NovoRapid® a mean difference of 0.05% in favour of meal-time 
NovoRapid® is expected. 
Based on experience from previous trials, and taking into account that the in trial observation period 
includes data collected after treatment discontinuation, the standard deviation for change in HbA1c
is assumed to be 1.3%. With this standard deviation, a sample size of 250 Subjects per group (750 
in total) will ensure more than 93% power to show non-inferiority, given that the actual treatment 
difference is 0%. This sample size will ensure a power of 85% to show non-inferiority of post-meal 
fast-acting insulin aspart compared to meal-time NovoRapid®.
The number of Subjects to prematurely discontinue trial product is expected to be less than 10% 
based on previous trials. The number of Subject to withdraw from trial is expected to be less than 
5%.
2.1.1
Sample size calculation for the CGM and meal test subgroup
The CGM and meal test subgroup is included in the trial in order to compare additional assessments 
for evaluation of postprandial and overall glucose regulation between the treatment arms. As this 
additional assessment is exploratory in nature, this subgroup is not strictly powered to demonstrate 
a statistical significant difference between treatment arms in any particular endpoint. Fifty (50) 
Subjects per treatment arm have been chosen as this number is considered enough to provide 
sufficient information for evaluation in this exploratory analysis, and as this is a similar number to 
what have been included in previous trials using CGM subgroups.
2.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance1:
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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!
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 that comply with 
inclusion and exclusion criteria. Subjects in the PP set will contribute to the evaluation “as
treated”
!
SAS includes all Subjects receiving at least one dose of the investigational product or its 
comparator. Subjects in the safety set will contribute to the evaluation “as treated” 
Randomised Subjects who are lost to follow up, and where no exposure information of the 
investigational product or its comparator is available after randomisation, will be handled as 
unexposed.
Before data are released for statistical review after 26 weeks, a blinded review of all data will take 
place to identify protocol deviations 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. 
If any Subjects or observations are excluded, 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.
2.3
Primary endpoint
The primary endpoint to address all three confirmatory objectives is:
Change from baseline in HbA1c 26 weeks after randomisation 
Primary analysis
1) The primary estimand will be addressed by the below primary analysis on all Subjects included 
in 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, actual missing data will 
occur. The primary analysis will be implemented as a statistical model using multiple 
imputation where the Subjects without any available HbA1c measurements at scheduled visits 
will have their change from baseline HbA1c value(s) 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. Subjects without post-randomisation 
measurements contribute to the analysis, as the missing values will be imputed. The analysis 
will be implemented as follows: 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
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Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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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 region and strata as factors and baseline HbA1c as covariate is fitted to the change in 
HbA1c from baseline to week 12 for each treatment group separately. The estimated 
parameters, and their variances, from these models are used to impute missing values at 
week 12 for Subjects in each treatment group, based on region, strata, and baseline HbA1c.
!
In the third step, for each of the 100 copies of the dataset, missing values at week 26 are 
imputed in the same way as for week 12. The imputations are based on an analysis of 
variance model with region and strata as factors and baseline HbA1c and HbA1c at week 12 
as covariates.
!
For each of the complete data sets, the change from baseline to week 26 is analysed using an 
analysis of variance model with treatment, region and strata as factors, and baseline HbA1c
as a covariate. 
!
The estimates and standard deviations for the 100 data sets are pooled to one estimate and 
associated standard deviation using Rubin’s formula:
m =
1
100 
 m,


SD =  1
100
 SD



+ 1 + 1
100
1
100 −1
(m −m)


,
!
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. 
All three objectives will be addressed by treatment differences and associated 95% confidence 
interval obtained from the same primary statistical model described above. 
Non-inferiority of meal-time fast-acting insulin aspart will be considered confirmed if the upper 
boundary of the two-sided 95% confidence interval 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 (meal-time fast-acting 
insulin aspart minus meal-time NovoRapid®). 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
12 of 27
If the primary objective is confirmed, the effect of treatment with post-meal fast-acting insulin 
aspart in terms of glycaemic control is to be investigated by showing that post-meal fast-acting 
insulin aspart is non-inferior to NovoRapid® both in combination with insulin degludec in terms of 
glucose lowering effect, as assessed by change from baseline in HbA1c 26 weeks after 
randomisation. This will be determined in the same way as above where treatment difference is set 
to (post-meal fast-acting insulin aspart minus meal-time NovoRapid®). 
Finally, if both the primary and the first secondary confirmatory hypotheses are fulfilled, the 
superiority of the meal-time fast-acting insulin aspart as compared to meal-time NovoRapid® will 
be tested in terms of glycaemic control. This will be assessed by comparing the upper limit of the 
95% CI from the primary analysis to 0. If the upper 95% CI is below 0 then superiority will be 
confirmed.
Sensitivity analyses for the primary analysis addressing the primary estimand
2) First, the primary analysis in 1) will be repeated, but excluding all factors except 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. The 
analysis will use the in-trial observation period.
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 withdrawing at own will 
or at the discretion of the Investigator. Therefore the statistical model using multiple imputation 
will be repeated with the following alterations:
a.
Imputation will be done from the treatment arm that the Subject was randomised to 
and a value of 0.4% (the non-inferiority margin) is added to the change in HbA1c at 
26 weeks for Subjects, on either of the fast-acting insulin aspart arms, with an 
imputed value at week 262. This will serve as a sensitivity analyses for the non-
inferiority analyses. The analysis will use the in trial observation period.
b. Imputation will be done from the comparator arm (NovoRapid ®). This will serve as a 
sensitivity analysis for the superiority analysis. The imputation will be done 
conditional on observed information for Subjects on fast-acting insulin aspart 
without a measurement at week 26 such that the treatment effect diminishes 
gradually (copy reference/conditional imputation). It does not rely on the MAR 
assumption, but assumes that Subjects on fast-acting insulin aspart without a 
measurement at week 26 switch to NovoRapid®. The analysis will use the in trial 
observation period.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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c.
Imputation will be done from the comparator arm (NovoRapid ®). This will serve as a 
supplementary sensitivity analysis for the superiority analysis. The imputation will 
be done with no regard to observed information for Subjects on fast-acting insulin 
aspart without a measurement at week 26 such that the treatment effect diminishes 
immediately (jump to reference/unconditional imputation). It does not rely on the 
MAR assumption, but assumes that Subjects on fast-acting insulin aspart without a 
measurement at week 26 switch to NovoRapid®. The analysis will use the in trial 
observation period. 
d. A tipping point analysis based on a statistical model using multiple imputations 
similar to 1), using the in trial 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 under investigation are given a penalty. Specifically, for 
treatment differences involving the meal-time fast-acting insulin aspart group, only 
Subjects in this group are given a penalty, and vice versa for treatment differences 
involving the postmeal fast-acting insulin aspart group. 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 under investigation 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 26 in the fast-acting insulin aspart group under 
investigation. This is done repeatedly, gradually increasing the penalty until the 
conclusions of the primary analysis no longer hold. The specific value of the penalty 
that changes the conclusion will be used to evaluate the robustness of the conclusion 
of the primary analysis. 
Analyses addressing the secondary estimand
4) The secondary estimand will be analysed using the same statistical model using multiple 
imputation as the primary analysis in 1) except using the on treatment observation period. The 
analysis will use the FAS.
5) A tipping point analysis based on a statistical model using multiple imputation, similar to 
sensitivity analysis 3)-d except using the on treatment observation period.
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 of Section 6.6 in the trial protocol) in the fast-acting insulin aspart 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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group under investigation 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. The analysis will use the on treatment observation period.
7) The same statistical model using multiple imputation as the primary 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 deviate from the ideal treatment during the on treatment 
observation period and will serve as a sensitivity analysis for the non-inferiority analysis.
2.4
Secondary endpoints
2.4.1
Supportive secondary endpoints
For all supportive secondary endpoints, meal-time fast-acting insulin aspart will be compared to 
meal-time NovoRapid®, and post-meal fast-acting insulin aspart will be compared to meal-time 
NovoRapid®. Change from baseline refers to the change from randomisation to 26 weeks after 
randomisation. 
2.4.1.1
Efficacy endpoints
All endpoints except insulin dose 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 will only be 
presented using the on treatment observation period.
The following endpoints will be assessed 26 weeks after randomisation: 
Change from baseline in 8-point profiles. 
PPG increments based on the 8-point profiles will be derived separately for plasma glucose 
(PG) measurements made 1 hour after the meal. In the following section this distinction will 
be considered implicit and without further explanation. PPG will be recorded by the Subject
as part of two 8-point profiles prior to the visits. PPG increment for each meal (breakfast, 
lunch, main evening meal) will be derived from the 8-point 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 PPG increment over all 
meals will be derived as the mean of all corresponding mean meal increments.
!
Change from baseline in mean PPG and PPG increment over all three meals
Mean PPG and PPG increment will be analysed separately using a model similar to 1), 
except with the corresponding baseline value as covariate.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
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Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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!
Change from baseline in individual meal (breakfast, lunch and main evening meal) 
PPG and PPG increment from 8-point profile
PPG and PPG increment endpoints for the individual meals (breakfast, lunch, main 
evening meal) will be analysed separately using a model similar to 1) except with the 
corresponding baseline value as covariate.
!
Change from baseline in mean of the 8-point profile
The mean of the 8-point profile is defined as the area under the profile divided by the 
measurement time, and is calculated using the trapezoidal method. Mean of the 8-point 
profile will be analysed using a model similar to 1) except with the corresponding 
baseline value as covariate.
!
Fluctuation in 8-point profile
The fluctuation in the 8-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. Fluctuation in the 8-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 values 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 from baseline in FPG
Change from baseline in FPG will be analysed using a model similar to 1) except with 
baseline FPG as covariate.
!
Change from baseline in 1,5-anhydroglucitol 
Change from baseline in 1,5-anhydroglucitol will be using a model similar to 1) except with 
baseline 1,5-anhydroglucitol as covariate.
!
Percentage of Subjects reaching HbA1c target (HbA1c <7.5%) according to ISPAD 
guidelines3
This dichotomous (responder/non-responder) endpoint will be defined based on whether a 
Subject has met the ISPAD HbA1c target (HbA1c < 7.5%) 26 weeks after randomisation.  
This responder endpoint will be analysed based on a logistic regression model using 
treatment, region and strata as factors, and baseline HbA1c as covariate. In the in trial 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
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Trial ID: NN1218-4101
Version:
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UTN: U1111-1158-1170
Status:
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observation period analysis, Subjects withdrawn from trial are included as non-responders. 
In the on treatment observation period analysis, both Subjects who prematurely discontinue 
fast-acting insulin aspart/NovoRapid® or withdraw from trial are included as non-
responders. Subjects without HbA1c at week 26 will be treated as non-responders for both 
the in trial and on treatment observation period analyses.
!
Percentage of Subjects reaching HbA1c target (HbA1c <7.5%) according to ISPAD 
guidelines, without severe hypoglycaemia3.
This dichotomous (responder/non-responder) endpoint will be defined based on whether a 
Subject has met the ISPAD HbA1c target (HbA1c < 7.5%) 26 weeks after randomisation 
without treatment emergent severe hypoglycaemic episodes3. 
This responder endpoint will be analysed based on a logistic regression model using 
treatment, region and strata as factors, and baseline HbA1c as covariate. In the in trial 
observation period analysis, Subjects withdrawn from trial are included as non-responders. 
In the on treatment observation period analysis, both Subjects who prematurely discontinue 
fast-acting insulin aspart/NovoRapid® or withdraw from trial are included as non-
responders. Subjects without HbA1c at week 26, will be treated as non-responders for both 
the in trial and on treatment observation period analyses.
!
Insulin dose (total basal, total bolus and individual meals insulin dose). 
Bolus insulin doses will be recorded together with time of administration. 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). Insulin doses will be summarised using the on treatment observation period and 
using the SAS.
Supportive secondary CGM related efficacy endpoints
The following endpoints will be assessed 26 weeks after randomisation:
!
Change from baseline of time spent in low interstitial glucose (IG) (IG ≤ 3.9 mmol/L [70 
mg/dL])
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 from the first valid sensor value divided by the actual 
duration of the entire profile. To report the endpoint in minutes per 24 hours the ratio is multiplied 
by 1440. The endpoint will be analysed using an analysis of variance model including treatment, 
region and strata as factors and the baseline value of time in low IG as covariate.
!
Incidence of episodes and percentage of time spent with IG ≤2.5, 3.0, 3.9 mmol/l [45, 54, 70 
mg/dL]) and IG >10.0, 12.0, 13.9 mmol/l [180, 216, 250 mg/dL]) 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
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!
Percentage of time spent within IG target range 4.0-10.0 mmol/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.
IG measurements during meal test will be excluded. 
All CGM endpoints will be summarised descriptively by treatment.
Supportive secondary CGM and meal-characteristics efficacy endpoints 
The following endpoints will be assessed 26 weeks after randomisation:
Change from baseline in meal characteristics of IG profile (4 hours after start of each meal), 
measured as:
!
Change from baseline in mean IG increment (0-1 hours 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 1 hours (or 2 hours, respectively) after the meal and IG 
before the meal
!
Change from baseline in mean IG peak after start of meal
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
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Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
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EudraCT No.: 2014-002568-33
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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. The endpoints will be analysed 
separately, using an analysis of variance model including treatment, region and strata as factors and 
the corresponding baseline value as covariate.
All CGM endpoints will be summarised descriptively by treatment.
Supportive secondary meal test related efficacy endpoints
The following endpoints will be assessed 26 weeks after randomisation:
!
Change from baseline in 30-min PPG and PPG increment
!
Change from baseline in 1-hour PPG and PPG increment
!
Change from baseline in 2-hour PPG and PPG increment
Laboratory measured plasma glucose from the meal test will be analysed for 30-min, 1-hour and 2-
hour PPG separately. The corresponding PPG increments will be derived separately using each PPG 
measurement minus the pre-prandial PG.
Change from baseline 26 weeks after randomisation in PPG and PPG increment endpoints will be 
analysed separately using an analysis of variance model including treatment, region and strata as 
factors and the corresponding baseline value as covariate.
All PPG endpoints will be summarised descriptively by treatment.
Supportive secondary CGM and meal test related efficacy endpoints
Endpoints listed below will be assessed during meal test and based on CGM measurements.
The following endpoints will be assessed 26 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
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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!
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 area 
under the IG curve using the trapezoidal method and weighted by duration. The endpoint will also 
be calculated as increment where an average of the IG concentrations immediately before the meal 
is subtracted from the weighted AUC. Each endpoint will be analysed using an analysis of variance 
model including treatment, region and strata as factors and the corresponding baseline value as 
covariate. 
IG peak and time to IG peak 26 weeks after randomisation will be compared separately between 
treatments using an analysis of variance model including treatment, region and strata as factors and 
with the corresponding baseline value as covariate. 
All CGM endpoints will be summarised descriptively by treatment.
2.4.1.2
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. 
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 treatment with investigational medicinal product 
(IMP) after randomisation, and no later than 1 day after the last day on IMP.
Nocturnal hypoglycaemic episodes: are episodes occurring between 23:00 and 07.00 both inclusive.
Hypoglycaemic episodes are classified according to ISPAD’s definition of severe hypoglycaemia4, 
as well as Novo Nordisk classification of hypoglycaemia (see Figure 2–1) and the ADA 
classification of hypoglycaemia5 (see Figure 2–2).
Novo Nordisk classification of hypoglycaemia in paediatrics
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L (56 
mg/dL)6. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-off 
point in the definition of blood glucose (BG) confirmed hypoglycaemia.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
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Novo Nordisk uses the following classification (see Figure 2–1) in addition to the ADA 
classification: 
!
Severe hypoglycaemia according to the ISPAD classification4: Was the hypoglycaemic 
episode associated with severe neuroglycopenia, usually resulting in coma or seizure and 
requiring parenteral therapy (glucagon or intravenous glucose)?
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
< 3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by PG value 
< 3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according 
to the ISPAD classification4 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with
symptoms consistent with hypoglycaemia. 
!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a PG value < 3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
!
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ISPAD 
classification4 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with or without
symptoms consistent with hypoglycaemia. 
Hypo-
glycaemic
episode
SMBG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomatic BG 
confirmed 
hypoglycaemia
No
Yes
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Severe 
hypoglycaemia
(ISPAD 2014)
Was the 
hypoglycaemic 
episode 
associated with 
severe 
neuroglyco-
penia, usually 
resulting in 
coma or seizure 
and requiring 
parenteral 
therapy 
(glucagon or 
intravenous 
glucose)?
Figure 2–1 Novo Nordisk classification of hypoglycaemia in paediatrics
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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ADA5/ISPAD classification of hypoglycaemia in paediatrics
!
Severe hypoglycaemia according to the ISPAD classification4: Was the hypoglycaemic 
episode associated with severe neuroglycopenia, usually resulting in coma or seizure and 
requiring parenteral therapy (glucagon or intravenous glucose)?
!
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).
Hypo-
glycaemic 
episode 
SMBG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
Yes
No
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
Was the 
hypoglycaemic 
episode 
associated with 
severe 
neuroglyco-
penia, usually 
resulting in 
coma or seizure 
and requiring 
parenteral 
therapy 
(glucagon or 
intravenous 
glucose)?
Severe 
hypoglycaemia
(ISPAD 2014)
Figure 2–2
ADA/ISPAD classification of hypoglycaemia in paediatrics
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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The following safety endpoints will be assessed:
!
Number of treatment emergent hypoglycaemic episodes
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
!
Number of treatment emergent hypoglycaemic episodes subdivided into daytime and 
nocturnal (23:00-7:00, both included) 
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
!
Number of treatment emergent meal related (from start of meal until 1, 2, and 4 hours after 
start of meal and from 1 [exclusive] to 2 hours [inclusive], 2 [exclusive] to 3 hours 
[inclusive], 3 [exclusive] to 4 hours [inclusive], and from 2 hours [exclusive] to 4 hours 
[inclusive] after start of meal, respectively) hypoglycaemic episodes 
!
According to ADA/ISPAD classification
!
According to Novo Nordisk/ISPAD classification
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 (the ISPAD criterion for severe hypoglycaemia 4) considering all episodes, 
nocturnal and daytime episodes using Novo Nordisk and ADA classified episodes. Episodes will 
also be summarised overall and by category in relation to time since start of meal, as occurring 
within the following time intervals: 
!
During first 1, 2, and 4 hours after start of 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 hours (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) will be analysed using a negative binomial regression model with a log -link function and 
the logarithm of the time period for which a hypoglycaemic episode is considered treatment 
emergent as offset. The model will include treatment, region and strata as factors, and will be based 
on the FAS. To the extent where data allow, separate analyses will be performed for severe episodes 
(all).
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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!
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 7 days after the last day of 
randomised treatment. 
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 Subjects years of 
exposure. These summaries are done by seriousness, severity, relation to insulin treatment, relation 
to device, withdrawal due to AEs and outcome.
Furthermore summary tables based on system organ class and preferred term 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 injection site reactions 
Injection site reactions occurring during the trial, related to either basal and/or bolus insulin will be 
summarised and listed. No formal statistical analysis will be made.
!
Change from baseline in clinical evaluations
!
Physical examination (head, ears, eyes, nose, throat, neck, respiratory system, 
cardiovascular system, gastrointestinal system incl. mouth, musculoskeletal system, 
central and peripheral nervous system, skin, Tanner stage) 
The physical examination parameters, and their change from baseline, will be 
summarised descriptively in shift tables. All findings will be listed. 
!
Vital signs (blood pressure, pulse)
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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Vital signs include diastolic blood pressure, systolic blood pressure and pulse. The 
measurements and their change from baseline will be summarised descriptively. 
!
Change from baseline in body weight, height, body mass index (BMI) and SD-score of body 
weight and BMI (z-score)
SD-scores are defined to be able to normalise the body weight in the various age groups. To 
estimate the growth of children, standardised weight is calculated for each year of age and 
for each sex. Thus, a child with a weight equal to the mean value for its age and sex has an 
SD score of 0, while a child with a weight 2 SDs above the mean value for its age and sex 
has an SD score of +2. The SD scores are derived from the age and sex of the Subjects and 
the body weight together with growth curves defined for a reference population. SD scores 
for BMI will be determined in a similar way as SD scores for weight by use of a suitable
reference population based on age and sex. For all countries except Japan and India the 
reference values for the US will be used. The SD scores for Japanese Subjects will be based 
on country specific references whereas SD scores for Indian Subjects below 5 years of age 
will be based on World Health Organization (WHO) references and otherwise country 
specific references.
The measurements and their change from baseline will be summarised descriptively. In 
addition, the endpoints will be analysed separately using a statistical model using multiple 
imputation similar to 1) including treatment, region and age group as factors and the 
corresponding baseline measurement as covariate. The analyses will be based on the SAS
and the on treatment observation period.
!
Change from baseline in laboratory assessments 
!
Haematology (haemoglobin, haematocrit, erythrocytes, thrombocytes, and 
leucocytes)
!
Biochemistry (creatinine, , alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (AP), sodium, potassium, albumin, 
and total bilirubin)
!
Lipid profile (total cholesterol, high density lipoprotein (HDL), low density 
lipoproteins (LDL))
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.
Lipid endpoints (LDL, HDL, and total cholesterol) will be log-transformed and analysed separately 
using a statistical model using multiple imputation similar to 1) including treatment, region and 
strata as factors and the corresponding log-transformed baseline measurement as covariate. The 
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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analyses will be based the FAS and the in trial observation period and repeated using the on 
treatment observation period. 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. 
NovoRapid® will be used as reference.
!
Change from baseline in anti-insulin aspart (specific and cross-reacting with human insulin)
antibody development
The measurements and their change from baseline will be summarised descriptively. The 
correlation to other relevant variables such as insulin dose and HbA1c are illustrated using graphs.
3
Changes to the statistical analyses planned in the protocol
Minor editorial corrections have been made throughout the document.
General considerations
As a consequence of the small number of Subjects below 3 years of age included in the trial, the 
text “Selected tables and figures will also be presented by strata (age).” is changed to Selected 
tables and figures will also be presented by age group, where age group refers to the following 
categorisation of age: 1 ≤ age < 6 years, 6 ≤ age < 12 years and 12 ≤ age < 18 years.
Statistical analysis
In the sensitivity analysis 2) for change from baseline in HbA1c, It has been clarified that baseline 
HbA1c is included in the model as a covariate. 
The descriptions of sensitivity analyses have been revised to clarify that all Subjects without a 
measurement at week 26 (not subjects withdrawing from trial in general) should have their values 
imputed. The new description is aligned with the primary analysis.
In order to emphasize the difference between sensitivity analyses 3)-b and 3)-c the wording have 
been rearranged.
The tipping point analyses have been described in more detail and tipping point analysis 5) has been 
repeated for the in trial observation period in the additional sensitivity analyses 3)-d.
In the statistical analysis for percentage of Subjects reaching HbA1c target, it has been clarified that 
Subjects without an HbA1c measurement at week 26 will be handled as non-responders for analyses 
on both the in trial and on treatment observation periods.
In the statistical analysis for percentage of Subjects reaching HbA1c target without severe 
hypoglycaemia, it has been clarified that Subjects without an HbA1c measurement at week 26 will 
be handled as non-responders for analyses on both the in trial and on treatment observation periods.
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
26 of 27
Fluctuation in 8-point
In the analysis of fluctuation of the 8-point self-measured plasma glucose (SMPG) profile “Change 
from baseline” has been removed. This is done because data are logarithmically transformed and 
change from baseline potentially include negative values.
CGM endpoints
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. Likewise mean, variation, and CV% has been 
added to further evaluate the effect and safety of fast-acting insulin aspart.
In order to align with previous trials the endpoints IG peak and time to IG peak will be analysed 
using an analysis of variance model including treatment, region and strata as factors and the 
corresponding baseline value as covariate. Consequently, the sentence “An additive model will be 
used to estimate the treatment means and treatment differences with a 95% confidence interval.” 
has been deleted.
AEs where additional information is recorded
For AEs where additional information is recorded, this will only be listed.
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.
Change from baseline in body weight, height, body mass index (BMI) and SD-score of body 
weight and BMI (z-score)
In order to align with previous trials, analyses of change from baseline in body weight, height, body 
mass index (BMI) and SD-score of body weight and BMI (z-score) will be based on the safety 
analysis set and the on treatment observation period. 
It has been specified that for all countries except Japan and India the reference values for the US 
will be used to calculate SD-scores for weight and BMI. The SD scores for Japanese Subjects will 
be based on country specific references whereas SD scores for Indian Subjects below 5 years of age 
will be based on WHO references and otherwise country specific references.
Lipid endpoints
In order to align with previous trials, the analyses of lipid endpoints will be based on FAS and the in 
trial observation period and repeated using the on treatment observation period .
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
18 January 2018
1RYR1RUGLVN
Trial ID: NN1218-4101
Version:
1.0
UTN: U1111-1158-1170
Status:
Final
EudraCT No.: 2014-002568-33
Page:
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4
References
1.
ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International 
Conference on Harmonisation E9 Expert Working Group. Stat Med. 1999;18(15):1905-42.
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.
Rewers MJ, Pillay K, de Beaufort C, Craig ME, Hanas R, Acerini CL, et al. ISPAD Clinical 
Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in 
children and adolescents with diabetes. Pediatr Diabetes. 2014;15 Suppl 20:102-14.
4.
International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice 
Consensus Guidelines 2014 Compendium. Pediatr Diabetes. 2014;15 Suppl. 20:1-290.
5.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
6.
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.
CONFIDENTIAL