Clinical trial NCT04588259
Conditions: Diabetes Mellitus, Type 1 Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2020-10-09; Completion date: 2022-08-05
Enrollment: 331 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Fast-acting insulin aspart (faster aspart) will be tested to see how well it works and if it is safe. The study compares 2 medicines for type 1 and type 2 diabetes - faster aspart (a new medicine) and insulin aspart (a medicine doctors can already prescribe). Participants will either get faster aspart or insulin aspart (NovoRapid®) - which treatment is decided by chance. Both medicines will be taken together with insulin degludec. Participants will need to take 1 injection 4 times every day: 3 injections 0-2 minutes before breakfast, lunch and dinner and 1 injection at the same time every day. All study medicines are provided in pens. A pen is a tool to inject insulin under the skin.The study will last for about 7 months (30 weeks). Participants will have 11 clinic visits and 17 phone contacts with the study doctor. At 8 clinic visits participants will have blood samples taken. At 3 clinic visits participants cannot eat or drink (water is allowed) 8 hours before the visits - at 2 of these visits participants will be asked to drink a liquid meal and to stay at the clinic for about 5 hours. Participants will fill in a diary the last 3 days before the visits/phone contacts. Women cannot take part if pregnant, breast-feeding or planning to become pregnant during the study period.

Detailed description:

Arms: arm 1: 4 daily injections of faster aspart given with insulin degludec and with or without metformin arm 2: 4 daily injections of insulin aspart given with insulin degludec and with or without metformin
Interventions: intervention 1: Faster aspart intervention 2: Insulin aspart intervention 3: Insulin degludec
Intervention descriptions: intervention 1: Administered s.c. (subcutaneously, under the skin) for 16 weeks intervention 2: Administered s.c. (subcutaneously, under the skin) for 16 weeks intervention 3: Administered s.c. (subcutaneously, under the skin) for 16 weeks

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04588259 
Sponsor trial ID: 
NN1218-4357 
Official title of study: 
Efficacy and Safety of Fast-acting Insulin Aspart Compared to 
NovoRapid® both in Combination with Insulin Degludec with 
or without Metformin in Adults with Diabetes 
Document date: 
30 November 2020 
 
* Document date refers to the date on which the document was most recently updated. 
Note: The date in the header of page 2 is the date of compilation of the documents and not of an 
update to content. 




Protocol
Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
UTN: U1111-1197-8289
Status:
Final 
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Protocol version 5.0 including:
Protocol Amendment No 3 to final protocol version 4.0, dated 3rd April
2020
Trial ID: NN1218-4357
Efficacy and Safety of Fast-acting Insulin Aspart 
Compared to NovoRapid® both in Combination with Insulin 
Degludec with or without Metformin in Adults with Diabetes
Trial phase: 3a
China trial
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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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
Date:
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Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
UTN: U1111-1197-8289
Status:
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Protocol amendment summary of changes table
DOCUMENT HISTORY
Document version
Date
Applicable in country(-ies) and/or 
site(s) 
Protocol version 4.0
03 April 2020
China
Protocol version 3.0
01 July 2019
China
Protocol version 2.0
01 December 2017
China
Original protocol version 1.0
24 October 2017
China
Overall rationale for preparing protocol, version 5.0
The overall primary rationale for updating the protocol was due to an error discovered in the 
Titration Guideline a1. In addition, minor updates to the protocol were implemented as outlined 
below. 
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Trial ID: NN1218-4357
Version:
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UTN: U1111-1197-8289
Status:
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Section # and name
Description of change
Brief rationale
Section 2 Flowchart
Deleted X for 4 point profile at visit 
2
The subjects will receive blood 
glucose meter at visit 2 and hence 
will not be able to perform 4 point 
profile prior to visit 2.
Section 2 Flowchart
Deleted X for Medication Error at 
V27 and P28
Medication Error should not be 
reported because the trial treatment 
has ended.
Section 2 Flowchart
Added footnote (f) for V10 ECG
Updated to align with timelines for 
ECG similar to visit 26.
Section 2 Flowchart
Deleted X for Drug Accountability at 
visit 9 
Visit 9 this is not a dispensing visit 
and the subjects are not supposed to 
bring their trial product to the site at 
this visit, unless they do not continue 
in the trial.
Section 2 Flowchart
Footer description for footer f 
updated.
Text deleted to also cover visit 10 
ECG.
Section 8.4.2 Hypoglycaemic 
episodes
Deleted text regarding reporting of 
hypoglycaemic episodes between 
visit 27 and phone visit 28.
Data on hypoglycaemic episodes 
between follow-up visit 1 (visit 27) 
and follow-up visit 2 (phone visit 28) 
is not collected since the subjects are 
using commercially obtained 
medication for which hypoglycaemic 
episodes should not be reported in 
the trial.
Section 8.4.4 Electrocardiogram 
(ECG)
Inserted visit 10
Updated to align with timelines for 
ECG similar to visit 26.
Section 8.5.2 Laboratory 
assessments for safety
Updated abbreviation of AST from 
Aspartate phosphatase to Aspartate 
aminotransferase. 
Updated to be aligned throughout the 
protocol.
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Trial ID: NN1218-4357
Version:
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UTN: U1111-1197-8289
Status:
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Appendix A1: Insulin Titration 
Guideline for T1DM subjects, Table 
3
Updated table 3 as follows: Calculate 
the total daily dose of insulin. Adjust 
the basal-to-bolus ratio to be 
between 40:60 and 60:40. Use table
2 to find the total number of bolus 
insulin units and divide this value 
into three even or uneven doses of 
NovoRapid® to be taken with 
breakfast, lunch and dinner. 
Calculate the daily bolus units from 
the bolus component of the total 
daily dose. Divide the calculated 
number into three even or uneven
doses of NovoRapid® to be taken 
with breakfast, lunch and dinner.
Updated to correct bolus insulin dose 
calculation.
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30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
UTN: U1111-1197-8289
Status:
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Table of contents
Page
Protocol amendment summary of changes table...........................................................................................2 
Table of contents...............................................................................................................................................5 
Table of figures.................................................................................................................................................9 
Table of tables.................................................................................................................................................10 
List of abbreviations.......................................................................................................................................11 
1 
Summary..................................................................................................................................................12 
2 
Flowchart .................................................................................................................................................15 
3 
Background information and rationale for the trial............................................................................21 
3.1 
Background information..............................................................................................................21 
3.1.1 
Therapeutic area.........................................................................................................21 
3.1.2 
NovoRapid® (Insulin aspart)......................................................................................22 
3.1.3 
Fast-acting insulin aspart ...........................................................................................22 
3.1.4 
Insulin Degludec........................................................................................................24 
3.2 
Rationale for the trial ...................................................................................................................24 
4 
Objectives and endpoints........................................................................................................................25 
4.1 
Objectives ....................................................................................................................................25 
4.1.1 
Primary objective.......................................................................................................25 
4.1.2 
Secondary objective...................................................................................................25 
4.1.3 
Primary estimand.......................................................................................................25 
4.2 
Endpoints .....................................................................................................................................25 
4.2.1 
Primary endpoint........................................................................................................25 
4.2.2 
Secondary endpoints..................................................................................................25 
4.2.2.1 
Supportive secondary efficacy endpoints............................................25 
4.2.2.2 
Supportive secondary safety endpoints ...............................................26 
5 
Trial design ..............................................................................................................................................27 
5.1 
Type of trial .................................................................................................................................27 
5.2 
Rationale for trial design..............................................................................................................28 
5.2.1 
Rationale for choice of non-inferiority margin..........................................................28 
5.3 
Treatment of subjects...................................................................................................................29 
5.4 
Treatment after discontinuation of trial product ..........................................................................30 
5.5 
Rationale for treatment ................................................................................................................30 
6 
Trial population.......................................................................................................................................31 
6.1 
Number of subjects ......................................................................................................................31 
6.2 
Inclusion criteria ..........................................................................................................................31 
6.3 
Exclusion criteria.........................................................................................................................32 
6.4 
Run-in period exclusion criteria...................................................................................................33 
6.5 
Randomisation criterion...............................................................................................................33 
6.6 
Criteria for premature discontinuation of trial products ..............................................................33 
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6.7 
Withdrawal from trial ..................................................................................................................34 
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 
Screening (V1)...........................................................................................................37 
8.1.2 
Run-in (V2)................................................................................................................38 
8.1.3 
Randomisation (V10).................................................................................................39 
8.1.4 
Phone contacts ...........................................................................................................39 
8.1.5 
Fasting visits ..............................................................................................................39 
8.1.6 
Rescheduled visits......................................................................................................39 
8.1.7 
End of treatment (V26)..............................................................................................39 
8.1.8 
Follow-up period........................................................................................................39 
8.1.9 
Premature discontinuation of trial products...............................................................40 
8.1.10 
Withdrawal from trial ................................................................................................41 
8.1.10.1 
Lost to follow-up.................................................................................41 
8.1.11 
Review of results .......................................................................................................42 
8.2 
Subject related information/assessments .....................................................................................42 
8.2.1 
Demography...............................................................................................................42 
8.2.2 
Diabetes history .........................................................................................................43 
8.2.3 
Hypoglycaemia unawareness.....................................................................................43 
8.2.4 
Concomitant illness and medical history ...................................................................43 
8.2.5 
Concomitant medication............................................................................................44 
8.2.6 
Concomitant medication (diabetes) ...........................................................................44 
8.2.7 
Childbearing potential................................................................................................45 
8.2.8 
Tobacco use ...............................................................................................................45 
8.3 
Efficacy assessments....................................................................................................................45 
8.3.1 
Meal test.....................................................................................................................45 
8.3.2 
Self-measured plasma glucose...................................................................................48 
8.3.3 
Insulin dose................................................................................................................50 
8.4 
Safety assessments.......................................................................................................................51 
8.4.1 
Adverse events...........................................................................................................51 
8.4.1.1 
Medication error..................................................................................51 
8.4.1.2 
Adverse events requiring additional data collection ...........................51 
8.4.2 
Hypoglycaemic episodes ...........................................................................................52 
8.4.3 
Eye examination ........................................................................................................55 
8.4.4 
Electrocardiogram (ECG)..........................................................................................55 
8.4.5 
Body Measurements ..................................................................................................56 
8.4.6 
Physical examination.................................................................................................56 
8.4.7 
Vital signs ..................................................................................................................56 
8.5 
Laboratory assessments ...............................................................................................................56 
8.5.1 
Laboratory assessments for efficacy..........................................................................57 
8.5.2 
Laboratory assessments for safety .............................................................................58 
8.6 
Other assessments........................................................................................................................59 
8.6.1 
Training in the pen-injector .......................................................................................59 
8.6.2 
Diary ..........................................................................................................................59 
8.7 
Subject compliance......................................................................................................................59 
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Version:
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9 
Trial supplies ...........................................................................................................................................61 
9.1 
Trial products...............................................................................................................................61 
9.2 
Labelling......................................................................................................................................61 
9.3 
Storage .........................................................................................................................................62 
9.4 
Drug accountability and destruction ............................................................................................62 
9.5 
Auxiliary supplies........................................................................................................................63 
10 Interactive web response system............................................................................................................64 
11 Randomisation procedure and breaking of blinded codes ..................................................................64 
11.1 
Breaking of blinded codes ...........................................................................................................64 
12 Adverse events, and technical complaints and pregnancies................................................................65 
12.1 
Definitions ...................................................................................................................................65 
12.1.1 
Adverse event ............................................................................................................65 
12.1.2 
Serious adverse event.................................................................................................66 
12.1.3 
Non-serious adverse event.........................................................................................67 
12.1.4 
Medication errors.......................................................................................................67 
12.1.5 
Adverse events requiring additional data collection..................................................67 
12.1.6 
Technical complaints.................................................................................................68 
12.2 
Reporting of adverse events.........................................................................................................68 
12.3 
Follow-up of adverse events........................................................................................................70 
12.4 
Technical complaints and technical complaint samples ..............................................................71 
12.4.1 
Reporting of technical complaints .............................................................................71 
12.4.2 
Collection, storage and shipment of technical complaint samples ............................72 
12.5 
Pregnancies..................................................................................................................................72 
12.5.1 
Pregnancies in female subjects ..................................................................................72 
12.6 
Precautions and/or overdose ........................................................................................................74 
12.7 
Committees related to safety........................................................................................................74 
12.7.1 
Novo Nordisk safety committee ................................................................................74 
13 Case report forms....................................................................................................................................75 
13.1 
Corrections to case report forms..................................................................................................75 
13.2 
Case report form flow..................................................................................................................76 
14 Monitoring procedures ...........................................................................................................................76 
15 Data management....................................................................................................................................78 
16 Computerised systems.............................................................................................................................78 
17 Statistical considerations ........................................................................................................................79 
17.1 
Sample size calculation................................................................................................................79 
17.2 
Definition of analysis sets............................................................................................................80 
17.3 
Primary endpoint..........................................................................................................................81 
17.4 
Secondary endpoints....................................................................................................................82 
17.4.1 
Supportive secondary endpoints ................................................................................82 
17.4.1.1 
Efficacy endpoints...............................................................................82 
17.4.1.2 
Safety endpoints..................................................................................86 
18 Ethics........................................................................................................................................................91 
18.1 
Benefit-risk assessment of the trial..............................................................................................91 
18.2 
Informed consent .........................................................................................................................93 
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Trial ID: NN1218-4357
Version:
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UTN: U1111-1197-8289
Status:
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Table of figures 
Page
Figure 5–1 
Trial design.............................................................................................................................27 
Figure 12–1 
Reporting of AEs....................................................................................................................69 
Figure 17–1 
Novo Nordisk classification of hypoglycaemia......................................................................87 
Figure 17–2 
ADA classification of hypoglycaemia....................................................................................88 
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Table of tables
Page
Table 8–1 
Meal test schedule...................................................................................................................47 
Table 8–2 
7-point SMPG profiles with additional 9-point SMPG profile...............................................50 
Table 9–1 
Trial products (IMPs) .............................................................................................................61 
Table 9–2 
Storage conditions ..................................................................................................................62 
Table 17–1  
The power for non-inferiority for different scenarios.............................................................80 
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List of abbreviations
ADA
American Diabetes Association
IEC
independent ethics committee
AE
adverse event
IMP
investigational medicinal product
ALT
alanine aminotransferase
IRB
institutional review board
AST
aspartate aminotransferase
IWRS
interactive web response system
BG
blood glucose
LDL
low-density lipoprotein
CDS
Chinese Diabetes Society
LSFV
last subject first visit
CFDA
China Food and Drug administration
LSLV
last subject last visit
CRO
contract research organisation
NYHA
New York Heart Association
CTR
clinical trial report
OAD
oral antidiabetic drug
DUN
dispensing unit number
PCD
primary completion date
ECG
electrocardiogram
PG
plasma glucose
eCRF
electronic case report form
PPG
post prandial glucose
EASD
European Association for the Study of 
Diabetes
SAE
serious adverse event
EMA
European Medicines Agency
s.c.
subcutaneous(ly)
FAS
full analysis set
SD
Standard deviation
FDA
U.S. Food and Drug Administration
SmPC
summary of product characteristics
FPG
fasting plasma glucose
SMPG
self-measured plasma glucose
FSFV
first subject first visit
SUSAR
suspected unexpected serious adverse 
reaction
GCP
Good Clinical Practice
T1DM
Type 1 diabetes mellitus
HbA1c
glycosylated haemoglobin
T2DM
Type 2 diabetes mellitus
hCG
human chorionic gonadotrophin
TEAE
treatment emergent adverse event
HDL
high-density lipoprotein
TMM
Trial Materials Manual
IB
Investigators Brochure
UTN
Universal Trial Number
ICH
International Conference on 
Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medical 
Journal Editors
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Version:
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1
Summary
Objectives and endpoints:
Primary objective:
To confirm the effect in terms of glycaemic control of treatment with fast-acting insulin aspart 
compared to NovoRapid® both in combination with insulin degludec with or without metformin in 
Chinese adults with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM)
inadequately treated with a basal-bolus or a premix regimen, using a non-inferiority approach.
Secondary objective:
To compare the safety of fast-acting insulin aspart to NovoRapid® both in combination with insulin 
degludec with or without metformin in Chinese adults with T1DM or T2DM inadequately treated 
with a basal-bolus or a premix regimen.
Primary endpoint:
Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) to 16 weeks after 
randomisation.
Secondary endpoints:
Supportive secondary efficacy endpoints:
x
Change from baseline in 30- minutes, 1- hour, 2- hour and 3- hour post prandial glucose (PPG)
increment to 16 weeks after randomisation (meal test)
x
Change from baseline in 30- minutes, 1- hour, 2- hour and 3- hour PPG to 16 weeks after 
randomisation (meal test)
x
Change from baseline in fasting plasma glucose (FPG) to 16 weeks after randomisation
x
If a subject achieves HbA1c target 16 weeks after randomisation:
x
HbA1c < 7.0%
x
HbA1c < 7.0% without severe hypoglycaemia
x
Change from baseline in 7-9-7-point self-measured plasma glucose (SMPG) to 16 weeks after 
randomisation:
x
Mean of the 7-9-7-point profile
x
1-hour PPG and PPG increment (mean, breakfast, lunch, main evening meal)
x
Fluctuation in 7-9-7-point profile
x
If a subject achieves PPG target (overall mean of daily PPG measurements in SMPG) 16 weeks 
after randomisation:
x
Overall PPG (1-hour) ≤7.8 mmol/L
x
Overall PPG (1-hour) ≤7.8 mmol/L without severe hypoglycaemia
x
Insulin dose (Units/day and Units/kg/day; total basal, total bolus and individual meal insulin 
dose) 16 weeks after randomisation
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Status:
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Supportive secondary safety endpoints:
x
Number of treatment emergent adverse events during the 16 weeks after randomisation
x
Number of treatment emergent injection site reactions during the 16 weeks after randomisation
x
Number of treatment emergent hypoglycaemic episodes classified both according to the 
American Diabetes Association (ADA) definition and Novo Nordisk definition during the 16
weeks after randomisation
x
Overall
x
Daytime and nocturnal hypoglycaemic episodes (00:01-05:59 – both inclusive)
x
Hypoglycaemic episodes from start of meal until 30 minutes, 1, 2, 4 hours and from 2 hours 
(exclusive) to 4 hours (inclusive) after start of meal 
Trial design:
This is a phase 3a, 16-week, multicentre, 1:1 randomised, double-blind, active controlled, treat-to-
target, two-arm parallel group trial with an 8-week run-in period comparing the effect and safety of 
fast-acting insulin aspart to NovoRapid® both in combination with insulin degludec with or without 
metformin in subjects with T1DM or T2DM inadequately treated with a basal-bolus or a premix 
regimen. The trial includes two blinded dosing arms – mealtime fast-acting insulin aspart and 
mealtime NovoRapid®.
Trial population:
A total of 505 subjects are planned to be screened and 300 subjects are planned to be randomised.
Key inclusion criteria:
x
Male or female, age above or equal to18 years at the time of signing informed consent
x
Diagnosed with T1DM ≥ 1 year prior to screening or diagnosed with T2DM ≥5 years prior to 
of screening 
x
Treated with a basal-bolus insulin regimen or a premix insulin regimen ≥ 1 year prior to 
screening. Insulin regimen must be unchanged within 60 days prior to screening. A basal-bolus 
insulin regimen is defined as basal insulin once or twice daily and bolus insulin taken with 
meals at least thrice daily. A premix insulin regimen is defined as premix insulin twice or thrice
daily 
x
For subjects with T1DM: not treated with any oral anti-diabetes drugs (OADs) for at least 90 
days prior to screening
For subjects with T2DM: not treated with any OADs or treated with 1-2 OADs within 90 days 
prior to screening. Allowed OADs are metformin, alpha-glucosidase inhibitor, SGLT2i and 
DPP4i. Change in OAD and dose prior to screening is allowed.
x
HbA1c 7.5-9.5% (both inclusive) as assessed by central laboratory at screening
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Trial ID: NN1218-4357
Version:
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UTN: U1111-1197-8289
Status:
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Key exclusion criteria:
x
Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris
or transient ischaemic attack within the past 180 days prior to the day of screening 
x
Subjects presently classified as being in New York Heart Association (NYHA) Class IV 
x
Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
x
Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 90 days prior to the day of screening
x
Anticipated initiation or change in concomitant medications (for more than 14 consecutive days) 
known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or 
corticosteroids)
Randomisation criterion:
x
HbA1c ≤ 9.0% measured by the central laboratory at visit 9 (week -1)
Assessments:
x
HbA1c
x
PPG and PPG increment (meal test)
x
PPG and PPG increment (7-9-7-point SMPG)
x
Hypoglycaemic episodes
x
Adverse events (AEs)
Trial products:
Investigational medicinal products (IMPs):
x
Test products:
x
Fast-acting insulin aspart, 100 U/mL solution for s.c. injection, 3 mL PDS290 pen-injector
(blinded)
x
Insulin degludec (Tresiba®), 100 U/mL solution for s.c. injection, 3 mL PDS290 pen-
injector
x
Reference therapy:
x
Insulin aspart (NovoRapid®), 100 U/mL solution for s.c. injection, 3 mL PDS290 pen-
injector (blinded)
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki. 
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, may reduce 
the incidence of complications and delay the progression of existing complications in people with 
T1DM and T2DM.2, 3 Postprandial hyperglycaemia contributes significantly to the HbA1c level and 
its control is thus essential for achieving the HbA1c target level.4 Postprandial hyperglycaemia is 
associated with increased risk of micro- and macro-vascular complications.5 Lowering of 
postprandial hyperglycaemia may reduce the progression of atherosclerosis and cardiovascular 
events in patients with T2DM.6
Basal-bolus insulin therapy aims at mimicking the physiological insulin response in the healthy 
state to the largest possible extent. For that purpose, rapid-acting insulin analogues were developed 
to more effectively control the PPG excursions compared to subcutaneously injected human regular 
insulin, primarily through offering a faster onset and shorter duration of action. However, unmet 
needs exist within prandial insulin therapy for people with diabetes. The current insulin analogues 
are not able to match the speed of the normal physiological post meal insulin secretion, leading to 
suboptimal control of blood glucose, and an exogenous insulin with a faster glucose lowering effect 
is needed for tighter PPG control. In addition, 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.7
For an assessment of benefits and risks of the trial, see Section 18.1.
3.1.1
Therapeutic area
T1DM is a chronic disorder characterised by insulin deficiency and progressive complications due 
to hyperglycaemia. In T1DM a common treatment regimen is a basal-bolus therapy which was 
confirmed to be effective in reducing the incidence of late diabetic complications in the Diabetes 
Control and Complication Trial (DCCT).2 The ADA recommends an HbA1c target of less than 7.0% 
(<53 mmol/mol), without substantial hypoglycaemia.8
Due to the progressive nature of T2DM, many patients are likely to be candidates for intensified 
insulin therapy. Prandial insulin supplementation is recommended by European Association for the 
Study of Diabetes (EASD)/ADA guidelines9 for treatment intensification in patients with T2DM 
who do not reach an HbA1c target below 7.0% on oral antidiabetic drugs (OADs) and basal insulin 
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alone. The recommendation is a stepwise addition of bolus insulin when significant PPG excursions 
occur. A trial investigating step-wise addition of bolus insulin (basal-plus regimen) showed that 
around 75% of patients enrolled in the trial needed three boluses after 36 weeks of treatment in
order to achieve an HbA1c below 7.0%.10 Results from the PREFER11 trial indicated that one-third 
of the total prandial insulin dose is delivered with each meal in the majority of patients achieving 
HbA1c ≤7.0%. When used as part of a basal-bolus regimen in patients with T2DM who had 
previously received other insulin and/or OAD regimens, insulin aspart in combination with insulin 
degludec was a safe, well tolerated and effective treatment associated with clinically relevant 
reductions in hyperglycaemia.12
3.1.2
NovoRapid® (Insulin aspart)
Insulin aspart has been marketed in China since 2002, is marketed worldwide as NovoRapid® (US: 
NovoLog®) and is a rapid-acting insulin analogue indicated for the treatment of diabetes. In the 
remainder of this protocol, NovoRapid® will be applied as the trade name for insulin aspart in the 
marketed formulation.
NovoRapid® is homologous to human insulin, with the exception of the substitution of proline with 
aspartic acid at position B28. The rapid action of NovoRapid® is related to a weakened tendency of 
the insulin molecules to self-associate due to this modification and thereby is related to faster 
absorption as compared with regular human insulin. Compared with human insulin, NovoRapid®
has a faster onset and a shorter duration of action, resulting in superior postmeal glucose control by 
means of lowering total glucose excursion following a meal, both in subjects with T1DM13, 14 and in 
subjects with T2DM.15-17 This also allows NovoRapid® to be injected immediately before a meal, in 
contrast to regular human insulin which should be injected 30 minutes prior to the meal. For further 
details, please refer to the current version of the NovoRapid® local labelling.18, 19
3.1.3
Fast-acting insulin aspart
Fast-acting insulin aspart (hereafter referred to as faster aspart, marketed as Fiasp®) is an innovative 
formulation of insulin aspart with two additional excipients which results in an increased early 
absorption of insulin aspart following subcutaneous injection. This leads to a greater early glucose-
lowering effect compared to NovoRapid®.20 Faster aspart aims at approaching 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 aspart and NovoRapid® have shown that faster aspart resulted in 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 aspart also 
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resulted in a greater early glucose-lowering effect than NovoRapid®, but no statistically significant 
difference was found between faster aspart and NovoRapid® in total glucose-lowering effect.
In the global phase 3a programme, treatment with mealtime faster aspart effectively improved 
HbA1c in both subjects with T1DM and subjects with T2DM confirming non-inferiority between 
faster aspart and NovoRapid®. 21, 22 In a therapeutic confirmatory basal-bolus trial in adult subjects 
with T1DM, mealtime faster aspart in combination with insulin detemir effectively improved 
glycaemic control and the reduction in HbA1c was statistically significantly greater than with 
NovoRapid®. Mealtime faster aspart provided superior PPG control compared to 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 mealtime faster aspart. No 
statistically significant difference was seen in overall rate of severe or blood glucose (BG)
confirmed hypoglycaemic episodes between mealtime faster aspart and NovoRapid®. The rate 
during the first one hour after start of a meal, constituting a smaller fraction of all severe or BG 
confirmed hypoglycaemic episodes was statistically significantly higher for faster aspart compared 
to NovoRapid®. The overall safety profile for faster aspart and NovoRapid® was similar and as 
expected for insulin aspart. 
In a therapeutic confirmatory basal-bolus trial in adult subjects with T2DM, adding and titrating 
mealtime faster aspart in combination with insulin glargine also effectively improved glycaemic 
control. Non-inferiority to NovoRapid® regarding HbA1c change from baseline was confirmed. A 
statistically significant benefit in 2-hour PPG increment (meal test) could not be confirmed for 
faster aspart compared to NovoRapid®. A statistically significant difference was demonstrated for 
1-hour PPG increment (meal test) in favour of faster aspart compared to NovoRapid®. No 
statistically significant difference was seen in overall rate of severe or BG confirmed 
hypoglycaemic episodes between faster aspart and NovoRapid®. The rate during the first two hours 
after start of a meal, constituting a small fraction of all severe or BG confirmed hypoglycaemic 
episodes was statistically significantly higher for faster aspart compared to NovoRapid®. The 
overall safety profile for faster aspart and NovoRapid® was similar and as expected for insulin 
aspart.
Across the global phase 3a trials, faster aspart was well tolerated with similar safety profile as 
compared to NovoRapid®, with the most common adverse event being hypoglycaemia, similar to 
the levels observed with NovoRapid®.21, 23 The insulin aspart molecule has a well-known safety 
profile based on more than 19 years of clinical experience. Compared to NovoRapid® faster aspart 
contains excipients which results in a faster initial absorption of insulin aspart following 
subcutaneous injection. The added excipients are included in the U.S. Food and Drug 
Administration’s (FDA) list for approved drug products for injections, and no toxicological 
concerns have been predicted from subcutaneous use in humans at the proposed concentrations. For 
further details, please refer to the current edition of the Investigator’s Brochure (IB)24 and any 
updates hereof.
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At the time of this protocol issuance, faster aspart is approved in more than 40 countries including 
USA, the European Union, Australia, Canada, Switzerland, South Korea and India. Submission and 
approval processes are currently ongoing in multiple countries worldwide.
3.1.4
Insulin Degludec
Insulin degludec (marketed as Tresiba®) was approved in China in September 2017, and is a basal 
insulin with an ultra-long duration of action for once-daily subcutaneous administration at any time 
of the day, preferably at the same time every day. After subcutaneous injection, soluble and stable 
multi-hexamers are formed creating a depot of insulin in the subcutaneous tissue. Insulin degludec 
monomers gradually separate from the multihexamers 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.
For further details please refer to the current version of the Tresiba® local labelling. 25, 26
At the time of this protocol issuance, insulin degludec is approved in more than 90 countries
including US, all EU countries and Japan.
3.2
Rationale for the trial
The purpose of this trial is to confirm the effect and evaluate the safety of faster aspart compared to 
NovoRapid® both in combination with insulin degludec with or without metformin in Chinese 
subjects with T1DM or T2DM. 
In the European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA) and China 
Food and Drug administration (CFDA) 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 
endpoint.27-29
The results from this trial will be used in the registration file in China to document the efficacy and 
safety of faster aspart as meal time insulin in combination with basal insulin (basal-bolus regimen) 
in Chinese subjects with T1DM or T2DM. 
The trial is intended to confirm the effect of faster aspart by demonstrating non-inferiority (at 0.4 % 
level) of faster aspart compared to NovoRapid® in terms of glycaemic control and testing for
superiority of faster aspart in terms of glycaemic control in Chinese subjects with T1DM or T2DM.
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4
Objectives and endpoints
4.1
Objectives
4.1.1
Primary objective
To confirm the effect in terms of glycaemic control of treatment with faster aspart compared to 
NovoRapid® both in combination with insulin degludec with or without metformin in Chinese 
adults with T1DM or T2DM inadequately treated with a basal-bolus or a premix regimen, using a 
non-inferiority approach.
4.1.2
Secondary objective
To compare the safety of faster aspart to NovoRapid® both in combination with insulin degludec
with or without metformin in Chinese adults with T1DM or T2DM inadequately treated with a 
basal-bolus or a premix regimen.
4.1.3
Primary estimand
The primary estimand is defined as the treatment difference in change from baseline in HbA1c 16
weeks after randomisation between treatment with faster aspart and treatment with NovoRapid®
both in combination with insulin degludec with or without metformin in adult subjects with T1DM 
or T2DM on basal-bolus regimen with a basal optimisation if all had adhered to randomised 
treatment. This estimand aims to reflect the treatment effect for subjects that are actually able to 
take the drug during the intended treatment period.
4.2
Endpoints
Baseline is defined as randomisation (V10, week 0).
4.2.1
Primary endpoint
x
Change from baseline (week 0) in HbA1c to 16 weeks after randomisation
4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary efficacy endpoints
x
Change from baseline in 30-minutes, 1-hour, 2-hour and 3-hour PPG increment to 16 weeks 
after randomisation (meal test)
x
Change from baseline in 30-minutes, 1-hour, 2-hour and 3-hour PPG to 16 weeks after 
randomisation (meal test)
x
Change from baseline in FPG to 16 weeks after randomisation
x
If a subject achieves HbA1c target 16 weeks after randomisation:
x
HbA1c < 7.0%
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x
HbA1c < 7.0% without severe hypoglycaemia
x
Change from baseline in 7-9-7-point SMPG to 16 weeks after randomisation:
x
Mean of the 7-9-7-point profile
x
1-hour PPG and PPG increment (mean, breakfast, lunch, main evening meal)
x
Fluctuation in 7-9-7-point profile
x
If a subject achieves PPG target (overall mean of daily PPG measurements in SMPG) 16 weeks 
after randomisation:
x
Overall PPG (1-hour) ≤7.8 mmol/L
x
Overall PPG (1-hour) ≤7.8 mmol/L without severe hypoglycaemia
x
Insulin dose (Units/day and Units/kg/day; total basal, total bolus and individual meal insulin 
dose) 16 weeks after randomisation
4.2.2.2
Supportive secondary safety endpoints
x
Number of treatment emergent adverse events during the 16 weeks after randomisation
x
Number of treatment emergent injection site reactions during the 16 weeks after randomisation
x
Number of treatment emergent hypoglycaemic episodes classified both according to the ADA
definition and Novo Nordisk definition during the 16 weeks after randomisation
x
Overall
x
Daytime and nocturnal hypoglycaemic episodes (00:01-05:59 – both inclusive)
x
Hypoglycaemic episodes from start of meal until 30 minutes, 1, 2, 4 hours and from 2 hours 
(exclusive) to 4 hours (inclusive) after start of meal
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period. All subjects eligible for the trial will receive the basal insulin degludec once daily. After the 
run-in period, subjects eligible for randomisation (HbA1c ≤ 9.0% measured at visit 9) will be 
randomised (1:1) to receive double blinded treatment with either faster aspart or NovoRapid® both
in combination with once daily insulin degludec with or without metformin. To aim for an even 
distribution of treatment groups within T1DM and T2DM, the randomisation will be stratified 
according to the type of diabetes.
All subjects will have a standardised meal test at baseline (V10 before randomisation) and at end of 
treatment (V26/V26A). The meal test will be described in more details in Section 8.3.1.
After the 16-week treatment period, the subject will have a 30-day safety follow-up period.
5.2
Rationale for trial design
The 8-week run-in period has been included to ensure the subjects are being trained in the trial 
procedures and that the basal insulin titration is optimised. A 16-week treatment period is needed to 
obtain valid and adequate efficacy and safety data.
The rationale for the meal test is to evaluate PPG regulation after a standardised meal when 
injecting faster aspart compared to NovoRapid®.
The treat-to-target approach, and thereby the high frequency of contacts, has been chosen in order 
to ensure optimal titration of faster aspart and NovoRapid®.
The 7-day follow-up visit, and the 30-day follow up contact are introduced in order to collect 
information on AEs occurring in the follow-up period.
5.2.1
Rationale for choice of non-inferiority margin
In a recently finalised faster aspart trial (NN1218-4049, data on file) with 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]. In this trial the addition of three times daily faster aspart 
led to a reduction in HbA1c of 1.16% after 18 weeks of treatment. In a similar phase 4 trial30
investigating the stepwise addition of NovoRapid® to a full basal-bolus regimen in bolus naïve 
T2DM adults the observed reduction in HbA1c after 21 weeks of treatment was 1.15% (data ANA-
3786, data on file) with 3 times daily NovoRapid® added to basal insulin. This gives some 
indication that the effect of NovoRapid® versus placebo would be close to the 0.94% observed in 
trial NN1218-4049. Thus using a non-inferiority margin of 0.4%, one of the suggested margins in 
the FDA guidance28, an improvement of approximately 0.54% would have been preserved using the 
0.4% non-inferiority margin. In a faster aspart trial (NN1218-3852) with a T1DM adult population, 
the HbA1c reduction from baseline to end of trial was larger with mealtime faster aspart when 
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compared to mealtime NovoRapid®. Therefore using a non-inferiority margin of 0.4% in a 
population with both T1DM and T2DM subjects, the improvement would be expected to be 
preserved.
5.3
Treatment of subjects
At V2, eligible subjects will be enrolled in a run-in period where all subjects will be switched from 
their pre-trial insulin treatment to basal insulin degludec once daily and bolus insulin NovoRapid®
thrice daily as described in the titration guideline (Appendix A1 and A2) with or without 
metformin. 
Subjects with T2DM treated with metformin prior to the trial should continue with their pre-trial 
dose of metformin. The dose and dosing frequency of metformin should not be changed at any time 
during the trial, unless due to safety concerns. For T2DM subjects treated with alpha-glucosidase
inhibitor, SGLT2i and DPP4i prior to the trial, the OAD(s) must be stopped at the run-in visit (V2).
Initiation of any other diabetes treatment is not allowed during the screening, run-in or treatment 
period and must be reported (see Section 8.2.5). This includes metformin for subjects with T2DM 
not treated with metformin prior to the trial. During the run-in period, the investigator will focus on 
optimising the basal insulin treatment using a treat-to-target approach following the titration 
guideline (Appendix A1 and A2). The bolus insulin will not be titrated during the run-in period 
unless the investigator finds it necessary to adjust the bolus insulin for safety reasons. 
All subjects should consume three main meals (breakfast, lunch and dinner) daily throughout the 
trial.
In the treatment period, eligible subjects will receive double blinded treatment with either faster 
aspart or NovoRapid® both in combination with once daily insulin degludec with or without 
metformin. The investigator should focus on optimising the bolus insulin treatment following the 
bolus dosing algorithm as described in the titration guideline (Appendix A1 and A2). Surveillance 
of insulin titration will be performed by Novo Nordisk.
Throughout the trial the bolus insulin (faster aspart or NovoRapid®) should be administered 0-2
minutes prior to the three main meals (i.e. breakfast, lunch and main evening meal). Additional 
bolus dosing is allowed at the discretion of the investigator.
The maximum duration of treatment will be 24 weeks including the run-in period. No maximum 
dose is specified. Doses are adjusted according to SMPG values (Appendix A1 and A2).
Use of flash glucose monitoring or a real time continuous glucose monitoring system is not allowed 
throughout the trial.
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5.4
Treatment after discontinuation of trial product
When discontinuing trial products (either prematurely or at end of treatment), the subject should be 
switched to a suitable marketed product at the discretion of the investigator. Doses of subsequent 
anti-diabetic treatment should be carefully titrated based on BG measurements.
5.5
Rationale for treatment
Based on the currently available pharmacokinetic data on faster aspart, it is anticipated that 
treatment with faster aspart as a mealtime insulin will enable insulin therapy to more closely 
approach a physiologic insulin secretory pattern. Consequently, the PPG excursions may be more 
effectively controlled. For further details, please refer to the current version of the faster aspart IB.24
NovoRapid® will be used as a comparator to faster aspart in order to compare the effect and safety 
of faster aspart to the currently marketed insulin aspart formulation. As this is a double-blind trial, 
NovoRapid® and faster 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 its
effect and safety has been confirmed in adult diabetic subjects in global trials. The flat and stable 
glucose-lowering effect of insulin degludec makes it optimal when assessing the properties of bolus 
insulin (faster aspart compared to NovoRapid®).
Combination of insulin treatment with metformin in T2DM subjects is associated with better 
glycaemic control, fewer hypoglycaemic events, and less weight gain than treatment with insulin 
alone, therefore metformin should be continued when T2DM subjects are on insulin therapy.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 505
Number of subjects planned to be included in the run-in period: 353
Number of subjects planned to be randomised: 300
At least 20% of the subjects randomised are expected to be subjects with T1DM.
A screening failure rate of approximately 30% and a run-in failure rate of approximately 15% are 
anticipated for this trial.
6.2
Inclusion criteria
For an eligible subject, all inclusion criteria must be answered “yes”. 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial
2. Male or female, age above or equal to 18 years at the time of signing informed consent
3. Diagnosed with T1DM ≥ 1 year prior to screening (V1) or diagnosed with T2DM ≥ 5 years 
prior to screening (V1)
4. Treated with a basal-bolus insulin regimen or a premix insulin regimen ≥ 1 year prior to the 
day of screening (V1). Insulin regimen must be unchanged within 60 days prior to 
screening. A basal-bolus insulin regimen is defined as basal insulin once or twice daily and 
bolus insulin taken with meals at least thrice daily. A premix insulin regimen is defined as 
premix insulin twice or thrice-daily
5. For subjects with T1DM: not treated with any OADs for at least 90 days prior to screening
(V1).
For subjects with T2DM: not treated with any OADs or treated with 1-2 OADs within 90
days prior to screening (V1). Allowed OADs are metformin, alpha-glucosidase inhibitor,
SGLT2i and DPP4i. Change in OAD and dose is allowed prior to screening
6. HbA1c 7.5-9.5% (both inclusive) as assessed by central laboratory at screening (V1)
7. Able and willing to adhere to the protocol including performance of SMPG profiles and 
meal tests
8. Able and willing to consume 3 main meals (breakfast, lunch and dinner) daily throughout 
the trial
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
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6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”
1. Known or suspected hypersensitivity to trial product(s) or related products
2. Previous participation in this trial. Participation is defined as signed informed consent
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method. Adequate contraceptive measures
in China are defined as sterilisation, intrauterine device (IUD), oral contraceptives or barrier 
methods
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 30 days before screening (V1). Clinical trials do not include non-
interventional studies
5. Any disorder, except for conditions associated with diabetes, which in the investigator’s 
opinion might jeopardise subject’s safety or compliance with the protocol
6. Anticipated change in lifestyle (such as eating, exercise or sleeping pattern) during the trial
7. Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina 
pectoris or transient ischaemic attack within the past 180 days prior to the day of screening
(V1)
8. Subjects presently classified as being in New York Heart Association (NYHA) Class IV 
9. Planned coronary, carotid or peripheral artery revascularisation known on the day of 
screening (V1)
10. Inadequately treated blood pressure defined as Grade 3 hypertension or higher (systolic 
≥180 mmHg or diastolic ≥110 mmHg) at screening (V1)
11. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within the past 90 days prior to the day of screening (V1)
12. Anticipated initiation or change in concomitant medications (for more than 14 consecutive 
days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid
hormones, or corticosteroids)
13. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
fundus examination performed within the past 90 days prior to screening or in the period 
between screening and run-in (V2). Pharmacological pupil-dilation is a requirement unless 
using a digital fundus photography camera specified for non-dilated examination
14. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed
15. Any episodes of diabetic ketoacidosis within the past 90 days prior to the day of screening
(V1)
16. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
< 30 mL/min/1.73 m2 as defined by KDIGO 2012
17. Impaired liver function, defined as Alanine Aminotransferase (ALT) ≥ 2.5 times or Bilirubin 
>1.5 times upper normal limit at screening (V1)
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18. For subjects treated with metformin: Any contraindications or restrictions to use of 
metformin (according to local labelling) at investigator’s discretion
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
6.4
Run-in period exclusion criteria
The subject must be withdrawn from the trial during the run-in period if the following applies after 
the screening visit (V1), and before or at randomisation (V10):
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Pregnancy
3. Intention of becoming pregnant
4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product
5. Any disorder which in the investigator’s opinion might jeopardise subject’s safety or
compliance with the protocol
6. Inability or lack of willingness to adhere to the protocol, based on the investigator’s 
judgement
6.5
Randomisation criterion
To be randomised, the randomisation criterion must be answered “yes”
1. HbA1c ≤ 9.0% measured by the central laboratory at V9 - one week before randomisation
6.6
Criteria for premature discontinuation of trial products
Efforts must be made so that subjects attend and complete all scheduled visit procedures. Subjects 
should stay in the trial irrespective of lack of adherence to randomised treatment, lack of adherence 
to visit schedule or missing assessments. Only subjects who decline any further contact with the site 
in relation to the trial will be considered as withdrawn from the trial (see section 6.7).
The subject may be prematurely discontinued from trial products at the discretion of the investigator 
due to a safety concern and must be prematurely discontinued from trial products if the following 
applies after randomisation:
1. Included in the trial in violation of the inclusion and/or exclusion criteria and/or randomised 
in violation of the randomisation criterion 
2. Pregnancy 
3. Intention of becoming pregnant 
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4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product anytime during the treatment period
See Section 8.1.9 for procedures to be performed for subjects discontinuing trial products 
prematurely.
6.7
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. 
A subject is considered withdrawn from trial if the following applies before V26:
1. Subject is lost to follow up (see Section 8.1.10.1)
2. Subject withdraws consent
3. Death
Subjects withdrawing from trial before randomisation are considered screening or run-in failures. 
See Section 8.1.10 for procedures to be performed for subjects withdrawing consent after 
randomisation.
6.8
Subject replacement
Subjects who discontinue trial products prematurely or withdraw from trial will not be replaced.
6.9
Rationale for trial population 
The trial population consists of adult subjects with T1DM or T2DM who have been treated with a 
basal-bolus insulin or a premix insulin regimen for at least 1 year, but are not optimally controlled
as demonstrated by an HbA1c ≥ 7.5% at screening, and may benefit from intensified insulin 
treatment using a treat-to-target approach. The treatment strategy e.g. basal-bolus insulin regimen 
and glycaemic target are similar for both groups, as recommended by EASD/ADA and Chinese 
Diabetes Society (CDS) guidelines for diabetes.9, 31, 32 The basal-bolus treatment has been 
confirmed to be effective in both T1DM subjects and advanced T2DM subjects. For subjects with 
T2DM, the clinical diagnosis should be at least 5 years prior to screening to ensure more progressed 
disease requiring a full basal-bolus insulin supplementation. The subjects need to be on a basal-
bolus insulin regimen or a premix insulin regimen for at least 1 year in order to ensure that they 
have been adequately educated and are familiar with using the intensive regimen required in this 
trial. This will also help to avoid including newly diagnosed patients that could enter in the 
metabolic remission period.
Subjects with an HbA1c > 9.5% are not included in this trial. This is because the trial protocol 
requires strict adherence and good subject compliance and a likely cause of elevated HbA1c > 9.5% 
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in a diabetic subject is poor compliance with treatment regimens or an atypical course of the 
disease. The upper HbA1c limit is also expected to select a population that can achieve adequate 
basal insulin coverage in the 8-week run-in basal insulin titration period. Subjects in relative good 
glycaemic control defined as HbA1c <7.5 % may not significantly benefit from this trial and hence 
the lower cut-off value has been chosen. 
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7
Milestones
Planned duration of recruitment period (i.e. First Subject First Visit (FSFV) to Last Subject First
Visit (LSFV)) is 18 months.
End of trial is defined as Last Subject Last Visit (LSLV).
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. The ratio of randomised subjects with 
T1DM (minimum 20%) and subjects with T2DM (maximum 80%) will be controlled by the IWRS. 
All investigators will be notified immediately when the recruitment period ends or when the 
maximum number of subjects with T2DM has been reached, after which no further subjects may be 
screened and the IWRS will be closed for further screening. Subjects screened and found eligible 
can be randomised.
Trial registration:
Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn and 
novonordisk-trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure33, it will also be disclosed according to other applicable requirements such as those of 
the International Committee of Medical Journal Editors (ICMJE)34, the Food and Drug 
Administration Amendment Act (FDAAA)35 European Commission Requirements36, 37 and other 
relevant recommendations or regulations including requirements by the China Food and Drug 
administration (CFDA). 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.
The Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
trial Last Subject First Treatment + 16 weeks corresponding to V26. If the last subject is 
withdrawn/dropout early the PCD is considered the date when the last subject would have 
completed V26. The PCD determines the deadline for the results disclosure at clinicaltrials.gov
according to FDAAA.
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8
Methods and assessments
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see Section 2) along with their timing. 
8.1
Visit procedures
8.1.1
Screening (V1)
Informed consent must be obtained before any trial related activity, see Section 18.2.
All subjects must be provided with a copy of their own signed and dated informed consent form.
Subjects will continue on their current diabetes treatment until start of the run-in period (V2) and 
they will not be supplied with any trial products until then.
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit.
A screening session must be performed in the IWRS, see Section 10. Each subject will be assigned 
a unique 6-digit subject number which will remain the same throughout the trial. The investigator 
must keep a subject screening log, a subject identification code list and a subject enrolment log. 
Only subjects who have signed the informed consent form should be included on the logs. The 
subject screening log and subject enrolment log may be combined in one log.
Inclusion or exclusion criteria should not be answered “Yes” or “No” in the electronic case report 
form (eCRF) before source data is available. For central laboratory results, ECG and eye 
examination evaluations “Result pending” can be answered. Answers to these criteria should be 
changed to “Yes” or “No” when results and/or evaluations are available.
The investigator is required to make a reasonable effort to obtain necessary additional information 
from external sources e.g. primary physician and other hospitals/departments to document the 
subjects’ eligibility. Unless otherwise mentioned, all concomitant illness and medical history related 
to the inclusion and exclusion criteria are based on source documents such as the subject's medical 
record. It is the responsibility of the investigator to have sufficient evidence to ensure eligibility. 
Screening failures
For screening failures, the end of trial form in the eCRF must be completed with the reason for not 
continuing in the trial. A minimal set of screen failure information is required to
ensure transparent reporting of screen failure subjects to meet requirements from regulatory
authorities. Minimal information includes date of informed consent, demography, screen failure 
details, eligibility criteria, and any SAE (serious adverse events). SAEs from screening failures 
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must be transcribed by the investigator into the eCRF. Follow-up on SAEs must be carried out 
according to Section 12.
A screening failure session must be made in the IWRS and the case book must be signed.
Re-screening is not allowed if the subject has failed one of the inclusion, exclusion or 
randomisation criteria, this includes re-sampling if the subject has failed one of the inclusion,
exclusion or randomisation criteria related to laboratory parameters.
8.1.2
Run-in (V2)
If the subject is found eligible to continue in the trial the subject will enter an 8-week run-in period.
V2 can take place as soon as the subject has been found eligible and must take place no later than 
17 days after V1.
At start of the run-in period (V2), the subject will receive the trial products; basal insulin (insulin-
degludec) and bolus insulin (NovoRapid®) (Section 9). The subject must be trained in how to 
handle the insulin pen-injectors (Section 8.6.1). Training may be repeated during the trial. Date of
first trial products must be recorded in the eCRF.
A run-in dispensing session must be performed in the IWRS. A drug accountability session 
confirming dispensing of allocated trial products should also be performed.
The BG meter, BG meter test strips and a diary must be provided to the subject at V2. Subjects 
must be trained in use of the BG meter and completion of the diary.
Run-in failures
Subjects fulfilling any of the run-in period exclusion criteria, not fulfilling the randomisation 
criterion or withdrawing from trial during the run-in period are considered as run-in failures. 
Consequently, a run-in failure session must be made in the IWRS and a run-in failure form must be 
completed in the eCRF together with the reason for not continuing in the trial. The last date of trial 
product must be captured in the eCRF. No follow-up visit should take place and no additional 
assessments are needed.
SAEs and non-serious AEs from run-in failures must be recorded by the investigator in the eCRF. 
Follow-up of AEs must be carried out according to Section 12.3.
When data has been monitored and queries have been resolved the casebook must be signed in the 
eCRF.
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8.1.3
Randomisation (V10)
If the subject meets the randomisation criterion as measured at V9, the subject will at V10 be 
randomised into one of the two treatment arms using an IWRS randomisation session. A drug 
accountability session confirming dispensing of allocated trial products should also be performed.
First date of the randomised trial product (bolus insulin) must be recorded in the eCRF.
The subject must attend the randomisation visit fasting. For definition of fasting, please see Section 
8.1.5.
8.1.4
Phone contacts
Before any phone contact, both the investigator and subject should agree on the timing and direction 
of the call. The investigator remains responsible for ensuring that the phone contacts occur even if it 
is agreed that the subject should call the site. A phone contact may be converted to a site visit if 
needed.
8.1.5
Fasting visits
The subject must attend the visits specified in the flowchart (Section 2) in a fasting condition. 
Fasting is defined as at least eight hours without drink or food intake prior to the visit except for 
water.
Insulin dosing (including basal insulin) and medication which should be taken with or after a meal 
should be withheld until blood sampling has been performed. If a subject attends the visit non-
fasting, then the subject’s blood samples, meal test and body weight measurement should be re-
scheduled within the visit window and at V10 before randomisation to trial product.
8.1.6
Rescheduled visits
The date of the rescheduled assessment in the eCRF should reflect the actual date of the rescheduled 
assessment (i.e. the actual visit date will differ from the assessment date under the same visit).
8.1.7
End of treatment (V26)
At end of treatment (V26) trial products must be discontinued and an IWRS completion session 
must be performed. Last date on the basal and bolus trial insulins must be recorded in eCRF.
The subject should be switched to a suitable marketed product(s) at the discretion of the 
investigator.
8.1.8
Follow-up period
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The follow-up visit 1 (V27) is a site visit and should take place 7-12 days after the end of treatment 
visit. Follow-up contact 2 (P28) is a phone contact and should take place 30-35 days after the end of 
treatment visit.
Follow-up visit 1
The following data will be collected:
x
AEs 
x
Concomitant medication
x
Current diabetes medication
x
Hypoglycaemic episodes
x
Additional information on injection site reactions (see Section 8.4.1.2)
Follow-up contact 2
The following data will be collected:
x
AEs
x
Concomitant medication
x
Current diabetes medication
8.1.9
Premature discontinuation of trial products 
If a subject prematurely discontinues trial products after randomisation (V10), the investigator must 
undertake procedures as included for V26A as soon as possible (see flowchart Section 2). Subjects 
who prematurely discontinue trial products during the run-in period before randomisation are 
considered run-in failures.
Subjects should perform a 7-9-7 point SMPG profile before discontinuing trial products.
Subjects should attend V26A in a fasting state and should undergo the meal test before 
discontinuing trial products. The meal test should be performed with bolus trial insulin. If it is not 
feasible due to safety reasons including pregnancy as judged by the investigator the meal test should 
be performed with the marketed bolus analogue the subject is switched to. The meal test should not 
be performed if the subject is switched to premix insulin treatment or basal-bolus treatment using 
regular human insulin as bolus insulin. 
In addition, a blood sample for measuring HbA1c must be collected.
The primary reason for premature discontinuation of trial products must be specified in the eCRF, 
and final drug accountability must be performed. A treatment discontinuation session must be made 
in the IWRS after the final meal test.
The subject should be switched to a suitable marketed product at the discretion of the investigator. 
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The subject should also complete the follow-up visits (FU1 and FU2) 7 days (+5 days) and 30 days
(+ 5 days) after discontinuation of trial product. 
Finally, subjects prematurely discontinued from trial products should attend V26B at the time 
corresponding to 16 weeks after randomisation, where the following assessments will be done:
x
Blood sample to measure HbA1c
x
SAEs
x
Concomitant medication (diabetes)
A subject that permanently discontinues trial product before the End of Treatment visit (V26), will 
be considered to be a treatment non-completer. 
8.1.10
Withdrawal from trial
If a subject withdraws consent, and the subject agrees, the investigator must aim to undertake 
procedures similar to those for V26A as soon as possible (see flowchart Section 2). The investigator 
should encourage the subject to undergo the meal test at V26A, which should be done in a fasting 
state and before trial product is discontinued. The meal test should be performed with bolus trial 
insulin. If it is not feasible due to safety reasons including pregnancy as judged by the investigator 
the meal test should be performed with the marketed bolus analogue the subject is switched to. The 
meal test should not be performed if subject is switched to premix insulin treatment or basal-bolus 
treatment using regular human insulin as bolus insulin. 
If the subject agrees, the follow up visits (FU1 (V27) and FU2 (P28)) must be performed 7 (+5 
days) and 30 days (+5 days) after discontinuation of trial product. 
The end of treatment and end of trial form in the eCRF must be completed, and final drug 
accountability must be performed even if the subject is not able to come to the trial site. A treatment 
discontinuation session must be made in the IWRS. The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end of-trial-form in the eCRF.
A subject that is withdrawn from trial before the End of Treatment Visit (V26), will be considered 
to be a treatment non-completer and a trial non-completer. 
8.1.10.1
Lost to follow-up
The following actions must be taken in relation to a subject who fails to attend the site for a 
required visit:
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x
The site must attempt to contact the subject and reschedule the missed visit as soon as possible
x
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. via e-mail or certified letter to the subject as applicable). These 
contact attempts must be documented in the subject’s medical records. Should the subject continue 
to be unreachable, only then will he/she be considered to have withdrawn from the trial with the 
primary reason being “lost to follow-up”.
8.1.11
Review of results
Review of ECG results, eye examination report, laboratory reports, data entered in the diaries etc. 
must be documented either on the documents, printouts, or in the subject’s medical record. The 
documents must be retained at the site as source documentation. 
If it is needed to clarify entries or discrepancies in the diary, the subject must be questioned and a 
conclusion made in the subject’s medical record. Care must be taken not to bias the subject. Any 
discrepancies or missing data points available elsewhere related to a 7-9-7 point profile or 
hypoglycaemic episodes must be corrected or added.
For ECGs, physical examinations and eye examinations, the evaluations must follow the categories:
x
Normal
x
Abnormal
–
Was the result clinically significant? (yes/no)
The evaluation should be based on investigator’s judgement.
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not clinically significant. Review of laboratory reports must be 
documented either on the documents and/or in the subject’s medical record. 
8.2
Subject related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
x
Date of birth (according to local regulation)
x
Sex
x
Ethnicity (according to local regulation)
x
Race (according to local regulation)
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8.2.2
Diabetes history
Diabetes history will be recorded at screening and consists of:
x
Date of diagnosis of T1DM or T2DM
8.2.3
Hypoglycaemia unawareness
Information on hypoglycaemia unawareness will be recorded at screening according to
Clarke’s questionnaire, question 8.38
The investigator must ask the subject whether he/she has ever experienced a hypoglycaemic 
episode? If the subject answers “yes”, the investigator must ask the subject in the following way: 
“To what extent can you tell by your symptoms that your blood glucose is low?” The subject can 
answer never, rarely, sometimes, often or always.
Subjects answering ‘never, rarely or sometimes’ are considered as having impaired awareness of 
hypoglycaemia.
8.2.4
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (V1) or found as a result 
of a screening procedure or other trial procedures performed before exposure to trial product. 
Date of diagnosis of T1DM or T2DM should be reported separately in the Diabetes History Form in 
the eCRF.
Medical history is a medical event that the subject has experienced in the past. Only relevant 
medical history, as judged by the investigator, should be reported. 
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
Diabetes complications will be recorded at screening as part of the Concomitant illness and medical 
history and consists of;
Information regarding diabetes complications including date of onset:
x
Diabetic retinopathy
x
Diabetic neuropathy
x
Diabetic nephropathy
x
Macroangiopathy (including peripheral vascular disease)
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 (Section 12.2).
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It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted.
8.2.5
Concomitant medication
A concomitant medication is any medication, other than the trial product(s), which is taken during 
the trial, including the screening, run-in, treatment and follow-up periods.
Details of any concomitant medication must be recorded at V1. Changes in concomitant medication 
must be recorded at each visit as they occur. 
The information collected for each concomitant medication includes: 
x
trade name or generic name
x
indication
x
start date and stop date or continuation
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.6
Concomitant medication (diabetes)
Any diabetes medication, other than the trial product(s) which is taken during the trial, including the 
screening, run-in, treatment and follow-up periods must be recorded in a separate concomitant 
medication (diabetes) form in the eCRF, including:
x
trade name or generic name
x
total daily dose
x
frequency
x
start date and stop date or continuation 
For subjects treated with metformin it is the start date and dose of last metformin dose which should 
be reported.
At the run-in visit (V2), pre-trial insulin(s) and OADs except for metformin for T2DM subjects
must be discontinued and a stop date recorded. For T2DM subjects treated with metformin, 
investigator should at each weekly contact (visit or phone contact), confirm with the subject that 
dose and frequency of metformin has been unchanged. This should be documented in the medical 
records. 
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At the randomisation visit (V10) run-in bolus insulin (NovoRapid®) must be discontinued and a 
stop date recorded.
8.2.7
Childbearing potential  
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.5.2. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods (sterilisation, IUD, oral contraceptives or barrier methods) throughout the 
trial and until 1 week after end of treatment.
Female of non-childbearing potential is defined as:
x
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal ligation 
x
Postmenopausal defined as no menses for 12 months without an alternative medical cause
x
Other medical reasons preventing childbearing potential 
8.2.8
Tobacco use 
Details of tobacco use must be recorded at V1. Smoking is defined as smoking at least one cigarette 
or equivalent daily. 
Smoking status:
x
Never smoked
x
Previous smoker, smoking stop date
x
Current smoker
8.3
Efficacy assessments
8.3.1
Meal test
The subject will undergo a standardised liquid meal test at two visits (V10 and V26/V26A) (see 
flowchart Section 2) and will have their -2, 30, 60, 120 and 180 minutes PPG measured. The total 
duration of the meal test is expected to be up to 5 hours including preparations. During that time 
blood samples will be drawn for plasma glucose, as specified in Table 8–1.
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Before initiation of the meal test 
The subject should be instructed to: 
x
Follow normal routine regarding eating and exercise habits on the day prior to the meal test
x
Refrain from intake of alcohol and use of medications that affect motility (i.e. prokinetics, 
anticholinergics, tricyclic antidepressants) on the day prior to the meal test, unless the subject 
was on this medication at trial entry and does not change the product or product dose
x
Remember to bring their current/trial bolus and basal insulins, diary and BG meter to the meal 
test visits
x
Attend the meal test visits in a fasting condition. For definition of fasting, please refer to Section 
8.1.5. If subjects are normally dosing basal insulin in the morning, as well as metformin dosing 
in the morning, it is important they wait until after completion of the meal test
x
Achieve an SMPG value within a range of 4.0-8.8 mmol/L [71-160 mg/dL] before beginning 
the meal test. The SMPG value should be verified at the site before starting the meal test
The meal test should be re-scheduled within the visit window and at V10 before randomisation to 
trial product in case:
x
Any hypoglycaemic episode occurs from midnight before the meal test 
x
The subject is not fasting or 
x
The SMPG value is outside the range
At V10 (randomisation visit) the investigator must evaluate if the subject is eligible to continue in 
the trial before the meal test is performed. Only subjects eligible for randomisation should have the 
V10 meal test performed. Thus, this assessment should not be performed for run-in failure subjects. 
Randomisation should not take place before the meal test has ended.
Bolus insulin dose and meal test carbohydrate amount
The standardised liquid meal will be provided by Novo Nordisk and contains approximately 90
grams of carbohydrates. The volume of the liquid meal to be consumed should be measured out by 
the investigator to be the equivalent to approximately 90 grams of carbohydrates. 
The bolus insulin dose should be calculated by the investigator based on the dose level of 0.2
unit/kg body weight. Body weight must be measured prior to the meal test. The calculated dose 
should be rounded to the nearest whole unit. The 0.2 unit/kg dose is chosen as an approximation of 
a clinically relevant bolus dose needed for the given size of a standardised meal.
The insulin should be administered subcutaneously in the abdomen in accordance with Table 8–1.
Initiation of meal test
The subject’s body weight must be measured before start and a blood sample must be drawn two 
minutes before intake of the standardised meal. 
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If SMPG values ≤3.9 mmol/L [70 mg/dL] are measured, then the hypoglycaemia should be treated 
with glucose rescue treatment according to local practice and the meal test should continue 
according to the investigator’s discretion. The hypoglycaemic episode must be reported. Please see 
Section 8.4.2.
After the end of the meal test, the investigator should make sure that the subject is safe to leave the 
site by performing an additional SMPG measurement.
When the meal test at V10 is completed, the subject will be instructed to discontinue NovoRapid®
and start treatment with randomised trial product. When the meal test at V26/V26A is completed, 
the subjects will be switched to a marketed insulin product according to investigator's discretion as 
detailed in section 8.1.7 and 8.1.9.
Data collection
The following must be recorded in relation to the meal test: 
x
Body weight
x
Fasting status
x
SMPG value measured before the meal test within allowed ranges and the time of the 
measurement
x
Actual clock start and end time of standardised meal
x
Volume of meal consumed
x
Confirmation that the subject consumed the required volume of the standardised meal
x
Batch number of the standardised meal consumed
x
Actual clock time and dose of bolus insulin 
x
Actual clock time of blood samples
x
Hypoglycaemic episodes, if relevant
o
SMPG value, time of intervention and amount of glucose rescue treatment and 
hypoglycaemic episode form
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 LPLV in order to 
keep the blinding of the subject and investigator.
8.3.2
Self-measured plasma glucose  
At V2, subjects will be provided with a BG meter including auxiliaries as well as instructions for 
use. The subjects will be instructed in how to use the device.
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display. 
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Only the BG meter provided by Novo Nordisk should be used for the measurements required in the 
protocol. 
Subjects must be instructed in how to transfer/record the results of the SMPG values into the diary.
For each SMPG value date, time and value will be included. 
4-point self-measured plasma glucose profile 
For insulin titration purposes, the subjects will be instructed to perform 4-point profiles in the diary 
on the three days prior to a scheduled site visit/phone contact every week from V2 to V26, or V26A 
for subjects who discontinue prematurely. The measurements should be performed at the following 
time points:
x
Before breakfast
x
Before lunch
x
Before main evening meal (dinner)
x
At bedtime
For 4-point SMPG measurements date and value should be transferred to/recorded in the diary, 
where each measurement should be assigned to the corresponding time point.
SMPG values measured before breakfast, lunch, main evening meal, and at bedtime should be 
performed before any injection of bolus insulin and just before the start of the meal (breakfast, 
lunch or main evening meal). SMPG values measured before breakfast should be performed in a 
fasting condition. The 4-point profile is part of the 7- or 9-point profiles which are measured prior 
to selected site visits.
7-9-7 point self-measured plasma glucose profile
The 7- and 9-point SMPG profiles will be used for titration purposes and for efficacy analysis of the 
trial. The subject will be instructed to perform a 7-9-7 point profile on the 3 consecutive days just 
before selected visits as outlined in the flowchart in Section 2. See (7-point profiles indicated as X 
and the 9-point profile indicated as √). 
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T2DM, respectively. At each visit/phone contact the investigator will titrate the subjects by making 
prescribed dose adjustments based on the recommendations described in Appendix A1 and A2 if
applicable and provide the new prescribed dose to the subject. 
Please refer to Appendix A for data to be collected. Information on the first and last date of trial 
products must be recorded in the eCRF.
8.4
Safety assessments  
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the concomitant illness form if it is present at screening. Any new finding fulfilling the definition 
stated in Section 12 during the trial and any clinically significant worsening from baseline must be 
reported as an AE.
8.4.1
Adverse events
AEs must be reported at each visit in accordance with the procedures outlined in Section 12.
8.4.1.1
Medication error
If a medication error is observed during the trial, the following information is required, and a 
specific event form must be completed in the eCRF in addition to the AE form: 
x
Trial product(s) involved 
x
Classification of medication error
x
Whether the subject experienced any hypoglycaemic episode and/or adverse event(s) as a result 
of the medication error 
x
Suspected primary reason for the medication error 
For definition of medication errors, see Section 12.1.4.
8.4.1.2
Adverse events requiring additional data collection
For AEs related to injection site reaction additional data collection is required and specific event 
forms must be completed in the eCRF in addition to the AE form. 
In case any of these events fulfil the criteria for an SAE, please report accordingly, see Section 12.
Injection site reaction
If an event of injection site reaction is observed the following additional information must be 
obtained if available on the injection site reaction form:
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x
Type of reaction – local or generalised
x
Symptoms associated with the event
x
Treatment given for the event
x
Association with the trial product(s)
x
Relevant risk factors associated with the event
8.4.2
Hypoglycaemic episodes
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected. 
All PG values:
x
≤ 3.9 mmol/L (70 mg/dL) or 
x
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary by the subject from V2 to V27 (FU1) In case a subject is not able to 
fill in the diary e.g. in case of a fatal event, then investigator will be allowed to report the 
hypoglycaemic episode in the eCRF.
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance to current guidelines.39
A SMPG value ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 min after onset on a hypoglycaemic episode, will by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is >3.9 
mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form. SMPG measurements ≤3.9 mmol/L (70 mg/dL) or hypoglycaemic 
symptoms after the 60 min period shall trigger the reporting of a new hypoglycaemia episode and 
prompt the subject to fill out a new hypoglycaemic episode form until a succeeding measurement is 
>3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.
In case of several low SMPG values within the 60 minutes interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
The record should include the following information:
x
Start date and time of the hypoglycaemic episode 
x
The PG 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 PG value 
for the episode, the remaining values will be kept as source data in the diary
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x
Whether the episode was symptomatic (Yes/No)
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode. The subject is therefore to be questioned 
whether there are changes to symptoms for each low SMPG value within the 60 minutes period 
or until the subject has confirmed that the hypoglycaemic episode is symptomatic
x
Whether the subject was able to treat him/herself  
x
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported reflecting the most severe degree of hypoglycaemia. The subject is therefore to be 
questioned whether he/she is able to self-treat for each low SMPG value within the 60 minutes 
period or until the subject respond that he/she is not able to self-treat. Date, time and dose of last 
bolus insulin administration prior to the episode
x
Date, time and dose of last basal insulin administration prior to the episode 
x
Date and time of last main meal (not including snacks) prior to the episode
x
Whether the episode occurred in relation to physical activity
x
Change in any concomitant illness
x
Any sign of fever and/or other acute disease 
x
Whether the subject was asleep when the episode occurred
–
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. PG concentrations may not be available during an event, but 
neurological recovery following the return of PG to normal is considered sufficient evidence that 
the event was induced by a low PG concentration.39
Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
x
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person)?
x
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)
x
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose or 
other)
x
Were symptoms alleviated after administration of treatment?
x
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. overdose, mix-up between products, incorrect use of device), miscalculation of dose 
of antidiabetic medication, other factors not listed or unknown)
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x
Did the subject experience seizure?
x
Was the subject unconscious/comatose?    
x
Did the subject experience any of the following symptoms40 (layman term used in the diary is 
specified in brackets if different from the protocol term)? 
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
x
Other symptoms 
The investigator must review the diary data for correct reporting of SMPGs and hypoglycaemic 
episodes. In case of incomplete or incorrect data in the diary, the subject must be questioned 
whether there have been any severe hypoglycaemic episodes since the last visit, i.e. any 
hypoglycaemic episodes where the subject was not able to self-treat. Any severe hypoglycaemic 
episodes must be reported.
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data41, 42.
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
unreported hypoglycaemic episodes.  
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form (SIF) must also be filled in, see Section 12. One AE form and SIF can cover 
several hypoglycaemic episodes if the subject has not recovered between the episodes
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8.4.3
Eye examination 
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention, but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist, or equally qualified certified 
health care provider (e.g. optometrist) must be available and evaluated by the investigator before V2
to assess eligibility (see Section 8.1.11). The eye examination should be performed as a fundus 
photography (e.g. 2-field 60 degree or better, colour or red-free) or by slit-lamp biomicroscopy 
examination (e.g. using a pre-corneal or corneal contact lens examination) and performed with 
pharmacologically dilated pupils unless using a digital fundus photography camera specified for 
non-dilated examination.
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base their evaluation upon the results of that examination. The examination must 
be repeated before V2 if the subject has experienced worsening of visual function since the last 
examination. If the applicable eye examination was performed before the subject signed the 
informed consent form, it must be documented that the reason for performing the examination was 
not related to this trial.
After V2 an eye examination performed according to above must be performed as per the flowchart 
in Section 2. An eye examination must be performed at the randomisation visit (V10) or within 14 
days prior to V10 (the results do not need to be available for randomisation). If the eye examination 
is performed at V10, it must be performed prior to administration of randomised treatment.  Eye 
examination obtained within 3 weeks prior to V26 is acceptable if the result is available at the visit.
The investigator should indicate the outcome of each eye examination. Relevant findings prior to 
randomisation must be recorded as concomitant illness/medical history. Relevant findings occurring 
after randomisation should be reported as an AE, if applicable according to section 8.4.
8.4.4
Electrocardiogram (ECG)
A 12-lead ECG must be performed as per flow-chart (see Section 2) and the assessment must be 
reviewed as described in Section 8.1.11.
Abnormal and clinically significant findings must be recorded as described in Section 8.4.
If an ECG-12 lead has been performed within 3 weeks prior to screening (V1), and the results are 
available at V1, the ECG does not need to be repeated at V1. If performed before the subject 
consents to participate in the trial it must be stated in the subject’s medical records that this 
procedure was not performed in relation to the trial.
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ECG obtained within 3 weeks prior to V10 and V26 is acceptable if the result is available at the 
visit.
8.4.5
Body Measurements
Height (without shoes) will be measured at site in centimetres (cm) or inches (in) and recorded to 
one decimal place in the eCRF.
Body weight should be measured in kilograms (kg) or pounds (lb) without shoes and wearing only 
light clothing. Body weight must be measured prior to the start of the meal test at V10 and 
V26/V26A.
Body weight will be recorded to one decimal place. The body weight should be assessed on the 
same weighing scale throughout the trial, if possible. 
BMI will automatically be calculated by the eCRF.
8.4.6
Physical examination
Physical examination will include examination of:
x
Respiratory system
x
Cardiovascular system
x
Central and peripheral nervous system
x
Gastrointestinal system, including the mouth
x
Skin
Abnormal and clinically significant findings must be recorded as described in Section 8.4.
8.4.7
Vital signs
Diastolic blood pressure, systolic blood pressure and pulse should be measured while the subject is 
in a sitting position and after 5 minutes of rest.
At screening (V1) blood pressure needs to be measured three times and all values should be 
recorded in the eCRF. The mean value will be calculated by the eCRF, and must be used to assess 
the relevant exclusion criterion; please see Section 6.3.
8.5
Laboratory assessments
Except for urine pregnancy testing, which will be performed locally, all laboratory analyses will be 
performed by a central laboratory contracted by Novo Nordisk. The central laboratory will provide 
all laboratory supplies for the sampling and transportation of all blood samples taken during the 
trial.
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A detailed description of the procedures for obtaining the samples, handling, storage, and shipment 
of the samples is specified in a trial-specific laboratory manual provided to the sites by the central 
laboratory. Information regarding laboratory materials such as tubes and labels is 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, as stated in the flowchart in Section 2.
If laboratory samples need to be retaken due to missing result(s) (e.g. haemolysed, sample leaked 
during transit, sample not being conclusive, lost in transit, etc.), the subject should be called in for 
resampling. Please see the laboratory manual for further guidance.
Samples will be coded in order to keep subject’s identity anonymous. 
The laboratory provides results to the trial sites on an ongoing basis. The results will be transferred 
to the trial database.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to Section 8.2.4 and Section 12. Review 
of laboratory reports must be performed as described in Section 8.1.11.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory.
Laboratory samples will be destroyed no later than the finalisation of the clinical trial report, or 
according to local regulations for the destruction of blood samples.
8.5.1
Laboratory assessments for efficacy
Glucose metabolism 
PG will be measured during the meal test. See Section 8.3.1.
FPG is measured in order to evaluate metabolic control. The subject must attend these visits fasting. 
For definition of fasting, see Section 8.1.5
A FPG result ≤3.9 mmol/L (70 mg/dL) should not be reported as a hypoglycaemic episode but as a 
AE at the discretion of the investigator (see Section 12.1.1).
Blood samples will be drawn to determine the HbA1c level in order to evaluate metabolic control. 
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Lipids
Blood samples for lipids will be analysed to determine:
x
Triglycerides
x
Total cholesterol
x
High density lipoprotein (HDL) cholesterol
x
Low density lipoprotein (LDL) cholesterol
8.5.2
Laboratory assessments for safety
Biochemistry
Blood samples for biochemistry will be analysed to determine:
x
alanine aminotransferase (ALT)
x
aspartate aminotransferase (AST)
x
albumin
x
alkaline phosphatase
x
creatinine
x
creatinine clearance
x
potassium
x
sodium
x
total bilirubin
x
total protein
x
eGFR at screening
eGFR will be calculated by the central laboratory based on the creatinine value using the CKD-EPI 
equation in order to access exclusion criteria 16.
Haematology
Blood samples for haematology will be analysed to determine:
x
haemoglobin
x
haematocrit
x
erythrocytes
x
leucocytes
x
thrombocytes 
Pregnancy testing
For females of childbearing potential (see Section 8.2.7), a blood human Chorion Gonadotropin 
(hCG) pregnancy test will be performed at the visits indicated in the flowchart in Section 2. In 
addition, urine pregnancy tests will be performed locally during the trial if pregnancy is suspected 
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or if required by local law. A positive urine test should be followed by a confirmatory serum-hCG 
(central laboratory).
The central laboratory will provide the pregnancy kits for urine testing performed locally at the site.
8.6
Other assessments
8.6.1
Training in the pen-injector
The subjects must be trained in how to handle the pen-injector when handed out the first time. 
Training must be repeated during the trial at regular intervals in order to ensure correct use of the 
device. 
The following should be emphasised:
x
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
x
Remember to prime the pen to ensure product flow 
x
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
x
Always check that the correct pen is used (bolus or basal) e.g. by colour coding and label. Use 
the differentiation guide as a reference
x
In-use time and storage conditions of pen-injectors (Section 9.3)
8.6.2
Diary
At visit 1 the subjects will be provided with a diary to capture health issues (adverse events and 
changes in concomitant medication) only. At the run-in visit (V2) the subjects will be provided with 
a diary to capture health issues (adverse events and changes in concomitant medication),
hypoglycaemia, SMPGs and dose data. The investigator must carefully instruct the subject in how 
to use the diary. All data entered in the diary is considered source data, as described in sections 
8.3.2, 8.3.3 and 8.4.2. The recordings must be reviewed as described in Section 8.1.11 and 
transcribed, as applicable. Entries in the diaries are only to be made by the subject, unless otherwise 
specified.
Selected titration data (e.g. certain SMPGs and dose data) will only be used during the trial for 
central titration surveillance, to ensure compliance with the titration guideline (Appendix A1 and 
A2), and will not be reported in the clinical trial report (CTR). All data will be stored by Novo 
Nordisk (Section 24).
8.7
Subject compliance
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. 
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Treatment compliance: During treatment with trial products, the investigator will at each weekly 
contact (visit or phone contact) assess the subject’s compliance by evaluating the glycaemic control, 
adherence to treatment and completion of the subject’s diary including the SMPG profiles, dose and 
hypoglycaemia reporting. In addition, subject compliance will be assessed by monitoring of drug 
accountability at specified visits, please refer to the flow chart (Section 2).
If a subject is found to be non-compliant, the investigator will remind the subject of the importance 
of following the instructions given including taking the trial products as prescribed.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM). 
Trial products must not be dispensed to any person not included in the trial. 
Trial products must not be used, if they do not appear clear and colourless.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products (IMPs)
Trial product
Strength
Dosage form
Route of 
administration
Container/
delivery device
Faster aspart (test product,
blinded)
100 U/mL
Solution for 
injection
Subcutaneously
3 mL PDS290 
pen-injector
Insulin aspart
(reference therapy, blinded)
Insulin deglude (open label)
100 U/mL
Solution for 
injection
Subcutaneously
3 mL PDS290 
pen-injector
Insulin aspart (open label 
for the run-in period)
100 U/mL
Solution for 
injection
Subcutaneously
3 mL PDS290 
pen-injector
Metformin is a Non-Investigational Medicinal Product (NIMP) and will not be supplied by Novo 
Nordisk. However, metformin will be reimbursed if required according to local regulations.
In the treatment period the investigational medicinal products (IMPs) faster aspart and insulin aspart
are visually identical.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1343, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an ongoing basis 
controlled by the IWRS. Trial products will be distributed to the trial sites according to enrolment 
and randomisation. 
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The investigator must document that direction for use (DFU) is given to the subject orally and in 
writing at the first dispensing visit (V2). Additionally, the pen differentiation guide must be 
provided to subjects at randomisation (V10). DFU and pen differentiation guide can be provided as 
needed at the following dispensing visits.
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
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
Store at 2°C- 30°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 that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the TMM.
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Each trial product package is referred to as a dispensing unit (DU) and is uniquely numbered with a
Dispensing Unit Number (DUN).
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
Investigator should instruct the subjects in what to be returned at the next visit.
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Non-allocated trial products (expired, damaged or available) must be accounted as unused at the 
latest at closure of the trial site.
Destruction of trial products can be performed on an ongoing basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS.
9.5
Auxiliary supplies
The following will be provided by Novo Nordisk in accordance with the TMM:
x
DFU for the prefilled pens 
x
Novo Nordisk needles for the pen devices
x
BG meters and auxiliaries for the BG meters
x
Standardised liquid meal (for the meal test) 
Only needles provided by Novo Nordisk with a maximum length of 6 mm must be used for 
administration of trial product.
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10  Interactive web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet. Access to 
the IWRS must be restricted to and controlled by authorised persons. 
IWRS is used for: 
x
Medication arrival
x
Dispensing verification (when barcode scanner is used)
x
Screening
x
Screening failure 
x
Run-in dispensing
x
Randomisation
x
Treatment discontinuation 
x
Completion
x
Run-in failure
x
Code break
x
Dispensing
x
Drug accountability
x
Data change
IWRS user manuals will be provided to each trial site.
11 Randomisation procedure and breaking of blinded codes
At the randomisation visit (V10), eligible subjects will be randomised via the IWRS into two 
treatment arms in a 1:1 manner. See Section 5.1.
The investigator, subject and sponsor will be blinded to the bolus treatment.
The randomisation will be stratified according to the type of diabetes in order to aim for an even 
distribution of treatments groups within T1DM and T2DM. 
11.1
Breaking of blinded codes
The IWRS 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 IWRS, 
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 IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I.
If the code has been broken by the investigator, the subject must discontinue treatment with trial 
products and a treatment discontinuation session must be completed in IWRS.
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12 Adverse events, and technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An AE is any untoward medical occurrence in a subject administered a medicinal product, and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
x
A clinically significant worsening of a concomitant illness
x
Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgement of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected.
x
Abuse: Persistent or sporadic, intentional excessive use of medical product, which is 
accompanied by harmful physical or psychological effects (e.g. overdose with the intention to 
cause harm).
x
Misuse: Situation where the medicinal product is intentionally and appropriately used not in 
accordance with the protocol or the terms of the marketing authorization.
The following should not be reported as AEs:
x
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness)
x
Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads to the 
procedure, should be reported as the AE. 
x
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see Section 8.4.2
The following three definitions are used when assessing an AE:
x
Severity 
–
Mild – no or transient symptoms, no interference with the subject’s daily activities
–
Moderate – marked symptoms, moderate interference with the subject’s daily activities
–
Severe – considerable interference with the subject’s daily activities; unacceptable
x
Causality 
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship
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–
Possible - A causal relationship is conceivable and cannot be dismissed
–
Unlikely - The event is most likely related to aetiology other than the trial product
•
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related activity 
after the subject signed the informed consent
–
Recovering/resolving - The condition is improving and the subject is expected to 
recover from the event. This term is only applicable if the subject has completed the trial
or has died from another AE
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported 
as an SAE
–
Unknown - This term is only applicable if the subject is lost to follow-up
12.1.2
Serious adverse event
An SAE is an experience that at any dose results in any of the following:
x
Death
x
A life-threateninga experience
x
In-patient hospitalisationb or prolongation of existing hospitalisation
x
A persistent or significant disability or incapacityc
x
A congenital anomaly or birth defect
x
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 
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–
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
x
suspicion of transmission of infectious agents via the trial product 
x
risk of liver injury defined as ALT or AST >3 x UNL and total bilirubin >2 x UNL, where no 
alternative aetiology exists (Hy's law)
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
x
Administration of wrong drug 
Note: Use of wrong DUN is not considered a medication error.
x
Wrong route of administration, such as intramuscular instead of subcutaneous
x
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
Medication errors must be reported on an AE form and a specific event form, see Section 8.4.1.1.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the safety of the trial product.
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In this trial the following AEs require the completion of specific event forms in the eCRF:
x
Injection site reaction
For details, see Section 8.4.1.2.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
x
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
x
All packaging material including labelling
x
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push
button or interface between the pen and the needle)  
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period (FU2). For subjects discontinuing trial product prematurely, 
only SAEs should be reported between FU2 and end of trial (V26B). The events must be recorded 
in the applicable eCRF forms in a timely manner, see timelines below and Figure 12–1.
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?”
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. 
All AEs must be recorded by the investigator on an AE form. The investigator should report the 
diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms.  
For SAEs, a safety information form must be completed in addition to the AE form. If several 
symptoms or diagnoses occur as part of the same clinical picture, one safety information form can 
be used to describe all the SAEs. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
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investigator will be informed of any trial-related SAEs that may warrant a change in any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and ICH GCP44,
unless locally this is an obligation of the investigator.
Novo Nordisk products used as concomitant medication:
If an AE 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:
x
SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
x
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
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of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days
from the date of receipt of the request, unless otherwise specified in the follow-up request.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial. 
12.4
Technical complaints and technical complaint samples
12.4.1
Reporting of technical complaints 
All technical complaints on any of the following products: 
x
Faster aspart, 100 U/mL solution for subcutaneous injection, 3 mL PDS290 pen-injector 
(blinded)
x
NovoRapid®, 100 U/mL solution for subcutaneous injection, 3 mL PDS290 pen-injector (open
label and blinded)
x
Insulin degludec, 100 U/mL solution for subcutaneous injection, 3 mL PDS290 pen-injector
(open label)
which occur from the time of first usage of the product until the time of the last usage of the
product, must be collected and reported to Customer Complaint Center, Novo Nordisk.
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol.
The investigator must assess whether the technical complaint is related to any AEs and/or SAEs.
Technical complaints must be reported on a separate technical complaint form: 
x
One technical complaint form must be completed for each affected DUN 
x
If DUN is not available, a technical complaint form for each batch, code or lot number must be 
completed 
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint:
x
Technical complaint assessed as related to an SAE within 24 hours
x
All other technical complaints within 5 calendar days
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If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF. For reporting of technical complaints on the BG meter and auxiliaries, see Attachment I.
12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and notify the monitor within 5 
calendar days of obtaining the sample at trial site. The monitor must coordinate the shipment to 
Customer Complaint Center, Novo Nordisk (the address is provided in Attachment I) and ensure 
that the sample is sent as soon as possible. A copy of the technical complaint form must be included 
in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
12.5
Pregnancies
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 new born infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the new born infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
new born infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
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1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the new born infant(s) has to be 
reported on Maternal Form 1A and 1B, respectively.
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or during 
autopsy), and/or when a congenital anomaly is diagnosed within the first month, further information 
has to be reported for the female subject on Maternal Form 2. In addition, information from the 
male partner has to be reported on the Paternal Form, after an informed consent has been obtained 
from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information. 
2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
new born infant(s). The SAEs that must be reported include abnormal outcome, such as foetal death 
(including spontaneous abortion), and congenital anomalies (including those observed at gross 
examination or during autopsy of the foetus), as well as other pregnancy complications fulfilling the 
criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
x
AE forma: Data must be recorded in the eCRF as soon as possible, preferably within 5 working 
days (see section 13.2)
SAEs: 
x
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
x
Safety information form within 5 calendar days of the investigator’s first knowledge of the 
SAE.
x
SAE follow-up information to the AE form and/or safety information form within 24 hours of
the investigator’s first knowledge of the follow-up information.
a
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or new born infant. If the AE occurred in the foetus or new born infant, the 
AE can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
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12.6
Precautions and/or overdose
During treatment with insulin, there is a risk of hypoglycaemia (see Section 8.4.2). Symptoms of
hypoglycaemia usually occur suddenly and may include cold sweat, nervousness or tremor, anxious
feelings, unusual tiredness, confusion, difficulty in concentration, excessive hunger, temporary
vision changes, headache, nausea, and palpitation. Prolonged or severe hypoglycaemia can lead to a
loss of self-control, spasms, and/or unconsciousness and, in extreme cases, death. Asymptomatic 
hypoglycaemia and symptoms of hypoglycaemia should be treated with carbohydrates. Mild to 
moderate symptoms can be treated by ingestion of carbohydrate (for example, juice). Severe 
hypoglycaemia resulting in the loss of consciousness should be treated with parenteral glucose, 
glucagon or dextrose.
For further details, please refer to the current version of faster aspart IB24, for NovoRapid® and 
Tresiba® please refer to the current versions of the local labelling.18, 19, 25, 26
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal faster aspart safety committee to perform ongoing safety 
surveillance. The faster 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.
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13 Case report forms 
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
x
Pregnancy forms
The following will be provided as paper forms to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
x
AE forms 
x
Safety information forms 
x
Technical complaint forms (also to be used to report complaints that are not subject related (e.g. 
discovered at trial site before allocation) 
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the case book in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct.
13.1
Corrections to case report forms 
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit/phone contact. The SMPG measurements and corresponding trial drug 
doses for titration purpose should be entered within 24 hours after the site visit/phone contact on
week days throughout the trial.
Once data has been entered, it will be available to Novo Nordisk for data verification and validation 
purposes. Queries will be generated in the eCRF, and the investigator should solve these queries on 
an ongoing basis throughout the trial.
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site.
14 Monitoring procedures 
Monitoring will be conducted using a risk-based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. 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 centralised monitoring of the eCRFs
(remote assessment of data by Novo Nordisk), the trial site's recruitment rate and the compliance of 
the trial site to the protocol and GCP.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition, the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone). All data must be verifiable in source 
documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element. Source data 
generated by the trial site can be corrected by another person than the person entering the source 
data if accepted by local regulations; any correction must be explained, signed and dated by the 
person making the correction. The monitor will ensure that the eCRFs are completed and that paper 
CRFs are collected.
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The following data will be source data verified for screening failures: 
x
Date for obtaining informed consent 
x
Demography
x
Screening failure reason
x
SAEs, if applicable
Monitors will review the subject’s medical records and other source data to ensure consistency 
and/or identify omissions compared to the eCRF. If discrepancies are found, the investigator must 
be questioned about these.
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15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a CRO. 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
If necessary, a statistical analysis plan may be written in addition to the protocol, including a more 
technical and detailed elaboration of the statistical analyses. The statistical analysis plan will be 
finalised before database lock.
General considerations
In general, for endpoints evaluated as a change from baseline and/or where a baseline adjustment is 
made, baseline is defined as information collected at randomisation (V10). In case a measurement is 
not available at randomisation, the most recent measurement prior to randomisation will be used as 
baseline. 
All efficacy endpoints will be summarised and analysed using the full analysis set (FAS), unless 
otherwise stated. Safety endpoints will be summarised using the safety analysis set and analysed 
using the FAS. The FAS is defined in Section 17.2.
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(LSMeans) for change from baseline, if applicable. Estimated mean treatment differences (or ratios) 
will be presented together with two-sided 95% confidence interval (CI) for all endpoints analysed 
statistically. 
The primary objective of the trial is to confirm the effect in terms of glycaemic control of treatment 
with faster aspart compared to NovoRapid® both in combination with insulin degludec with or 
without metformin in Chinese adults with T1DM or T2DM inadequately treated with a basal-bolus 
or a premix regimen, using a non-inferiority approach. 
More specifically the upper limit of the 95% confidence interval for the difference between faster 
aspart and NovoRapid® should be compared to a non-inferiority margin of 0.4%. If it is below or 
equal to 0.4%, non-inferiority will be considered established and effect demonstrated. 
Estimand
The estimand is defined as the treatment difference in change from baseline in HbA1c 16 weeks 
after randomisation between faster aspart and NovoRapid® both in combination with insulin 
degludec with or without metformin in Chinese adults with T1DM or T2DM treated on basal-bolus 
regimen with a basal optimisation if all had adhered to randomised treatment. This estimand aims to 
reflect the treatment effect for subjects that are actually able to take the drug during the intended 
treatment period.
17.1
Sample size calculation
The sample size is determined to ensure a sufficient power for the primary analysis. This is 
determined using a non-inferiority limit of 0.4%. 
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In the global phase 3a programme where treatment with faster aspart has been investigated, the 
completion rates have been high, i.e. approximately 88-94%. Therefore it will not be unexpected 
that treatment discontinuation might be as low as 10%.
It is expected that a larger portion of the trial population will constitute subjects with T2DM. For 
these calculations the proportion of subjects with T1DM is assumed to be 20%. Combining 
expected differences for T1DM and T2DM subjects and weighting by the proportion of expected 
T1DM subjects we will assume a treatment difference of -0.02% (i.e., in favour of faster aspart). 
The power for the primary (non-inferiority) analysis is based on a t-statistic under the assumption of 
a one-sided test of size 2.5 %, a non-inferiority margin of 0.4% and SD of 1.2%. Using these values 
we get a power of 81.7% for the primary analysis with a sample size of 270. Adjusting further for a 
dropout rate of approximate 10%, 300 subjects will be randomised.
The power for non-inferiority for scenarios where SD = 1.0% or 1.2% and mean difference of 
0.00% or -0.02% based on sample size 270 is shown in Table 17–1.
Table 17–1
The power for non-inferiority for different scenarios
Power for non-inferiority
Treatment difference = 0%
Treatment difference =  -0.02%
SD = 1.0%
90.6%
93.0%
SD = 1.2%
77.9%
81.7%
The power calculation is done using proc power in SAS Version 9.4.
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E945 guidance
x
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”
x
Per Protocol (PP) Analysis Set includes all subjects in the FAS, excluding subjects who:
o
Have violated any inclusion criteria
o
Have fulfilled any exclusion criteria
Subjects in the PP analysis set will contribute to the evaluation “as treated” 
x
Safety Analysis Set includes all subjects receiving at least one dose of randomised treatment. 
Subjects in the safety analysis set will contribute to the evaluation “as treated” 
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Randomised subjects, who are lost to follow-up, and where no exposure information of the trial 
product or its comparator is available after randomisation, will be handled as unexposed.
Before data are released for statistical review, a blinded review of all data will take place to identify 
serious non-adherence to the protocol that may potentially affect the results. Furthermore, extreme 
values and outliers will be identified by the statistician during programming and data review, 
according to ICH-E9.45 This will be performed by using a fake randomisation.
The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report.
17.3
Primary endpoint
The primary endpoint is change from baseline (week 0) in HbA1c to 16 weeks after randomisation. 
Primary analysis:
The estimand will be addressed by the primary analysis on all subjects included in the full analysis 
set and using the data collected from date of first dose of randomised NovoRapid®/faster aspart and 
to 7 days after the day of last dose of randomised NovoRapid®/faster aspart. Change from baseline 
in HbA1c after 16 weeks of randomised treatment will be analysed using a mixed-effect model for 
repeated measurements (MMRM) where all calculated changes in HbA1c from baseline at visits will 
be included in the analysis. This model will include treatment and stratification (T1DM/T2DM) as 
fixed factors, HbA1c at baseline as covariate and interactions between all fixed factors and visit. An 
unstructured covariance matrix will be used to describe the variability for the repeated 
measurements for a subject. This approach relies on the assumption that data are missing at random 
(MAR). From this model, the treatment difference after 16 weeks will be estimated with a 95% 
confidence interval calculated.
Non-inferiority 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 (faster aspart minus 
NovoRapid®).
The trial also aims to confirm the superiority of treatment with faster aspart for the change from 
baseline HbA1c 16 weeks after randomisation. Here superiority will be based on the same 95% CI 
that was used for addressing the primary analysis. Superiority will be confirmed if the upper 
boundary of the two-sided 95% confidence interval of the mean treatment difference is below 0%. 
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Additional analysis
Differences between the two populations will be investigated further by estimating the treatment 
differences separately for subjects with T1DM and T2DM. These treatment differences will be 
estimated based on the same data and a similar statistical model as the primary analysis but
including interaction terms between treatment, stratification (T1DM and T2DM), and visit. 
Sensitivity analysis for the primary analysis addressing the estimand
1) A tipping point analysis will be made based on the data and a similar statistical model as the 
primary analysis addressing the estimand but using multiple imputation. In this analysis 
observations for subjects with missing values are imputed based on the treatment arm they were 
randomised to and subjects in the faster aspart group are given a penalty. This is done to 
investigate the robustness of the conclusion in the primary analysis with respect to the MAR 
assumption and mimics a scenario where the HbA1c of the subjects in the faster aspart groups 
evolve less favourably than predicted. As a first step imputations will be done without penalty 
assuming MAR. Second, the imputed values for week 16 in the faster aspart group will be added 
a penalty. This is done repeatedly, gradually increasing the penalty until the conclusion from the 
non-inferiority analysis no longer holds. This will serve as a sensitivity analysis for the non-
inferiority analysis and the specific value of the penalty that changes the conclusion will be used 
to evaluate the robustness of the conclusion of the non-inferiority analysis.
2) A tipping point analysis using multiple imputation similar to 1) but with the modification that 
subjects discontinuing treatment due to non-eligibility (discontinuation due to criteria 1- 4,
Section 6.6) in the faster aspart group will not have a penalty added. These analyses are 
motivated by the fact that data from subjects prematurely discontinuing randomised treatment 
due to non-eligibility can reasonably be assumed to be missing completely at random. 
3) The same statistical model using MMRM and data as in the primary analysis, but restricted to 
the PP analysis set. This analysis will investigate the situation that subjects might have deviated 
from the inclusion and exclusion criteria and will serve as sensitivity analysis for the non-
inferiority analysis.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
All endpoints except insulin dose in this section will be assessed using the FAS. Insulin dose will be 
presented using the safety analysis set.
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Change from baseline in 30- minutes, 1- hour, 2- hour, and 3- hour PPG increment and 30-
minutes, 1- hour, 2- hour, and 3- hour PPG to 16 weeks after randomisation (meal test)
Laboratory measured PG from the meal test will be analysed for 30 minutes, 1-hour, 2-hours, and 3-
hours PPG separately. The corresponding PPG increments will be derived separately using each 
PPG measurement minus the pre-prandial PG measurement.
Change from baseline in PPG and PPG increment endpoints 16 weeks after randomisation will be 
analysed based on the FAS using an ANOVA model including treatment and stratification 
(T1DM/T2DM) as factors, and with the corresponding baseline value as covariate. 
Change from baseline in FPG to 16 weeks after randomisation
Change from baseline in FPG to 16 weeks after randomisation will be analysed based on all planned 
post baseline measurements until or at 16 weeks after randomisation using a model similar to the 
primary analysis except with baseline FPG as covariate.
If a subject achieves HbA1c target 16 weeks after randomisation
HbA1c < 7.0%
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
met the HbA1c target (HbA1c <7.0%) 16 weeks after randomisation.  
This responder endpoint will be analysed based on a logistic regression model using treatment and
stratification (T1DM/T2DM) as factors, and baseline HbA1c as covariate. In the analysis, subjects 
who prematurely discontinue trial product and subjects with missing HbA1c  at 16 weeks will be
included as non-responders.
HbA1c < 7.0% without severe hypoglycaemia
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
met the HbA1c target (HbA1c <7.0%) 16 weeks after randomisation without treatment emergent 
severe hypoglycaemic episodes.
This responder endpoint will be analysed based on a logistic regression model using treatment and
stratification (T1DM/T2DM) as factors and baseline HbA1c as covariate. In the analysis, subjects 
who prematurely discontinue trial product and subjects with missing HbA1c  at 16 weeks will be 
included as non-responders.
Change from baseline in endpoints derived from the 7-9-7-point SMPG profile to 16 weeks
after randomisation
In general, analyses will be based on the entire 7-9-7-point SMPG profile.
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PPG and PPG increments based on the 7-9-7-point SMPG profiles will be derived separately for PG 
measurements made 1 hour after the meal. In the following section this distinction will be 
considered implicit and without further explanation.
Pre-prandial PG and PPG will be recorded by the subjects as part of the 7-9-7-point SMPG profile 
prior to three defined visits. Individual mean mealtime PPG (post-breakfast, post-lunch, post-main
evening meal) will be derived from the three profiles. Overall mean PPG will be derived from the 
individual derived mealtime PPG values.
PPG increment for each meal (breakfast, lunch, main evening meal) will be derived from the 7-9-7-
point SMPG profile as the difference between PPG values and the PG value before meal in each 
separate profile. The mean of the derived increments will then be calculated separately for each 
meal. Mean 1-hour PPG increments over all meals will be derived as the mean of all corresponding 
mean meal increments. 
x
Change from baseline in mean of the 7-9-7-point SMPG profile
The mean of the 7-9-7-point SMPG profile is defined as the area under the curve (AUC) 
profile divided by the measurement time, and is calculated using the linear trapezoidal 
technique.
Change from baseline in the mean of the 7-9-7-point SMPG profile 16 weeks after 
randomisation will be analysed based on all planned post baseline measurements until or at 
16 weeks after randomisation using a model similar to the primary analysis except with the 
corresponding baseline value as covariate.
x
Change from baseline in 1-hour PPG and PPG increment (mean, breakfast, lunch and main 
evening meal)
Change from baseline in 1-hour PPG and PPG increment endpoints 16 weeks after 
randomisation for mean over all three meals and the individual meals will be analysed 
separately based on all planned post baseline measurements until or at 16 weeks after 
randomisation using a model similar to the primary analysis except with the corresponding 
baseline value as covariate.
x
Fluctuation in 7-9-7-point SMPG profile
The fluctuation in the 7-9-7-point SMPG profile is defined as:
ͳ
ܶනȁܲܩሺݐሻെܲܩ
തതതതȁ
்
଴
݀ݐ
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where T, PG(t) and ܲܩ
തതതതdenotes the length of the profile, the PG value at time t and the mean 
of the profile, respectively. It will be calculated using the linear trapezoidal technique.
Fluctuation in the 7-9-7-point SMPG profile will be logarithmically transformed and 
analysed based on all planned post baseline measurements until or at 16 weeks after 
randomisation using a model similar to the primary analysis except with the corresponding 
log-transformed baseline value as covariate. Estimated treatment means and the estimated 
treatment differences with corresponding 95% CI will be back-transformed to the original 
scale, resulting in estimated geometric means, a treatment ration and a 95% CI for the 
treatment ratio.
If a subject achieves PPG target (based on overall mean of daily PPG measurements in 7-9-7-
point SMPG profile) 16 weeks after randomisation:
Overall PPG (1-hour) d7.8 mmol/L 
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
reached an overall mean 1-hour PPG d7.8 mmol/L [140 mg/dL] 16 weeks after randomisation, 
where PPG is derived from the 7-9-7-point SMPG profile. 
This responder endpoint will be analysed based on a logistic regression model using treatment and
stratification (T1DM/T2DM) as factors, and baseline overall mean 1-hour PPG as covariate. In the 
analysis, subjects who prematurely discontinue randomised treatment will be included as non-
responders.
Overall PPG (1-hour) d7.8 mmol/L without severe hypoglycaemia
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
reached an overall 1-hour PPG d7.8 mmol/L [140 mg/dL] 16 weeks after randomisation without 
any treatment emergent severe hypoglycaemic episodes. 
This responder endpoint will be analysed based on a logistic regression model using treatment and 
stratification (T1DM/T2DM) as factors, and baseline overall mean 1-hour PPG as covariate. In the 
analysis, subjects who prematurely discontinue randomised treatment will be included as non-
responders.
Insulin dose (Units/day and Units/kg/day; total basal, total bolus, and individual meal insulin 
dose) 16 weeks after randomisation
The insulin doses will be summarised descriptively by treatment week according to regimen, by 
meal type in units and units/kg (separately for each mealtime dose). Insulin doses will be 
summarised using the safety analysis set.
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Lipids-lipoproteins profile 16 weeks after randomisation
Lipid endpoints (total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride) will be 
logarithmically transformed and analysed separately based on all planned post baseline 
measurements until or at 16 weeks after randomisation using a model similar to the primary 
analysis except with the corresponding log-transformed baseline 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.
17.4.1.2
Safety endpoints
In terms of AEs, as a minimum, SAEs will be tabulated.
Number of treatment emergent adverse events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
presented based on system organ class and preferred terms.
A Treatment Emergent Adverse Event (TEAE) is defined as an event that has an onset date on or 
after the first day of exposure to randomised treatment, and no later than seven days after the last 
day of exposure to randomised treatment.
TEAEs are summarised descriptively, whereas AEs not defined as treatment emergent are presented 
in listings, including AEs reported in the 30-day follow-up period. The summaries of TEAEs are 
made displaying the number of subjects with at least one event, the percentage of subjects with at 
least one event, the number of events and the event rate per 100 subject years of exposure. These 
summaries are done by seriousness, severity, relation to insulin treatment, relation to technical 
complaint, premature treatment discontinuation due to AEs, AEs leading to withdrawal from trial 
and outcome.
Furthermore, summary tables based on system organ class and preferred terms are made for:
x
All TEAEs
x
Serious TEAEs
x
Possibly and probably related TEAEs
x
Severe TEAEs
x
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.
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Number of treatment emergent injection site reactions
Treatment emergent injection site reactions occurring during the trial will be summarised and listed.
Classification of Hypoglycaemia
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs on or after the first day of exposure to randomised treatment, and no later than 
one day after the last day of exposure to randomised treatment.
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.   
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the ADA classification of hypoglycaemia (see Figure 17–2).
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a 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: 
x
Severe hypoglycaemia according to the ADA classification.39
x
Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification39 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with or without 
symptoms consistent with hypoglycaemia. 
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomat c BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomat c 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed w th capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
Figure 17–1
Novo Nordisk classification of hypoglycaemia
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ADA classification39 of hypoglycaemia 
x
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or take other corrective actions. PG concentrations may not be 
available during an event, but neurological recovery following the return of PG to normal is 
considered sufficient evidence that the event was induced by a low PG concentration.
x
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).
x
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).
x
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.
x
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).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo- 
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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 
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(E) and the event rate per 100 years of exposure (R). Separate summaries are made by severity 
considering all episodes, nocturnal and daytime episodes using Novo Nordisk and ADA classified 
episodes. All episodes will also be summarised by category, including summaries in relation to time 
since start of meal, as occurring during 0.5, 1, 2, and 4 hours after start of meal, and from 2 hours 
(exclusive) to 4 hours (inclusive) after start of meal, respectively.
The number of treatment emergent severe or BG confirmed hypoglycaemic episodes (all, daytime, 
nocturnal, 0.5, 1, 2, and 4 hours and from 2 hours (exclusive) to 4 hours (inclusive) after start of the 
meal) will be analysed based on the FAS using a negative binomial regression model with a log-link 
function and the logarithm of the time period in which a hypoglycaemic episode is considered 
treatment emergent as offset. The model will include treatment and stratification (T1DM/T2DM), as 
factors. To the extent where data allow, separate analysis will be performed for severe 
hypoglycaemic episodes.
Change from baseline in clinical evaluations 16 weeks after randomisation:
Physical examination
The physical examination parameters (respiratory system, cardiovascular system, gastrointestinal 
system incl. mouth, central and peripheral nervous system, skin), and their change from baseline, 
will be summarised descriptively. All findings will be listed.
Vital signs
Vital signs include diastolic blood pressure, systolic blood pressure and pulse. The measurements 
will be summarised descriptively including summaries of the change from baseline.
Electrocardiogram
ECG findings will be summarised descriptively including summaries of the change from baseline. 
Change from baseline will be summarised as normal/abnormal not clinically significant/abnormal 
clinically significant categorisation in shift tables.
Eye examination
Eye examination findings, including right eye ophthalmoscopy and left eye ophthalmoscopy, will 
be summarised descriptively including summaries of the change from baseline. 
Change from baseline in clinical laboratory assessments 16 weeks after randomisation
Change from baseline 16 weeks after randomisation in central laboratory assessments:
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x
Haematology (haemoglobin blood, erythrocytes, haematocrit blood, leucocytes, thrombocytes)
x
Biochemistry (AST serum, calculated creatinine clearance serum, sodium serum, potassium 
serum, creatinine serum, total protein serum, albumin serum, alkaline phosphatase serum, ALT
serum, total bilirubin serum, GFR from creatinine adjusted for BSA)
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 both the actual values and 
the low/normal/high categorisation in shift tables.
Change from baseline in body weight and body mass index 16 weeks after randomisation
The measurements will be summarised descriptively using the actual values as mean change.
Change from baseline in body weight will be analysed based on all planned post baseline 
measurements until or at 16 weeks after randomisation using a statistical model similar to the 
primary analysis except with the corresponding baseline measurement as covariate.
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18 Ethics
18.1
Benefit-risk assessment of the trial
Benefits
All subjects included in the trial will be treated with basal-bolus regimen with insulin degludec
(marketed in China under the brand name Tresiba®) as the basal insulin. Inclusion and exclusion 
criteria have been chosen to ensure that subjects enrolling in the trial have T1DM or T2DM at a 
stage where basal-bolus treatment is needed (i.e. subjects must have been diagnosed with T1DM for 
one year or more or with T2DM for five years or more and must have been on a basal-bolus or
premix insulin treatment regimen at least 1 year prior to screening).
T2DM subjects taking metformin at the enrolment in the trial should continue the metformin 
treatment unchanged. Metformin plus basal/bolus insulin is a recommended treatment for subjects 
with T2DM and the combination of metformin and basal-bolus insulin therapy with faster aspart or 
NovoRapid® as the bolus insulin was included in the phase 3A faster aspart trials in T2DM.
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, subjects 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 subject and the investigator and the thorough 
evaluation of SMPG values 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 dietary training.
Trial products will be provided by Novo Nordisk free of charge during the trial. When treatment 
with trial products ends, the subject and investigator will decide on the best available treatment on 
the market. Novo Nordisk will not offer any free medications after the completion of the trial.
Risks
For the individual subject, the anticipated risks include hypoglycaemia, systemic allergic reactions, 
injection site reactions, lipodystrophy, medication errors and antibody development. The risks will 
be mitigated by the close supervision of the subjects.
The most common side effect of all available insulin preparations is hypoglycaemia. The 
investigator will explain to the subject how they should check their BG with the BG meter provided 
by Novo Nordisk and what precautions to take in case of low BG measurement. No maximum dose 
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of insulin is specified as doses are titrated individually. All subjects will perform 4-point profiles on 
a daily basis throughout the trial for safety purposes and for the purpose of insulin titration.
A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia 
occurs, it may occur earlier after an injection than with soluble human insulin. A phase 3A trial with
faster aspart in T2DM showed a slight shift in distribution of the occurrence of hypoglycaemic 
episodes in relation to a meal when comparing to NovoRapid®. A statistically significant higher rate 
of hypoglycaemic episodes was seen during the first 2 hours after a meal for faster aspart. This is
not unexpected and reflects the pharmacokinetic and pharmacodynamic properties of faster aspart.
All treatments are contraindicated in case of hypersensitivity to the active substances or any of the 
excipients. The risk of hypersensitivity is partly mitigated by excluding subject with known 
hypersensitivity towards any trials products or related products.
Injection site reactions can occur. The nature of the injection site reactions is expected to be mild, 
transient, and more of a visual character and is not expected to be of concern to the subject’s safety.
Lipodystrophy (including lipohypertrophy, lipoatrophy) at the injection site can occur. Continuous 
rotation of the injection site within the particular injection area may help to reduce the risk of 
developing these reactions.
The blood samples during meal tests might be inconvenient to the subjects, but are not of any safety 
concern.
Subjects in this trial will be using bolus and basal insulin administered via two differently colour 
coded prefilled 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. Subjects will be trained in distinguishing between the pens.
Summary of clinical trials
The pharmacokinetic and pharmacodynamic profiles of faster aspart consistently demonstrated a 
left shift compared to that of NovoRapid® in subjects with T1DM and the profiles for faster aspart 
and NovoRapid® were similar in overall shape. Faster aspart produced a faster onset of exposure 
and increased initial absorption rate compared to NovoRapid® resulting in a faster onset of action 
and increased early glucose-lowering effect. Overall, the differences in the pharmacokinetic and 
pharmacodynamic properties for faster aspart compared to NovoRapid® were consistent across 
trials.24 No safety concerns were raised during any of the trials.
Similar clinical pharmacology trials have not been performed in subjects with T2DM, however the 
phase 3A programme for faster aspart included trials in bolus naïve T2DM subjects. Non-inferiority 
to NovoRapid® with regard to HbA1c change from baseline was demonstrated. In subjects with 
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T2DM faster aspart statistically significantly improved control of the 1-hour PPG increment when 
compared to NovoRapid®.24 No safety issues for faster aspart have been identified based on data
from the clinical development programme, and the safety profile is similar to NovoRapid®.24
Conclusion
Subjects in this trial are expected to 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 aspart in non-clinical and clinical studies taken together with review of the 
additional excipients in the faster aspart formulation have not revealed any safety issues that would 
prohibit the administration of faster 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 aspart outweigh the potential risks of participating in this trial.
18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP44 and the requirements in the Declaration of 
Helsinki47.
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.  
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
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If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue trial product.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled
as follows:
x
Data already collected and any data collected at the end-of-trial visit including follow up visits 
will be retained by Novo Nordisk, entered into the database and used for the CTR.
x
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
The subject may receive a “welcome to the trial letter” and a “thank you for your participation 
letter” after completion of the trial. Further the subject may receive letters during the trial. 
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. 
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process, 
see Section 19.1. Novo Nordisk will monitor protocol deviations on an ongoing basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff).
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20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk
must be received and the following documents must be available to Novo Nordisk:
x
Regulatory approval and/or acknowledgement of notification as required 
x
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
x
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
x
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
x
Signed receipt of Investigator’s Brochure, SmPC or similar labelling.
x
Signed and dated Agreement on Protocol
x
Signed and dated Agreement on Protocol Amendment, if applicable
x
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
x
Source document agreement
x
Central laboratory certification and normal ranges
x
Insurance statement, if applicable
x
Financial disclosure form from investigator and sub-investigator(s)
Novo Nordisk will analyse and report data from all sites together. By signing the protocol 
agreement, each investigator agrees to comply fully with ICH GCP44 applicable regulatory 
requirements and the Declaration of Helsinki47.
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorised persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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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 CTR for this trial.
One or two investigator(s) will be appointed by Novo Nordisk to review and sign the CTR
(signatory investigator) on behalf of all participating investigators. The signatory investigator(s)
will be appointed based upon the criteria defined by the ICMJE for research publications48.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure33.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the CTR is available. This includes the right not to release the results of interim 
analyses, because the release of such information may influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
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statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within 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 Editors48 (sometimes referred to as the Vancouver 
Criteria). Novo Nordisk will appoint investigator(s) to prepare publications in collaboration with 
Novo Nordisk.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion. 
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation 
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems
supplied by Novo Nordisk. These data must be retained by the trial site. If the provided data (e.g. 
the CD-ROM) is not readable during the entire storage period, the investigator can request a new 
copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.  
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs 
where a causal relationship cannot be ruled out, protocol amendments according to local 
requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the 
trial (including new benefit-risk analysis in case it will have an impact on the planned follow-up of 
the subjects), annually written summaries of the trial status, and other documents as required by the 
local IRB/IEC.
The investigator must ensure submission of the CTR synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the CTR according to national requirements.
For China, an international cooperative relevant report of related China’s Human Genetic Resources 
will be submitted based on local regulation requirements. 
26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence. Novo Nordisk assumes no liability in the event of negligence, or any other liability of 
the sites or investigators conducting the trial, or by persons for whom the said site or investigator 
are responsible.
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27 References
1.
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2 ), 
Current Step 4 version. 09 Nov 2016.
2.
Diabetes Control and Complications Trial Research Group. The effect of intensive treatment 
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N Engl J Med. 1993;329(14):977-86.
3.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications 
in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
4.
Woerle HJ, Neumann C, Zschau S, Tenner S, Irsigler A, Schirra J, et al. Impact of fasting 
and postprandial glycemia on overall glycemic control in type 2 diabetes - Importance of 
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5.
International Diabetes Federation Guideline Development G. Guideline for management of 
postmeal glucose in diabetes. Diabetes Res Clin Pract. 2014;103(2):256-68.
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Leiter LA, Ceriello A, Davidson JA, Hanefeld M, Monnier L, Owens DR, et al. Postprandial 
glucose regulation: New data and new implications. Clinical Therapeutics. 2005;27(Suppl 
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Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin 
aspart. A randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care. 
1999;22(5):801-5.
8.
American Diabetes Association. Standards of Medical Care in Diabetes - 2017. Diabetes 
Care. 2017;40(Supplement 1):48-56.
9.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position 
statement of the American Diabetes Association (ADA) and the European Association for 
the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-96.
10.
Meneghini L, Mersebach H, Kumar S, Svendsen AL, Hermansen K. A comparison of two 
intensification regimens with rapid-acting insulin aspart in type 2 diabetes inadequately 
controlled by once-daily insulin detemir and oral antidiabetes drugs: the STEP-Wise 
randomized study. Endocr Pract. 2011:1-26.
11.
Liebl A, Prager R, Binz K, Kaiser M, Bergenstal R, Gallwitz B, et al. Comparison of insulin 
analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: a 
randomized controlled trial. Diabetes Obes Metab. 2009;11(1):45-52.
12.
Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, et al. Insulin 
degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment 
with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, 
randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1498-
507.
13.
Home PD, Lindholm A, Riis A, European Insulin Aspart Study Group. Insulin aspart vs. 
human insulin in the management of long-term blood glucose control in Type 1 diabetes 
mellitus: a randomized controlled trial. Diabet Med. 2000;17(11):762-70.
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14.
Raskin P, Riis A, Guthrie RA, Jovanovic L, Leiter L. Use of insulin aspart, a fast-acting 
insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. 
Diabetes Care. 2000;23(5):583-8.
15.
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.
16.
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):606-11.
17.
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):1023-7.
18.
Novo Nordisk A/S. NovoRapid® FlexTouch® (insulin aspart), China Product Insert, 22 April 
2016.
19.
Novo Nordisk A/S. NovoRapid® Penfill®, (insulin aspart), Hong Kong Product Insert, 27
Feb 2015.
20.
Heise T, Pieber TR, Danne T, Erichsen L, Haahr H. A Pooled Analysis of Clinical 
Pharmacology Trials Investigating the Pharmacokinetic and Pharmacodynamic 
Characteristics of Fast-Acting Insulin Aspart in Adults with Type 1 Diabetes. Clin 
Pharmacokinet. 2017;56(5):551-9.
21.
Russell-Jones D, Bode BW, De Block C, Franek E, Heller SR, Mathieu C, et al. Fast-Acting 
Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: 
Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, 
Parallel-Group Trial (onset 1). Diabetes Care. 2017;40(7):943-50.
22.
Bowering K, Case C, Harvey J, Reeves M, Sampson M, Strzinek R, et al. Faster Aspart 
Versus Insulin Aspart as Part of a Basal-Bolus Regimen in Inadequately Controlled Type 2 
Diabetes: The onset 2 Trial. Diabetes Care. 2017;40(7):951-7.
23.
Bowering K CC, Harvey J ea. Faster-acting insulin aspart vs insulin aspart as part of basal-
bolus therapy improves postprandial glycemic control in uncontrolled T2D in the double-
blinded onset® 2 trial. Diabetes, 2016;65(suppl1):A63. 2016.
24.
Novo Nordisk A/S. Investigator's Brochure, Fast-acting Insulin Aspart, (12th Edition). 2018.
25.
Novo Nordisk A/S. Tresiba® FlexTouch® (insulin degludec), China Product Insert. 20 Sep 
2017.
26.
Novo Nordisk A/S. Tresiba® FlexTouch® (insulin degludec), Hong Kong Product Insert. 29
Nov 2017.
27.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on clinical investigation of medicinal products in the treatment or prevention of 
diabetes mellitus (CPMP/EWP/1080/00 Rev. 1). Adoption by CHMP. 14 May 2012.
28.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment 
and Prevention, Draft Guidance. February 2008.
29.
China Food and Drug Administration. Guidance on developing drugs and therapeutic 
biologics for treatment of diabetes mellitus. May 2012.
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30.
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):30-7.
31.
Chinese Diabetes Society. Chinese guideline of insulin therapy for type 1 diabetes. Chin J 
Diabetes Mellitus. 2016;8(10):591-7.
32.
Chinese Diabetes Society. Chinese Guideline for Type 2 Diabetes. Chinese Journal of 
Diabetes Mellitus. 2014;6:447-98.
33.
Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx.
34.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
35.
U.S. Food and Drug Administration. Food and Drug Administration Amendments Act of 
2007 as amended by the Final Rule "Clinical Trials Registration and Results Information 
Submission". 21 September 2016.
36.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 01 May
2001.
37.
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 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.
38.
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22.
39.
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.
40.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
41.
US Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims. December 
2009.
42.
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42.
43.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products. Brussels. 03 February 2010.
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44.
Harmonisation ICo. ICH Harmonised Tripartite Guideline: Guideline for Good Clinical 
Practice E6 (R1), Step 4. 1996.
45.
ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9, Current 
step 4 version. 5 Feb 1998.
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):777-81.
47.
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. 1 Oct 2013.
48.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
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Protocol - Appendix A1 T1DM
Status:
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Appendix A1: Insulin Titration Guideline for T1DM subjects
Trial ID: NN1218-4357
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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Table of Contents
Page
Table of Contents..............................................................................................................................................2 
List of in-text tables..........................................................................................................................................2 
1 
Introduction...............................................................................................................................................3 
2 
Treatment regimens..................................................................................................................................4 
2.1 
Run-in ............................................................................................................................................4 
2.1.1 
Basal treatment ............................................................................................................4 
2.1.2 
Bolus treatment............................................................................................................4 
2.2 
Randomisation ...............................................................................................................................4 
2.3 
Treatment period............................................................................................................................4 
2.4 
Injection area..................................................................................................................................4 
2.5 
Time of injection............................................................................................................................5 
3 
Initiation and titration ..............................................................................................................................6 
3.1 
Initiation at Visit 2.........................................................................................................................6 
3.1.1 
Initiation of insulin degludec .......................................................................................6 
3.1.2 
Initiation of NovoRapid®.............................................................................................8 
3.2 
Titration during run-in (Visit 2 – Visit 9)......................................................................................8 
3.2.1 
Titration of insulin degludec........................................................................................8 
3.2.2 
Titration of NovoRapid®..............................................................................................9 
3.3 
Titration during treatment period (Visit 10 – Visit 26)..................................................................9 
3.3.1 
Titration of insulin degludec........................................................................................9 
3.3.2 
Titration of faster aspart/NovoRapid® .........................................................................9 
3.4 
Deviations from the algorithm.....................................................................................................10 
4 
Data collection .........................................................................................................................................11 
5 
Review procedure....................................................................................................................................12 
6 
References................................................................................................................................................13 
List of in-text tables
Page
Table 1 
Initiation of basal insulin (insulin degludec)..................................................................................6 
Table 2 
Start doses of total basal (insulin degludec) and bolus insulins (faster aspart or 
NovoRapid®).................................................................................................................................7 
Table 3 
Initiation of bolus insulin...............................................................................................................8 
Table 4 
Insulin degludec dose escalation....................................................................................................8 
Table 5 
Insulin degludec dose reduction.....................................................................................................9 
Table 6 
Faster aspart/NovoRapid® dose adjustment.................................................................................10 
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1
Introduction
The goal of insulin therapy is to achieve near normoglycemia, i.e. to reach a pre-defined glycated 
haemoglobin (HbA1c) level with a low rate of hypoglycaemic episodes and as little weight gain as 
possible. Several trials have shown that this is difficult to achieve, unless plasma glucose (PG) 
values are intensively monitored and the insulin dose(s) frequently adjusted1-7.
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/her clinical judgement to avoid safety hazards. The investigator is responsible for the treatment 
of the subjects and can therefore overrule the guideline.
To optimise and maintain glycaemic control, the investigator should, throughout the trial, be at least 
in weekly contact with the subjects to assist the subjects in adjusting insulin doses and to ensure the 
subjects’ welfare.
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2
Treatment regimens
First dosing will take place on the day of Visit 2 (start of run-in) or the day following Visit 2.
There are no minimum or maximum doses of insulin degludec or faster aspart/NovoRapid®.
2.1
Run-in
2.1.1
Basal treatment
At Visit 2 eligible subjects will be transferred from their previous basal insulin dose or premix 
insulin dose to insulin degludec once daily (OD) according to Table 1.
During the following 8 weeks the investigator will focus on adjusting the insulin degludec dose 
according to Section 3.2.1.
2.1.2
Bolus treatment
In addition, the subjects will at Visit 2 start on or be transferred to NovoRapid® as bolus insulin 
(Table 2) and adjusted according to Section 3.1.2.
2.2
Randomisation
At randomisation Visit 10 (after 8 weeks) eligible subjects will be randomised 1:1 into two parallel 
treatment groups:
1. Faster aspart + insulin degludec
2. NovoRapid® + insulin degludec
2.3
Treatment period
During the 16-week treatment period the investigator will focus on adjusting the bolus dose 
according to Section 3.3.2.
2.4
Injection area
Insulin degludec should be injected subcutaneously into the abdomen, the thigh or the upper arm.
Faster aspart or NovoRapid® should be injected into the abdomen or upper arm.
The chosen region should be the same throughout the trial. Rotation of injection sites within a given 
region is recommended.
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2.5
Time of injection
Insulin degludec should be injected once daily at any time of the day, but approximately at the same 
time of the day throughout the trial.
Faster aspart or NovoRapid® should be injected 0-2 minutes prior to the main meals.
Main meals are defined as breakfast, lunch and dinner. Extra bolus dosing is allowed at the 
investigator’s recommendation.
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3
Initiation and titration  
3.1
Initiation at Visit 2
3.1.1
Initiation of insulin degludec 
Subjects should be transferred to insulin degludec OD according to Table 1.
Table 1
Initiation of basal insulin (insulin degludec)
Pre-trial treatment
Visit 2
Basal OD/BID
Consider reducing total daily dose by 20%
Premix BID/TID
Calculate the total daily dose of insulin. Adjust
the basal-to-bolus ratio* to be between 40:60 
and 60:40
* According to the Chinese Diabetes Society (CDS)
The desired total daily basal and bolus doses can be found in Table 2.
Example on transfer from premix two times daily (BID) or three times daily (TID) to insulin 
degludec:
x
The total daily dose a given subject should receive is 28 Units (U) per day. 
x
According to Table 2, the subject should receive a total of 11U of insulin degludec and a 
total of 17U of bolus insulin, if the basal: bolus ratio is 40:60. If the ratio is 60:40, the
subject should receive a total of 17U of insulin degludec and a total of 11U of bolus insulin.
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Date:
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Trial ID: NN1218-4357
Version:
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Protocol - Appendix A1 T1DM
Status:
Final
UTN: U1111-1197-8289 
Page:
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Table 2
Start doses of total basal (insulin degludec) and bolus insulin ( NovoRapid®)
Total daily insulin dose
Basal:bolus ratio 40:60
Basal:bolus ratio 60:40
Total insulin degludec
Total bolus insulin
Total insulin degludec
Total bolus insulin
10
4
6
6
4
12
5
7
7
5
14
6
8
8
6
16
6
10
10
6
18
7
11
11
7
20
8
12
12
8
22
9
13
13
9
24
10
14
14
10
26
10
16
16
10
28
11
17
17
11
30
12
18
18
12
32
13
19
19
13
34
14
20
20
14
36
14
22
22
14
38
15
23
23
15
40
16
24
24
16
42
17
25
25
17
44
18
26
26
18
46
18
28
28
18
48
19
29
29
19
50
20
30
30
20
52
21
31
31
21
54
22
32
32
22
56
22
34
34
22
58
23
35
35
23
60
24
36
36
24
62
25
37
37
25
64
26
38
38
26
66
26
40
40
26
68
27
41
41
27
70
28
42
42
28
72
29
43
43
29
74
30
44
44
30
76
30
46
46
30
78
31
47
47
31
80
32
48
48
32
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A1 T1DM
Status:
Final
UTN: U1111-1197-8289 
Page:
8 of 13
3.1.2
Initiation of NovoRapid®
Subjects should be switched to/start on NovoRapid® TID daily according to Table 3.
Table 3
Initiation of bolus insulin
Pre-trial treatment
Visit 2
Bolus insulin
U to U, continue using same number of units 
with breakfast, lunch and dinner as pre-trial
Premix BID/TID
Calculate the total daily dose of insulin. Adjust 
the basal-to-bolus ratio to be between 40:60 and 
60:40. Use table 2 to find the total number of 
bolus insulin units and divide this value into 
three even or uneven doses of NovoRapid® to 
be taken with breakfast, lunch and dinner.
3.2
Titration during run-in (Visit 2 – Visit 9)
3.2.1
Titration of insulin degludec 
Insulin degludec will be adjusted once weekly by the investigator during the run-in period in 
connection with the scheduled visit/phone contacts.
The dose of insulin degludec should be adjusted based on the mean of three pre-breakfast self-
measured plasma glucose (SMPG) values measured on Day -2, Day -1 and on the day of titration. 
The adjustment should be according to Table 4.
Table 4
Insulin degludec dose escalation
Mean pre-breakfast SMPG values
Dose adjustment
mmol/L
mg/dL
U
4.0 – 5.0
71 – 90
0
5.1 – 10.0
91 – 180
2
10.1 – 15.0
181 – 270
4
> 15.0
> 270
6
If one or more pre-meal SMPG value(s) are < 4.0 mmol/L (< 71 mg/dL) subjects should 
reduce insulin degludec dose according to Table 5
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A1 T1DM
Status:
Final
UTN: U1111-1197-8289 
Page:
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Table 5
Insulin degludec dose reduction
Lowest pre-breakfast SMPG value
Dose adjustment
mmol/L
mg/dL
U
3.1 – 3.9
56 – 70
-2
< 3.1
< 56
-4
3.2.2
Titration of NovoRapid®
Titration of NovoRapid® for safety reasons can be done at the discretion of the investigator.
3.3
Titration during treatment period (Visit 10 – Visit 26)
3.3.1
Titration of insulin degludec 
Titration of insulin degludec for safety reasons can be done at the discretion of the investigator.
3.3.2
Titration of faster aspart/NovoRapid®
At Visit 10, subjects will be randomised to receive either faster aspart or NovoRapid® as bolus 
insulin in a double-blind manner. Faster aspart/NovoRapid® will hereafter be called bolus insulin.
Titration of bolus insulin should be done following the bolus dosing algorithm.
Bolus insulin will be adjusted weekly by the investigator during the treatment period. 
The dose of bolus insulin will be based on SMPG values measured on the last 3 days (days – 3, –2
and – 1) before the day of titration.
The adjustment should be according to Table 6 :
x
Breakfast dose will be titrated according to pre-lunch SMPG values measured on the 
previous 3 days
x
Lunch dose will be titrated according to pre-dinner SMPG values measured on the previous 
3 days
x
Dinner dose will be titrated according to bedtime SMPG values measured on the previous 3 
days 
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A1 T1DM
Status:
Final
UTN: U1111-1197-8289 
Page:
10 of 13
Table 6
Faster aspart/NovoRapid® dose adjustment
Pre-prandial or bedtime SMPG values
Dose adjustment
Rules for dose adjustment
mmol/L
mg/dL
U
< 4.0
< 71
-1
≥ 1 SMPG below target
4.0 – 6.0
71 – 108
0
0-1 SMPG above target
No SMPG below target
> 6.0
> 108
+1
≥ 2 SMPGs above target
No SMPG below target
Additional bolus dosing is allowed at the investigator’s recommendation. The dose should be 
entered in the eCRF.
3.4
Deviations from the algorithm
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust the insulin doses is based on all relevant information as described in Section 1. A reason for 
deviating from the algorithm should be entered in the eCRF.
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A1 T1DM
Status:
Final
UTN: U1111-1197-8289 
Page:
11 of 13
4
Data collection
The following data should be available for Novo Nordisk’s Insulin Titration Group within 24 hours
(on weekdays) after a site visit/phone contact:
x
SMPG values 
x
Date, dose and time point of insulin doses taken 
x
New insulin doses prescribed after titration
x
Reason for deviation between the recommended and the prescribed basal insulin dose
x
Reason for deviation between the recommended and actual bolus insulin dose
x
Hypoglycaemic episodes (Protocol Section 8.4.2)
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A1 T1DM
Status:
Final
UTN: U1111-1197-8289 
Page:
12 of 13
5
Review procedure
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased manner. It 
is important that titration data and hypoglycaemic episodes are entered the eCRF within 24 hours
(on weekdays). If delays occur, action cannot be taken in due time before the subject’s next site 
visit/phone contact. The aim is to reduce the time periods in which a subject may receive 
suboptimal treatment.
The data listed in Section 4 will be reviewed by Novo Nordisk within 24 hours (on weekdays). The 
reviewer may contact the investigator to get clarification regarding the reason for deviation or to 
request entry of missing data.
When the investigator receives an inquiry, a response should be received at Novo Nordisk within 24 
hours (on weekdays). 
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the 
glycaemic control. Novo Nordisk may be in contact with sites (visit or phone contact) to discuss 
progress in glycaemic control and titration of individual subjects based on SMPGs and HbA1c.
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A1 T1DM
Status:
Final
UTN: U1111-1197-8289 
Page:
13 of 13
6
References  
1.
Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 
52-week, treat-to-target trial comparing insulin detemir with insulin glargine when 
administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 
diabetes. Diabetologia. 2008;51(3):408-16.
2.
Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, Home P, et al. A 26-week, 
randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as 
add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. 
Diabetes Care. 2006;29(6):1269-74.
3.
Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. 
Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral 
antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28(10):1569-81.
4.
Riddle MC, Rosenstock J, Gerich J, Insulin Glargine Study Investigators. The treat-to-target 
trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 
diabetic patients. Diabetes Care. 2003;26(11):3080-6.
5.
Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, et al. Insulin 
degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment 
with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, 
randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1498-
507.
6.
Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. Insulin degludec, an ultra-
longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime 
insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-
label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-97.
7.
Christiansen JS, Vaz JA, Metelko Z, Bogoev M, Dedov I. Twice daily biphasic insulin 
aspart improves postprandial glycaemic control more effectively than twice daily NPH 
insulin, with low risk of hypoglycaemia, in patients with type 2 diabetes. Diabetes Obesity 
& Metabolism. 2003;5(6):446-54.
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
1 of 11
Appendix A2: Insulin Titration Guideline for T2DM subjects
Trial ID: NN1218-4357
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
2 of 11
Table of Contents
Page
Table of Contents..............................................................................................................................................2 
List of in-text tables..........................................................................................................................................2 
1 
Introduction...............................................................................................................................................3 
2 
Treatment regimens..................................................................................................................................4 
2.1 
Run-in ............................................................................................................................................4 
2.1.1 
Basal treatment ............................................................................................................4 
2.1.2 
Bolus treatment............................................................................................................4 
2.2 
Randomisation ...............................................................................................................................4 
2.3 
Treatment period............................................................................................................................4 
2.4 
Injection area..................................................................................................................................4 
2.5 
Time of injection............................................................................................................................5 
3 
Initiation and titration ..............................................................................................................................6 
3.1 
Initiation at Visit 2.........................................................................................................................6 
3.1.1 
Initiation of insulin degludec .......................................................................................6 
3.1.2 
Initiation of NovoRapid®.............................................................................................6 
3.2 
Titration during run-in (Visit 2 – Visit 9)......................................................................................6 
3.2.1 
Titration of insulin degludec........................................................................................6 
3.2.2 
Titration of NovoRapid®..............................................................................................7 
3.3 
Titration during treatment period (Visit 10 – Visit 26)..................................................................7 
3.3.1 
Titration of insulin degludec........................................................................................7 
3.3.2 
Titration of faster aspart/NovoRapid® .........................................................................7 
3.4 
Deviations from the algorithm.......................................................................................................8 
4 
Data collection ...........................................................................................................................................9 
5 
Review procedure....................................................................................................................................10 
6 
References................................................................................................................................................11 
List of in-text tables
Page
Table 1 
Initiation of basal insulin (insulin degludec).................................................................................6 
Table 2 
Initiation of bolus insulin..............................................................................................................6 
Table 3 
Insulin degludec dose escalation....................................................................................................7 
Table 4 
Insulin degludec dose reduction.....................................................................................................7 
Table 5 
Faster aspart/NovoRapid® dose adjustment...................................................................................8 
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
3 of 11
1
Introduction
The goal of insulin therapy is to achieve near normoglycemia, i.e. to reach a pre-defined glycated 
haemoglobin (HbA1c) level with a low rate of hypoglycaemic episodes and as little weight gain as 
possible. Several trials have shown that this is difficult to achieve, unless plasma glucose (PG) 
values are intensively monitored and the insulin dose(s) frequently adjusted1-7.
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/her clinical judgement to avoid safety hazards. The investigator is responsible for the treatment 
of the subjects and can therefore overrule the guideline.
To optimise and maintain glycaemic control, the investigator should, throughout the trial be at least 
in weekly contact with the subjects to assist the subjects in adjusting insulin doses and to ensure the 
subjects’ welfare.
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
4 of 11
2
Treatment regimens
First dosing will take place on the day of Visit 2 (start of run-in) or the day following Visit 2.
There are no minimum or maximum doses of insulin degludec or faster aspart/NovoRapid®.
2.1
Run-in
2.1.1
Basal treatment
At Visit 2 eligible subjects will be transferred from their previous basal insulin dose or premix 
insulin dose to insulin degludec once daily (OD) according to Table 1.
During the following 8 weeks the investigator will focus on adjusting the basal insulin dose 
according to Section 3.2.1
2.1.2
Bolus treatment
In addition, the subjects will at Visit 2 start on or be transferred to NovoRapid® as bolus insulin 
(Table 2) and adjusted according to Section 3.1.2.
2.2
Randomisation
At randomisation Visit 10 (after 8 weeks) eligible subjects will be randomised 1:1 into two parallel 
treatment groups:
1. Faster aspart + insulin degludec ± metformin
2. NovoRapid® + insulin degludec ± metformin
2.3
Treatment period
During the 16-week treatment period the investigator will focus on adjusting the bolus insulin dose 
according to Section 3.3.2.
2.4
Injection area
Insulin degludec should be injected subcutaneously into the abdomen, the thigh or the upper arm. 
Faster aspart or NovoRapid® should be injected into the abdomen or upper arm. 
The chosen region should be the same throughout the trial. Rotation of injection sites within a given 
region is recommended.
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
5 of 11
2.5
Time of injection
Insulin degludec should be injected once daily at any time of the day and should approximately be 
the same time of the day throughout the trial.
Faster aspart or NovoRapid® should be injected 0-2 minutes prior to the main meals.
Main meals are defined as breakfast, lunch and dinner. Extra bolus dosing is allowed at the 
investigator’s recommendation.
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
6 of 11
3
Initiation and titration  
3.1
Initiation at Visit 2
3.1.1
Initiation of insulin degludec 
Subjects should be transferred to insulin degludec OD according to Table 1.
Table 1
Initiation of basal insulin (insulin degludec)
Pre-trial treatment
Visit 2
Basal OD
U to U
Basal BID
Reduce total daily basal dose by 20%
Premix BID/TID
Calculate the basal component of the total daily 
dose (basal & bolus) and reduce the basal dose 
by 20%
Two times daily (BID), three times daily (TID), Units (U).
3.1.2
Initiation of NovoRapid®
Subjects should be switched to/start on NovoRapid® TID according to Table 2.
Table 2
Initiation of bolus insulin
Pre-trial treatment
Visit 2
Bolus insulin
U to U, continue using same number of units 
with breakfast, lunch and dinner as pre-trial
Premix BID/TID
Calculate the daily bolus units from the bolus 
component of the total daily dose.
Split the calculated number into three even or 
uneven doses of NovoRapid® to be taken with
breakfast, lunch and dinner
3.2
Titration during run-in (Visit 2 – Visit 9)
3.2.1
Titration of insulin degludec 
Insulin degludec will be adjusted once weekly by the investigator during the run-in period in 
connection with the scheduled visit/phone contacts.
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Date:
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Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
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Insulin degludec should be adjusted based on the mean of three pre-breakfast SMPG values 
measured on Day -2, Day -1 and on the day of titration. The adjustment should be according to 
Table 3.
Table 3
Insulin degludec dose escalation
Mean pre-breakfast SMPG values
Dose adjustment
mmol/L
mg/dL
U
4.0 – 5.0
71 – 90
0
5.1 – 7.0
91 – 126
+2
7.1 – 8.0
127 – 144
+4
8.1 – 9.0
145 – 162
+6
> 9.0
> 162
+8
If one or more pre-meal SMPG value(s) are < 4.0 mmol/L (< 71 mg/dL) subjects should reduce 
insulin degludec dose according to Table 4.
Table 4
Insulin degludec dose reduction
Lowest pre-breakfast SMPG value
Dose adjustment
mmol/L
mg/dL
U
3.1 – 3.9
56 – 70
-2
< 3.1
< 56
-4
3.2.2
Titration of NovoRapid®
Titration of NovoRapid® for safety reasons can be done at the discretion of the investigator.
3.3
Titration during treatment period (Visit 10 – Visit 26)
3.3.1
Titration of insulin degludec 
Titration of insulin degludec for safety reasons can be done at the discretion of the investigator.
3.3.2
Titration of faster aspart/NovoRapid®
At V10, subjects will be randomised to receive either faster aspart or NovoRapid® as bolus insulin 
in a double-blind manner. Faster aspart/NovoRapid® will hereafter be called bolus insulin.
Bolus insulin will be adjusted weekly by the investigator during the treatment period. 
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
8 of 11
The dose of bolus insulin will be based on self-measured plasma glucose (SMPG) values measured 
on the 3 days (days – 3, –2 and – 1) before day of titration. 
The adjustment should be according to 
Table 5:
x
Breakfast dose will be titrated according to pre-lunch SMPG values measured on the 
previous 3 days
x
Lunch dose will be titrated according to pre-dinner SMPG values measured on the previous 
3 days
x
Dinner dose will be titrated according to bedtime SMPG values measured on the previous 3 
days 
Table 5
Faster aspart/NovoRapid® dose adjustment
Pre-prandial or bedtime SMPG values
Dose adjustment
Rules for dose adjustment
mmol/L
mg/dL
U
< 4.0
< 71
-1
≥ 1 SMPG below target
4.0 – 6.0
71 – 108
0
0-1 SMPG above target
No SMPG below target
> 6.0
> 108
+1
≥ 2 SMPGs above target
No SMPG below target
Additional bolus dosing is allowed at the investigator’s recommendation. The dose will be entered 
in the eCRF.
3.4
Deviations from the algorithm
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust the insulin doses is based on all relevant information as described in Section 1. A reason for 
deviating from the algorithm should be entered in the eCRF .
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
9 of 11
4
Data collection
The following data should be available for Novo Nordisk’s Insulin Titration Group within 24 hours
(on weekdays) after a site visit/phone contact:
x
SMPG values 
x
Date, dose and time point of insulin doses taken 
x
New insulin doses prescribed after titration
x
Reason for deviation between the recommended and the prescribed basal insulin dose
x
Reason for deviation between the recommended and actual bolus insulin dose
x
Hypoglycaemic episodes (Protocol Section 8.4.2)
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
Page:
10 of 11
5
Review procedure
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased manner. It 
is important that titration data regarding dose titration is entered into the eCRF within 24 hours (on 
weekdays). If delays occur, action cannot be taken in due time before the subject’s next site 
visit/phone contact. The aim is to reduce the time periods in which a subject may receive 
suboptimal treatment.
The data listed in Section 4 will be reviewed by Novo Nordisk within 24 hours (on weekdays). The 
reviewer may contact the investigator to get clarification regarding the reason for deviation or to 
request entry of missing data.
When the investigator receives an inquiry, a response should be received at Novo Nordisk within 24 
hours (on weekdays). 
During the trial HbA1c will be monitored by Novo Nordisk for additional surveillance of the 
glycaemic control. Novo Nordisk may be in contact with sites (visit or phone contact) to discuss 
progress in glycaemic control and titration of individual subjects based on SMPGs and HbA1c.
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Date:
30 November 2020
Novo Nordisk
Trial ID: NN1218-4357
Version:
5.0
Protocol - Appendix A2 T2DM
Status:
Final
UTN: U1111-1197-8289 
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):408-16.
2.
Hermansen K, Davies M, Derezinski T, Ravn GM, Clauson P, Home P, et al. A 26-week, 
randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as 
add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. 
Diabetes Care. 2006;29(6):1269-74.
3.
Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. 
Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral
antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28(10):1569-81.
4.
Riddle MC, Rosenstock J, Gerich J, Insulin Glargine Study Investigators. The treat-to-target 
trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 
diabetic patients. Diabetes Care. 2003;26(11):3080-6.
5.
Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, et al. Insulin 
degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment 
with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, 
randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1498-
507.
6.
Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. Insulin degludec, an ultra-
longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime 
insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-
label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-97.
7.
Christiansen JS, Vaz JA, Metelko Z, Bogoev M, Dedov I. Twice daily biphasic insulin 
aspart improves postprandial glycaemic control more effectively than twice daily NPH 
insulin, with low risk of hypoglycaemia, in patients with type 2 diabetes. Diabetes Obesity 
& Metabolism. 2003;5(6):446-54.
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Log of Protocols 
 
Date: 
01 July 2022 
Novo Nordisk 
Trial ID: NN1218-4357 
Version: 
1.0 
 UTN: U1111-1197-8289 
Status: 
Final 
  
Page: 
1 of 1 
 
	
 
Date 
 
Final, version 
Protocol includes the following amendments 
24 October 2017 
1.0 
NA 
01 December 2017 
2.0 
Protocol update 2.0 rationale (VV-TMF-526750) 
01 July 2019 
3.0 
Amendment 1.0 dated 1July2019 (VV-TMF-
1095147) 
03 April 2020 
4.0 
Amendment 2.0 dated 03 Apr 2020 (VV-TMF-
1349704) 
30 November 2020 
5.0 
All changes are documented in the 
Protocol track-changes version: VV-TMF-
3967346 
 
 
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Log of Protocol Amendments
UTN: U1111-1197-8289
Date:
01 December 2020
Status:
Final
Novo Nordisk
Trial ID: NN1218-4357
Version:
1.0
Page:
1 of 2
Log of Protocol Amendments
Protocol
amendment no
Date
Final,
Version
Country(ies) and/or trial 
site(s) affected
Brief content
1
01 July 2019
1.0
China
Protocol Version 2.0 dated 01 Dec 2017 has 
been updated with substantial- and minor 
changes.
-
Inclusion criteria 4 and 5 have been 
modified to better reflect clinical practice
-
Exclusion criterion No 7 and 14 have
been deleted and modified, respectively.
Criterion 7 is covered by exclusion 
criterion No 12. Criterion 14 has been 
updated to reflect clinical practice.
-
PK has been taken out of protocol as 
sufficient data is obtained from NN1218-
4316 phase 1 trial and supportive global 
PK data.
-
Titration approach has been simplified 
from twice to once weekly titration
-
Carbohydrate counting has been taken 
out as it is not clinical practice in China
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Log of Protocol Amendments
UTN: U1111-1197-8289
Date:
01 December 2020
Status:
Final
Novo Nordisk
Trial ID: NN1218-4357
Version:
1.0
Page:
2 of 2
Protocol
amendment no
Date
Final,
Version
Country(ies) and/or trial 
site(s) affected
Brief content
-
Changes to section 12 to align with 
current safety definitions and reporting 
practice
-
All the changes are documented in 
protocol version 3.0 dated 1. July 2019 
with track changes
2
03 Apr 2020
1.0
China
-
All changes are documented in protocol 
version 4.0 date 03 Apr 2020 with track 
changes (VV-TMF-1349791)
3
30 Nov 2020
1.0
China
All changes are documented in protocol version 5.0 , 
Protocol amendment summary of changes table on
page 2, as well as in track changes version of the 
protocol and the appendices a1 and a2 available in 
Veeva Vualt. 
Please note that there are no changes to Appendix a2 
other than aligning date and version with the 
protocol.
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9.1.01
Protocol Attachment
Protocol Attachment I is located in the Trial Master File.
If applicable, Protocol Attachment II is also located in the Trial Master File.
Content: Global key staff and Country key staff.
Date:
Novo Nordisk
Version:
Status:
Faster acting insulin aspart
Study ID: NN1218 4357
Clinical Study Report
Appendix 9.1.1
16 January 2023
1.0
Final
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CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04588259 
Sponsor trial ID: 
NN1218-4357 
Official title of study: 
Efficacy and Safety of Fast-acting Insulin Aspart Compared to 
NovoRapid® both in Combination with Insulin Degludec with 
or without Metformin in Adults with Diabetes 
Document date* 
26 September 2022 
 
* Document date refers to the date on which the document was most recently updated. 
Note: The date in the header of page 2 is the date of the compilation of the documents and not of an update to content. 


Link
List of contents
Statistical analysis plan......................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Faster acting insulin aspart
Study ID: NN1218 4357
Clinical Study Report
Appendix 9.1.9
16 January 2023
1.0
Final
9.1.9 Documentation of statistical methods
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
Page: 
1 of 22 
Statistical Analysis Plan 
Trial ID: NN1218-4357 
Efficacy and Safety of Fast-acting Insulin Aspart Compared to 
NovoRapid® both in Combination with Insulin Degludec with 
or without Metformin in Adults with Diabetes 
Author: 
Biostatistics Insulin & Devices 3 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
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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.
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
Page: 
2 of 22 
 
Table of contents 
 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 3 
Table of tables ................................................................................................................................................... 4 
Version History ................................................................................................................................................. 5 
List of abbreviations ......................................................................................................................................... 6 
1 Introduction ................................................................................................................................................. 7 
1.1 
Objectives, Endpoints, and Estimands ................................................................................................ 7 
1.2 
Study Design ....................................................................................................................................... 8 
1.2.1 
Trial information ................................................................................................................. 8 
2 Statistical Hypothesis ................................................................................................................................ 10 
3 Analysis Sets .............................................................................................................................................. 11 
4 Statistical Analyses .................................................................................................................................... 12 
4.1 
General considerations ...................................................................................................................... 12 
4.2 
Estimand ........................................................................................................................................... 12 
4.3 
Primary endpoint analysis ................................................................................................................. 12 
4.3.1 
Definition of Endpoint ....................................................................................................... 12 
4.3.2 
Main Analytical Approach ................................................................................................ 12 
4.3.3 
Additional analysis ............................................................................................................ 13 
4.3.4 
Sensitivity analysis for the primary analysis addressing the estimand .............................. 13 
4.4 
Secondary endpoints analyses ........................................................................................................... 14 
4.4.1 
Supportive secondary endpoints ........................................................................................ 14 
4.4.1.1 
Efficacy endpoints .......................................................................................... 14 
4.4.1.2 
Safety Analysis .............................................................................................. 17 
4.5 
Changes to Protocol-planned Analysis ............................................................................................. 20 
5 Sample size determination ........................................................................................................................ 21 
6 References .................................................................................................................................................. 22 
 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
Page: 
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Table of figures 
 
Page 
Figure 1-1 
 Trial design ................................................................................................................................. 9 
Figure 4-1 
Novo Nordisk classification of hypoglycaemia ......................................................................... 18 
Figure 4-2 
ADA classification of hypoglycaemia ....................................................................................... 19 
 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
Page: 
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Table of tables 
 
Page 
Table 5-1 
The power for non-inferiority for different scenarios ................................................................ 21 
 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
Page: 
5 of 22 
 
 
Version History 
 
This Statistical Analysis Plan (SAP) for study NN1218-4357 is based on the protocol version 5.0 
dated 30 Nov 2020. 
SAP Version 
Date 
Change 
Rationale 
1.0 
26Sep2022 
Not Applicable 
Original version 
 
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Statistical Analysis Plan 
 
Date: 
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Study ID:  NN1218-4357 
Version: 
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UTN: U1111-1197-8289 
Status: 
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Page: 
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List of abbreviations 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
BMI 
body mass index 
ECG 
electrocardiogram 
FAS 
full analysis set 
FPG 
fasting plasma glucose 
HbA1c 
glycosylated haemoglobin 
HDL 
high-density lipoprotein 
LDL 
low-density lipoprotein 
LLoQ 
lower limit of quantification 
MAR 
missing at random 
MMRM 
mixed model for repeated measurements 
PG 
plasma glucose 
PK 
pharmacokinetics 
SAE 
serious adverse event 
SMPG 
self-measured plasma glucose 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment-emergent adverse events 
UTN 
Universal Trial Number 
 
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Statistical Analysis Plan 
 
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Study ID:  NN1218-4357 
Version: 
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Status: 
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1 
Introduction 
1.1 
Objectives, Endpoints, and Estimands 
Primary Objective 
To confirm the effect in terms of glycaemic control of treatment with faster aspart compared to 
NovoRapid® both in combination with insulin degludec with or without metformin in Chinese 
adults with T1DM or T2DM inadequately treated with a basal-bolus or a premix regimen, using a 
non-inferiority approach 
 
Secondary objective 
To compare the safety of faster aspart to NovoRapid® both in combination with insulin degludec 
with or without metformin in Chinese adults with T1DM or T2DM inadequately treated with a 
basal-bolus or a premix regimen 
 
Primary estimand 
The primary estimand is defined as the treatment difference in change from baseline in HbA1c 16 
weeks after randomisation between treatment with faster aspart and treatment with NovoRapid® 
both in combination with insulin degludec with or without metformin in adult subjects with T1DM 
or T2DM on basal-bolus regimen with a basal optimisation if all had adhered to randomised 
treatment. This estimand aims to reflect the treatment effect for subjects that are actually able to 
take the drug during the intended treatment period. 
 
Primary endpoint 
 
• Change from baseline (week 0) in HbA1c to 16 weeks after randomisation 
 
Secondary endpoints 
 
Supportive secondary efficacy endpoints 
 
• Change from baseline in 30-minutes, 1-hour, 2-hour and 3-hour PPG increment to 16 weeks 
after randomisation (meal test) 
 
• Change from baseline in 30-minutes, 1-hour, 2-hour and 3-hour PPG to 16 weeks after 
randomisation (meal test) 
 
• Change from baseline in FPG to 16 weeks after randomisation 
• If a subject achieves HbA1c target 16 weeks after randomisation: 
• HbA1c < 7.0% 
• HbA1c < 7.0% without severe hypoglycaemia 
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Statistical Analysis Plan 
 
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Version: 
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Status: 
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• Change from baseline in 7-9-7-point SMPG to 16 weeks after randomisation: 
• Mean of the 7-9-7-point profile 
• 1-hour PPG and PPG increment (mean, breakfast, lunch, main evening meal) 
• Fluctuation in 7-9-7-point profile 
• If a subject achieves PPG target (overall mean of daily PPG measurements in SMPG) 16 weeks 
after randomisation: 
 
• Overall PPG (1-hour) ≤7.8 mmol/L 
• Overall PPG (1-hour) ≤7.8 mmol/L without severe hypoglycaemia 
• Insulin dose (Units/day and Units/kg/day; total basal, total bolus and individual meal insulin 
dose) 16 weeks after randomisation. 
 
Supportive secondary safety endpoints 
 
• Number of treatment emergent adverse events during the 16 weeks after randomisation 
• Number of treatment emergent injection site reactions during the 16 weeks after randomisation 
• Number of treatment emergent hypoglycaemic episodes classified both according to the ADA 
definition and Novo Nordisk definition during the 16 weeks after randomisation 
• Overall 
• Daytime and nocturnal hypoglycaemic episodes (00:01-05:59 – both inclusive) 
• Hypoglycaemic episodes from start of meal until 30 minutes, 1, 2, 4 hours and from 2 hours 
(exclusive) to 4 hours (inclusive) after start of meal 
1.2 
Study Design 
1.2.1 
Trial information 
This is a phase 3a, 16-week, multicentre, 1:1 randomised, double-blind, active controlled, treat-to-
target, two-arm parallel group, non-inferiority trial with an 8-week run-in period comparing the 
effect and safety of faster aspart to NovoRapid® both in combination with insulin degludec with or 
without metformin in subjects with T1DM or T2DM inadequately treated with a basal-bolus or a 
premix regimen. 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
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UTN: U1111-1197-8289 
Status: 
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Page: 
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Figure 1-1 
 Trial design 
 
*Treatment with metformin is only applicable for subjects with T2DM treated with metformin prior 
to the trial. 
The trial design is summarised in Figure 1-1. 
The total duration of the trial is approximately 30 weeks divided into the following periods: 
• An approximately 2-week screening period 
• An 8-week run-in period primarily for optimisation of the basal insulin treatment 
• A 16-week treatment period 
• A 30-day follow-up period: FU1; 7 days after end of treatment and FU2; 30 days after end of 
treatment 
The trial includes a screening visit to assess subject’s eligibility and additional weekly visits/phone 
contacts during the trial. After screening, all eligible subjects will be enrolled in an 8-week run-in 
period. All subjects eligible for the trial will receive novorapid and the basal insulin degludec with 
or without metformin once daily. After the run-in period, subjects eligible for randomisation (HbA1c 
≤ 9.0% measured at visit 9) will be randomised (1:1) to receive double blinded treatment with either 
faster aspart or NovoRapid® both in combination with once daily insulin degludec with or without 
metformin. To aim for an even distribution of treatment groups within T1DM and T2DM, the 
randomisation will be stratified according to the type of diabetes. 
All subjects will have a standardised meal test at baseline (V10 before randomisation) and at end of 
treatment (V26/V26A). The meal test is described in more details in the protocol Section 8.3.1.  
After the 16-week treatment period, the subject will have a 30-day safety follow-up period. 
For further details see the trial protocol. 
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Statistical Analysis Plan 
 
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Study ID:  NN1218-4357 
Version: 
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UTN: U1111-1197-8289 
Status: 
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2 
Statistical Hypothesis 
The primary endpoint is relative change from baseline (week 0) in HbA1c to 16 weeks after  
randomisation. 
Non-inferiority 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 (faster aspart minus 
NovoRapid®). 
Superiority will be based on the same 95% CI that was used for addressing the primary analysis.  
Superiority will be confirmed if the upper boundary of the two-sided 95% confidence interval of the  
mean treatment difference is below 0%. 
 
 
 
 
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Statistical Analysis Plan 
 
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Study ID:  NN1218-4357 
Version: 
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UTN: U1111-1197-8289 
Status: 
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3 
Analysis Sets 
The following analysis sets are defined in accordance with the ICH-E91 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 FAS, excluding subjects who: 
o Have violated any inclusion criteria 
o Have fulfilled any exclusion criteria 
Subjects in the PP analysis set will contribute to the evaluation “as treated”  
 Safety Analysis Set includes all subjects receiving at least one dose of randomised 
treatment. Subjects in the safety analysis set will contribute to the evaluation “as treated”  
Randomised subjects, who are lost to follow-up, and where no exposure information of the trial 
product or its comparator is available after randomisation, will be handled as unexposed. 
Before data are released for statistical review, a blinded review of all data will take place to identify 
serious non-adherence to the protocol that may potentially affect the results. Furthermore, extreme 
values and outliers will be identified by the statistician during programming and data review, 
according to ICH-E91. This will be performed by using a fake randomisation. 
The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented and signed by those responsible before database lock. The subjects and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
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Statistical Analysis Plan 
 
Date: 
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Study ID:  NN1218-4357 
Version: 
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UTN: U1111-1197-8289 
Status: 
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4 
Statistical Analyses 
4.1 
General considerations 
In general, for endpoints evaluated as a change from baseline and/or where a baseline adjustment is 
made, baseline is defined as information collected at randomisation (V10). In case a measurement is 
not available at randomisation, the most recent measurement prior to randomisation will be used as 
baseline.  
All efficacy endpoints will be summarised and analysed using the full analysis set (FAS), unless 
otherwise stated. Safety endpoints will be summarised using the safety analysis set and analysed 
using the FAS. The FAS is defined in Section 3.   
Presentation of results from a statistical analysis will include the estimated mean treatment effects 
(LSMeans) for change from baseline, if applicable. Estimated mean treatment differences (or ratios) 
will be presented together with two-sided 95% confidence interval (CI) for all endpoints analysed 
statistically.  
The primary objective of the trial is to confirm the effect in terms of glycaemic control of treatment 
with faster aspart compared to NovoRapid® both in combination with insulin degludec with or 
without metformin in Chinese adults with T1DM or T2DM inadequately treated with a basal-bolus 
or a premix regimen, using a non-inferiority approach.  
More specifically the upper limit of the 95% confidence interval for the difference between faster 
aspart and NovoRapid® should be compared to a non-inferiority margin of 0.4%. If it is below or 
equal to 0.4%, non-inferiority will be considered established and effect demonstrated.  
4.2 
Estimand 
The estimand is defined as the treatment difference in change from baseline in HbA1c 16 weeks 
after randomisation between faster aspart and NovoRapid® both in combination with insulin 
degludec with or without metformin in Chinese adults with T1DM or T2DM treated on basal-bolus 
regimen with a basal optimisation if all had adhered to randomised treatment. This estimand aims to 
reflect the treatment effect for subjects that are actually able to take the drug during the intended 
treatment period. 
4.3 
Primary endpoint analysis 
4.3.1 
Definition of Endpoint 
The primary endpoint is change from baseline (week 0) in HbA1c to 16 weeks after randomisation.  
4.3.2 
Main Analytical Approach 
The estimand will be addressed by the primary analysis on all subjects included in the full analysis 
set and using the data collected from date of first dose of randomised NovoRapid®/faster aspart and 
to 7 days after the day of last dose of randomised NovoRapid®/faster aspart. Change from baseline 
in HbA1c after 16 weeks of randomised treatment will be analysed using a mixed-effect model for 
repeated measurements (MMRM) where all calculated changes in HbA1c from baseline at visits will 
be included in the analysis. This model will include treatment and stratification (T1DM/T2DM) as 
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Statistical Analysis Plan 
 
Date: 
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Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
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fixed factors, HbA1c at baseline as covariate and interactions between all fixed factors and visit. An 
unstructured covariance matrix will be used to describe the variability for the repeated 
measurements for a subject. This approach relies on the assumption that data are missing at random 
(MAR). From this model, the treatment difference after 16 weeks will be estimated with a 95% 
confidence interval calculated. 
Non-inferiority 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 (faster aspart minus 
NovoRapid®). 
The trial also aims to confirm the superiority of treatment with faster aspart for the change from 
baseline HbA1c 16 weeks after randomisation. Here superiority will be based on the same 95% CI 
that was used for addressing the primary analysis. Superiority will be confirmed if the upper 
boundary of the two-sided 95% confidence interval of the mean treatment difference is below 0%.  
 
4.3.3 
Additional analysis 
Differences between the two populations will be investigated further by estimating the treatment 
differences separately for subjects with T1DM and T2DM. These treatment differences will be 
estimated based on the same data and a similar statistical model as the primary analysis but 
including interaction terms between treatment, stratification (T1DM and T2DM), and visit.  
4.3.4 
Sensitivity analysis for the primary analysis addressing the estimand  
1) A tipping point analysis will be made based on the data and a similar statistical model as the 
primary analysis addressing the estimand but using multiple imputation. In this analysis 
observations for subjects with missing values are imputed based on the treatment arm they 
were randomised to and subjects in the faster aspart group are given a penalty. This is done 
to investigate the robustness of the conclusion in the primary analysis with respect to the 
MAR assumption and mimics a scenario where the HbA1c of the subjects in the faster aspart 
groups evolve less favourably than predicted. As a first step imputations will be done 
without penalty assuming MAR. Second, the imputed values for week 16 in the faster aspart 
group will be added a penalty. This is done repeatedly, gradually increasing the penalty until 
the conclusion from the non-inferiority analysis no longer holds. This will serve as a 
sensitivity analysis for the non-inferiority analysis and the specific value of the penalty that 
changes the conclusion will be used to evaluate the robustness of the conclusion of the non-
inferiority analysis. 
2) A tipping point analysis using multiple imputation similar to 1) but with the modification 
that subjects discontinuing treatment due to non-eligibility (discontinuation due to criteria 1- 
4, protocol Section 6.6) in the faster aspart group will not have a penalty added. These 
analyses are motivated by the fact that data from subjects prematurely discontinuing 
randomised treatment due to non-eligibility can reasonably be assumed to be missing 
completely at random.  
3) The same statistical model using MMRM and data as in the primary analysis, but restricted 
to the PP analysis set. This analysis will investigate the situation that subjects might have 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
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deviated from the inclusion and exclusion criteria and will serve as sensitivity analysis for 
the non-inferiority analysis. 
 
4.4 
Secondary endpoints analyses 
4.4.1 
Supportive secondary endpoints 
4.4.1.1 
Efficacy endpoints 
All endpoints except insulin dose in this section will be assessed using the FAS. Insulin dose will be 
presented using the safety analysis set. 
Change from baseline in 30- minutes, 1- hour, 2- hour, and 3- hour PPG increment and 30- 
minutes, 1- hour, 2- hour, and 3- hour PPG to 16 weeks after randomisation (meal test) 
Laboratory measured PG from the meal test will be analysed for 30 minutes, 1-hour, 2-hours, and 3-
hours PPG separately. The corresponding PPG increments will be derived separately using each 
PPG measurement minus the pre-prandial PG measurement. 
Change from baseline in PPG and PPG increment endpoints 16 weeks after randomisation will be 
analysed based on the FAS using an ANOVA model including treatment and stratification 
(T1DM/T2DM) as factors, and with the corresponding baseline value as covariate.   
Change from baseline in FPG to 16 weeks after randomisation 
Change from baseline in FPG to 16 weeks after randomisation will be analysed based on all planned 
post baseline measurements until or at 16 weeks after randomisation using a model similar to the 
primary analysis except with baseline FPG as covariate. 
If a subject achieves HbA1c target 16 weeks after randomisation 
HbA1c < 7.0% 
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
met the HbA1c target (HbA1c <7.0%) 16 weeks after randomisation.   
This responder endpoint will be analysed based on a logistic regression model using treatment and 
stratification (T1DM/T2DM) as factors, and baseline HbA1c as covariate. In the analysis, subjects 
who prematurely discontinue trial product and subjects with missing HbA1c  at 16 weeks will be 
included as non-responders. 
HbA1c < 7.0% without severe hypoglycaemia 
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
met the HbA1c target (HbA1c <7.0%) 16 weeks after randomisation without treatment emergent 
severe hypoglycaemic episodes. 
This responder endpoint will be analysed based on a logistic regression model using treatment and 
stratification (T1DM/T2DM) as factors and baseline HbA1c as covariate. In the analysis, subjects 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
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who prematurely discontinue trial product and subjects with missing HbA1c  at 16 weeks will be 
included as non-responders. 
Change from baseline in endpoints derived from the 7-9-7-point SMPG profile to 16 weeks 
after randomisation 
In general, analyses will be based on the entire 7-9-7-point SMPG profile.   
PPG and PPG increments based on the 7-9-7-point SMPG profiles will be derived separately for PG 
measurements made 1 hour after the meal. In the following section this distinction will be 
considered implicit and without further explanation. 
Pre-prandial PG and PPG will be recorded by the subjects as part of the 7-9-7-point SMPG profile 
prior to three defined visits. Individual mean mealtime PPG (post-breakfast, post-lunch, post-main 
evening meal) will be derived from the three profiles. Overall mean PPG will be derived from the 
individual derived mealtime PPG values. 
PPG increment for each meal (breakfast, lunch, main evening meal) will be derived from the 7-9-7-
point SMPG profile as the difference between PPG values and the PG value before meal in each 
separate profile. The mean of the derived increments will then be calculated separately for each 
meal. Mean 1-hour PPG increments over all meals will be derived as the mean of all corresponding 
mean meal increments.  
 Change from baseline in mean of the 7-9-7-point SMPG profile 
The mean of the 7-9-7-point SMPG profile is defined as the area under the curve (AUC) profile 
divided by the measurement time, and is calculated using the linear trapezoidal technique. 
Change from baseline in the mean of the 7-9-7-point SMPG profile 16 weeks after randomisation 
will be analysed based on all planned post baseline measurements until or at 16 weeks after 
randomisation using a model similar to the primary analysis except with the corresponding baseline 
value as covariate. 
 Change from baseline in 1-hour PPG and PPG increment (mean, breakfast, lunch and main 
evening meal) 
Change from baseline in 1-hour PPG and PPG increment endpoints 16 weeks after randomisation 
for mean over all three meals and the individual meals will be analysed separately based on all 
planned post baseline measurements until or at 16 weeks after randomisation using a model similar 
to the primary analysis except with the corresponding baseline value as covariate. 
 Fluctuation in 7-9-7-point SMPG profile 
The fluctuation in the 7-9-7-point SMPG profile is defined as: 
 
1
𝑇∫|𝑃𝐺(𝑡) −𝑃𝐺
̅̅̅̅|
𝑇
0
𝑑𝑡 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
Page: 
16 of 22 
 
 
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. It will be calculated using the linear trapezoidal technique. 
Fluctuation in the 7-9-7-point SMPG profile will be logarithmically transformed and analysed based 
on all planned post baseline measurements until or at 16 weeks after randomisation using a model 
similar to the primary analysis except with the corresponding log-transformed baseline value as 
covariate. Estimated treatment means and the estimated treatment differences with corresponding 
95% CI will be back-transformed to the original scale, resulting in estimated geometric means, a 
treatment ration and a 95% CI for the treatment ratio. 
If a subject achieves PPG target (based on overall mean of daily PPG measurements in 7-9-7-
point SMPG profile) 16 weeks after randomisation: 
Overall PPG (1-hour) £7.8 mmol/L  
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
reached an overall mean 1-hour PPG £7.8 mmol/L [140 mg/dL] 16 weeks after randomisation, 
where PPG is derived from the 7-9-7-point SMPG profile.  
This responder endpoint will be analysed based on a logistic regression model using treatment and 
stratification (T1DM/T2DM) as factors, and baseline overall mean 1-hour PPG as covariate. In the 
analysis, subjects who prematurely discontinue randomised treatment will be included as non-
responders.  
Overall PPG (1-hour) £7.8 mmol/L without severe hypoglycaemia 
A dichotomous (responder/non-responder) endpoint will be defined based on whether a subject has 
reached an overall 1-hour PPG £7.8 mmol/L [140 mg/dL] 16 weeks after randomisation without 
any treatment emergent severe hypoglycaemic episodes.  
This responder endpoint will be analysed based on a logistic regression model using treatment and 
stratification (T1DM/T2DM) as factors, and baseline overall mean 1-hour PPG as covariate. In the 
analysis, subjects who prematurely discontinue randomised treatment will be included as non-
responders.  
Insulin dose (Units/day and Units/kg/day; total basal, total bolus, and individual meal insulin 
dose) 16 weeks after randomisation 
The insulin doses will be summarised descriptively by treatment week according to regimen, by 
meal type in units and units/kg (separately for each mealtime dose). Insulin doses will be 
summarised using the safety analysis set. 
Lipids-lipoproteins profile 16 weeks after randomisation 
Lipid endpoints (total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride) will be 
logarithmically transformed and analysed separately based on all planned post baseline 
measurements until or at 16 weeks after randomisation using a model similar to the primary 
analysis except with the corresponding log-transformed baseline as covariate. Estimated treatment 
means and the estimated treatment difference with corresponding 95% CI will be back-transformed 
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Statistical Analysis Plan
Date:
26 September 2022
Novo Nordisk
Study ID:  NN1218-4357
Version:
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UTN: U1111-1197-8289
Status:
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Novo Nordisk uses the following classification (see Figure 4-1) in addition to the ADA 
classification: 

Severe hypoglycaemia according to the ADA classification.3

Severe or BG confirmed hypoglycaemia: An episode that is severe according to the ADA 
classification3 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with or without 
symptoms consistent with hypoglycaemia. 
Figure 4-1
Novo Nordisk classification of hypoglycaemia
Hypoglycaemic
episode
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
PG < 3.1 mmol/L
(56 mg/dL)
with symptoms
PG < 3.1 mmol/L
(56 mg/dL)
without
symptoms
Symptomatic BG 
confirmed 
hypoglycaemia
Asymptomat c BG 
confirmed 
hypoglycaemia
Yes
No
Severe or 
BG confirmed 
symptomatic 
hypoglycaemia
BG confirmed 
hypoglycaemia
Severe or BG 
confirmed 
hypoglycaemia
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
BG: blood glucose  PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
ADA classification3 of hypoglycaemia

Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. PG concentrations may 
not be available during an event, but neurological recovery following the return of PG to 
normal is considered sufficient evidence that the event was induced by a low PG 
concentration.

Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL).

Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 
mg/dL).

Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 
mg/dL) but approaching that level.

Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a PG determination but that was presumably caused 
by a PG concentration ≤ 3.9 mmol/L (70 mg/dL).
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Statistical Analysis Plan
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Novo Nordisk
Study ID:  NN1218-4357
Version:
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UTN: U1111-1197-8289
Status:
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Figure 4-2
ADA classification of hypoglycaemia
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo- 
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
Treatment emergent hypoglycaemic episodes are presented in terms of the number of subjects with 
at least one event (N), the percentage of subjects with at least one event (%), the number of events 
(E) and the event rate per 100 years of exposure (R). Separate summaries are made by severity 
considering all episodes, nocturnal and daytime episodes using Novo Nordisk and ADA classified 
episodes. All episodes will also be summarised by category, including summaries in relation to time 
since start of meal, as occurring during 0.5, 1, 2, and 4 hours after start of meal, and from 2 hours 
(exclusive) to 4 hours (inclusive) after start of meal, respectively.
The number of treatment emergent severe or BG confirmed hypoglycaemic episodes (all, daytime, 
nocturnal, 0.5, 1, 2, and 4 hours and from 2 hours (exclusive) to 4 hours (inclusive) after start of the 
meal) will be analysed based on the FAS using a negative binomial regression model with a log-link 
function and the logarithm of the time period in which a hypoglycaemic episode is considered 
treatment emergent as offset. The model will include treatment and stratification (T1DM/T2DM), as 
factors. To the extent where data allow, separate analysis will be performed for severe 
hypoglycaemic episodes.
Change from baseline in clinical evaluations 16 weeks after randomisation:
Physical examination
The physical examination parameters ( respiratory system, cardiovascular system, gastrointestinal 
system incl. mouth, musculoskeletal system, central and peripheral nervous system, skin), and their 
change from baseline, will be summarised descriptively. All findings will be listed.
Vital signs
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
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Vital signs include diastolic blood pressure, systolic blood pressure and pulse. The measurements 
will be summarised descriptively including summaries of the change from baseline. 
Electrocardiogram 
ECG findings will be summarised descriptively including summaries of the change from baseline. 
Change from baseline will be summarised as normal/abnormal not clinically significant/abnormal 
clinically significant categorisation in shift tables. 
Eye examination 
 
Eye examination findings, including right eye ophthalmoscopy and left eye ophthalmoscopy, will 
be summarised descriptively including summaries of the change from baseline.  
Change from baseline in clinical laboratory assessments 16 weeks after randomisation 
Change from baseline 16 weeks after randomisation in central laboratory assessments: 
 Haematology (haemoglobin blood, erythrocytes, haematocrit blood,  leucocytes, 
thrombocytes) 
 Biochemistry (AST serum, calculated creatinine clearance serum, sodium serum, potassium 
serum, creatinine serum, total protein serum, albumin serum, alkaline phosphatase serum, 
ALT serum, total bilirubin serum, GFR from creatinine adjusted for BSA) 
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 both the actual values and 
the low/normal/high categorisation in shift tables. 
Change from baseline in body weight and body mass index 16 weeks after randomisation 
The measurements will be summarised descriptively using the actual values as mean change. 
Change from baseline in body weight will be analysed based on all planned post baseline 
measurements until or at 16 weeks after randomisation using a statistical model similar to the 
primary analysis except with the corresponding baseline measurement as covariate. 
 
4.5 
Changes to Protocol-planned Analysis 
No change to the protocol. 
 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
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5 
Sample size determination 
The sample size is determined to ensure a sufficient power for the primary analysis. This is 
determined using a non-inferiority limit of 0.4%.  
In the global phase 3a programme where treatment with faster aspart has been investigated, the 
completion rates have been high, i.e. approximately 88-94%. Therefore it will not be unexpected 
that treatment discontinuation might be as low as 10%. 
It is expected that a larger portion of the trial population will constitute subjects with T2DM. For 
these calculations the proportion of subjects with T1DM is assumed to be at least 20%. Combining 
expected differences for T1DM and T2DM subjects and weighting by the proportion of expected 
T1DM subjects we will assume a treatment difference of -0.02% (i.e., in favour of faster aspart).  
The power for the primary (non-inferiority) analysis is based on a t-statistic under the assumption of 
a one-sided test of size 2.5 %, a non-inferiority margin of 0.4% and SD of 1.2%. Using these values 
we get a power of 81.7% for the primary analysis with a sample size of 270. Adjusting further for a 
dropout rate of approximate 10%, 300 subjects will be randomised. 
The power for non-inferiority for scenarios where SD = 1.0% or 1.2% and mean difference of 
0.00% or -0.02% based on sample size 270 is shown in Table 5-1. 
 
Table 5-1 
The power for non-inferiority for different scenarios 
Power for non-inferiority 
Treatment difference = 0% 
Treatment difference =  -0.02% 
SD = 1.0% 
90.6% 
93.0% 
SD = 1.2% 
77.9% 
81.7% 
 
The power calculation is done using proc power in SAS Version 9.4. 
 
 
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Statistical Analysis Plan 
 
Date: 
26 September 2022 Novo Nordisk 
Study ID:  NN1218-4357 
Version: 
1.0 
UTN: U1111-1197-8289 
Status: 
Final 
     
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22 of 22 
 
 
6 
References 
1. 
ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9, Current 
step 4 version. 5 Feb 1998. 
2. 
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. 
3. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
 
 
 
 
 
 
 
 
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