Clinical trial NCT04848480
Conditions: Diabetes Mellitus, Type 1
Sponsor: Novo Nordisk A/S
Start date: 2021-04-30; Completion date: 2022-12-02
Enrollment: 582 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares insulin icodec (a new insulin) to insulin degludec (an insulin already available on the market) in people with type 1 diabetes.

The study will look at how well insulin icodec taken weekly controls blood sugar compared to insulin degludec taken daily.

Participants will either get insulin icodec that participants will have to inject once a week on the same day of the week, or insulin degludec that participants will have to inject once a day at the same time every day. Which treatment participants get is decided at random. Participants will also get a mealtime insulin.

The insulin is injected with a needle in a skin fold in the thigh, upper arm or stomach.

The study will last for about 1 year and 2 months. Participants will have 28 clinic visits and 28 phone calls with the study doctor. At 11 clinic visits participants will have blood samples taken.

At 6 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit.

Participants will be asked to wear a sensor that measures your blood sugar all the time. Participants will be asked to wear it for a total of 57 weeks (around 1 year).

Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.

Detailed description:

Arms: arm 1: insulin icodec once a week in combination with 2-4 times daily injections of insulin aspart at meal times. arm 2: insulin degludec once a day in combination with 2-4 times daily injections of insulin aspart at meal times.
Interventions: intervention 1: insulin icodec intervention 2: insulin degludec intervention 3: insulin aspart
Intervention descriptions: intervention 1: insulin icodec 700 units/mL, subcutaneously (under the skin), solution for injection once weekly intervention 2: insulin degludec 100 units/mL, subcutaneously (under the skin), solution for injection once daily intervention 3: insulin aspart 100 units/mL, subcutaneously (under the skin), solution for injection daily

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04848480 
Sponsor trial ID: 
NN1436-4625 
Official title of study: 
Efficacy and Safety of Once Weekly Insulin Icodec Compared 
to Once Daily Insulin Degludec 100 Units/mL, Both in 
Combination With Insulin Aspart, in Adults With Type 1 
Diabetes. A 26-week, Randomised, Multicentre, Open-label, 
Active-controlled, Parallel Group, Two Armed, Treat-to-target 
Trial Investigating the Effect on Glycaemic Control and Safety 
of Treatment With Once Weekly Insulin Icodec Compared to 
Once Daily Insulin Degludec, Both in Combination With 
Insulin Aspart in Adults With Type 1 Diabetes, With a 26-
week Extension Investigating Long Term Safety 
Document date: 
27 June 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 compilation of the documents and not of an update to content.


Link
Link
Link
Link
List of contents
Protocol version 4.0 (Global).............................................................................................................
UK Memo for protocol version 4.0 ...................................................................................................
Protocol version 5.0 (Japan)..............................................................................................................
Protocol attachment ...........................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Insulin icodec
Trial ID: NN1436-4625 ONWARDS 6
Clinical Trial Report (ext-1)
Appendix 16.1.1
17 March 2023
1.0
Final
16.1.1 Protocol and protocol amendments
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Protocol 
Efficacy and safety of once weekly insulin icodec compared to once daily insulin degludec 
100 units/mL, both in combination with insulin aspart, in adults with type 1 diabetes. 
A 26-week, randomised, multicentre, open-label, active-controlled, parallel group, two armed, 
treat-to-target trial investigating the effect on glycaemic control and safety of treatment with once 
weekly insulin icodec compared to once daily insulin degludec, both in combination with insulin 
aspart in adults with type 1 diabetes, with a 26-week extension investigating long term safety. 
ONWARDS 6 
Substance name: Insulin icodec 
Universal Trial Number: U1111-1251-7315 
EudraCT Number: 2020-002374-27 
IND Number: 137406 
Trial phase: 3a 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


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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 
14 April 2021  
All countries 
Protocol version 3.0 
22 February 2021 
For Japan only 
Protocol version 2.0 
07 January 2021 
All countries, except Japan 
Original protocol version 1.0 
20 October 2020 
Not submitted 
 
Protocol version 4.0 (14 April 2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union1, because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 4.0: 
The protocol has been amended to correct typos and exclude Germany from co-participation in 
clinical trials evaluating medicinal products for prevention or treatment of COVID-19 disease or 
postinfectious conditions as per local health authority request. 
Section # and name 
Description of change 
Brief rationale 
2.3.1 Risk assessment 
“section 8.9.2.” is deleted from the 
sentence “For further information on 
injection site reactions, please refer to 
section 8.9.2 and Appendix 3 (Section 
10.3)”. 
Correction of reference. 
5.1 Inclusion criteria 
“basal and bolus insulin analogue 
regimes” is corrected to “basal and 
bolus insulin analogue regimens” 
Correction of typo 
10.1.7 Dissemination of clinical trial 
data 
The primary completion date (PCD) is 
corrected to last subject first treatment 
(LSFT) + 26 weeks corresponding to 
visit 28. 
Correction of typo, since the primary 
endpoint will be assessed at week 26 
(visit 28). 
10.1.9 Source documents 
“ePROs” is deleted. 
Correction due to no ePROs in this 
trial. 
10.8 Appendix 8 Titration guideline 
Table for V2 and V3 weekly dose: 
For “Total daily dose before 
randomisation (U): 82 “ 
Correction of typo 
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Section # and name 
Description of change 
Brief rationale 
“V2 insulin icodec dose (U)”: 960 is 
corrected to 860 
10.9 Appendix 9: Country/Region-
specific requirements 
Footnotes related to co-participation 
in clinical trial for COVID-19 in 
exclusion criteria 4 and 
discontinuation criteria 4 are not 
applicable for Germany 
To meet local Health Authority 
request. 
 
 
10.11 Appendix 11 Protocol 
amendment history  
Amendment history is updated by 
moving protocol v3.0 history to 
appendix 11 
Due to the new protocol v4.0 
11 References 
Reference 32 to CTFG guidance is 
added in appendix 4. 
Reference update 
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Table of Contents    
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 4 
1 
Protocol summary ..................................................................................................................................... 7 
1.1 
Synopsis ........................................................................................................................................... 7 
1.2 
Flowchart ......................................................................................................................................... 9 
1.3 
Flow charts – Phone visits ............................................................................................................. 12 
2 
Introduction ............................................................................................................................................. 13 
2.1 
Trial rationale ................................................................................................................................. 13 
2.2 
Background .................................................................................................................................... 13 
2.3 
Benefit-risk assessment .................................................................................................................. 14 
2.3.1 
Risk assessment ............................................................................................................... 14 
2.3.2 
Benefit assessment ........................................................................................................... 16 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 17 
3 
Objectives and endpoints ........................................................................................................................ 17 
3.1 
Primary, secondary and exploratory objectives and estimand ....................................................... 17 
3.1.1 
Primary objective ............................................................................................................. 17 
3.1.2 
Secondary objective ......................................................................................................... 17 
3.2 
Primary, secondary and exploratory endpoints .............................................................................. 18 
3.2.1 
Primary endpoint ............................................................................................................. 18 
3.2.2 
Secondary endpoints ........................................................................................................ 18 
3.2.2.1 
Supportive secondary efficacy endpoints ........................................................ 18 
3.2.2.2 
Secondary safety endpoints ............................................................................. 19 
3.2.3 
Exploratory endpoints ..................................................................................................... 20 
4 
Trial design .............................................................................................................................................. 20 
4.1 
Overall design ................................................................................................................................ 20 
4.2 
Scientific rationale for trial design ................................................................................................. 21 
4.2.1 
Subject input into design ................................................................................................. 22 
4.3 
Justification for dose ...................................................................................................................... 22 
4.4 
End of trial definition ..................................................................................................................... 23 
5 
Trial population ....................................................................................................................................... 23 
5.1 
Inclusion criteria ............................................................................................................................ 23 
5.2 
Exclusion criteria ........................................................................................................................... 23 
5.3 
Lifestyle considerations ................................................................................................................. 24 
5.3.1 
Meals and dietary restrictions .......................................................................................... 24 
5.3.2 
Caffeine, alcohol and tobacco ......................................................................................... 24 
5.4 
Screen failures ................................................................................................................................ 25 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria...................................................... 25 
6 
Treatments ............................................................................................................................................... 25 
6.1 
Treatments administered ................................................................................................................ 25 
6.1.1 
Medical devices ............................................................................................................... 27 
6.1.1.1 
Investigational medical device ........................................................................ 27 
6.1.1.2 
Non-investigational medical devices .............................................................. 27 
6.2 
Preparation/handling/storage/accountability .................................................................................. 27 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 28 
6.4 
Treatment compliance .................................................................................................................... 28 
6.5 
Concomitant medication ................................................................................................................ 28 
6.6 
Dose modification .......................................................................................................................... 29 
6.7 
Treatment after end of trial ............................................................................................................ 29 
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7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 29 
7.1 
Discontinuation of trial treatment .................................................................................................. 30 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 31 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 31 
7.2.1 
Replacement of subjects .................................................................................................. 32 
7.3 
Lost to follow-up ........................................................................................................................... 32 
8 
Trial assessments and procedures ......................................................................................................... 32 
8.1 
Efficacy assessments ...................................................................................................................... 33 
8.1.1 
Self-measured plasma glucose......................................................................................... 33 
8.1.2 
Continuous glucose monitoring ....................................................................................... 33 
8.1.3 
Clinical outcome assessments ......................................................................................... 34 
8.1.4 
Clinical efficacy laboratory assessments ......................................................................... 35 
8.2 
Safety assessments ......................................................................................................................... 35 
8.2.1 
Insulin dose ...................................................................................................................... 35 
8.2.2 
Physical examinations ..................................................................................................... 36 
8.2.3 
Vital signs ........................................................................................................................ 36 
8.2.4 
Electrocardiograms .......................................................................................................... 37 
8.2.5 
Eye examination .............................................................................................................. 37 
8.2.6 
Clinical safety laboratory assessments ............................................................................ 38 
8.3 
Adverse events and serious adverse events .................................................................................... 38 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 40 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 40 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 40 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 40 
8.3.5 
Pregnancy ........................................................................................................................ 41 
8.3.6 
Cardiovascular and death events ..................................................................................... 41 
8.3.7 
Technical complaints ....................................................................................................... 41 
8.4 
Treatment of overdose ................................................................................................................... 41 
8.5 
Pharmacokinetics ........................................................................................................................... 42 
8.6 
Pharmacodynamics ........................................................................................................................ 42 
8.7 
Genetics ......................................................................................................................................... 42 
8.8 
Biomarkers ..................................................................................................................................... 42 
8.9 
Immunogenicity assessments ......................................................................................................... 42 
8.9.1 
Anti-drug antibodies ........................................................................................................ 42 
8.9.2 
Hypersensitivity ............................................................................................................... 43 
8.10 
Health economics ........................................................................................................................... 44 
9 
Statistical considerations ........................................................................................................................ 44 
9.1 
Statistical hypotheses ..................................................................................................................... 44 
9.2 
Sample size determination ............................................................................................................. 44 
9.3 
Populations for analyses ................................................................................................................ 45 
9.4 
Statistical analyses ......................................................................................................................... 46 
9.4.1 
General considerations .................................................................................................... 46 
9.4.2 
Primary endpoint ............................................................................................................. 47 
9.4.3 
Secondary endpoints ........................................................................................................ 48 
9.4.3.1 
Supportive secondary endpoints ..................................................................... 48 
9.4.4 
Exploratory endpoints ..................................................................................................... 51 
9.4.5 
Other safety analyses ....................................................................................................... 51 
9.4.6 
Other analyses ................................................................................................................. 51 
9.4.6.1 
Pharmacokinetic modelling ............................................................................. 51 
9.5 
Interim analyses ............................................................................................................................. 52 
9.6 
Data monitoring committee ........................................................................................................... 52 
9.7 
Reporting of the main part of the trial............................................................................................ 52 
10 Supporting documentation and operational considerations ............................................................... 53 
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10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 53 
10.1.1 
Regulatory and ethical considerations ............................................................................. 53 
10.1.2 
Financial disclosure ......................................................................................................... 53 
10.1.3 
Informed consent process ................................................................................................ 53 
10.1.4 
Information to subjects during trial ................................................................................. 54 
10.1.5 
Data protection ................................................................................................................ 54 
10.1.6 
Committees structure ....................................................................................................... 55 
10.1.6.1 Novo Nordisk safety committee...................................................................... 55 
10.1.6.2 Trial safety group ............................................................................................ 55 
10.1.6.3 Data monitoring committee............................................................................. 55 
10.1.6.4 Event adjudication committee ......................................................................... 55 
10.1.7 
Dissemination of clinical trial data .................................................................................. 55 
10.1.8 
Data quality assurance ..................................................................................................... 56 
10.1.8.1 Case report forms ............................................................................................ 56 
10.1.8.2 Monitoring ...................................................................................................... 56 
10.1.8.3 Protocol compliance ........................................................................................ 57 
10.1.9 
Source documents ............................................................................................................ 57 
10.1.10 Retention of clinical trial documentation ........................................................................ 57 
10.1.11 Trial and site closure ....................................................................................................... 58 
10.1.12 Responsibilities................................................................................................................ 58 
10.1.13 Indemnity statement ........................................................................................................ 59 
10.1.14 Publication policy ............................................................................................................ 59 
10.1.14.1 Communication of results ............................................................................... 59 
10.1.14.2 Authorship ....................................................................................................... 60 
10.1.14.3 Site-specific publication(s) by investigator(s)................................................. 60 
10.1.14.4 Investigator access to data and review of results ............................................ 60 
10.2 
Appendix 2: Clinical laboratory tests ............................................................................................ 61 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting ............................................................................................................................ 63 
10.3.1 
Definition of AE .............................................................................................................. 63 
10.3.2 
Definition of an SAE ....................................................................................................... 63 
10.3.3 
Description of events for adjudication and AEs requiring additional data collection ..... 64 
10.3.4 
Recording and follow-up of AE and/or SAE ................................................................... 66 
10.3.5 
Reporting of SAEs ........................................................................................................... 68 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ............................ 70 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ................................................................................................................. 73 
10.5.1 
Definition of technical complaint .................................................................................... 73 
10.5.2 
Recording and follow-up of technical complaints ........................................................... 73 
10.5.3 
Reporting of technical complaints ................................................................................... 74 
10.6 
Appendix 6: Retention of human biosamples ................................................................................ 75 
10.7 
Appendix 7: Hypoglycaemic episodes ........................................................................................... 76 
10.8 
Appendix 8: Titration guideline ..................................................................................................... 78 
10.9 
Appendix 9: Country-specific requirements .................................................................................. 85 
10.10 Appendix 10: Abbreviations .......................................................................................................... 88 
10.11 Appendix 11: Protocol amendment history ................................................................................... 90 
11 References ................................................................................................................................................ 91 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments. 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
Insulin icodec is a novel long-acting insulin analogue which is developed to safely cover the basal 
insulin requirements for a full week with a single subcutaneous injection.  
This is a 26-week trial designed to investigate the effect and safety of once weekly insulin icodec 
compared to once daily insulin degludec 100 units/mL, both in combination with insulin aspart in 
subjects with type 1 diabetes, with a 26-week extension phase. The first 26 weeks of the trial 
constitute the main phase, after which the primary analysis is planned. The focus of the 26-week 
extension phase is to evaluate long-term safety and provide long-term exposure data. 
Objectives and endpoints: 
Primary objective  
To confirm the effect on glycaemic control of once weekly insulin icodec in combination with 
insulin aspart, in subjects with type 1 diabetes. This includes comparing the difference in change 
from baseline in HbA1c between once weekly insulin icodec and once daily insulin degludec both in 
combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%.  
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline (week 0) to week 26 
%-point 
 
Estimand 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec and insulin degludec of the change in HbA1c from baseline to week 26 for all randomised 
subjects, irrespective of adherence to randomised treatment and changes to anti-diabetic background 
medication. The following intercurrent events will be handled by the treatment policy strategy: 
discontinuation of randomised insulin treatment, and withdrawal from the trial (measurements 
collected after these intercurrent events are used in the primary analysis).  
Overall design: 
This is a 26-week randomised, multicentre, multinational, open-label, active controlled, parallel 
group, two-armed, treat-to-target trial with two treatment arms. Subjects will be randomised (1:1) to 
receive either insulin icodec or once daily insulin degludec, both in combination with 2-4 daily 
bolus injections of insulin aspart. Randomisation of subjects will be stratified based on pre-trial 
basal insulin regimen and by HbA1c (either <8% or ≥ 8%) at screening.  
Key inclusion criteria: 
1. Male or female aged ≥ 18 years at the time of signing informed consent. 
2. Diagnosed with type 1 diabetes mellitus ≥ 1 year prior to the day of screening. 
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3. Treated with multiple daily insulin injections (basal and bolus insulin analogue regimes) ≥ 1 
year prior to the day of screening. 
4. HbA1c <10% at screening visit based on analysis from central laboratory.  
Key exclusion criteria: 
1. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
2. Chronic heart failure classified as New York Heart Association (NYHA) Class IV at screening. 
3. 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). 
4. 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 randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination.  
Number of subjects: 
Approximately 774 subjects will be screened to achieve 580 subjects randomly assigned to trial 
product. 
Treatment groups and duration: 
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
an initial 26-week randomised treatment period, a 26-week extension phase and a 5-week follow-up 
period. All subjects will be centrally randomised in a 1:1 manner and assigned to receive once 
weekly insulin icodec or once daily insulin degludec, both in combination with 2-4 times daily 
injections of insulin aspart throughout the 52-week treatment period. After end of treatment, 
subjects will be transferred to a marketed product at the discretion of the investigator.  
 
The following trial products will be supplied by Novo Nordisk for the duration of the trial:  
• Insulin icodec 700 units/mL, subcutaneous, solution for injection, 3 mL PDS290 pre-filled 
pen-injector 
• Insulin degludec 100 units/mL, subcutaneous, solution for injection, 3 mL PDS290 pre-
filled pen-injector 
• Insulin aspart 100 units/mL, subcutaneous, solution for injection, 3 mL pre-filled Flexpen 
Data monitoring committee: No 
 
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1.2 
Flowchart 
Procedure 
Protocol section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Early Discontinuation 
Follow-up 
Early Discontinuation 
Follow-up 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V38 
V42 
V46 
V50 
V51 
V52 
V53 
V54 
V55 
V56 
V28A 
V54A 
Weekly Phone contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
 
 
 
  
 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48 
P49 
 
 
 
 
 
 
 
 
 
Timing of visit (weeks) 
 
≤-2 
0 
1 
2 
3 
4 
5 
6 
10 
14 
18 
22 23 24 25 
26 
28 
32 
36 
40 44 48 49 50 51 
52 
54 
57 
26 
52 
Visit window (days) 
 
 
 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
+3 
±3 
±3 
Informed consent and 
demography 
App 1 
10.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco use 
5.3.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
5.1 
5.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Attend visit fasting 
5.3.1 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Concomitant illness/medical 
history 
8.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
Vital signs 
8.2.3 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Physical examination 
8.2.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Body measurements 
8.2.2 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Clinical outcome 
assessment: DTSQs  
8.1.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
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Procedure 
Protocol section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Early Discontinuation 
Follow-up 
Early Discontinuation 
Follow-up 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V38 
V42 
V46 
V50 
V51 
V52 
V53 
V54 
V55 
V56 
V28A 
V54A 
Weekly Phone contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
 
 
 
  
 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48 
P49 
 
 
 
 
 
 
 
 
 
Timing of visit (weeks) 
 
≤-2 
0 
1 
2 
3 
4 
5 
6 
10 
14 
18 
22 23 24 25 
26 
28 
32 
36 
40 44 48 49 50 51 
52 
54 
57 
26 
52 
Visit window (days) 
 
 
 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
+3 
±3 
±3 
Clinical outcome 
assessment: International 
Physical Activity 
Questionnaire 
8.1.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eye examination 
8.2.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
ECG 
8.2.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pregnancy test 
8.3.5 
App.4 
10.4  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Laboratory assessments 
App.2 
10.2 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
HbA1c 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
Antibodies (anti-insulin 
icodec antibodies) 
8.9.1 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X  
 
 
PK (insulin icodec serum 
concentration) 
8.5 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
  
 
4-point SMPG profile 
8.1.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
 
CGM 
8.1.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
 
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Procedure 
Protocol section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Early Discontinuation 
Follow-up 
Early Discontinuation 
Follow-up 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V38 
V42 
V46 
V50 
V51 
V52 
V53 
V54 
V55 
V56 
V28A 
V54A 
Weekly Phone contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
 
 
 
  
 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48 
P49 
 
 
 
 
 
 
 
 
 
Timing of visit (weeks) 
 
≤-2 
0 
1 
2 
3 
4 
5 
6 
10 
14 
18 
22 23 24 25 
26 
28 
32 
36 
40 44 48 49 50 51 
52 
54 
57 
26 
52 
Visit window (days) 
 
 
 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
+3 
±3 
±3 
Adverse event 
8.3 
App. 3 
10.3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
Hypoglycaemic episodes 
8.3 
App7 
10.7   
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X  
Training in trial Product, 
Pen-handling 
6.1 
 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Drug dispensing 
6.2 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Hand out and instruct in 
devices 
6.1.1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Trial 
4.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
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1.3 
Flow charts – Phone visits  
Phone contacts during treatment period (P) 
Time shown in site visit flow chart 
P9-P49 
Visit window (days) 
±3 
Concomitant medication (6.5) 
X 
4-point SMPG profile (8.1.1) 
X 
Adverse events (8.3 Appendix 3) 
X 
Hypoglycaemic episodes (8.3, Appendix 7) 
X 
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2 
Introduction 
Diabetes mellitus is a metabolic disorder characterised by the presence of hyperglycaemia due to 
defective insulin secretion, insulin action or both. The chronic hyperglycaemia of diabetes mellitus 
is associated with significant long-term complications, particularly damage, dysfunction and failure 
of various tissues – especially the kidney, eye, nerves, heart and blood vessels.2 Diabetes is 
generally classified according to aetiological factors, where type 1 diabetes (T1D) and type 2 
diabetes (T2D) constitute the vast majority of cases. In the latest edition of the International 
Diabetes Federation’s Diabetes Atlas (2019), the estimated worldwide diabetes prevalence was 463 
million, with a prediction that by 2045, the number of people with diabetes will have increased to 
700 million.3  
Insulin icodec (proposed INN) is a novel long-acting insulin analogue which is developed to safely 
cover the basal insulin requirements for a full week with a single subcutaneous (s.c.) injection. 
Insulin icodec has a terminal elimination half-life of approximately 196 hours. For patients with 
diabetes there is still an unmet medical need for products with the potential to improve clinical 
outcomes through reduced treatment burden and increased treatment adherence and persistence4 
compared to once or twice daily basal insulin administration. The aim of the development 
programme for insulin icodec is to improve clinical outcomes for patients with diabetes by limiting 
the burden associated with insulin treatment.  
2.1 
Trial rationale 
The present trial is designed to investigate the effect and long-term safety of once weekly insulin 
icodec in comparison to once daily insulin degludec 100 units/mL (hereafter referred to as insulin 
degludec) both in combination with insulin aspart in adult subjects with T1D. The effect of insulin 
icodec is evaluated after the 26-week main phase, followed by a 26-week extension phase with a 
primary aim to assess long-term safety. 
2.2 
Background 
Diabetes mellitus 
T1D is a heterogeneous disorder characterised by T cell-mediated autoimmune destruction of 
insulin-producing beta cells in the pancreas.5 The destruction of beta cell function leads to insulin 
deficiency and the requirement of lifelong administration of exogenous insulin. Results from the 
DCCT study and the follow-up study (EDIC) have demonstrated the importance of maintaining 
tight glycaemic control to reduce the risk of long-term complications associated with diabetes.6 As 
such, the fundamental principle for insulin treatment of T1D is to mimic normal physiological 
patterns as closely as possible. The current gold standard of care is based on intensive insulin 
therapy with multiple daily injections of prandial and basal insulin or continuous subcutaneous 
insulin infusion.7, 8 
Insulin icodec 
Insulin icodec is a novel long-acting insulin analogue which is developed to safely cover the basal 
insulin requirements for a full week with a single subcutaneous injection. Insulin icodec has a 
terminal elimination half-life of approximately 196 hours. The molecule consists of a peptide 
backbone and a fatty acid-containing side-chain. The peptide backbone is more resistant towards 
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proteolytic degradation compared to human insulin and the side chain gives a strong binding to 
albumin. Both features contribute to the long action of insulin icodec.  
The development programme for insulin icodec is currently ongoing. Three phase 2 trials 
NN1436-4383 [T2D], NN1436-4465 [T2D] and NN1436-4466 [T2D] and four clinical 
pharmacology trials, NN1436-4314 [T2D], NN1436-4226 [renal impaired], NN1436-4422 [T1D], 
and NN1436-4225 [T1D]) have been completed. No unexpected safety concerns were identified. 
One clinical pharmacology trial (NN1436-4462 [T2D] is ongoing.  
Data from NN1436-4225 were used in the development of the insulin icodec titration guideline, see 
Appendix 8 (Section 10.8).  
A comprehensive review of results from the non-clinical and clinical studies of insulin icodec can 
be found in the current edition of the investigator’s brochure (IB)9 and any updates hereof. 
Insulin degludec 
For further details on insulin degludec, please refer to the current insulin degludec IB10, the current 
EMA summary of product characteristics (SmPC) for insulin degludec (Tresiba®)11, the U.S. 
Prescribing Information (US PI)12, or any locally approved label.  
Insulin aspart 
For further details on insulin aspart, please refer to the current insulin aspart IB13, the current EMA 
summary of product characteristics (SmPC) for insulin aspart (NovoRapid)14, the U.S. Prescribing 
Information (US PI) (NovoLog)15, or any locally approved label.   
Trial population 
The trial population will consist of subjects with T1D. For more information on the trial population, 
see Section 4.2, or the inclusion and exclusion criteria, Sections 5.1 and 5.2, respectively. 
2.3 
Benefit-risk assessment 
Main benefits and risks are described in the below sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events of insulin icodec, 
insulin degludec and insulin aspart may be found in the respective IB, SmPC or US PI.   
2.3.1 
Risk assessment 
Identified risks for insulin icodec in this section are described as undesirable clinical outcomes for 
which there is sufficient evidence that they are caused by insulin icodec. Potential risks in this 
section describe undesirable clinical outcomes for which there is scientific evidence to suspect the 
possibility of a causal relationship with insulin icodec, but where there is currently insufficient 
evidence to conclude that this association is causal.  
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Identified/Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Trial treatment (Insulin Icodec) 
Identified risk:  
Hypoglycemia  
Hypoglycemia is an anticipated 
undesirable effect related to the 
pharmacological mechanism of 
insulin.   
Frequent blood glucose 
measurements will be made 
throughout drug exposure and will 
prevent worsening of hypoglycaemia 
by early detection and administration 
of carbohydrates and medical 
treatment, if necessary.  
The risk of hypoglycaemia is 
addressed in the SI-IC and IB. 
Patients are provided with a 
guidance on hypoglycaemia 
awareness and rescue actions. 
Identified risk:  
Injection site reactions 
Injection site reactions may occur 
with all injectable drugs. Injection 
site reactions were reported in trials 
NN1436-4422, NN1436-4383, 
NN1436-4465, NN1436-4466, 
NN1436-4226. All were mild and 
resolved during continued treatment 
with insulin icodec. 
Subjects are instructed by the 
investigators on the most appropriate 
injection techniques. 
Recommendations on rotation of the 
site of injection are included in the 
trial protocol. Investigators and 
subjects will be asked to pay careful 
attention to injection site reactions. 
Investigators should ensure careful 
monitoring and medical evaluation 
in case of injection site reaction 
occurrence.  
For further information on injection 
site reactions, please refer to 
Appendix 3 (Section 10.3) 
Potential risk: Hypersensitivity 
Severe systemic hypersensitivity 
reactions may potentially occur 
following injection of therapeutic 
proteins. No systemic 
hypersensitivity reactions were 
observed in trials NN1436-4314, 
NN1436-4383, NN1436-4465, 
NN1436-4466, NN1436-4226 and 
NN1436-44422. 
Known of suspected hypersensitivity 
to trial product(s) or related products 
is an exclusion criterion in the 
clinical trial.  
Subjects and investigators will be 
instructed in signs and symptoms of 
hypersensitivity reactions and 
subjects will be instructed to contact 
the site immediately in case of signs 
of systemic hypersensitivity.  
Blood sampling for assessment of 
antibodies against insulin icodec, as 
well as other assessments will be 
conducted in the case of systemic 
hypersensitivity reaction. Confirmed 
anti-insulin icodec antibody positive 
samples will have an antibody titer 
value determined and will be further 
tested for cross-reactivity to 
endogenous insulin.  
The risk of hypersensitivity reactions 
is described in the IB and SI-IC. 
For further information on 
hypersensitivity reactions, please 
refer to Sections 8.9.2 and Appendix 
3 (Section 10.3.3). 
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Potential risks: Antibody formation 
leading to changes in clinical effects 
Antibodies to exogenously delivered 
insulins are common with insulin 
treatment but are not often clinically 
significant. In NN1436-4383 clinical 
trial, the proportion of subjects with 
anti-insulin antibodies was higher 
with insulin icodec (82.1%) than 
insulin glargine (35.0%). Maximum 
level of antibody response was 
higher against insulin icodec than 
insulin glargine. 
No apparent relationship between 
antibody titres and change in HbA1c 
or weekly insulin dose was observed.   
In case lack of clinical effect is 
observed, rescue actions will be 
initiated if deemed necessary.  
In the case of systemic 
hypersensitivity reaction blood 
sampling for assessment of 
antibodies against insulin icodec, as 
well as other assessments will be 
conducted. For more information 
please refer to Section 8.9.1 and 
Appendix 3 (Section 10.3) 
Trial treatment (Insulin Degludec & Insulin Aspart) 
For more information regarding the known and expected benefits and risks of insulin degludec, please refer to the 
insulin degludec IB10, EMA Summary of Product Characteristics (SmPC)11 and the US Prescribing Information 
(PI)12, or any locally approved label.  
For more information regarding the known and expected benefits and risks of insulin aspart, please refer to the 
insulin aspart IB13, the (NovoRapid) EMA SmPC14,  (NovoLog) US PI15 or any locally approved label.  
Trial procedures 
Potential risk: 
COVID-19 infection in relation to 
participation in trial 
 
Subjects may be exposed to the risk 
of COVID-19 transmission and 
infection in relation to site visits if 
an outbreak is ongoing in the given 
country. 
The risk of COVID-19 transmission 
in relation to site visits is overall 
considered to be low, however this 
may vary between geographical 
area. To minimize the risk as much 
as possible, the following measures 
have been taken: 
• Cautious subject recruitment 
planning ensures controlled subject 
enrolment in countries where the 
COVID-19 pandemic is evaluated to 
be sufficiently under control, and at 
sites where health care resources are 
evaluated to be adequate. 
• On-site visits will be well-prepared 
and as short as possible. Physical 
contact between subjects and site 
staff will be limited to the extent 
possible, and protective measures 
will be implemented (e.g. use of 
masks, sanitizers, no aerosol-
generating procedures etc. according 
to the local practice). 
• A COVID-19 mitigation plan has 
been developed for this trial which 
lists the additional actions to 
consider in case a site or country are 
locked down and subjects cannot 
attend on-site visits. 
 
2.3.2 
Benefit assessment 
Insulin icodec is currently in development for treatment of diabetes mellitus. In both clinical and 
non-clinical trials, insulin icodec has shown to have a long and stable PK and PD profile, supporting 
a once weekly treatment. Currently available long-acting basal insulin products need to be 
administered once or twice daily to provide 24-hour coverage. Market research has shown that 
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people with diabetes, put value in reducing the number of insulin injections16. Therefore, the 
treatment adherence and quality of life are expected to increase by introducing a once weekly basal 
insulin treatment. 
 
The trial population will consist of subjects with T1D. For all subjects participating in this 52-week 
trial, the anticipated benefits include improved glycaemic control. The titration algorithm 
(Appendix 8, Section 10.8), which specifies recommended adjustments of both basal and bolus 
insulin dose at different plasma glucose levels, will be used to ensure that subjects receive optimal 
treatment.  
2.3.3 
Overall benefit-risk conclusion 
Insulin icodec is efficacious at clinically relevant doses. Titration guidance for phase 3a trials aims 
to achieve good glycaemic control without increasing the risk of hypoglycaemic events.  
No new significant safety information that changes the current benefit-risk profile of insulin icodec 
emerged from the ongoing and completed clinical trials. The safety profile of insulin icodec remains 
in line with the cumulative experience.  
As an overall assessment, Novo Nordisk evaluates that the benefit-risk balance of insulin icodec 
remains favourable.  
Considering the measures taken to minimise risk to subjects participating in this trial, the risks 
identified in association with insulin icodec are justified by the anticipated benefits that may be 
afforded to subjects with diabetes mellitus.  
More detailed information about the known and expected benefits and risk of insulin icodec can be 
found in the IB9 and any updates hereof.   
3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objectives and estimand 
3.1.1 
Primary objective 
To confirm the effect on glycaemic control of once weekly insulin icodec in combination with 
insulin aspart, in subjects with T1D. This includes comparing the difference in change from 
baseline in HbA1c between once weekly insulin icodec and once daily insulin degludec both in 
combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%.  
3.1.2 
Secondary objective 
To compare the safety and patient reported outcomes of once weekly insulin icodec versus once 
daily insulin degludec, both in combination with insulin aspart, in subjects with T1D.  
Estimand 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec and insulin degludec of the change in HbA1c from baseline to week 26 for all randomised 
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subjects, irrespective of adherence to randomised treatment and changes to anti-diabetic background 
medication. The following intercurrent events will be handled by the treatment policy strategy: 
discontinuation of randomised insulin treatment, and withdrawal from the trial (measurements 
collected after these intercurrent events are used in the primary analysis).  
3.2 
Primary, secondary and exploratory endpoints 
3.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline (week 0) to week 26 
%-point 
 
3.2.2 
Secondary endpoints 
3.2.2.1 
Supportive secondary efficacy endpoints 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose 
(FPG)  
From baseline (week 0) to week 26 
mmol/L 
Time in range 3.9-10.0 mmol/L 
(70-180 mg/dL)* 
From week 22 to week 26  
% of readings  
Change in DTSQs (Diabetes 
Treatment Satisfaction 
Questionnaire) in total treatment 
satisfaction 
From baseline (week 0) to week 26 
Score 0-36 
6 items scored on a 
scale of 0 to 6. The 
higher the score the 
greater the satisfaction with 
treatment 
Change in HbA1c 
From baseline (week 0) to week 52 
%-point 
*using continuous glucose monitoring (CGM) system, Dexcom G6 
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3.2.2.2 
Secondary safety endpoints  
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter)   
From baseline (week 0) to week 26 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter)   
From baseline (week 0) to week 57 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Time spent < 3.0 mmol/L (54 
mg/dL)* 
From week 22 to week 26  
% of readings 
Time spent > 10 mmol/L (180 
mg/dL)* 
From week 22 to week 26  
% of readings 
Mean total weekly insulin dose 
From week 24 to week 26  
U 
Mean total weekly insulin dose 
From week 50 to week 52 
U 
Change in body weight 
From baseline (week 0) to week 26  
Kg 
*using continuous glucose monitoring (CGM) system, Dexcom G6 
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3.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter)   
From baseline (week 0) to week 52 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
 
4 
Trial design 
4.1 
Overall design 
This is a 26-week, randomised, multicentre, multinational, open-label, active-controlled, parallel 
group, two-armed, treat-to-target trial investigating the effect on glycaemic control and safety of 
treatment with once weekly insulin icodec compared to once daily insulin degludec, both in 
combination with insulin aspart in subjects with T1D, with a 26-week extension phase. The first 26 
weeks of the trial constitute the main phase, after which the primary analysis is planned. The focus 
of the 26-week extension phase is to evaluate long-term safety and provide long-term exposure 
data. 
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
an initial 26-week randomised treatment period, a 26-week extension phase and a 5-week follow-up 
period. Primary analysis is planned after the initial 26-week main phase.  
The overall trial design and visit schedule are outlined in Figure 4-1 and trial flowchart 
(Section 1.2), respectively.  
Subjects will be randomised (1:1) to a treat-to-target basal-bolus insulin regimen with either once 
weekly insulin icodec or once daily insulin degludec, both in combination with insulin aspart. The 
randomisation of subjects will be stratified by pre-trial basal insulin regimen (either twice daily/ 
insulin glargine U300 or once daily) and HbA1c (either <8% or ≥8%) at screening. During the 52-
week treatment period, subjects will have weekly contact with the site either at site visits or by 
phone contacts. The end of treatment visit (V54) will be one week after the last dose of insulin 
icodec and on the day of or day after the last dose of insulin degludec. The end of trial visit (V56) 
will be performed 5 weeks after end of treatment visit (V54). This will allow for appropriate wash-
out of trial drug, following at least 5 half-lives of insulin icodec. After the end of treatment subjects 
will be transferred to a marketed product at the discretion of the investigator (Section 6.7 and 
Appendix 8, Section 10.8). 
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Subjects will carry a continuous glucose monitoring (CGM) device for the entire trial duration 
including the follow-up period. Subjects wearing a personal CGM or flash glucose monitoring 
(FGM) device prior to entering the trial, will discontinue the use of the personal pre-trial CGM or 
FGM device and switch to a trial CGM. The trial CGM receiver will be unblinded for both subjects 
and investigators.  
Event adjudication will be performed for acute coronary syndrome events (acute myocardial 
infarction or unstable angina pectoris requiring hospitalisation), cerebrovascular events (stroke or 
transient ischemic attack), heart failure (requiring hospitalisation or urgent heart failure visit) and 
all-cause death.     
 
Figure 4-1 
Trial design 
4.2 
Scientific rationale for trial design 
The trial is designed to investigate the effect on glycaemic control and safety of once weekly insulin 
icodec versus once daily insulin degludec in combination with insulin aspart. A treatment duration 
of 26 weeks is evaluated as adequate for assessing effect on glycaemic control and safety; the 
extension of 26 weeks is included to provide long-term insulin icodec exposure for safety 
evaluation.  
Subjects included in the trial will be representative of a broad T1D population that may benefit from 
insulin titration using a treat-to-target titration algorithm. To safeguard the subjects, the inclusion 
and exclusion criteria defined in this trial will limit the population to subjects not suffering from 
advanced underlying diseases other than T1D. This is to avoid compromising the safety of the 
subjects participating in the trial and to strengthen conclusions regarding the effect and safety of 
once weekly insulin icodec. 
Currently, basal insulins are dosed once or twice daily. In order to compare to well established and 
widely used basal insulin analogues with once daily dosing, insulin degludec has been chosen as 
comparator.  
Treatment in both arms will be open label as it was not considered feasible to blind the two 
treatments; the dosing regimen is not the same between treatment groups and there is a risk of pen-
injector mix-up if a double-blind, double-dummy design was used as it would require the use of 
three different pen-injectors (two basal and one bolus pen-injector) in both treatment arms.  
The treat-to-target approach has been chosen in order to ensure optimal titration of insulin based on 
self-measured plasma glucose (SMPG) values with the aim of improving HbA1c. The initial 26 
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weeks will allow sufficient time for up-titrating of the basal and bolus insulins and sufficient time in 
maintenance period for HbA1c analysis. 
Titration of insulin icodec, insulin degludec and insulin aspart is outlined in the titration guidelines, 
Appendix 8, Section 10.8. Titration of insulin icodec and insulin degludec will be based on 
pre-breakfast SMPG values and adjusted once weekly in connection with the scheduled visits/phone 
contacts. Titration of insulin aspart will be adjusted once weekly in connection with the scheduled 
visit/phone contacts based on pre-prandial and bedtime SMPG values as outlined in the titration 
guidelines or based on carbohydrate counting per investigator's discretion.  
CGM will be used both to monitor subjects’ glycaemic control and to generate profiles for 
evaluating the effect on glycaemic control, as per section 3.1.2. CGM data from the receiver will be 
collected as specified in the flowchart (see Section 1.2). A minimum duration of 4 weeks data 
collection of CGM for the endpoint assessments has been chosen to accommodate evaluation of 
hypoglycaemia exposure.17 CGM values must not be used for hypoglycaemic episode reporting. If a 
hypoglycaemic episode is captured by the CGM, the subjects should use their BG meter to assess 
their PG level, and if hypoglycaemia is confirmed, it will be recorded in the eDiary, please refer to 
Appendix 7 (Section 10.7). 
A sufficient assay-sensitivity for the non-inferiority evaluation will be supported by the treat-to-
target trial design, the applied titration target/algorithm together with close titration surveillance and 
by having focus on adherence and discontinuation.  
4.2.1 
Subject input into design 
Not applicable for this trial  
4.3 
Justification for dose 
Subjects will be switched from pre-trial basal insulin analogues to insulin degludec according to 
local label, while insulin icodec will be initiated according to the principles outlined in the titration 
guideline in Appendix 8 (Section 10.8). A loading dose will be applied to avoid glycaemic slip 
during the first week of treatment. A 50% loading dose will be applied for subjects with an 
HbA1c < 8% at screening to reduce the risk of experiencing hypoglycaemic events at the beginning 
of the trial. While a 100% loading dose will be applied for subjects with an HbA1c ≥ 8% at 
screening to mitigate the occurrence of hyperglycaemic episodes in subjects entering the trial with 
poor glycaemic control. Subjects that prior to randomisation received insulin glargine U300 or basal 
insulin twice daily should receive a 50% loading dose regardless of their HbA1c at screening.   
One unit of insulin icodec has similar glucose lowering effect as one unit of insulin degludec, and 
therefore once weekly dosing corresponds to seven times the daily dose of the once daily 
comparator insulin degludec.  
The PK and PD properties of insulin icodec following five weeks of once weekly dosing in subjects 
with T2D (trial NN1436-4314) and T1D (trials NN1436-4225 & NN1436-4422) showed that 
insulin icodec exposure was well distributed across the dosing interval, with a PK and PD profile 
suitable for once weekly dosing.  
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After randomisation, subjects should start once weekly insulin icodec or once daily insulin degludec 
on the same day as randomisation. Due to the longer half-life of insulin icodec, the last dose of 
insulin icodec will be administered 51 weeks after randomisation, while once daily insulin degludec 
injections will continue until 52 weeks after randomisation. The follow up period for both insulin 
icodec and insulin degludec will be 5 weeks from end of treatment (V54) to end of trial (V56). 
Insulin aspart should also be initiated same day as randomisation and should be taken 2-4 times 
daily with meals throughout the 52 weeks treatment duration. Switch from other rapid-acting insulin 
analogues should be done unit-to-unit.  
Further details on dose adjustment can be found in Appendix 8 (Section 10.8).  
4.4 
End of trial definition 
A subject is considered to have completed the trial if he/she has completed all phases of the trial 
including the last visit. 
The end of the trial is defined as the date of the last visit of the last subject in the trial globally. 
5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
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 aged ≥18 years at the time of signing informed consent. 
3. Diagnosed with type 1 diabetes mellitus ≥ 1 year prior to the day of screening. 
4. Treated with multiple daily insulin injections (basal and bolus insulin analogue regimens) ≥ 1 
year prior to the day of screening. 
5. HbA1c <10% at screening visit measured by central laboratory. 
5.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
1. Known or suspected hypersensitivity to trial products or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice). 
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screeninga. 
5. Any disorder, except for conditions associated with T1D which in the investigator’s opinion 
might jeopardise subject’s safety or compliance with the protocol. 
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6. 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). 
7. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
8. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at 
screening. 
9. Planned coronary, carotid or peripheral artery revascularisation. 
10. Renal impairment with estimated Glomerular Filtration Rate (eGFR) value of 
<30 ml/min/1.73m2 at screening measured by central laboratory. 
11. Impaired liver function, defined as Alanine Aminotransferase (ALT) ≥2.5 times or 
Bilirubin >1.5 times upper normal limit at screening measured by central laboratory.   
12. Known hypoglycaemic unawareness as indicated by the investigator according to Clarke’s 
questionnaire question 8.18  
13. Recurrent severe hypoglycaemic episodes within the last year as judged by the investigator. 
14. Inadequately treated blood pressure defined as systolic ≥180 mmHg or diastolic ≥110 mmHg at 
screening. 
15. 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 randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination. 
16. Presence or history of malignant neoplasm (other than basal or squamous cell skin cancer, in-
situ carcinomas of the cervix, or in situ prostate cancer) within 5 years prior to the day of 
screening. 
17. 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. 
a Simultaneous participation in a trial with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is 
allowed, if the last dose of the investigational medicinal product has been received more than 30 days before 
screening. 
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
The subjects should be fasting when attending some of visits (Section 1.2). Fasting is defined as at 
least 8 hours without food and drink intake, except for water and other prescribed medication. Trial 
product and other glucose lowering agents should be withheld on the day of fasting visit until blood 
sampling has been performed. Any other prescribed medication should be taken as usual. If the 
subject attends a fasting visit in a non-fasting state, the blood sampling procedures should be 
re-scheduled.  
5.3.2 
Caffeine, alcohol and tobacco 
Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
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5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. 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 informed consent date, 
demography, screen failure details, and eligibility criteria. For UK: SAE is also included as minimal 
information (see Appendix 9, Section 10.9). 
A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria 
This section is not applicable for this trial. 
6 
Treatments 
6.1 
Treatments administered 
Investigational medicinal products (IMP) 
All investigational medical products (IMPs) are listed in Table 6-1. 
 
 
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Table 6-1 
Investigational medicinal product provided by Novo Nordisk A/S 
Trial product name and strength: 
 
Insulin icodec 
700 units/mL 
(IMP, test product) 
Insulin degludec, 
100 units/mL 
(IMP, reference therapy) 
 
Dosage form 
Solution for injection 
Solution for injection 
Route of administration  
Subcutaneous (into the thigh, 
upper arm or abdomen)   
Subcutaneous (into the thigh, 
upper arm or abdomen)   
Recommended initial dose 
Please refer to Appendix 8 
(Section 10.8) 
Please refer to Appendix 8 
(Section 10.8) 
Dosing instructions 
Administer insulin icodec once 
weekly, on the same day each 
week, at any time of the day. 
Rotation of injection site within 
the same area is recommended.  
Administer insulin degludec once 
daily at any time of the day, but 
preferably at the same time every 
day throughout the trial. Rotation 
of injection site within the same 
area is recommended. 
Packaging 
 
3 mL PDS290 pre-filled pen-
injector 
3 mL PDS290 pre-filled pen-
injector 
• 
Insulin icodec and insulin degludec DFU will be provided electronically via the eDiary and 
available to the subjects throughout the trial. 
• 
A pen differentiation guide will be provided  
• 
At randomisation visit (V2) subjects should administer trial product at site. 
• 
Subjects should be instructed to discard the needle after each injection and store the pen-
injector without a needle attached.  
Non-investigational medicinal products (NIMP) 
Table 6-2 
Non-investigational medicinal product  
Trial product name: 
 
Insulin aspart 
100 units/mL 
(NIMP, auxiliary therapy) 
Dosage form 
Solution for injection 
Route of administration  
Subcutaneous    
Recommended initial dose 
Please refer to Appendix 8 (Section 10.8) 
Dosing instructions 
Administer insulin aspart with meals, 2-4 times 
daily 
Packaging 
3 mL prefilled Flexpen 
Provider 
Novo Nordisk A/S 
• 
Insulin aspart DFU will be provided electronically via the eDiary and available to the 
subjects throughout the trial. 
Auxiliary supplies 
Auxiliary supplies comprise supplies other than trial products. Auxiliary supplies will be provided 
in accordance with the trial materials manual (TMM), please see Table 6-3.  
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Table 6-3 
Auxiliary supplies 
Auxiliary supply  
Details 
Needles 
Needles for pre-filled pen injector. NovoFine needles no longer than 6 mm will be 
used for administration of trial product. Only needles approved by Novo Nordisk 
must be used for administration of trial product. 
Blood glucose meter 
Roche Accu Check 
At randomisation (V2) subjects must be instructed in how to use the BG meter and 
the BG meter should be linked to the eDiary as described in the eDiary site guide.  
Please refer to the Roche manufacturer’s guide provided  
Continuous Glucose 
Monitoring system  
Dexcom G6 
At randomisation (V2) subjects must be instructed in handling of the CGM. Please 
refer to the CGM manual for more information.  
eDiary  
Subject Mobile app, HCP Web Portal & Cloud service  
Please refer to the eDiary site guide.   
 
6.1.1 
Medical devices 
6.1.1.1 
Investigational medical device 
This section is not applicable for this trial 
6.1.1.2 
Non-investigational medical devices 
Non-investigational medical devices including needles for pre-filled pen injector, BG meter and 
CGM are listed as auxiliary supplies in Table 6-3. 
For countries where BG meter and CGM are not approved, please refer to Appendix 9, Section 10.9 
country-specific requirements for further information. 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply trial product. 
• 
Acceptable temperature ranges and conditions for storage and handling of each trial product 
when not in use and when in use are described in the trial materials manual (TMM). 
• 
Each site will be supplied with sufficient trial products for the trial on an ongoing basis. 
Trial product will be distributed to the sites according to screening and randomisation. 
• 
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all trial products received, and that any discrepancies are 
reported and resolved before use of the trial products. 
• 
All trial products must be stored in a secure, controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and delegated site staff. 
• 
The investigator must inform Novo Nordisk immediately if any trial product has been 
stored outside specified conditions. The trial product must not be dispensed to any subject 
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before it has been evaluated and approved for further use by Novo Nordisk. Additional 
details regarding handling of temperature deviations can be found in the TMM. 
• 
The investigator or designee is responsible for drug accountability and record maintenance 
(i.e. receipt, accountability and final disposition records). 
• 
The investigator or designee must instruct the subject in what to return at next visit. 
• 
Each single pen should be accounted for.  
• 
Destruction of trial products can be performed on an ongoing basis and will be done 
according to local procedures after accountability is finalised by the site and reconciled by 
the monitor. 
• 
All returned, un-used, expired or damaged trial products (for technical complaint samples, 
see Section 10.5) must be stored separately from non-allocated trial products. No 
temperature monitoring is required. 
• 
Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
6.3 
Measures to minimise bias: Randomisation and blinding 
This is an open label trial; however, the specific treatment for a subject will be assigned using an 
IWRS. The site will access the IWRS before the start of trial product administration for each 
subject. Potential bias will be reduced by central randomisation and adjudication. 
All subjects will be centrally screened and randomised using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Randomisation will be stratified by pre-
trial basal insulin treatment (either twice daily/insulin glargine U300 or once daily) and HbA1c 
(either <8% or ≥ 8%) at screening. Within each stratum, each subject will be randomly allocated to 
receive once weekly insulin icodec once daily insulin degludec. Trial product will be 
dispensed/allocated at the trial visits summarised in the flowchart (Section 1.2).  
 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. 
When subjects self-administer trial product at home, compliance with trial product administration 
will be assessed by cross checking the following sources and comparing these to the expected use: 
• 
Drug accountability information  
• 
Review of eDiaries including SMPG profiles, insulin dose and hypoglycaemia reporting 
• 
Evaluating glycaemic control and adherence to the visit schedule 
• 
If any suspicion of non-compliance arises the site must enter into a dialogue with the 
subject, re-emphasizing the importance of compliance and uncover barriers to compliance. 
This dialogue must be documented in the medical record.  
6.5 
Concomitant medication 
Any medication other than the trial product and anti-diabetic medication that the subject receives 
from screening (V1) until end of trial visit (V56) must be recorded along with: 
• 
Generic name or trade name 
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• 
Indication 
• 
Dates of administration including start and stop date. 
Concomitant medication (diabetes) 
Any anti-diabetic medication other than the trial product that the subject receives from screening 
(V1) until end of trial visit (V56) must be recorded in a separate concomitant medication (diabetes) 
form in the electronic case report form (eCRF).  
The following information must be recorded for any anti-diabetic drugs including pre-trial insulin 
and post-treatment insulin in the follow-up period: 
• Generic name or trade name (for insulin products: only trade name). 
• Dates of administration including start and stop date. 
• Doses and frequency (e.g. once daily, twice daily). 
Until end of treatment (V54) only randomised treatment are allowed, unless due to safety reasons at 
the discretion of the investigator. If the investigator chooses to initiate anti-diabetic medication prior 
to end of treatment (V54), this should be registered in the eCRF as change in concomitant 
medication (diabetes). 
Changes in concomitant medication including anti-diabetic medication and other indications must 
be recorded at each visit. If a change is due to an adverse event, then this must be reported 
according to Section 8.3. 
For information regarding concomitant medication collection including anti-diabetic medication 
and other indications for subjects who discontinue trial product, see Section 7. 
6.6 
Dose modification 
Doses are adjusted according to SMPG values as described in Appendix 8 (Section 10.8).  
6.7 
Treatment after end of trial 
When discontinuing trial products, the subject should be transferred to a suitable marketed product 
at the discretion of the investigator and according to local clinical practice. Please refer to the 
titration guideline in Appendix 8 (Section 10.8).  
7 
Discontinuation of trial treatment and subject 
discontinuation/withdrawal 
Treatment of a subject may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have the subjects who discontinue trial product attend the end of treatment 
visit (V54) as soon as possible to collect the required data for the analysis of the primary endpoint. 
Two follow-up visits, V55 and V56, must be performed after discontinuation of the trial product. 
Visits V55 and V56 must be conducted 3 and 6 weeks respectively after discontinuation of once 
weekly insulin icodec and 2 and 5 weeks respectively after discontinuation of once daily insulin 
degludec. It is stressed that the visit window is plus 3 days for both visits V55 and V56. 
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Further, it is important that discontinued subjects come in for discontinuation follow-up visit V28A, 
26 weeks after the randomisation visit and V54A, 52 weeks after the randomisation visit. V54A will 
be the last visit for discontinued subjects. 
Subjects who prematurely discontinue trial product should keep and use the eDiary, and return it at 
the V56.  
The investigator should change subject status in the healthcare professional (HCP) web portal to 
'Follow-up' at the end of treatment visit to ensure that the subject should no longer report insulin 
dose. 
Continue to collect, record and report AEs as described in Section 8.3.2. AEs and anti-diabetic 
medication should be collected and recorded in the eCRF until the discontinuation follow-up visit 
(V54A) for discontinued subjects, no other concomitant medication will be collected. Please, refer 
to Section 6.7 for treatment after end of trial. 
In case of any uncertainty regarding the scheduling of the visits after discontinuation or questions to 
said visits, the investigator should consult Novo Nordisk for further guidance. 
Only subjects who withdraw consent will be considered as withdrawn from the trial. Subjects must 
be educated about the continued scientific importance of their data, even if they discontinue trial 
product. Further, the site should stay in contact with discontinued subjects by phone and/or site 
visits to motivate subjects to attend the visits until the discontinuation follow-up visit (V54A). Site 
contact with discontinued subjects should be documented in the medical record 
7.1 
Discontinuation of trial treatment 
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern related to trial product or unacceptable intolerability 
2. Pregnancy 
3. Intention of becoming pregnant 
4. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical triala 
5. Lack of efficacy, defined as fulfilment of ALL 4 criteria below: 
a. No reduction in HbA1c measured by central laboratory from randomisation (V2) to 
V12, or to V20, or to V28 or to V38, or to V46 AND 
b. the pre-breakfast SMPG readings on 3 consecutive days higher than 240 mg/dL 
(13.3 mmol/L) within the last two weeks period despite appropriate dose 
adjustments, AND  
c. a confirmatory fasting plasma glucose exceeding 240 mg/dL (13.3 mmol/L) 
measured by central laboratory. The subject should come in for an unscheduled visit 
as soon as possible (within one week), the next scheduled visit should not be 
awaited, AND  
d. no treatable intercurrent cause (e.g. non-compliance) for the hyperglycaemia at the 
investigator’s judgment. 
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a Simultaneous participation in a trial with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is 
allowed at the investigator discretion without discontinuing trial product. 
 
The primary reason for discontinuation of trial product must be specified in the end of treatment 
form in the eCRF, and final drug accountability must be performed. A treatment status session must 
be made in the IWRS. 
A subject, who does not fulfil the eligibility (inclusion/exclusion) criteria, must not be randomised. 
Randomisation in violation of any of the eligibility criteria is good clinical practice (GCP) non-
compliance and must be reported to the sponsor without delay. This will be handled as an important 
protocol deviation, and the independent ethics committee/institutional review board (IEC/IRB) and 
regulatory authorities must be notified according to local requirements.  
If a subject is randomised in violation of inclusion and exclusion criteria erroneously, the nature of 
the specific violation to in- or exclusion criteria will be evaluated carefully both by the principal 
investigator and Novo Nordisk medical specialist, independently. Subject can be allowed to 
continue in the trial and receive trial product if the violation is minimal or with no significant 
clinical relevance, and there are no safety concerns as evaluated by both the investigator and Novo 
Nordisk medical specialist (not applicable for UK, please see Appendix 9, Section 10.9). 
7.1.1 
Temporary discontinuation of trial treatment 
The subject should adhere to the treatment to the extent possible, with the exception of any adverse 
events such as hospitalisation or safety concerns, at the discretion of the investigator. Subjects who 
have temporarily discontinued trial product are allowed to restart trial product, unless any of the 
discontinuation criteria specified in Section 7.1 applies. Treatment status session must be made in 
the IWRS when the subject is temporarily discontinued and also when the subject resumes 
treatment. 
7.2 
Subject discontinuation/withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request. If a subject withdraws consent, 
the investigator must ask the subject if he/she is willing, as soon as possible, to have assessment 
performed according to V54. See the flowchart (Section 1.2) for data to be collected.  
Final drug accountability must be performed even if the subject is not able to come to the site. A 
treatment status session must be made in the IWRS. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, 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 withdrawal must be specified in the end of trial 
form in the CRF. 
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7.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
trial. 
• 
Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
• 
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
8 
Trial assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart (see Section 1.2). 
• 
Informed consent must be obtained before any trial related activity, see Section 10.1.3. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all inclusion criteria and none of the exclusion criteria. 
• 
The investigator will maintain a screening log (e.g. electronic or paper) to record details of 
all subjects screened and to confirm eligibility or record reason for screen failure, as 
applicable. 
• 
At screening, subjects will be provided with a card stating that they are participating in a 
trial and giving contact details of relevant site staff that can be contacted in case of 
emergency.  
• 
Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
• 
Assessments should be carried out according to the clinic’s standard of practice unless 
specified in the current section. Efforts should be made to limit the bias between the 
assessments. The suggested order of the assessments at randomisation visit (V2) is as 
follows: 
o Blood sample collection  
o Other assessments to confirm eligibility 
o Randomisation in IWRS 
o Continuous glucose monitoring fitting and training 
o The investigator should create a subject profile and record administrative 
information (e.g. subject ID, year of birth and gender and treatment arm in the HCP 
web portal  
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o Subjects should be provided with an eDiary and instructed in how to use it.  
o The BG meter should be connected with the eDiary  
o A fasting SMPG should be measured using the BG meter 
o Dosing of trial product 
• 
For information regarding the eDiary and HCP web portal please refer to the site guide.  
• 
Please refer to Section 6.4 for drug treatment compliance. 
• 
All data entered in the eDiary is considered source data. The investigator should review all 
the data for the subjects through the HCP web portal, before or during each visit/phone 
contact. 
• 
Review of eDiaries, PRO instruments, ECG, CGM data, laboratory reports, eye- and 
physical examinations must be documented either on the documents or in the subject's 
source documents. If clarification of entries or discrepancies in the eDiary is needed, the 
subject must be questioned, and a conclusion made in the subject's source documents, the 
eDiary should be updated retrospectively if applicable. Care must be taken not to bias the 
subject. 
• 
Repeat samples may be taken for technical issues and unscheduled samples or assessments 
may be taken for safety reasons. Please refer to Appendix 2 (Section 10.2) for further 
details on laboratory samples. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2) 
8.1.1 
Self-measured plasma glucose  
Subjects will be provided with a BG meter including auxiliaries. 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. 
The BG meter provided by Novo Nordisk should be used for measurements required in the 
protocol, as described in the flowchart (see Section 1.2). 
A baseline SMPG value, in fasting condition, should be collected using the BG meter at V2. 
Subjects must be instructed in how to transfer the results of the SMPG values daily into the eDiary. 
4-point daily SMPG 
Subjects should be instructed to measure their pre-prandial and bedtime SMPGs daily from week 0 
(V2) to end of trial (V56) at the following time points: pre-breakfast, pre-lunch, pre-dinner, and at 
bedtime. The subject should transfer the measured SMPG values into the eDiary. 
Selected titration data (e.g. certain SMPGs and dose data) from the eDiary will be used during the 
trial for central titration surveillance, to ensure compliance with the titration guideline in 
Appendix 8 (Section10.8) and will not be reported in the clinical trial report. All data will be stored 
by Novo Nordisk (see Appendix 1, Section 10.1). 
8.1.2 
Continuous glucose monitoring  
Subjects will be equipped with a CGM device during the entire duration of the trial (i.e. from week 
0 (V2) to week 57 (V56)). 
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The CGM system used in this trial will be the Dexcom G6®. 
The CGM readings will be open to both the subject and the investigator. 
If a subject withdraws consent during the trial, a site visit should be scheduled in order to remove 
the CGM sensor and upload the data from the receiver. 
CGM fitting and training  
The site staff will closely supervise and assist on fitting of the sensor and transmitter on the subject 
during the site visits. Training in the CGM is the responsibility of the investigator or site staff at the 
relevant visits. For information on fitting, and changing of the CGM parts, please refer to the CGM 
manual and subject guide provided. 
CGM Sensor Check  
The site staff should ensure that the subject has fitted the sensor correctly and that the CGM 
receiver is working. This will be done in person during the clinic visit, as specified in the flowchart 
(see Section 1.2). The site should ensure the subject can change the sensor at home weekly during 
trial periods when the subject will not attend site visits. 
CGM Upload 
Data stored on the CGM receiver must be uploaded at the site by the site staff to the CGM software 
following the instruction provided to the sites. Data upload will occur at each site visit, see 
flowchart (Section 1.2). Data upload will occur every week from V2 (week 0) to V8 (week 6), from 
V24 (week 22) to V28 (week 26), and from V50 (week 48) to V54 (week 52). Outside the specified 
periods, upload will occur every second or forth week in conjunction with site visit, and at the 
follow-up visits 1 and 2. The upload will be documented by the system directly. 
The serial number of the CGM receiver must be recorded in the eCRF at the randomisation visit 
(V2). In case the CGM receiver is replaced, the new receiver serial number should be entered in the 
eCRF as well. 
8.1.3 
Clinical outcome assessments 
The patient reported outcome questionnaires are to be completed by the subject without assistance 
of the site personnel and should preferably be completed after all fasting-related activities are 
completed, but before any other visit related procedures are conducted. It takes approximately five 
minutes to complete the questionnaires.  
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The following patient reported outcome questionnaires will be supplied in linguistically validated 
versions in all languages relevant for this trial: 
• Diabetes Treatment Satisfaction Questionnaire (DTSQs)  
o The questionnaire has been designed to measure satisfaction with diabetes treatment 
regimens in people with diabetes. The DTSQs questionnaire will be measured at 
baseline (V2), week 26 (V28), and end of treatment visit (V54).  
• International Physical Activity Questionnaire  
o The questionnaire has been designed to measure physical activity. It will be 
measured at baseline (V2) only. The questionnaire is for all subjects 18-69 years of 
age. 
8.1.4 
Clinical efficacy laboratory assessments  
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart.  
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product.  
Medical history is a medical event that the subject experienced prior to the time point from which 
AEs are collected. Only relevant medical history as judged by the investigator will be recorded in 
the eCRF.  
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form.  
Information on hypoglycaemia unawareness will be recorded according to Clarke's questionnaire, 
question 8. 18 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?" Subjects answering 'never, rarely or 
sometimes' are considered to have impaired awareness of hypoglycaemia, whereas those answering 
“often or always” are not. 
8.2.1 
Insulin dose 
The prescribed insulin doses will be determined by the investigator in accordance with the titration 
guideline (see Appendix 8, Section 10.8). 
During the trial, starting at randomisation (V2), subjects must be instructed to report date, dose and 
time of once weekly insulin or once daily insulin, and of bolus insulin in the eDiary. In the 
follow-up period if the subject switches to a new basal insulin and a new bolus insulin, the subject 
should also report date, dose and time of the new basal and bolus insulin in the eDiary. 
Please refer to Appendix 8 (Section 10.8) for more information. 
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The investigator must record the following in the eCRF 
• 
First and last date on trial product 
• 
First and last dose of trial product 
For dosing of anti-diabetic medication prescribed in the follow-up period please see Sections 6.5 
and 6.7 
8.2.2 
Physical examinations 
A physical examination will include assessments of: 
• 
Head, ears, eyes, nose, throat, neck 
• 
Cardiovascular system 
• 
Respiratory system 
• 
Gastrointestinal system 
• 
Central and Peripheral Nervous System 
• 
Musculoskeletal system 
• 
Skin. 
 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
 
The physical examination will be recorded in the eCRF as either ‘normal’ or ‘abnormal’. If 
‘abnormal’, a comment must be given together with an assessment of clinical significance (yes/no).  
Abnormal, clinically significant findings at screening should be recorded as concomitant illness in 
the eCRF. At the following visits, any new abnormal, clinically significant findings or clinically 
significant deteriorations from baseline should be reported as an adverse event (see 
Appendix 3, Section 10.3). 
Body measurements (height and weight) will also be measured and recorded. Height will be 
measured and recorded at screening visit (V1). Weight will be measured and recorded throughout 
the trial as specified in the flowchart (Section 1.2). 
• 
Body weight should be measured in kilogram (kg) or pounds (lb) without coat and shoes 
wearing only light clothing. Body weight will be recorded to one decimal.  
• 
Body weight should be assessed with the same equipment throughout the trial, if possible. 
• 
Height should be measured in centimetres (cm) or inches (in) without shoes. Height will be 
recorded to the nearest whole number. 
• 
From the body weight and height, the BMI will be calculated in the eCRF 
8.2.3 
Vital signs 
• 
Pulse rate, as well as systolic and diastolic blood pressure will be assessed. 
• 
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of 
rest for the subject in a quiet setting without distractions (e.g. no use of television, mobile 
phones). 
• 
Blood pressure and pulse rate measurements will be assessed sitting with a completely 
automated device. Manual techniques must be used only if an automated device is not 
available. 
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• 
Blood pressure and pulse rate will consist of 3 systolic and diastolic blood pressure 
measurements with intervals of at least 1-2 minutes. An additional fourth blood pressure 
measurement must be performed if the first two readings on systolic or diastolic blood 
pressure differ by >10 mmHg. Systolic blood pressure will be calculated as the mean of the 
last 2 systolic blood pressure readings, and diastolic blood pressure as the mean of the last 2 
diastolic blood pressure readings. Only the last 2 systolic and last 2 diastolic blood pressure 
readings must be recorded in the eCRF.  
• 
Pulse rate will be measured in connection to the blood pressure measurements. Record the 
pulse rate for the last 2 blood pressure measurements in the eCRF. The pulse rate will be 
calculated as the mean of the last 2 measurements 
8.2.4 
Electrocardiograms 
• 
A 12-lead ECG must be performed by the investigator or delegated staff as outlined in the 
flowchart (Section 1.2). 
• 
The ECG should be preceded by at least 5 minutes of rest for the subject in a supine/sitting 
position in a quiet setting without distractions (e.g. no use of television, mobile phones). 
• 
The ECG must be interpreted, signed and dated by the investigator to verify that the data 
has been reviewed. 
• 
The ECG required at screening can be obtained within 2 weeks prior to V2 but at the latest 
at V2. The results must be interpreted by the investigator prior to randomisation in order to 
determine the eligibility of the subject. 
• 
The ECG required at the end of treatment visit can be obtained within 2 weeks prior to the 
end of treatment visit. The results must be available for evaluation at the end of treatment 
visit. 
• 
Abnormal, clinically significant findings at screening should be recorded as concomitant 
illness in the eCRF. At the following visits, any new abnormal, clinically significant 
findings or clinically significant deteriorations from baseline should be reported as an 
adverse event (see Appendix 3, Section 10.3). . 
8.2.5 
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 another suitably qualified health 
care provider (e.g. optometrist) must be available and evaluated by the investigator before 
randomisation to assess eligibility. 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). Pharmacological pupil-
dilation is a requirement 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 his/her evaluation upon the results of that examination. The examination must 
be repeated before randomisation if the subject has experienced worsening of visual function since 
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the last examination. Eye examinations performed prior to randomisation visit (V2) are acceptable 
if results are available for evaluation before randomisation. 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. 
Eye examinations required at the end of treatment visit (V54) can be performed within 2 weeks 
prior to the visit, if results are available for evaluation at the visit. For discontinued subjects, eye 
examination can be performed up to 2 weeks after the end of treatment visit. The investigator 
should indicate the outcome of each eye examination. Relevant findings prior to randomisation 
must be recorded as concomitant illness/medical history. While relevant findings occurring after 
randomisation should be reported as an adverse event, please refer to Section 8.3. 
8.2.6 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the protocol flowchart (Section 1.2). 
8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.  
Some AEs require additional data collection on a specific event form. This always includes 
medication error, misuse and abuse of IMP. The relevant events are in Table 8-1, together with 
events for adjudication. 
The definition of AEs and SAEs can be found in Appendix 3 (Section 10.3), along with a 
description of events for adjudication and AEs requiring additional data collection.    
Hypoglycaemic episodes 
Hypoglycaemic episodes require data collection on a hypoglycaemic episode form in the eDiary. 
Non-serious hypoglycaemic episodes do not require an AE form to be completed in the eCRF. If the 
hypoglycaemic episode fulfils the criteria for an SAE, then, in addition to the hypoglycaemic 
episodes form, an AE form and a safety information form must be filled in the eCRF, please refer to 
Appendix 3 (Section 10.3). For more information on hypoglycaemic episodes, please refer to 
Appendix 7 (Section 10.7) 
 
 
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Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs) and 
events for adjudication  
Event type  
AE requiring additional data 
collection 
Event for adjudication 
 
Medication error 
X 
 
Misuse and abuse 
X 
 
Acute coronary syndrome (acute myocardial 
infarction or unstable angina pectoris requiring 
hospitalisation) 
 
X 
Cerebrovascular events* (stroke or transient 
ischemic attack) 
 
X 
Heart failure (requiring hospitalisation or urgent 
heart failure visit) 
 
X 
Death 
 
X 
Hypersensitivity 
X 
 
Injection Site Reaction 
X 
 
*All cerebrovascular events (stroke and transient ischemic attack) are to be reported and sent for adjudication, however 
the event adjudication committee will only confirm strokes. 
A detailed description of the events mentioned in the above table can be found in Appendix 3 
(Section 10.3.3). 
Events for Adjudication 
Event adjudication will be performed in randomised subjects and will be evaluated by an 
independent external EAC in a blinded manner, please refer to Appendix 1, Section 10.1.6.4. 
There are four ways to identify events relevant for adjudication as described below:  
• 
Investigator-reported events for adjudication: investigator selects the appropriate AE 
category relevant for adjudication (Appendix 3, Section 10.3.3). 
• 
AEs reported with fatal outcome.  
• 
AE search (standardised screening): All AEs not reported with an AE category relevant for 
adjudication will undergo screening to identify potential events for adjudication. 
Investigators will be notified of these events in the eCRF.  
• 
EAC-identified events: Unreported events relevant for adjudication identified by the EAC 
during review of source documents provided for another event for adjudication.  
Investigators will be notified of these events in the eCRF and has the option to report the 
EAC-identified event. 
For each event relevant for adjudication an event type specific adjudication form should be 
completed in the eCRF within 14 days. 
Copies of source documents should be uploaded to the event adjudication system (EAS) as soon as 
possible and preferably within 4 weeks. In cases where the EAS is not accessible the investigator 
should ensure that the relevant source documents are collected and saved locally until the EAS is 
ready. If no, or insufficient source documents are provided to the adjudication supplier, the 
investigator can be asked to complete a clinical narrative to be uploaded to the EAS.  
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If new information becomes available for an event sent for adjudication, it is the responsibility of 
the investigator to ensure the new information is uploaded to the EAS. 
An event adjudication site manual will be provided to each site detailing which source documents 
are relevant and how these should be provided to the adjudication supplier. The anonymization and 
labelling requirements are also described in the event adjudication site manual. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs must be collected from the randomisation visit and until the end of trial visit at 
the time points specified in the flowchart. For subjects discontinuing trial product prematurely AEs 
must be collected from the end of trial visit until the discontinuation follow-up visit (V54A). For 
AE reporting in UK, please refer to the UK specific requirements in Appendix 9 (Section 10.9). 
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3 (Section 10.3). All SAEs must be recorded and reported to Novo 
Nordisk within 24 hours, and the investigator must submit any updated SAE data to Novo Nordisk 
within 24 hours of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3) 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, should be followed until final outcome of the event or the 
subject is lost to follow-up as described in Section 7.3. Further information on follow-up and final 
outcome of events is given in Appendix 3 (Section 10.3) 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
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regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected serious 
adverse reactions (SUSAR). 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it along 
with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
Details of pregnancies in female subjects will be collected from first exposure to trial product and 
until the infant is one month of age. 
If a female subject becomes pregnant, the investigator should inform Novo Nordisk within 14 
calendar days of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3. 
8.3.7 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5 (Section 10.5). 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
8.4 
Treatment of overdose 
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.3 and Appendix 3 (Section 10.3) for further details. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities until the blood glucose is normalised and/or signs/symptoms 
have been relieved. 
A specific overdose for insulin icodec cannot be defined; however, hypoglycaemia may develop 
over sequential stages if the doses administered are too high relative to the subject’s requirements.  
• 
Mild hypoglycaemia can be treated by oral administration of glucose or sugary products.  
• 
Severe hypoglycaemia, where the subject is not able to treat him/herself, can be treated by 
glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or by 
glucose given intravenously by a medical professional. Glucose must also be given 
intravenously, if the subject dose not respond to glucagon within 10-15 minutes. If the 
subject has been unconscious, administration of oral carbohydrates is recommended for the 
subject upon regaining consciousness, in order to prevent a relapse. 
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Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject. 
For more information on overdose consult the current version of the insulin icodec investigator's 
brochure9. 
For more information on overdose for insulin degludec or insulin aspart, consult the relevant IB, 
EMA SmPC, US PI or locally approved label.  
8.5 
Pharmacokinetics 
Blood samples will be used to evaluate the pharmacokinetics (PK) of insulin icodec. PK samples 
will be collected at the visits outlined in the flowchart (Section1.2) for subjects randomised to 
insulin icodec. The date and exact clock time for blood sampling must be recorded. 
Bioanalysis of insulin icodec samples will be performed at a special laboratory using a validated 
luminescent oxygen channelling immunoassay. The exact method will be described in a 
bioanalytical report. 
Residual PK samples may be used for exploratory metabolite analysis. Potential metabolite analysis 
will be reported separately from the clinical trial report.  
Genetic analyses will not be performed on these plasma/serum/whole blood samples. Subject 
confidentiality will be maintained.  
Procedures for sampling, handling, storage, labelling and shipments of the specimens must be 
performed in accordance with the laboratory manual. A randomisation list will be provided to the 
special laboratory. Samples from randomised subjects will be analysed for insulin icodec 
concentration. 
Subjects should be instructed to report dosing information in the eDiary as per Section 8.2.1.  
8.6 
Pharmacodynamics 
Not applicable for this trial.  
8.7 
Genetics 
Not applicable for this trial. 
8.8 
Biomarkers 
Not applicable for this trial.  
8.9 
Immunogenicity assessments 
8.9.1 
Anti-drug antibodies  
Anti-drug antibody samples will be collected according to the flowchart (Section 1.2) for subjects 
randomised to insulin icodec. All samples must be drawn prior to trial product administration if trial 
product administration is planned on the sampling day. Assessment of antibodies against insulin 
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icodec (anti-drug antibodies) in serum will be performed at a Novo Nordisk appointed laboratory. 
For details on blood sampling, serum preparation and storage, please refer to the laboratory manual.  
Analysis for anti-drug antibody will be done as listed in flowchart with a binding anti-drug antibody 
assay. Positive samples will be further characterised for titre, and cross-reactivity to endogenous 
human insulin. 
Detailed description of the assay methods will be included in an analytical report. Antibody assays 
will be validated according to international guidelines and recommendations.  
At the end of the trial, the following data will be electronically transferred to the Novo Nordisk 
database: Anti-insulin icodec binding antibodies (pos/neg) and titre of anti-drug antibody positive 
samples, and anti-insulin icodec binding antibodies cross-reacting with endogenous human insulin 
status (pos/neg). 
The investigator will not be able to review the results of antibody measurements in relation to AEs 
as the samples are often analysed after last subject last visit. Results from the binding anti-drug 
antibody analyses will be available after the completion of the trial. 
8.9.2 
Hypersensitivity 
Subjects and investigators will be instructed to detect signs and symptoms of systemic 
hypersensitivity.  
For subjects randomised to insulin icodec: In the event of a systemic hypersensitivity (not locally at 
the injection site), the subject should be called in as soon as possible to have additional blood 
samples taken in order to analyse the following parameters: 
• 
Tryptase (optimal 0.5-2 hours post the hypersensitivity reaction) 
• 
Total immunoglobulin E (IgE) antibodies 
• 
Anti-insulin icodec IgE antibodies 
• 
Anti-insulin icodec binding antibodies 
• 
Anti-human insulin IgE antibodies. 
The blood sampling should be repeated 2-4 weeks following onset of the systemic hypersensitivity 
reaction. If possible, the tests should also be performed on samples drawn prior to first 
administration of trial drug. 
For details related to blood sampling, plasma preparation and storage, please refer to the laboratory 
manual. 
Analysis will be performed by Novo Nordisk or a Novo Nordisk appointed special laboratory 
(please refer to Attachment I). The results will be reported in a separate report and attached to the 
clinical trial report. 
For retention of residual hypersensitivity samples, please refer to Appendix 6, Section 10.6. 
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Digital pictures  
The investigator or the subject must take digital pictures of the affected area at time of 
identification, using any device available (mobile phone, camera etc.) and thereafter as often as 
judged necessary by the investigator. The pictures should include subject identification number, 
date and time, time after dosing and a ruler for scaling. All pictures must be stored as part of source 
documentation at site. 
8.10 
Health economics  
Not applicable for this trial.  
9 
Statistical considerations  
9.1 
Statistical hypotheses 
The primary hypothesis to be tested is that insulin icodec is non-inferior to insulin degludec in terms 
of change from baseline to week 26 in HbA1c. 
Formally, let D be the treatment difference ‘insulin icodec’ minus ‘insulin degludec’ of the change 
in HbA1c from baseline to week 26. The null-hypothesis will be tested against the alternative 
hypothesis of non-inferiority as given by   
H0: D ≥0.30% against HA: D <0.30%  
The non-inferiority margin of 0.3%-point is chosen based on the recommendation of health 
authority guidance for industry on developing drugs for treatment of diabetes.19, 20 Furthermore: 
• The margin does not represent an unacceptable loss of efficacy with insulin icodec relative 
to treatment with a basal insulin analogue 
• It represents less than 30% of a suitably conservative estimate of insulin degludec´s 
treatment effect on HbA1c in a placebo-controlled trial in a T1D population; The treatment 
effect of degludec versus placebo in a T1D population is unknown but in a progressed T2D 
population of subjects already treated with liraglutide, degludec was shown to be superior to 
placebo ( ETD: -0.92%-point [-1.00; -0.75] 95%CI). 
9.2 
Sample size determination  
The sample size is determined in order to have 90% power for declaring non-inferiority (NI) with a 
NI margin of 0.3%-point with respect to change in HbA1c for the specified estimand and the full 
analysis set (primary analysis set). All available data points for the primary endpoint will be used in 
the primary analysis and this has guided the treatment effect assumptions below.  
 
In studies with insulin degludec 100 units/mL in T1D subjects (NN1250-3583, NN1250-3770, and 
NN1250-3995) the percent withdrawing from treatment and/or trial during the initial 26 weeks was 
approximately 9%, 12% and 15%. Considering the increased focus on retention, 10% are expected 
to experience any of the specified intercurrent events before week 26 in this trial.  
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It is assumed that there is no difference in HbA1c between the treatment arms for subjects 
completing randomised treatment and a treatment difference of 0.3%-point in favour of the 
comparator for subjects either discontinuing treatment prematurely or withdrawing from trial. Thus, 
with 10% expected to experience any of the specified intercurrent events before week 26, this leads 
to an assumption of a mean treatment difference of 0.03%-point for the specified estimand in the 
overall population.   
The standard deviation (SD) is assumed to be 1.0%-point based on results from studies with insulin 
degludec in subjects with T1D (NN1250-3583, NN1250-3770 and NN1250-3995), where the SD 
was found to be 0.9, 0.9 and 0.93 respectively.   
From the above assumptions and requirements, 580 subjects will be randomised to trial product.  
This will ensure sufficient power (90%) of confirming non-inferiority.  
With an expected screening failure rate of 25%, approximately 774 subjects will be screened to 
achieve 580 subjects randomly assigned to trial product. 
This sample size appears to be reasonable also under deviations from the assumed treatment 
difference as illustrated in the table below (Table 9-1) displaying power for various alternative 
treatment differences and standard deviations.  
Table 9-1 
Power for various treatment differences and standard deviations 
SD 
(%-point) 
 
 
 
0.0/0.015 
True treatment 
difference/adjusted 
treatment difference 
(%-point) 
0.0/0.03 
 
 
 
0.0/0.045 
 
 
 
0.05/0.08 
0.9 
97% 
95% 
93% 
84% 
1.0 
93% 
90% 
87% 
75% 
1.1 
88% 
84% 
80% 
67% 
SD: standard deviation. Power is computed for 1:1 randomisation and 580 subjects randomised. 
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised.  
Full analysis set 
All subjects randomised. Subjects will be analysed according to the randomised 
treatment. 
Safety analysis set 
All subjects randomly assigned to trial treatment and who take at least one dose 
of trial product. Subjects are analysed according to the treatment they actually 
received.  
In exceptional cases, subjects or observations may be eliminated from the full analysis set. In such 
case the reasons for their exclusion will be documented before unblinding. 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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The following periods will be considered for the data collected:  
 
In-trial period  
The in-trial period starts at randomisation and ends at the date of:  
• 
The last direct subject-site contact  
• 
Withdrawal for subjects who withdraw their informed consent 
• 
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up (i.e. possibly an unscheduled phone visit)  
• 
Death for subjects who die before any of the above.  
 
Baseline assessments are always included in the in-trial observation period. 
 
On-treatment period  
The on-treatment period starts at the date of first dose of trial product as recorded on the eCRF, and 
ends at the first date of any of the following: 
• 
The end of trial visit (V56)  
• 
The last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once 
weekly insulin (corresponding to 5 weeks after the end of the dosing interval for both 
treatment arms) 
• 
The end-date for the in-trial observation period.  
 
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product.  
 
Main-on-treatment period  
The main-on-treatment period starts at the date of first dose of trial product as recorded on the 
eCRF, and ends at the first date of any of the following:  
• 
The end date of the on-treatment period  
• 
Week 26 (V28).  
 
Baseline assessments are always included in the on-treatment observation periods. 
All efficacy endpoints will be summarised and analysed using the full analysis set and the ‘in-trial’ 
period. Safety endpoints will be evaluated using both the main-on-treatment and the on-treatment 
period with descriptive statistics being based on the safety analysis set and statistical analyses being 
based on the full analysis set unless otherwise specified.  
9.4 
Statistical analyses 
The statistical analysis plan (SAP) will be finalised prior to first subject first visit (FSFV), and it 
will include a more technical and detailed description of the statistical analyses described in this 
section.  
9.4.1 
General considerations 
Presentation of results from a statistical analysis will include the estimated mean treatment 
difference (or ratio) presented together with the two-sided 95% confidence interval and the 
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corresponding two-sided p-value. 
 
In the statistical models, explanatory factors will be coded as follows: 
• 
Treatment: Once weekly insulin icodec, insulin degludec 
• 
Screening HbA1c < 8%: yes, no   
• 
Pre-trial basal insulin treatment: twice daily or insulin glargine U300: yes or no 
• 
Region: Asia, Europe, North America 
• 
The regions will be defined as follows: 
o Asia: India, Japan 
o Europe: Austria, Netherlands, Germany, Turkey, Italy, Russia, Spain, United 
Kingdom 
o North America: United States, Canada 
o  
The last available assessment made prior to the first dose will be used as the baseline value. All 
endpoints based on CGM measurements will be derived the following way. The percentage of time 
spent in a given glycaemic range will be calculated as 100 times the number of recorded 
measurements in the given glycaemic range, divided by the total number of recorded measurements. 
Following international consensus criteria it will be required that at least 70% of the planned CGM 
measurements during the last four weeks of treatment are available for endpoint data to be included 
in the analysis. 
9.4.2 
Primary endpoint 
The primary endpoint is change in HbA1c from baseline to week 26. 
The ‘treatment policy’ estimand, will be estimated based on the Full Analysis Set (FAS) using all 
HbA1c measurements obtained at the week 26 visit, especially including measurements from 
subjects discontinuing their randomised treatment. Missing HbA1c at the week 26 visit (regardless 
of treatment completion status) will be imputed from trial participants, who have discontinued their 
randomised treatment prior to the week 26 visit and have a measurement at the week 26 visit in the 
following way:   
• First, one thousand (1000) copies of the dataset will be generated for HbA1c.   
• Second, for subjects having discontinued their randomised treatment prior to the week 
26 visit and have a HbA1c visit measurement at the week 26 visit, the change in HbA1c 
from last available planned on-treatment (LAOT) value to the week 26 visit will be 
analysed for each dataset copy using an ANCOVA model with randomised treatment as 
fixed factor and LAOT value and the time point (study day) of this assessment as 
covariates. The estimated parameters, and their variances, from the model will be used to 
impute missing HbA1c values for the change from LAOT to the week 26 visit and 
subsequently the missing HbA1c value at the week 26 visit.  
• For each of the complete data sets, the primary endpoint will be analysed using an 
ANCOVA model with region, screening HbA1c < 8% (yes/no) pre-trial basal insulin 
treatment and randomised treatment as fixed factors, and baseline HbA1c as covariate. 
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The estimates and standard deviations for the 1000 data sets will be pooled to one 
estimate and associated standard deviation using Rubin’s rule.   
Explanatory factors will be coded as follows:  
• 
Treatment: Once weekly insulin icodec, insulin degludec  
• 
Region: Asia, Europe, North America 
• 
Screening HbA1c < 8%: yes, no 
• 
Pre-trial basal insulin treatment: twice daily or insulin glargine U300: yes or no 
 
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinues randomised treatment.  
The following sensitivity analysis evaluating the robustness of the assumptions about the missing 
data will be carried out:  
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
subjects having imputed HbA1c measurement at the week 26 visit are assumed to have a worse 
outcome in the insulin icodec arm and a better outcome in the insulin degludec arm compared to 
what was imputed in the primary analysis. This is done by adding or subtracting values Δi to the 
imputed HbA1c values before analysing the data. The value of Δi will be varied independently in the 
two treatment arms. The non-inferiority margin of 0.3% will be among the Δi values investigated. 
The plausibility of the values of Δi where the conclusion of the primary analysis change will be 
evaluated to assess the robustness of the primary analysis result. 
9.4.3 
Secondary endpoints 
9.4.3.1 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
Efficacy endpoints 
Change in fasting plasma glucose (FPG) from baseline week 0 (V2) to week 26 (V28) 
Missing FPG values at the week 26 visit (regardless of treatment completion status) for both 
treatment arms will be imputed with baseline value adding a random error term. The random error 
term is normally distributed with a standard deviation set equal to the estimated residual standard 
deviation of an ANCOVA analysis on the LAOT values. Specifically, the imputations and analyses 
will be carried out as follows: 
• 
First, an ANCOVA model with region, screening HbA1c < 8% (yes/no), pre-trial basal 
insulin treatment and randomised treatment as fixed factors, and a baseline value as a 
covariate will be fitted to the LAOT value. 
• 
Second, the estimated residual standard deviation, s, from this model will be used to impute 
missing values by the baseline value, adding a random normally distributed term with mean 
0 and standard deviation s. This will be done 1000 times. 
• 
For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and 
randomised treatment as fixed factors, and a baseline value as a covariate.  
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• 
The estimates and SDs for the 1000 data sets will be pooled to one estimate and associated 
SD using Rubin’s rule. 
 
Time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL) from week 22 (V24) to week 26 (V28) 
Missing time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL) (TIR) from week 22 to week 26 
will be imputed from trial participants who are from the insulin degludec group, and who have 
completed and adhered to their randomised insulin treatment - i.e., data will be imputed based on 
the assumption that, subjects with missing endpoint data will behave like subjects completing 
insulin degludec treatment. Specifically, the imputations and analyses will be carried out as follows: 
• 
First, one thousand (1000) copies of the dataset will be generated for TIR. 
• 
Second, for each dataset copy, an ANCOVA model will be fitted to TIR values for subjects 
who completed their randomised treatment in the insulin degludec group. The estimated 
mean, and variances, from the model will be used to impute missing values in both 
treatment groups. 
• 
For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and 
randomised treatment as fixed factors. The estimates and SDs for the 1000 data sets will be 
pooled to one estimate and associated SD using Rubin’s rule. 
 
Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment 
satisfaction from baseline week 0 (V2) to week 26 (V28) 
The change in DTSQs in total treatment satisfaction from baseline to week 26 will be analysed 
using the same model as specified for change in FPG, but the corresponding baseline value will be 
used as a covariate. 
Change in HbA1c from baseline week 0 (V2) to week 52 (V54) 
The change in HbA1c from baseline to week 52 will be analysed similar to the primary endpoint 
specified above. 
Safety endpoints 
Hypoglycaemic episodes 
The following hypoglycaemic endpoints will be analysed separately using the method described 
below: 
• 
Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 
26 (V28).  
• 
Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 26 (V28). 
• 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3) from baseline week 0 (V2) to week 26 (V28). 
• 
Number of nocturnal clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3) from baseline week 0 (V2) to week 26 (V28). 
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For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 visit (V56) to planned end of the main-on-treatment period) will be 
imputed using a multiple imputation technique, assuming that the event rate pre-follow-up 2 visit 
(V56) follows the respective treatment groups rate whilst post-follow-up 2 visit (V56) event rate is 
the rate of the comparator group. The imputation will be done as follows: 
• 
First, a Bayes negative binomial model with log-link function will be fitted to the event rate 
data to obtain the posterior distribution of model parameters. The model will include 
region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and randomised 
treatment as fixed factors and the logarithm of the main-on-treatment period as offset. 
• 
Second, based on the estimated parameters for the comparator group in this model, the 
number of episodes in the missing period will be imputed for subjects who discontinued 
their randomised treatment. Multiple copies (1000 copies) of a complete data set will be 
generated by sampling from the estimated distribution. 
• 
For each of the complete data sets, the number of episodes will be analysed using a 
negative binomial model with log-link, fixed factors and offset as described in step 1. The 
estimates and SDs for the 1000 data sets will be pooled to one estimate and associated SD 
using Rubin’s rule. 
 
The following hypoglycaemic endpoints will be analysed separately using the method described 
above, substituting the main-on-treatment period with the on-treatment period: 
• 
Number of severe hypoglycaemic episodes (level 3), from baseline week 0 (V2) to week 
57 (V56). 
• 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL) confirmed by BG meter), from baseline week 0 (V2) to week 57 
(V56). 
• 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3), from baseline week 0 (V2) to week 57 (V56). 
• 
Number of nocturnal clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3), from baseline week 0 (V2) to week 57 (V56). Nocturnal hypoglycaemic episodes 
are hypoglycaemic episodes occurring between 00:01 and 05:59 both inclusive.  
For the definition and classification of hypoglycaemic episodes refer to Appendix 7 (Section 10.7). 
Time spent < 3.0 mmol/L (54 mg/dL) and time spent > 10 mmol/L (180 mg/dL) from week 22 
(V24) to week 26 (V28)  
Time spent < 3.0 mmol/L (54 mg/dL) (below range) and time spent > 10 mmol/L (180 mg/dL) 
(above range) from week 22 to week 26 will be analysed separately in a similar manner as ‘time in 
target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ if deemed appropriate, i.e. if data can be 
considered normally distributed. However, if a large number of subjects have 0 % time spent, then 
an alternative analysis will be performed where time spent below or above range will be analysed 
separately using a negative binomial model on the number of recorded measurements below and 
above range, respectively, with a log-link function and the logarithm of the total number of 
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recorded measurements as offset. The model will include randomised treatment and region as 
factors. Further details will be provided in the SAP. 
Mean total weekly insulin dose from week 24 (V26) to week 26 (V28) and mean total weekly 
insulin dose from week 50 (V52) to week 52 (V54) 
Mean weekly insulin dose during the last 2 weeks of treatment (from week 50 to week 52) and 
during the last 2 weeks in the main part (from week 24 to 26) will be log-transformed and analysed 
separately using the same statistical model as specified for change in FPG. Pre-trial (baseline) total 
weekly insulin dose will be log-transformed and included as a covariate in the model. 
Change in body weight from baseline week 0 (V2) to week 26 (V28)  
Change in body weight from week 0 to week 26 will be analysed using the same statistical model as 
specified for the primary endpoint, but with the corresponding baseline value as a covariate.  
9.4.4 
Exploratory endpoints 
For details on analyses of exploratory endpoints, please refer to the SAP. 
9.4.5 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (SAEs, 
AEs, safety laboratory parameters, vital signs, etc.) will be reported descriptively based on both the 
main-on-treatment and the on-treatment period, including any notable changes of clinical interest in 
laboratory parameters. In addition, SAEs will be reported descriptively based on the in-trial period. 
9.4.6 
Other analyses  
For other analyses, please refer to the SAP.  
9.4.6.1 
Pharmacokinetic modelling 
Insulin icodec serum concentration data will be used for population PK analysis. The objective of 
the population PK analysis is to evaluate the effects of pre-specified covariates on serum 
concentrations of insulin icodec. 
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo 
Nordisk. A more technical and detailed elaboration of the population PK analysis will be given in a 
modelling analysis plan, which will be prepared before database lock. In brief, a previously 
developed PK model for insulin icodec will be applied. The absorption rate constant (Ka) in the 
model will be fixed, and the apparent clearance (CL/F) and the apparent volume of distribution 
(V/F) will be re-estimated. The covariates of interest will be incorporated into the PK model using 
criteria which will be specified in the modelling analysis plan. 
The population PK analysis will be reported in a separate modelling report, which will not be part 
of the clinical trial report. The individual insulin icodec serum concentration data will be tabulated 
in the bioanalytical report. 
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9.5 
Interim analyses  
The trial does not include a formal interim analysis. However, the reporting will be split into a 
main phase and an extension phase, where the results of the main phase can be reported possibly 
before LPLV. Subjects will provide consent for the full length of the trial. To preserve trial integrity 
during the extension phase, dissemination of results from the main phase will, during the extension 
phase, initially be limited to communication internally and with regulatory authorities. 
9.6 
Data monitoring committee  
This section is not applicable for this trial.  
9.7 
Reporting of the main part of the trial 
A database lock is planned shortly after last subject last visit of the main part of the trial. The results 
from this main part will thereafter be reported. The complete trial will be reported after database 
lock of the extension part. 
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki21 and applicable ICH Good Clinical Practice (GCP) Guideline22 
• 
Applicable laws and regulations 
• 
The protocol, informed consent form, investigator’s brochure (as applicable) and other 
relevant documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed 
and approved by the IRB/IEC before the trial is initiated. 
• 
Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the CTR according to national requirements. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
safety hazard to trial subjects. 
• 
Before a site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received. 
• 
The investigator will be responsible for: 
o providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the 
IRB/IEC and/or regulatory authorities 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of the conduct of the trial at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
o ensuring submission of the CTR synopsis to the IRB/IEC 
o reporting any potential serious breaches to the sponsor immediately after discovery 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
10.1.3 
Informed consent process 
• 
The investigator or his/her representative will explain the nature of the trial to the subject 
and answer all questions regarding the trial.  
• 
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
• 
Subjects must be informed that their participation is voluntary. 
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• 
Subjects must be informed about their privacy rights.  
• 
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines22, Declaration of Helsinki21 and the 
IRB/IEC or site. 
• 
The medical record must include a statement that written informed consent was obtained 
before any trial related activity and the date when the written consent was obtained. The 
authorised person obtaining the informed consent must also sign and date the informed 
consent form before any trial related activity. 
• 
The responsibility of 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. 
• 
Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial. 
• 
A copy of the informed consent form(s) must be provided to the subject.  
10.1.4 
Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further, the subject may receive other written information 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. 
10.1.5 
 Data protection 
• 
Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records 
or datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the subject are transferred to Novo Nordisk. 
• 
The subject and any biological material obtained from the subject will be identified by 
subject number, visit number and trial ID. Appropriate measures such as encryption or 
leaving out certain identifiers will be enforced to protect the identity of subjects as required 
by local, regional and national requirements.  
• 
The subject must be informed about his/her privacy rights, including that his/her personal 
trial related data will be used by Novo Nordisk in accordance with local data protection 
law. The disclosure of the data must also be explained to the subject.  
• 
The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 
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10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal trial independent ad hoc 
group will be established in order to maintain the blinding of the trial personnel. 
10.1.6.2 
Trial safety group 
This section is not applicable for this trial.  
10.1.6.3 
Data monitoring committee 
This section is not applicable for this trial. 
10.1.6.4 
Event adjudication committee 
An independent external EAC is established to perform ongoing blinded adjudication of selected 
AEs and deaths (see Table 8-1). 
The EAC will evaluate events sent for adjudication using pre-defined definitions and guidelines in 
accordance with the EAC charter. The evaluation is based on review of pre-defined clinical data 
collected by the sites. The EAC is composed of permanent members covering all required medical 
specialities. EAC members must disclose any potential conflicts of interest and must be independent 
of Novo Nordisk. The EAC will have no authority to impact trial conduct, trial protocol or 
amendments. The assessments made by both the event adjudication committee and the investigator 
will be evaluated and included in the CTR.  
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements, such as those of the International 
Committee of Medical Journal Editors (ICMJE)23, the Food and Drug Administration Amendment 
Act (FDAAA)24, European Commission Requirements1, 25, 26 and other relevant recommendations or 
regulations. If a subject requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint, and is for this 
trial last subject first treatment (LSFT) + 26 weeks corresponding to visit 28. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed 
visit 28. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
FDAAA. 
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10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
• 
Novo Nordisk or designee is responsible for the data management of this trial including 
quality checking of the data. 
• 
All subject data relating to the trial will be recorded on electronic CRFs (eCRFs) unless 
transmitted electronically to Novo Nordisk or designee (e.g. laboratory and eDiary data) or 
when applicable on paper CRF. The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the CRF.  
 
The following will be provided as paper CRFs:  
• 
Pregnancy forms 
 
The following will be provided as paper CRFs to be used when access to the CRF is revoked or the 
CRF is temporarily unavailable:  
• 
AE forms  
• 
Safety information forms  
• 
Technical complaint forms (also to be used to report complaints on trial product not yet 
allocated to a subject)  
Corrections to the CRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction. If corrections are made by the investigator’s delegated staff after the date when the 
investigator signed the CRF, the CRF must be signed and dated again by the investigator. 
The investigator must ensure that data is recorded in the CRF as soon as possible, preferably within 
5 working days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.  
10.1.8.2 
Monitoring 
• 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data 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 site staff 
should be available for discussions at monitoring visits and between monitoring visits (e.g. 
by telephone).  
• 
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
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• 
Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
• 
Monitors will review the subject’s medical records and other source data to ensure 
consistency and/or identify omissions compared to the CRF.  
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay 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 CRF or via listings from the trial database.  
10.1.9 
Source documents 
All data entered in the eCRF must be verifiable in source documentation, except for the following 
data that has been recorded directly into the eCRFs and will be considered source data. 
• 
Data in the service providers’ database is considered source data e.g. eDiaries, CGM and 
laboratory. 
• 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
• 
Data reported on the paper CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records. Also, current medical records must be available.  
• 
It must be possible to verify subject’s medical history in source documents, such as 
subject’s medical record.  
• 
The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested, and who was contacted. 
• 
Definition of what constitutes source data can be found in a source document agreement at 
each site. There will only be one source document defined at any time for any data element. 
10.1.10 Retention of clinical trial documentation 
• 
Records and documents, including signed informed consent forms, pertaining to the 
conduct of this trial must be retained by the investigator for 15 years after end of trial unless 
local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of Novo Nordisk. No 
records may be transferred to another location or party without written notification to Novo 
Nordisk.  
• 
The investigator must be able to access his/her trial documents without involving Novo 
Nordisk in any way. If applicable, electronic CRF (eCRF) and other subject data will be 
provided in an electronic readable format to the investigator before access is revoked to the 
systems supplied by Novo Nordisk. Site-specific CRFs and other subject data (in an 
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electronic readable format or as paper copies or prints) must be retained by the site. A copy 
of all data will be stored by Novo Nordisk. 
• 
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
10.1.11 Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or 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. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
• 
failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, Novo Nordisk procedures or GCP guidelines 
• 
inadequate recruitment of subjects by the investigator 
• 
discontinuation of further trial product development. 
10.1.12 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 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 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 that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
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must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
10.1.13 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.  
10.1.14 Publication policy 
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 investigators 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 investigators will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators.  
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
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The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. 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. 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. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.27 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre 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. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
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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10.2 
Appendix 2: Clinical laboratory tests 
• 
The tests detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory. 
• 
Additional tests may be performed at any time during the trial as determined necessary by 
the investigator or required by local regulations. Only laboratory samples specified in the 
protocol should be sent to the central laboratory for analysis; if additional laboratory 
sampling is needed, e.g. to follow up on AEs, this must be done at a local laboratory. 
• 
The central lab will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab SOPs. These data will not be transferred to the trial database. The 
investigator should review such values for AEs and report these according to this protocol. 
• 
The investigator must review all laboratory results for concomitant illnesses and AEs. 
• 
Laboratory samples will be destroyed no later than at finalisation of the CTR.  
• 
For haematology samples (differential count) where the test result is not normal, then a part 
of the sample may be kept for up to two years or according to local regulations.  
• 
Human biosamples for retention will be stored as described in Appendix 6, Section 10.6. 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Glucose metabolism  
(V1*, V2, V12, V20, V28, 
V38, V46*, V54, V28A*, 
V54A*) 
*HbA1c only 
• Fasting plasma glucose (FPG)1  
• HbA1c  
NOTE: 
1A FPG result <3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a 
hypoglycaemic episode but as an AE at the discretion of the investigator (Appendix 3, Section 10.3). 
A FPG result >16.7 mmol/L (300 mg/dL) should not be reported as a hyperglycaemic episode but as an AE at the 
discretion of the investigator (Appendix 3, Section 10.3). 
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Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory 
 assessments 
Parameters 
Haematology 
(V1, V12, V28, V38, V54) 
• Erythrocytes 
• Haematocrit 
• Haemoglobin 
• Leucocytes 
• Thrombocytes 
Biochemistry1 
(V1, V12, V28, V38, V54) 
• Alanine Aminotransferase (ALT)  
• Albumin 
• Alkaline phosphatase 
• Aspartate Aminotransferase (AST) 
• Creatinine 
• Potassium 
• Sodium 
• Bilirubin 
Lipids 
(V2, V12, V28, V38, V54) 
• Cholesterol 
• High density lipoprotein (HDL) cholesterol 
• Low density lipoprotein (LDL) cholesterol 
• or IRB/IECTriglycerides 
Pregnancy Testing (V2, 
V56) 
• Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test2 
Other tests 
• eGFR calculated by the central laboratory based on the creatinine value using the CKD-
EPI equation, eGRF is for screening purposes only. 
• In case of systemic hypersensitivity (Section 8.9.2): Tryptase (optimal 0.5-2 hours post 
the hypersensitivity reaction), total IgE antibodies, anti-insulin icodec IgE antibodies, 
anti-insulin icodec binding antibodies, anti-human insulin IgE antibodies. 
• Anti-insulin icodec antibodies (V2, V4, V8, V12, V20, V28, V38, V54, V56) 
• Insulin-icodec serum concentration (V4, V8, V12, V20, V28, V38, V54, V56) 
Notes: 
1Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Section 10.3 (Hy’s Law) and Section 7.1. 
2Local urine testing will be standard unless serum testing is required by local regulation . 
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10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting 
10.3.1 
Definition of AE 
AE definition 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated 
with the use of an investigational medicinal product (IMP), whether or not considered related to 
the IMP. 
An AE can therefore be any unfavorable and unintended sign, including an abnormal laboratory 
finding, symptom or disease (new or exacerbated) temporally associated with the use of an IMP. 
 
Events meeting the AE definition 
• Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgment of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected 
• Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected  
• Exacerbation/worsening of a chronic or intermittent condition including either an increase in 
frequency and/or intensity of the condition 
• Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction 
• Signs, symptoms or the clinical sequelae of a suspected overdose of IMP regardless of intent 
 
A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfil the definition. 
Events NOT meeting the AE definition  
• Conditions present prior to the time point from which AEs are collected and anticipated day-to-
day fluctuations of these conditions, including those identified during screening or other trial 
procedures performed before exposure to IMP.  
• Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
• Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads to the 
procedure is the AE. 
• Medical or surgical procedures not preceded by an AE or worsening of a known condition. 
10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' 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 were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the physician’s office 
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or outpatient setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfils any other seriousness criteria, the event is serious. When in 
doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalisation for elective treatment (e.g. elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note:  
• Hospitalisations for administrative, trial related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs.  
• Hospital admissions for medical or surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs.  
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experience of relatively minor medical significance, 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g. sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the subject 
or may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious and reported as SAEs 
using the important medical event criterion. 
• The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable: 
• Suspicion of transmission of infectious agents via the IMP  
• Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x UNL and total bilirubin >2 x UNL where no alternative aetiology exists (Hy's 
law) 
 
10.3.3 
Description of events for adjudication and AEs requiring additional data collection  
Description of events for adjudication and AEs requiring additional data collection (on 
specific event form)  
Events for adjudication 
An event for adjudication is a selected AE or death evaluated by an independent external EAC in 
a blinded manner, please refer to Table 8-1, Appendix 1 (Section 10.1.6.4) and Figure 10-1. 
Source data should be in accordance with Section 8.3. 
• Death 
• All cause death 
• Acute coronary syndrome 
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• All types of acute myocardial infarction and unstable angina pectoris requiring 
hospitalisation 
• Cerebrovascular event (stroke or transient ischemic attack) 
• Episode of focal or global neurological dysfunction that could be caused by brain, spinal 
cord, or retinal vascular injury as a result of haemorrhage or ischemia, with or without 
infarction 
• Heart failure (requiring hospitalisation or urgent heart failure visit) 
• New episode or worsening of existing heart failure leading to an urgent, unscheduled hospital 
admission or clinic/office/emergency department visit 
Adverse events requiring additional data collection 
AEs requiring additional data collection on a specific event form.  
Injection site reaction 
If an event of injection site reaction is observed, additional information must be obtained if 
available on a separate form. 
Hypersensitivity 
Systemic hypersensitivity can be manifested as isolated symptoms such as urticaria, angioedema, 
conjunctivitis, rhinitis, bronchospasm, gastrointestinal symptoms (nausea, vomiting, diarrhoea, 
abdominal pain), or as anaphylaxis or anaphylactic shock. 
 
Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden 
release of mast cell- and basophil-derived mediators into the circulation28. It most often results 
from immunologic reactions to foods, medications, and insect stings, although it can also be 
induced through nonimmunologic mechanisms by any agent capable of producing a sudden, 
systemic degranulation of mast cells or basophils29. Characteristic symptoms and signs, occurring 
minutes to a few hours after exposure to potential triggering agents or events may include: 
flushing, urticaria, angioedema, hoarseness, throat tightness, stridor, wheezing, coughing, 
shortness of breath, abdominal pain, vomiting, and/or hypotension, dizziness or collapse. 
Local hypersensitivity reactions, including rash, redness, pruritus and oedema, may occur at the 
site of investigational drug injection. 
Drug hypersensitivity reactions (DHRs) are the adverse effects of pharmaceutical formulations 
(including active drugs and excipients) that clinically resemble allergy30. They can be allergic and 
non-allergic. 
If a hypersensitivity event is suspected, the subjects must contact the site staff as soon as possible 
for further guidance. All events must be reported, and in case of systemic hypersensitivity, 
additional information must be provided on a separate form. 
Medication error 
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the subject, such as:  
• administration of wrong drug or use of wrong device 
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.  
• wrong route of administration, such as intramuscular instead of subcutaneous  
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• accidental administration of a lower or higher dose than intended. The administered dose must 
deviate from the intended dose to an extent where clinical consequences for the trial subject 
were likely to happen as judged by the investigator, although they did not necessarily occur. 
• missed doses or drug pauses are not to be reported as a medication error. 
 
Misuse and abuse  
• Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g. overdose to maximise effect) 
• Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm) 
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence (e.g. hypoglycaemia or other), this must be reported on an additional AE 
form. 
 
10.3.4 
Recording and follow-up of AE and/or SAE 
AE and SAE recording 
• The investigator will record all relevant AE/SAE information in the CRF. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) related to the 
event. 
• There may be instances when copies of source documents (e.g. medical records) for certain 
cases are requested by Novo Nordisk. In such cases, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the source documents before 
submission to Novo Nordisk. 
• 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. For sign-off of SAE related forms, refer to “AE and SAE 
reporting via paper CRF” later in this section. 
• Novo Nordisk products used as concomitant medication or NIMP: if an AE is considered to 
have a causal relationship with a Novo Nordisk marketed product used as NIMP (insulin 
aspart) or concomitant medication in the trial, it is important that the suspected relationship is 
reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information 
form. Novo Nordisk may need to report this adverse event to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess severity for each event reported during the trial and assign it to one of 
the following categories:  
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
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• Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with a SAE. Both AEs and 
SAEs can be assessed as severe.  
 
Assessment of causality 
• The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. 
• Relationship between an AE/SAE and the relevant IMP(s) should be assessed as:  
• Probable - Good reason and sufficient documentation to assume a causal relationship. 
• Possible - A causal relationship is conceivable and cannot be dismissed. 
• Unlikely - The event is most likely related to aetiology other than the IMP. 
• Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
• The investigator should use the investigator’s brochure and/or product information, for 
marketed products, for the assessment. For each AE/SAE, the investigator must document in 
the medical records that he/she has reviewed the AE/SAE and has provided an assessment of 
causality. 
• There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator 
always makes an assessment of causality for every event before the initial transmission of 
the SAE data. 
• The investigator may change his/her opinion of causality, in light of follow-up information, 
and update the causality assessment in the CRF. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
• Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented 
• Recovering/resolving: The condition is improving, and the subject is expected to recover from 
the event. This term may be applicable in cases of chronic conditions, cancer or AEs ongoing 
at time of death (where death is due to another AE).  
• Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
• 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.  
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE).  
• 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 a fatal outcome must be reported as an SAE. 
• Unknown: This term is only applicable if the subject is lost to follow-up. 
 
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Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions). 
This may include additional laboratory tests (e.g. skin prick test) or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a subject dies during participation in the trial or during a recognised follow-up period, the 
investigator should provide Novo Nordisk with a copy of autopsy report including 
histopathology. 
New or updated information will be recorded in the CRF. 
 
10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
• Relevant forms (AE and safety information form) must be completed in the CRF.  
• For reporting and sign-off timelines, see Figure 10-1 below. Source data should be in 
accordance with Section 8.3. 
•  If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form, and 
if the CRF is unavailable for more than 5 calendar days, then the site will use the safety 
information form (see box below). 
• The site will enter the SAE data into the CRF as soon as it becomes available. 
• After the trial is completed, the trial database will be locked, and the CRF will be 
decommissioned to prevent the entry of new data or changes to existing data. If a site receives 
a report of a new SAE from a subject or receives updated data on a previously reported SAE 
after CRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone. 
 
AE and SAE reporting via paper CRF 
• Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk in 
accordance with Section 10.1.5. 
• For SAEs, initial notification via telephone is acceptable, although it does not replace the need 
for the investigator to complete the AE and safety information form within the designated 
reporting timelines (as illustrated in the figure below): 
• AE form within 24 hours 
• Safety information form within 5 calendar days 
• Both forms must be signed within 7 calendar days after first knowledge by the investigator. 
• The specific event form for AEs requiring additional data collection within 14 calendar days  
 
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Source data should be in accordance with Section 8.3 
Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
Contact details for SAE reporting can be found in the investigator trial master file. 
Reporting of AEs for non-Novo Nordisk medical devices provided by Novo Nordisk for use 
in the trial 
Reporting of AEs on Roche Accu check and Dexcom G6: 
All complaints (including AEs) should be reported directly to the manufacturer. 
 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
If fertility is unclear (e.g. amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of trial treatment, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
• 
Documented total hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Females with permanent infertility due to an alternate medical cause other than the above (e.g. 
Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in determining 
trial enrolment. 
3. Postmenopausal female: 
• A postmenopausal state is defined as amenorrhoea for 12 months without an 
alternative medical cause.  
• Females ≥ 50 years of age can be considered postmenopausal (irrespective of 
treatment with a hormonal contraception or hormone replacement therapy (HRT)) 
if they have both: 
o Amenorrhoea and 
o Documentation of 2 high follicle stimulating hormone (FSH) measurements in the 
postmenopausal range and one of these was observed ≥1 year prior to screening. 
• Females ≥ 60 years of age can be considered postmenopausal. 
Females on HRT and whose menopausal status is in doubt are considered of childbearing potential 
and will be required to use at least an effective contraception method.  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of subject’s 
medical records, medical examination or medical history interview. 
Contraception guidance 
Male subjects  
No contraception measures are required as the risk of teratogenicity/fetotoxicity caused by transfer 
of insulin icodec or insulin degludec or insulin aspart in seminal fluid is unlikely31 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use at least an 
acceptable effective method of contraception consistently and correctly as described in Table 10-3 . 
As a minimum, contraception should be maintained until treatment discontinuation32. 
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Table 10-3 
Acceptable contraceptive methods 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
ACCEPTABLE METHODSb 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action 
• Male or female condom with or without spermicidec 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods). 
NOTES 
a) Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical trials. 
b) Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. 
c) Male condom and female condom should not be used together (due to risk of failure with 
friction). 
 
Pregnancy testing 
• 
Additional pregnancy testing should be performed during the treatment period, if required 
locally. Please refer to the Appendix 9 (Section 10.9). 
• 
WOCBP should only be included after a negative highly sensitive urine pregnancy test 
(refer to Appendix 2 (Section 10.2) and the trial flowchart (Section 1.2). 
• 
As a minimum, pregnancy test should be performed at the end of relevant systemic 
exposure (refer to Appendix 2, Section 10.2 and the trial flowchart, Section 1.2).Pregnancy 
testing should be performed whenever a menstruation is missed or when pregnancy is 
otherwise suspected. 
Collection of pregnancy information  
Female subjects who become pregnant  
• 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this trial. 
• 
Information will be recorded on the appropriate form and submitted to Novo Nordisk 
within 14 calendar days of learning of a subject's pregnancy (see Figure 10-2). 
• 
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate which will be forwarded to Novo 
Nordisk within 14 calendar days. Generally, follow-up will not be required for longer than 
1 month beyond the delivery date. 
• 
Any termination of pregnancy will be reported, regardless of foetal status (presence or 
absence of anomalies) or indication for procedure. 
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• 
While pregnancy itself is not considered to be an AE or SAE, any adverse event in 
connection with pregnancy or elective termination of a pregnancy for medical reasons will 
be reported as an AE or SAE. If relevant, consider adding ‘gestational’, ‘pregnancy related’ 
or a similar term when reporting the AE/SAE. 
• 
Pregnancy outcome should be documented in the subject's medical record. Abnormal 
pregnancy outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies 
and ectopic pregnancy) is considered an SAE. 
• 
Any SAE occurring as a result of a post-trial pregnancy which is considered 
possibly/probably related to the IMP by the investigator will be reported to Novo Nordisk 
as described in Section 10.3. While the investigator is not obligated to actively seek this 
information in former subjects, he or she may learn of an SAE through spontaneous 
reporting.  
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product.  
Maternal form 1b 
  14 calendar days after birth
Maternal form 1a
  14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2   14 calendar days
Paternal form*1   14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
Figure 10-2 Decision tree for determining the forms to complete with associated timelines 
for pregnancy.  
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10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.5.1 
Definition of technical complaint 
Technical complaint definition  
• 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: 
• 
Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination) 
• 
Problems with packaging material including labelling 
• 
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and the needle) 
Time period for detecting technical complaints  
All technical complaints which occur from the time of receipt of the product at site until the time 
of the last usage of the product must be collected for products predefined on the technical 
complaint form.  
 
10.5.2 
Recording and follow-up of technical complaints 
Contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN. 
2. 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 CRF within: 
• 5 days calendar for all technical complaints  
If the CRF is unavailable, or when reporting a technical complaint on a trial product that is not 
yet allocated to subject , the information must be provided on a paper form to Customer 
Complaint Center, Novo Nordisk, within the same timelines as stated above. When the CRF 
becomes available again, the investigator must enter the information on the technical complaint 
form in the CRF. 
 
Follow-up of technical complaints  
The investigator is responsible for ensuring that new or updated information will be recorded on 
the originally completed form. 
 
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Collection, storage and shipment of technical complaint samples 
The investigator must collect the technical complaint sample and all associated parts that were 
packed in the same DUN and notify the monitor within 5 calendar days of obtaining the sample at 
site. The sample and all associated parts must be sent as soon as possible to Customer Complaint 
Center, Novo Nordisk, together with a copy of the completed technical complaint form. The 
technical complaint sample should contain the batch, code or lot number and, if available, the 
DUN. If the technical complaint sample is unobtainable, the reason must be stated on the 
technical complaint form. If several samples are shipped in one shipment, the sample and the 
corresponding technical complaint form should be kept together. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
 
10.5.3 
Reporting of technical complaints 
Reporting of technical complaints for Novo Nordisk products not included in technical 
complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form 
should be reported to local Novo Nordisk. 
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10.6 
Appendix 6: Retention of human biosamples 
Hypersensitivity reaction samples 
In case of a systemic hypersensitivity reaction, the additional blood samples taken in relation to the 
reaction (Section 8.9.2) may be retained to follow-up on the hypersensitivity reaction. If deemed 
relevant by Novo Nordisk, relevant exploratory tests may be performed, e.g. histamine release 
(basophil activation). If measured, such data will be reported in a separate report. 
The samples will be stored at Novo Nordisk or a Novo Nordisk designated referral central 
bio-repository. The samples might be transferred to other countries, if not prohibited by local 
regulations. Only Novo Nordisk staff and bio-repository personnel will have access to the stored 
samples. The samples may be shipped to a contract research organisation (CRO) for analysis. 
The samples will be anonymised (identified only by a unique sample ID, visit number, trial 
identification number and sampling date). Confidentiality and personal data protection will be 
ensured during storage after the end of trial and no direct identification of the subject will be stored 
together with the samples.  
Potential further analyses of the samples will not have any consequences for the subject and their 
relatives. Subjects can contact the investigator if they wish to be informed about results derived 
from stored antibody samples obtained from their own body. 
The samples will be stored after end of trial and until marketing authorisation approval or until the 
research project terminates, but no longer than 15 years from end of trial after which they will be 
destroyed. 
Antibody samples 
Antibody samples may be retained for further characterisation of antibody responses towards drug, 
if required by health authorities or for safety reasons. The samples may also be used for further 
development of anti-insulin antibody assays, or for exploratory investigation of antibodies. 
The antibody samples will be stored after end of trial and until marketing authorisation approval or 
until the research project terminates, but no longer than 15 years from end of trial after which they 
will be destroyed. 
Metabolism samples (PK samples) 
Samples for metabolism analysis may be retained for later analysis of metabolites if needed. If 
samples are selected for metabolite analysis, they will be stored at Novo Nordisk after end of trial 
and until marketing authorisation approval or until the research project terminates, but no longer 
than 15 years from end of trial after which they will be destroyed 
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10.7 
Appendix 7: Hypoglycaemic episodes 
Table 10-4 
Classification of hypoglycaemia 
Classification of hypoglycaemia 
Level 
Glycaemic criteria 
Description 
Hypoglycaemia alert value 
(level 1) 
< 3.9 mmol/L (70 mg/dL) and  
≥ 3.0 mmol/L (54 mg/dL) 
Sufficiently low for treatment with fast-acting 
carbohydrate and dose adjustment of glucose-lowering 
therapy 
Clinically significant 
hypoglycaemia (level 2) 
< 3.0 mmol/L (54 mg/dL) 
Sufficiently low to indicate serious, clinically 
important hypoglycaemia 
Severe hypoglycaemia 
(level 3) 
No specific glucose threshold 
1Hypoglycaemia associated with severe cognitive 
impairment requiring external assistance for recovery 
Notes: The Novo Nordisk terms are adapted from IHSG33, ADA34, ISPAD35 type 1 diabetes outcomes program36, 
ATTD37. Severe hypoglycaemia as defined by Seaquist38 and ISPAD35. 
 
Severe hypoglycaemia 
1Severe hypoglycaemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be 
available during an event, but neurological recovery following the return of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.38 
In case of recurrent severe hypoglycaemia, the treatment of the subject is the responsibility of the 
investigator and the titration guidelines can be overruled at his/her discretion34 
Nocturnal hypoglycaemia 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive. 
Reporting of hypoglycaemic episodes in the eDiary  
Plasma glucose (PG) should always be measured by the trial BG meter and hypoglycaemic episodes 
should be recorded in the eDiary.  
The following should be reported in the eDiary as hypoglycaemic events: 
- PG values < 3.9 mmol/L (70 mg/dL) 
- Severe hypoglycaemic episodes without confirmed PG values  
The investigator should ensure correct reporting of the hypoglycaemic episode. Confirmation of the 
hypoglycaemic episode review must be documented in the web portal. In case a subject is not able 
to fill in the eDiary (e.g. in case of hospitalisation) at time of episode, the subject can report the 
episode in the eDiary retrospectively. 
If the hypoglycaemic episode fulfils the criteria for an SAE then in addition to the above patient 
reported data, an eCRF AE form and a safety information form must also be filled in. One AE form 
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and safety information form can cover several hypoglycaemic values, if the subject has not 
recovered between them and has reported them as one episode in the eDiary. 
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the PG value is ≥ 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance with current guidelines38. 
Repeated low PG measurements can be reported by the subject as one hypoglycaemic episode until 
a succeeding PG value is ≥ 3.9 mmol/L (70 mg/dL). In case of several low PG values within the 
hypoglycaemic episode, the lowest value is the one that will be reported as the PG value for the 
hypoglycaemic episode, but the start time of the episode will remain as the time for the first low PG 
value. The remaining values will be kept as source data. 
If the severity of a hypoglycaemic episode changes, only one hypoglycaemic episode will be 
reported, reflecting the most severe degree of hypoglycaemia. 
Regarding the question: “To feel better, did you need help to get a sugary drink, food, or 
medicine?” the investigator must instruct the subjects to answer “Yes”, if the episode was an event 
that required 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 concentration38. 
eDiary review 
At each contact the investigator should review the eDiary data for correct reporting of PG values 
and hypoglycaemic episodes. In case of incomplete or incorrect data in the eDiary, the subject must 
be questioned whether there have been any severe hypoglycaemic episodes since the last visit. The 
subject shall update the reported data in the eDiary accordingly. 
Re-training of subjects 
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low PG values not reported as hypoglycaemic episodes. The training should be documented by the 
investigator in source documents. 
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10.8 
Appendix 8: Titration guideline 
Titration guidelines have been developed, providing recommended dose adjustments at different PG 
levels to ensure that subjects receive an optimal treatment. However, it is recognised that insulin 
treatment should be individualised, and the specific titration algorithms may not be applicable in 
certain clinical situations. Hence, 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 is responsible for the treatment of the subjects and 
can therefore overrule the guidelines to avoid safety hazards. 
Initiation of trial products 
At randomisation eligible subjects will be randomised to receive insulin icodec or insulin degludec, 
both in combination with mealtime insulin aspart.  
• Insulin icodec should be taken once weekly on the same day of the week. 
o At randomisation (V2) 
▪ Subjects that prior to randomisation received insulin glargine U300 or 
received basal insulin twice daily should receive a dose which consists of 
total daily basal insulin dose before randomisation x7 + 50% (Table 510-6) 
regardless of their HbA1c at screening. 
▪ Subjects with HbA1c <8% (64 mmol/mol) at screening should receive a dose 
which consists of total daily basal insulin dose before randomisation 
x7 + 50% (Table 510-6) 
▪ Subjects with HbA1c ≥ 8% (64 mmol/mol) at screening should receive a dose 
which consists of total daily basal insulin dose before randomisation 
x7 + 100% (Table 10-7)  
The following weekly dose (V3) for all subjects should be the total daily dose x7. In the following 
table the weekly V2 and V3 doses for subjects receiving from 10 U to 100 U per day have been 
calculated. Please note that the displayed values are rounded off to the nearest dose divisible by 10. 
Table 510-6 V2 and V3 doses for subjects that prior to randomisation received insulin 
glargine U300 or received basal insulin twice daily, or subjects with HbA1c <8% 
(64 mmol/mol) at screening 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
10 
110 
70 
56 
590 
390 
11 
120 
80 
57 
600 
400 
12 
130 
80 
58 
610 
410 
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13 
140 
90 
59 
620 
410 
14 
150 
100 
60 
630 
420 
15 
160 
110 
61 
640 
430 
16 
170 
110 
62 
650 
430 
17 
180 
120 
63 
660 
440 
18 
190 
130 
64 
670 
450 
19 
200 
130 
65 
682 
460 
20 
210 
140 
66 
690 
460 
21 
220 
150 
67 
700 
470 
22 
230 
150 
68 
710 
480 
23 
240 
160 
69 
720 
480 
24 
250 
170 
70 
740 
490 
25 
260 
180 
71 
750 
500 
26 
270 
180 
72 
760 
500 
27 
280 
190 
73 
770 
510 
28 
290 
200 
74 
780 
520 
29 
300 
200 
75 
790 
530 
30 
320 
210 
76 
800 
530 
31 
330 
220 
77 
810 
540 
32 
340 
220 
78 
820 
550 
33 
350 
230 
79 
830 
550 
34 
360 
240 
80 
840 
560 
35 
370 
250 
81 
850 
570 
36 
380 
250 
82 
860 
570 
37 
390 
260 
83 
870 
580 
38 
400 
270 
84 
880 
590 
39 
410 
270 
85 
890 
600 
40 
420 
280 
86 
900 
600 
41 
430 
290 
87 
910 
610 
42 
440 
290 
88 
920 
620 
43 
450 
300 
89 
930 
620 
44 
460 
310 
90 
950 
630 
45 
470 
320 
91 
960 
640 
46 
480 
320 
92 
970 
640 
47 
490 
330 
93 
980 
650 
48 
500 
340 
94 
990 
660 
49 
510 
340 
95 
1000 
670 
50 
530 
350 
96 
1010 
670 
51 
540 
360 
97 
1020 
680 
52 
550 
360 
98 
1030 
690 
53 
560 
370 
99 
1040 
690 
54 
570 
380 
100 
1050 
700 
55 
580 
390 
 
 
 
 
Table 10-7 
V2 and V3 doses for subjects with HbA1c ≥ 8% (64 mmol/mol) at screening 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
10 
140 
70 
56 
780 
390 
11 
150 
80 
57 
800 
400 
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12 
170 
80 
58 
810 
410 
13 
180 
90 
59 
830 
410 
14 
200 
100 
60 
840 
420 
15 
210 
110 
61 
850 
430 
16 
220 
110 
62 
870 
430 
17 
240 
120 
63 
880 
440 
18 
250 
130 
64 
900 
450 
19 
270 
130 
65 
910 
460 
20 
280 
140 
66 
920 
460 
21 
300 
150 
67 
940 
470 
22 
310 
150 
68 
950 
480 
23 
320 
160 
69 
970 
480 
24 
340 
170 
70 
980 
490 
25 
350 
180 
71 
990 
500 
26 
360 
180 
72 
1010 
500 
27 
380 
190 
73 
1020 
510 
28 
390 
200 
74 
1040 
520 
29 
410 
200 
75 
1050 
530 
30 
420 
210 
76 
1060 
530 
31 
430 
220 
77 
1080 
540 
32 
450 
220 
78 
1090 
550 
33 
460 
230 
79 
1110 
550 
34 
480 
240 
80 
1120 
560 
35 
490 
250 
81 
1130 
570 
36 
500 
250 
82 
1150 
570 
37 
520 
260 
83 
1160 
580 
38 
530 
270 
84 
1180 
590 
39 
550 
270 
85 
1190 
600 
40 
560 
280 
86 
1200 
600 
41 
570 
290 
87 
1220 
610 
42 
590 
290 
88 
1230 
620 
43 
600 
300 
89 
1250 
620 
44 
620 
310 
90 
1260 
630 
45 
630 
320 
91 
1270 
640 
46 
640 
320 
92 
1290 
640 
47 
660 
330 
93 
1300 
650 
48 
670 
340 
94 
1320 
660 
49 
690 
340 
95 
1330 
670 
50 
700 
350 
96 
1340 
670 
51 
710 
360 
97 
1360 
680 
52 
730 
360 
98 
1370 
690 
53 
740 
370 
99 
1390 
690 
54 
760 
380 
100 
1400 
700 
55 
770 
390 
 
 
 
 
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• Insulin degludec should be taken once daily, at any time of the day but preferably at the 
same time every day. Switching from previous basal insulin should be in accordance with 
local label. 
• Insulin aspart should be taken with main meals 2-4 times per day. Switch from previous 
bolus insulin should be done unit-to-unit per meal. 
The treat-to-target approach will be applied to both treatment arms to optimise glycaemic control 
throughout the trial. 
There are no maximum or minimum insulin doses.  
Dose adjustment of trial products during the trial 
After randomisation the investigator should adjust the trial products once weekly in connection with 
the scheduled visits/phone contacts as described below: 
• The dose adjustment of insulin icodec and insulin degludec will be based on the three pre-
breakfast SMPG values measured on two days prior to titration and on the day of the 
contact. 
• If one or more pre-breakfast SMPG values are missing, the dose adjustment should be 
performed on the remaining SMPG value(s). 
• The prescribed dose should be determined by the investigator and recorded in the HCP web 
portal. 
Adjustment of insulin icodec and degludec will be done in accordance with the table below 
(Table 10-8).  
Table 10-8 
Adjustment of insulin icodec and insulin degludec 
Pre-breakfast SMPG 
Icodec 
adjustment 
Degludec 
adjustment 
Value to use 
mmol/L 
mg/dL 
U 
U 
Lowest of the 
SMPG values 
<4.4 
<80 
–20 
-3 
4.4–7.2 
80–130 
0 
0 
>7.2 
>130 
+20 
+3 
Titration of insulin aspart 
Titration of insulin aspart can either be adjusted weekly based on pre-prandial and bedtime SMPG 
values using the algorithm below or based on carbohydrate counting at the investigator’s discretion.  
Algorithm use: 
• 
In the first 8 weeks after randomisation insulin aspart should be only be adjusted for safety 
reasons. Thereafter the doses should be considered adjusted weekly by the investigator. 
• 
Dose adjustment will be based on the lowest pre-prandial or bedtime SMPG values 
measured in the week prior to titration in accordance with Table 10-9. 
o Breakfast dose will be adjusted based on the pre-lunch SMPG values 
o Lunch dose will be adjusted based on the pre-dinner SMPG values 
o Dinner dose will be adjusted based on the bedtime SMPG values. 
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If the patient eats more than four times a day the fourth dose will be adjusted in agreement with the 
investigator. 
Table 10-9 
Insulin aspart 
Lowest pre-prandial and bedtime SMPG 
Insulin aspart adjustment 
mmol/L 
mg/dL 
U 
<4.4 
<80 
-1 
4.4-7.2 
80-130 
0 
>7.2 
>130 
+1 
 
The subjects can take correction bolus doses in collaboration with the investigator. The investigator 
should consider using the “100 rule” (for mmol/L) or “1,800 rule” (for mg/dL) to estimate the 
correction bolus doses.  
Carbohydrate counting:  
• 
This method should be reserved to subjects that are willing and able to do so. The subject 
needs to have prior hands-on experience using this method of determining bolus insulin 
doses. It is the investigator’s responsibility to ensure that the subject is adequately trained. 
If more training is needed, this should be done in accordance with local practice.  
• 
Insulin aspart should be adjusted daily in accordance with the immediate pre-meal SMPG 
and carbohydrate content in the meal that the subject is about to eat. To use this method, the 
investigator needs to determine the insulin-to-carbohydrate ration (I:CHO ratio) and the 
insulin sensitivity factor (ISF) for each meal and adjust, when needed.  
• 
I:CHO ratio expresses the amount of carbohydrates (in grams) for which IU of bolus insulin 
that would effectively minimise the postprandial glucose excursion. ISF expresses the 
expected reduction in plasma glucose concentration, when IU is administered.  
• 
example: A subject has pre-prandial plasma glucose of 10.0 mmol/L (180 mg/dL) and 
intends to eat a meal containing 60 g of carbohydrates. For the given meal the I:CHO ratio 
has been estimated to 1U:10g and the ISF to be 2.0 mmol/L per 1U (36 mg/dL per 1U) and 
the target plasma glucose is 7.2 mmol/L (130 mg/dL) in this trial. The bolus dose for this 
meal can be calculated as follows: 
o To cover the meal carbohydrates: multiply grams of carbohydrates by I:CHO: 
o 60 g x 1U/10 g = 6U 
o To bring the pre-prandial glucose value to target: Subtract the target glucose value 
from the current pre-prandial glucose value and divide by ISF for this meal: 
o (10.0 mmol/L – 7.2 mmol/L)/2.0 mmol/L/U ~ 1U. 
o Thus, the bolus dose for this meal is 6U + 1U = 7U. 
Deviations from the algorithm 
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust insulin doses is based on all relevant information. A reason for deviating from the algorithm 
should be entered the into the HCP web portal by the investigator as applicable. 
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Missing insulin icodec dose guidance 
If an insulin icodec dose is missed for ≤ 3 days after the planned dosing day, subjects should inject 
the planned dose as soon as possible and perform control SMPG measurements and adjust bolus 
doses if needed. If the missing dose is missed for > 3 days, the subject should await the next 
planned day of injection. Subjects should perform frequent SMPG measurements to closely monitor 
their glycaemic control and adjust bolus doses, if needed.  
Dose recommendation from end of treatment and during follow up (insulin icodec) 
It is recommended that the subject is switched from insulin icodec to any available basal insulin at 
the discretion of the investigator. Regarding the switch from insulin icodec to post-trial basal insulin 
the following should be considered: 
• Calculate the new daily basal insulin dose by dividing the latest insulin icodec 
dose by 7. For subjects completing the trial the dose taken at V53 will be the latest 
dose. 
• Initiate basal insulin, when pre-breakfast SMPG daily in the follow up-period 
(after V54) exceeds 10.0 mmol/l (180 mg/dL). It is important that the investigator 
and the subjects are in close contact to prevent any misunderstanding. 
• Consider titrating the basal insulin once or twice weekly according to the 
pre-breakfast SMPG values and the local label of the chosen insulin. 
Data collection 
The subject should be instructed to report the following in the eDiary: 
• Date, dose and time of insulin icodec and insulin degludec or insulin aspart 
injections 
• Ensure transfer of SMPG values with an indication of “pre-breakfast”, “pre-
lunch”, “pre-dinner”, “bedtime” or “other” (Section 8.2.1). 
• Hypoglycaemic episodes as described in Appendix 7 (Section 10.7). 
While using the HCP web portal for titration the following will be entered by investigator: 
• Insulin degludec or insulin icodec and insulin aspart doses prescribed at this 
contact. 
• Reasons for deviation from the insulin icodec or insulin degludec titration 
algorithms, if applicable. 
Data surveillance 
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased or, if 
possible, a blinded manner. The data will be reviewed and significant deviations from the titration 
algorithm will be followed up.  
It is important that data regarding dose titration is entered into the eDiary and the HCP web portal. 
Timely registration is crucial in order to take appropriate actions 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. 
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The titration data should be reviewed by Novo Nordisk within 24 hours (on workdays). The 
reviewer may contact the investigator by e-mail or phone to clarify reasons 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 workdays). 
In addition, Novo Nordisk will monitor changes in HbA1c. Novo Nordisk may visit or phone sites to 
discuss progress in glycaemic control and titration of individual subjects. 
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10.9 
Appendix 9: Country-specific requirements  
For Austria: 
• 
Contraceptive guidance: A monthly pregnancy test is mandatory for female subjects of 
childbearing potential. 
For Canada 
• 
Retention of clinical trial documentation: Part C, Division 5 of the Food and Drug 
Regulations [C.05.012] requires a 25-year retention period  
For Germany 
• 
Demography: Subject’s full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF.  
• Exclusion criteria 4: the footnote, “Simultaneous participation in a trial with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the 
last dose of the investigational medicinal product has been received more than 30 days 
before screening”, is not applicable for Germany. 
• 
Discontinuation criteria 4, Section 7.1: the footnote, “Simultaneous participation in a trial 
with the primary objective of evaluating an approved or non-approved investigational 
medicinal product for prevention or treatment of COVID-19 disease or postinfectious 
conditions is allowed at the investigator discretion without discontinuing trial product”, is 
not applicable for Germany. 
For Japan: 
• 
Inclusion criteria 3: age ≥ 20 years at the time of signing informed consent 
• 
Preparation/Handling/Storage/Accountability: The head of the trial site or the trial product 
storage manager assigned by the head of the trial site (a pharmacist in principle) is 
responsible for control and accountability of the trial products. 
• Trial governance consideration: A seal is accepted as signature. 
• Exclusion criteria 4: the footnote, “Simultaneous participation in a trial with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the 
last dose of the investigational medicinal product has been received more than 30 days 
before screening”, is not applicable for Japan. 
• Discontinuation criteria 4, Section7.1: the footnote, “Simultaneous participation in a trial 
with the primary objective of evaluating an approved or non-approved investigational 
medicinal product for prevention or treatment of COVID-19 disease or postinfectious 
conditions is allowed at the investigator discretion without discontinuing trial product”, is 
not applicable for Japan. 
For Russia: 
• Trial governance considerations: The trial should be conducted in compliance with the 
protocol, Ministry of Healthcare of Russian Federation’ order #200H from April, 01, 2016 
“Approval of rules of good clinical practice” and legal requirements of the Russian 
Federation regulating circulation of medicines. 
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For Spain: 
• Retention of clinical trial documentation: 25 years according to the new Spanish Royal 
Decree 1090/2015. 
For Turkey  
• 
Blood samples from Turkey will be analysed by a central lab. 
•  This trial is a phase 3 trial. 
For USA: 
• Financial disclosure: Verification under disclosures per Code of Federal Regulations (CFR) 
of Financial Conflict of Interest. 
For Russia where BG meter is not approved at the time of the final protocol version 2.0:  
• The BG meter is regarded as investigational devices and will be labelled to indicate for 
investigational use only. This BG meter has been selected in order to have automatic 
transfer of SMPG data to the eDiary and thereby increase the accuracy of SMPG values. It is 
expected that the better accuracy in SMPG data will facilitate an improvement in the insulin 
titration efforts during the trial.  
Technical complaints on the BG meter, strips, lancets or control solutions, including 
technical complaints related to AEs and SAEs, must be reported to Roche on a special 
technical complaint paper form.  
Timelines for reporting, from the trial site obtaining knowledge of the technical complaint:  
o Technical complaint assessed as related to a SAE within 24 hours  
o  All other technical complaints within 5 calendar days  
AEs and SAEs related to the technical complaint must be reported both on the special 
technical complaint paper form and in the eCRF. In addition they must be reported in 
accordance with the standard protocol requirements for AE and SAE reporting as described 
in Section 8.3. At the end of the trial the BG meter must be collected by the investigator. 
If BG meter is approved during trial conduct, the procedures above are not applicable anymore and 
technical complaints reporting should follow the standard vigilance procedures. 
For UK: 
• Screen failures: Minimal information includes informed consent date, demography, screen 
failure details, eligibility criteria, and serious adverse event (SAE).   
• Discontinuation of trial treatment: Subjects that are randomised in violation of inclusion 
and exclusion criteria should be discontinued from the trial treatment. 
• Time period and frequency for collecting AE and SAE information: All AEs and SAEs 
must be collected from the time of informed consent and until the end of trial visit as 
specified in the flowchart. For subjects discontinuing trial product prematurely SAEs must 
be collected from the end of trial visit until the discontinuation follow-up 2 visit (V54A). 
For India and Russia where CGM is not approved at the time of the final protocol version 2.0: 
• 
The CGM is regarded as an investigational device and will be labelled to indicate for 
investigational use only.  
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The CGM has been selected in order to provide the best data accuracy and to be consistent 
in the global clinical programme. Technical complaints on the CGM must be reported to 
 on a special technical complaint paper form. 
Timelines for reporting, from the trial site obtaining knowledge of the technical complaint: 
o Technical complaint assessed as related to a SAE within 24 hours 
o All other technical complaints within 5 calendar days  
AEs and SAEs related to the technical complaint must be reported both on the special technical 
complaint paper form and in the eCRF. In addition they must be reported in accordance with the 
standard protocol requirements for AE and SAE reporting as described in Section 8.3. At the end of 
the trial CGM must be collected by the investigator. 
If the CGM is approved in any of the countries during the trial conduct, the procedures above are 
not applicable any more in the said country and technical complaints reporting should follow the 
standard vigilance procedures. 
 
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10.10 Appendix 10: Abbreviations  
 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BG 
blood glucose 
CGM 
continous glucose monitor 
CRF 
case report form 
CTR 
clinical trial report 
CRO 
contract research organisation 
DTSQs 
Diabetes Treatment Satisfaction Questionnaire 
DFU 
directions for use 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FGM 
flash glucose monitor 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
HbA1c 
glycated haemoglobin 
HCP 
health care professional  
HRT 
hormone replacement therapy 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgE 
immunoglobulin E 
IMP 
investigational medicinal product 
INN 
international non-proprietary name 
ISPAD 
International Society for Pediatric and Adolescent Diabetes 
IRB 
institutional review board 
IWRS 
interactive web response system 
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LDL 
low-density lipoprotein 
LSLV 
last subject last visit 
NIMP 
non-investigational medical product 
PCD 
primary completion date 
PG 
plasma glucose 
PRO 
patient reported outcomes 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMPG 
self-measured plasma glucose 
SUSAR 
suspected unexpected serious adverse reaction 
TMM 
trial materials manual 
WOCBP 
woman of child bearing potential 
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10.11 Appendix 11: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version 3.0 (22 February 2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union1, because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 3.0: 
The protocol has been amended to exclude Japan from co-participate in clinical trials evaluating 
medicinal products for prevention or treatment of COVID-19 disease or postinfectious conditions. 
Section # and name 
Description of change 
Brief rationale 
Protocol amendment summary of 
changes table 
New section added. 
Disclose version history. 
10.9 Appendix 9: Country/Region-
specific requirements 
Footnotes related co-participation in 
clinical trial for COVID-19 in 
exclusion criteria 4 and 
discontinuation criteria 4 are not 
applicable for Japan.  
To meet local Japanese Health 
Authority (PMDA) request. 
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11 References 
1.
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. 2001.
2.
American Diabetes Association. 2. Classification and Diagnosis of Diabetes:. Diabetes Care.
2019;42(Suppl 1):S13-S28.
3.
International Diabetes Federation. IDF Diabetes Atlas, 9th Edition. 2019.
4.
Alatorre C, Fernández Landó L, Yu M, Brown K, Montejano L, Juneau P, et al. Treatment
patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1
receptor agonists: Higher adherence and persistence with dulaglutide compared with once-
weekly exenatide and liraglutide. Diabetes Obes Metab. 2017;19(7):953-61.
5.
DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449-
62.
6.
Davies M, D’Alessio D, Fradkin J, Kernan W, Mathieu C, Mingrone G, et al. Management
of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes
Association (ADA) and the European Association for the Study of Diabetes (EASD).
Diabetes Care. 2018;41(12):2669-701.
7.
American Diabetes Association. 13. Children and Adolescents:. Diabetes Care.
2019;42(Suppl 1):S148-S64.
8.
Association AD. 9. Pharmacologic Approaches to Glycemic Treatment:. Diabetes Care.
2020;43(Suppl 1):S98-S110.
9.
Novo Nordisk A/S. Investigator’s Brochure, insulin icodec, project NN1436, (edition 7). 18
Nov 2020.
10.
Novo Nordisk A/S. Investigator's Brochure, Insulin Degludec (Tresiba®), project : NN1250
IDeg, (edition 15). 2018.
11.
Novo Nordisk A/S. Tresiba® (insulin degludec), EU Summary of Product Characteristics
(SmPC). 4 Nov 2020.
12.
Novo Nordisk A/S. Tresiba ®  (insulin degludec), US Prescribing Information (PI). 15 NOV
2019.
13.
Novo Nordisk A/S. Abbreviated Investigator’s Brochure, insulin aspart (NovoRapid®),
project EX1030, (edition 10). 23 Nov 2020.
14.
Novo Nordisk AS. NovoRapid® (insulin aspart), EU Summary of Product Characteristics
(SmPC). 23 Nov 2020.
15.
Novo Nordisk A/S. NovoLog ®   (insulin aspart), US Prescribing Information (PI). 15 NOV
2019.
16.
Polonsky WH, Fisher L, Hessler D, Bruhn D, Best JH. Patient perspectives on once-weekly
medications for diabetes. Diabetes Obesity & Metabolism. 2011;13(2):144-9.
17.
Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical Targets
for Continuous Glucose Monitoring Data Interpretation: Recommendations From the
International Consensus on Time in Range. Diabetes Care. 2019;42(8):1593-603.
18.
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.
19.
Food and Drug Administration, CDER. Guidance for Industry. Diabetes Mellitus:
Developing Drugs and Therapeutic Biologics for Treatment and Prevention, Draft Guidance.
February 2008.
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20. 
European Medicines Agency. Guideline on clinical investigation of medicinal products in 
the treatment or prevention of diabetes mellitus (CPMP/EWP/1080/00 Rev. 2) . Draft. 29 
Jan 2018. 
21. 
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. October 2013. 
22. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
23. 
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. 
24. 
U.S. Department of Health and Human Services, 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. 
25. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
26. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
27. 
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. 
28. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: summary report--
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
29. 
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin 
Immunol. 2002;110(3):341-8. 
30. 
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised 
nomenclature for allergy for global use: Report of the Nomenclature Review Committee of 
the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-6. 
31. 
Scialli AR, Bailey G, Beyer BK, Bøgh IB, Breslin WJ, Chen CL, et al. Potential seminal 
transport of pharmaceuticals to the conceptus. Reprod Toxicol. 2015;58:213-21. 
32. 
Clinical Trial Facilitation Group (CTFG), Heads of Medicines Agency. Recommendations 
related to contraception and pregnancy testing in clinical trials. 21 Sep 2020. 
33. 
International Hypoglycaemia Study Group. Glucose Concentrations of Less Than 3.0 
mmol/L (54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of 
the American Diabetes Association and the European Association for the Study of Diabetes. 
Diabetes Care. 2017;40(1):155-7. 
34. 
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64. 
35. 
Abraham MB, Jones TW, Naranjo D, Karges B, Oduwole A, Tauschmann M, et al. ISPAD 
Clinical Practice Consensus Guidelines 2018: Assessment and management of 
hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2018;19 Suppl 
27:178-92. 
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36. 
Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. 
Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 
Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, 
the American Association of Diabetes Educators, the American Diabetes Association, the 
Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable 
Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 
2017;40(12):1622-30. 
37. 
Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International 
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40. 
38. 
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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Novo Nordisk A/S 
  
Vandtårnsvej 108-110 
DK-2860 Søborg 
Denmark 
Telephone: 
+45 4444 8888  
Direct dial: 
  
E-mail: 
 
Internet: 
www.novonordisk.com 
 
 
 
Memo 
To: 
NN1436-4625 Clinical Sites 
Copy: 
NN1436-4625 Sponsor Trial Master File (TMF); NN1436-4625 Trial Squad 
From: 
 (
) and 
 (
) 
Date: 
09-Dec-2021 
Ref: NN1436-4625: Protocol Version 4.0, Flowchart  
 
In the ONWARDS 6/NN1436-4625 Protocol (Version 4.0, 14-Apr-2021), Section 1.2 Flowchart an error has been 
discovered. The error relates to “Hypoglycaemic episodes” for the “Early Discontinuation Follow-up” V28A and 
V58A: 
• 
For discontinued subjects, hypoglycaemic episodes should not be collected at V28A and V58A. There-
fore, the Flowchart should be as seen below. 
 
 
 
 
Novo Nordisk will not prepare a protocol amendment at the moment, it is important that you are aware of this 
error when conducting the discontinuation visits. Novo Nordisk does not foresee a risk to study participants of 
this error. 
Please keep this communication with the protocol (V4.0) at all times. 
Thank you for your cooperation. 
 
 
VV-CLIN-129761
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Page 2 of 2 
Ref: (only relevant to UK) NN1436-4625: Protocol Version 4.0, Appendix 9  
 
In the ONWARDS 6/NN1436-4625 Protocol (Version 4.0, 14-Apr-2021), Appendix 9: Country-specific requirements; 
For UK an error has been discovered. The error relates to “Time period and frequency for collecting AE and SAE 
information” for UK: 
• 
Time period and frequency for collecting AE and SAE information: All AEs and SAEs must be collected 
from the time of informed consent and until the end of trial visit as specified in the flowchart. For sub-
jects discontinuing trial product prematurely SAEs AEs must be collected from the end of trial visit until 
the discontinuation follow-up 2 visit (V54A). 
 
Novo Nordisk will not prepare a protocol amendment at the moment, it is important that investigators in UK 
are aware of this error. Novo Nordisk does not foresee a risk to study participants of this error. 
Please keep this communication with the protocol (V4.0) at all times. 
Thank you for your cooperation. 
 
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Protocol 
Efficacy and safety of once weekly insulin icodec compared to once daily insulin degludec 
100 units/mL, both in combination with insulin aspart, in adults with type 1 diabetes. 
A 26-week, randomised, multicentre, open-label, active-controlled, parallel group, two armed, 
treat-to-target trial investigating the effect on glycaemic control and safety of treatment with once 
weekly insulin icodec compared to once daily insulin degludec, both in combination with insulin 
aspart in adults with type 1 diabetes, with a 26-week extension investigating long term safety. 
ONWARDS 6 
Substance name: Insulin icodec 
Universal Trial Number: U1111-1251-7315 
EudraCT Number: 2020-002374-27 
IND Number: 137406 
Trial phase: 3a 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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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 5.0 
27 June 2022 
For Japan only 
Protocol version 4.0 
14 April 2021  
All countries 
Protocol version 3.0 
22 February 2021 
For Japan only 
Protocol version 2.0 
07 January 2021 
All countries, except Japan 
Original protocol version 1.0 
20 October 2020 
Not submitted 
 
Protocol version 5.0 (27 June 2022) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union1, because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 5.0: 
The protocol has been amended to specify Drug(s) used in the clinical trial except for IMP(s) as per 
local regulatory requirement. 
Section # and name 
Description of change 
Brief rationale 
10.11 Appendix 11 Protocol 
amendment history 
Amendment history is updated by 
moving protocol v4.0 history to 
appendix 11 
Due to the new protocol v5.0 
10.9 Appendix 9: Country/Region-
specific requirements 
Definition of Drug(s) used in the 
clinical trial except for IMP(s) is 
added for Japan. 
To meet new Japanese regulatory 
requirement. 
 
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Table of Contents    
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 3 
1 
Protocol summary ..................................................................................................................................... 6 
1.1 
Synopsis ........................................................................................................................................... 6 
1.2 
Flowchart ......................................................................................................................................... 8 
1.3 
Flow charts – Phone visits ............................................................................................................. 11 
2 
Introduction ............................................................................................................................................. 12 
2.1 
Trial rationale ................................................................................................................................. 12 
2.2 
Background .................................................................................................................................... 12 
2.3 
Benefit-risk assessment .................................................................................................................. 13 
2.3.1 
Risk assessment ............................................................................................................... 13 
2.3.2 
Benefit assessment ........................................................................................................... 15 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 16 
3 
Objectives and endpoints ........................................................................................................................ 16 
3.1 
Primary, secondary and exploratory objectives and estimand ....................................................... 16 
3.1.1 
Primary objective ............................................................................................................. 16 
3.1.2 
Secondary objective ......................................................................................................... 16 
3.2 
Primary, secondary and exploratory endpoints .............................................................................. 17 
3.2.1 
Primary endpoint ............................................................................................................. 17 
3.2.2 
Secondary endpoints ........................................................................................................ 17 
3.2.2.1 
Supportive secondary efficacy endpoints ........................................................ 17 
3.2.2.2 
Secondary safety endpoints ............................................................................. 18 
3.2.3 
Exploratory endpoints ..................................................................................................... 19 
4 
Trial design .............................................................................................................................................. 19 
4.1 
Overall design ................................................................................................................................ 19 
4.2 
Scientific rationale for trial design ................................................................................................. 20 
4.2.1 
Subject input into design ................................................................................................. 21 
4.3 
Justification for dose ...................................................................................................................... 21 
4.4 
End of trial definition ..................................................................................................................... 22 
5 
Trial population ....................................................................................................................................... 22 
5.1 
Inclusion criteria ............................................................................................................................ 22 
5.2 
Exclusion criteria ........................................................................................................................... 22 
5.3 
Lifestyle considerations ................................................................................................................. 23 
5.3.1 
Meals and dietary restrictions .......................................................................................... 23 
5.3.2 
Caffeine, alcohol and tobacco ......................................................................................... 23 
5.4 
Screen failures ................................................................................................................................ 24 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria...................................................... 24 
6 
Treatments ............................................................................................................................................... 24 
6.1 
Treatments administered ................................................................................................................ 24 
6.1.1 
Medical devices ............................................................................................................... 26 
6.1.1.1 
Investigational medical device ........................................................................ 26 
6.1.1.2 
Non-investigational medical devices .............................................................. 26 
6.2 
Preparation/handling/storage/accountability .................................................................................. 26 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 27 
6.4 
Treatment compliance .................................................................................................................... 27 
6.5 
Concomitant medication ................................................................................................................ 28 
6.6 
Dose modification .......................................................................................................................... 28 
6.7 
Treatment after end of trial ............................................................................................................ 28 
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7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 28 
7.1 
Discontinuation of trial treatment .................................................................................................. 29 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 30 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 30 
7.2.1 
Replacement of subjects .................................................................................................. 31 
7.3 
Lost to follow-up ........................................................................................................................... 31 
8 
Trial assessments and procedures ......................................................................................................... 31 
8.1 
Efficacy assessments ...................................................................................................................... 32 
8.1.1 
Self-measured plasma glucose......................................................................................... 32 
8.1.2 
Continuous glucose monitoring ....................................................................................... 33 
8.1.3 
Clinical outcome assessments ......................................................................................... 33 
8.1.4 
Clinical efficacy laboratory assessments ......................................................................... 34 
8.2 
Safety assessments ......................................................................................................................... 34 
8.2.1 
Insulin dose ...................................................................................................................... 34 
8.2.2 
Physical examinations ..................................................................................................... 35 
8.2.3 
Vital signs ........................................................................................................................ 35 
8.2.4 
Electrocardiograms .......................................................................................................... 36 
8.2.5 
Eye examination .............................................................................................................. 36 
8.2.6 
Clinical safety laboratory assessments ............................................................................ 37 
8.3 
Adverse events and serious adverse events .................................................................................... 37 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 39 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 39 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 39 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 39 
8.3.5 
Pregnancy ........................................................................................................................ 40 
8.3.6 
Cardiovascular and death events ..................................................................................... 40 
8.3.7 
Technical complaints ....................................................................................................... 40 
8.4 
Treatment of overdose ................................................................................................................... 40 
8.5 
Pharmacokinetics ........................................................................................................................... 41 
8.6 
Pharmacodynamics ........................................................................................................................ 41 
8.7 
Genetics ......................................................................................................................................... 41 
8.8 
Biomarkers ..................................................................................................................................... 41 
8.9 
Immunogenicity assessments ......................................................................................................... 41 
8.9.1 
Anti-drug antibodies ........................................................................................................ 41 
8.9.2 
Hypersensitivity ............................................................................................................... 42 
8.10 
Health economics ........................................................................................................................... 43 
9 
Statistical considerations ........................................................................................................................ 43 
9.1 
Statistical hypotheses ..................................................................................................................... 43 
9.2 
Sample size determination ............................................................................................................. 43 
9.3 
Populations for analyses ................................................................................................................ 44 
9.4 
Statistical analyses ......................................................................................................................... 45 
9.4.1 
General considerations .................................................................................................... 46 
9.4.2 
Primary endpoint ............................................................................................................. 46 
9.4.3 
Secondary endpoints ........................................................................................................ 47 
9.4.3.1 
Supportive secondary endpoints ..................................................................... 47 
9.4.4 
Exploratory endpoints ..................................................................................................... 50 
9.4.5 
Other safety analyses ....................................................................................................... 50 
9.4.6 
Other analyses ................................................................................................................. 50 
9.4.6.1 
Pharmacokinetic modelling ............................................................................. 50 
9.5 
Interim analyses ............................................................................................................................. 51 
9.6 
Data monitoring committee ........................................................................................................... 51 
9.7 
Reporting of the main part of the trial............................................................................................ 51 
10 Supporting documentation and operational considerations ............................................................... 52 
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10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 52 
10.1.1 
Regulatory and ethical considerations ............................................................................. 52 
10.1.2 
Financial disclosure ......................................................................................................... 52 
10.1.3 
Informed consent process ................................................................................................ 52 
10.1.4 
Information to subjects during trial ................................................................................. 53 
10.1.5 
Data protection ................................................................................................................ 53 
10.1.6 
Committees structure ....................................................................................................... 54 
10.1.6.1 Novo Nordisk safety committee...................................................................... 54 
10.1.6.2 Trial safety group ............................................................................................ 54 
10.1.6.3 Data monitoring committee............................................................................. 54 
10.1.6.4 Event adjudication committee ......................................................................... 54 
10.1.7 
Dissemination of clinical trial data .................................................................................. 54 
10.1.8 
Data quality assurance ..................................................................................................... 55 
10.1.8.1 Case report forms ............................................................................................ 55 
10.1.8.2 Monitoring ...................................................................................................... 55 
10.1.8.3 Protocol compliance ........................................................................................ 56 
10.1.9 
Source documents ............................................................................................................ 56 
10.1.10 Retention of clinical trial documentation ........................................................................ 56 
10.1.11 Trial and site closure ....................................................................................................... 57 
10.1.12 Responsibilities................................................................................................................ 57 
10.1.13 Indemnity statement ........................................................................................................ 58 
10.1.14 Publication policy ............................................................................................................ 58 
10.1.14.1 Communication of results ............................................................................... 58 
10.1.14.2 Authorship ....................................................................................................... 59 
10.1.14.3 Site-specific publication(s) by investigator(s)................................................. 59 
10.1.14.4 Investigator access to data and review of results ............................................ 59 
10.2 
Appendix 2: Clinical laboratory tests ............................................................................................ 60 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting ............................................................................................................................ 62 
10.3.1 
Definition of AE .............................................................................................................. 62 
10.3.2 
Definition of an SAE ....................................................................................................... 62 
10.3.3 
Description of events for adjudication and AEs requiring additional data collection ..... 63 
10.3.4 
Recording and follow-up of AE and/or SAE ................................................................... 65 
10.3.5 
Reporting of SAEs ........................................................................................................... 67 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ............................ 69 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ................................................................................................................. 72 
10.5.1 
Definition of technical complaint .................................................................................... 72 
10.5.2 
Recording and follow-up of technical complaints ........................................................... 72 
10.5.3 
Reporting of technical complaints ................................................................................... 73 
10.6 
Appendix 6: Retention of human biosamples ................................................................................ 74 
10.7 
Appendix 7: Hypoglycaemic episodes ........................................................................................... 75 
10.8 
Appendix 8: Titration guideline ..................................................................................................... 77 
10.9 
Appendix 9: Country-specific requirements .................................................................................. 84 
10.10 Appendix 10: Abbreviations .......................................................................................................... 87 
10.11 Appendix 11: Protocol amendment history ................................................................................... 89 
11 References ................................................................................................................................................ 90 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments. 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
Insulin icodec is a novel long-acting insulin analogue which is developed to safely cover the basal 
insulin requirements for a full week with a single subcutaneous injection.  
This is a 26-week trial designed to investigate the effect and safety of once weekly insulin icodec 
compared to once daily insulin degludec 100 units/mL, both in combination with insulin aspart in 
subjects with type 1 diabetes, with a 26-week extension phase. The first 26 weeks of the trial 
constitute the main phase, after which the primary analysis is planned. The focus of the 26-week 
extension phase is to evaluate long-term safety and provide long-term exposure data. 
Objectives and endpoints: 
Primary objective  
To confirm the effect on glycaemic control of once weekly insulin icodec in combination with 
insulin aspart, in subjects with type 1 diabetes. This includes comparing the difference in change 
from baseline in HbA1c between once weekly insulin icodec and once daily insulin degludec both in 
combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%.  
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline (week 0) to week 26 
%-point 
 
Estimand 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec and insulin degludec of the change in HbA1c from baseline to week 26 for all randomised 
subjects, irrespective of adherence to randomised treatment and changes to anti-diabetic background 
medication. The following intercurrent events will be handled by the treatment policy strategy: 
discontinuation of randomised insulin treatment, and withdrawal from the trial (measurements 
collected after these intercurrent events are used in the primary analysis).  
Overall design: 
This is a 26-week randomised, multicentre, multinational, open-label, active controlled, parallel 
group, two-armed, treat-to-target trial with two treatment arms. Subjects will be randomised (1:1) to 
receive either insulin icodec or once daily insulin degludec, both in combination with 2-4 daily 
bolus injections of insulin aspart. Randomisation of subjects will be stratified based on pre-trial 
basal insulin regimen and by HbA1c (either <8% or ≥ 8%) at screening.  
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Key inclusion criteria: 
1. Male or female aged ≥ 18 years at the time of signing informed consent. 
2. Diagnosed with type 1 diabetes mellitus ≥ 1 year prior to the day of screening. 
3. Treated with multiple daily insulin injections (basal and bolus insulin analogue regimes) ≥ 1 
year prior to the day of screening. 
4. HbA1c <10% at screening visit based on analysis from central laboratory.  
Key exclusion criteria: 
1. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
2. Chronic heart failure classified as New York Heart Association (NYHA) Class IV at screening. 
3. 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). 
4. 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 randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination.  
Number of subjects: 
Approximately 774 subjects will be screened to achieve 580 subjects randomly assigned to trial 
product. 
Treatment groups and duration: 
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
an initial 26-week randomised treatment period, a 26-week extension phase and a 5-week follow-up 
period. All subjects will be centrally randomised in a 1:1 manner and assigned to receive once 
weekly insulin icodec or once daily insulin degludec, both in combination with 2-4 times daily 
injections of insulin aspart throughout the 52-week treatment period. After end of treatment, 
subjects will be transferred to a marketed product at the discretion of the investigator.  
 
The following trial products will be supplied by Novo Nordisk for the duration of the trial:  
 Insulin icodec 700 units/mL, subcutaneous, solution for injection, 3 mL PDS290 pre-filled 
pen-injector 
 Insulin degludec 100 units/mL, subcutaneous, solution for injection, 3 mL PDS290 pre-
filled pen-injector 
 Insulin aspart 100 units/mL, subcutaneous, solution for injection, 3 mL pre-filled Flexpen 
Data monitoring committee: No 
 
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1.2 
Flowchart 
Procedure 
Protocol section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Early Discontinuation 
Follow-up 
Early Discontinuation 
Follow-up 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V38 
V42 
V46 
V50 
V51 
V52 
V53 
V54 
V55 
V56 
V28A 
V54A 
Weekly Phone contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
 
 
 
  
 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48 
P49 
 
 
 
 
 
 
 
 
 
Timing of visit (weeks) 
 
≤-2 
0 
1 
2 
3 
4 
5 
6 
10 
14 
18 
22 23 24 25 
26 
28 
32 
36 
40 44 48 49 50 51 
52 
54 
57 
26 
52 
Visit window (days) 
 
 
 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
+3 
±3 
±3 
Informed consent and 
demography 
App 1 
10.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco use 
5.3.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
5.1 
5.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Attend visit fasting 
5.3.1 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Concomitant illness/medical 
history 
8.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
Vital signs 
8.2.3 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Physical examination 
8.2.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Body measurements 
8.2.2 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
Clinical outcome 
assessment: DTSQs  
8.1.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
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Procedure 
Protocol section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Early Discontinuation 
Follow-up 
Early Discontinuation 
Follow-up 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V38 
V42 
V46 
V50 
V51 
V52 
V53 
V54 
V55 
V56 
V28A 
V54A 
Weekly Phone contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
 
 
 
  
 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48 
P49 
 
 
 
 
 
 
 
 
 
Timing of visit (weeks) 
 
≤-2 
0 
1 
2 
3 
4 
5 
6 
10 
14 
18 
22 23 24 25 
26 
28 
32 
36 
40 44 48 49 50 51 
52 
54 
57 
26 
52 
Visit window (days) 
 
 
 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
+3 
±3 
±3 
Clinical outcome 
assessment: International 
Physical Activity 
Questionnaire 
8.1.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eye examination 
8.2.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
ECG 
8.2.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pregnancy test 
8.3.5 
App.4 
10.4  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Laboratory assessments 
App.2 
10.2 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
HbA1c 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
Antibodies (anti-insulin 
icodec antibodies) 
8.9.1 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X  
 
 
PK (insulin icodec serum 
concentration) 
8.5 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
  
 
4-point SMPG profile 
8.1.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
 
CGM 
8.1.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
 
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Procedure 
Protocol section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Early Discontinuation 
Follow-up 
Early Discontinuation 
Follow-up 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V38 
V42 
V46 
V50 
V51 
V52 
V53 
V54 
V55 
V56 
V28A 
V54A 
Weekly Phone contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
 
 
 
  
 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48 
P49 
 
 
 
 
 
 
 
 
 
Timing of visit (weeks) 
 
≤-2 
0 
1 
2 
3 
4 
5 
6 
10 
14 
18 
22 23 24 25 
26 
28 
32 
36 
40 44 48 49 50 51 
52 
54 
57 
26 
52 
Visit window (days) 
 
 
 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 ±3 ±3 ±3 ±3 ±3 
±3 
+3 
+3 
±3 
±3 
Adverse event 
8.3 
App. 3 
10.3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
Hypoglycaemic episodes 
8.3 
App7 
10.7   
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X  
Training in trial Product, 
Pen-handling 
6.1 
 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Drug dispensing 
6.2 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Hand out and instruct in 
devices 
6.1.1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Trial 
4.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
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1.3 
Flow charts – Phone visits  
Phone contacts during treatment period (P) 
Time shown in site visit flow chart 
P9-P49 
Visit window (days) 
±3 
Concomitant medication (6.5) 
X 
4-point SMPG profile (8.1.1) 
X 
Adverse events (8.3 Appendix 3) 
X 
Hypoglycaemic episodes (8.3, Appendix 7) 
X 
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2 
Introduction 
Diabetes mellitus is a metabolic disorder characterised by the presence of hyperglycaemia due to 
defective insulin secretion, insulin action or both. The chronic hyperglycaemia of diabetes mellitus 
is associated with significant long-term complications, particularly damage, dysfunction and failure 
of various tissues – especially the kidney, eye, nerves, heart and blood vessels.2 Diabetes is 
generally classified according to aetiological factors, where type 1 diabetes (T1D) and type 2 
diabetes (T2D) constitute the vast majority of cases. In the latest edition of the International 
Diabetes Federation’s Diabetes Atlas (2019), the estimated worldwide diabetes prevalence was 463 
million, with a prediction that by 2045, the number of people with diabetes will have increased to 
700 million.3  
Insulin icodec (proposed INN) is a novel long-acting insulin analogue which is developed to safely 
cover the basal insulin requirements for a full week with a single subcutaneous (s.c.) injection. 
Insulin icodec has a terminal elimination half-life of approximately 196 hours. For patients with 
diabetes there is still an unmet medical need for products with the potential to improve clinical 
outcomes through reduced treatment burden and increased treatment adherence and persistence4 
compared to once or twice daily basal insulin administration. The aim of the development 
programme for insulin icodec is to improve clinical outcomes for patients with diabetes by limiting 
the burden associated with insulin treatment.  
2.1 
Trial rationale 
The present trial is designed to investigate the effect and long-term safety of once weekly insulin 
icodec in comparison to once daily insulin degludec 100 units/mL (hereafter referred to as insulin 
degludec) both in combination with insulin aspart in adult subjects with T1D. The effect of insulin 
icodec is evaluated after the 26-week main phase, followed by a 26-week extension phase with a 
primary aim to assess long-term safety. 
2.2 
Background 
Diabetes mellitus 
T1D is a heterogeneous disorder characterised by T cell-mediated autoimmune destruction of 
insulin-producing beta cells in the pancreas.5 The destruction of beta cell function leads to insulin 
deficiency and the requirement of lifelong administration of exogenous insulin. Results from the 
DCCT study and the follow-up study (EDIC) have demonstrated the importance of maintaining 
tight glycaemic control to reduce the risk of long-term complications associated with diabetes.6 As 
such, the fundamental principle for insulin treatment of T1D is to mimic normal physiological 
patterns as closely as possible. The current gold standard of care is based on intensive insulin 
therapy with multiple daily injections of prandial and basal insulin or continuous subcutaneous 
insulin infusion.7, 8 
Insulin icodec 
Insulin icodec is a novel long-acting insulin analogue which is developed to safely cover the basal 
insulin requirements for a full week with a single subcutaneous injection. Insulin icodec has a 
terminal elimination half-life of approximately 196 hours. The molecule consists of a peptide 
backbone and a fatty acid-containing side-chain. The peptide backbone is more resistant towards 
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proteolytic degradation compared to human insulin and the side chain gives a strong binding to 
albumin. Both features contribute to the long action of insulin icodec.  
The development programme for insulin icodec is currently ongoing. Three phase 2 trials 
NN1436-4383 [T2D], NN1436-4465 [T2D] and NN1436-4466 [T2D] and four clinical 
pharmacology trials, NN1436-4314 [T2D], NN1436-4226 [renal impaired], NN1436-4422 [T1D], 
and NN1436-4225 [T1D]) have been completed. No unexpected safety concerns were identified. 
One clinical pharmacology trial (NN1436-4462 [T2D] is ongoing.  
Data from NN1436-4225 were used in the development of the insulin icodec titration guideline, see 
Appendix 8 (Section 10.8).  
A comprehensive review of results from the non-clinical and clinical studies of insulin icodec can 
be found in the current edition of the investigator’s brochure (IB)9 and any updates hereof. 
Insulin degludec 
For further details on insulin degludec, please refer to the current insulin degludec IB10, the current 
EMA summary of product characteristics (SmPC) for insulin degludec (Tresiba®)11, the U.S. 
Prescribing Information (US PI)12, or any locally approved label.  
Insulin aspart 
For further details on insulin aspart, please refer to the current insulin aspart IB13, the current EMA 
summary of product characteristics (SmPC) for insulin aspart (NovoRapid)14, the U.S. Prescribing 
Information (US PI) (NovoLog)15, or any locally approved label.   
Trial population 
The trial population will consist of subjects with T1D. For more information on the trial population, 
see Section 4.2, or the inclusion and exclusion criteria, Sections 5.1 and 5.2, respectively. 
2.3 
Benefit-risk assessment 
Main benefits and risks are described in the below sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events of insulin icodec, 
insulin degludec and insulin aspart may be found in the respective IB, SmPC or US PI.   
2.3.1 
Risk assessment 
Identified risks for insulin icodec in this section are described as undesirable clinical outcomes for 
which there is sufficient evidence that they are caused by insulin icodec. Potential risks in this 
section describe undesirable clinical outcomes for which there is scientific evidence to suspect the 
possibility of a causal relationship with insulin icodec, but where there is currently insufficient 
evidence to conclude that this association is causal.  
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Identified/Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Trial treatment (Insulin Icodec) 
Identified risk:  
Hypoglycemia  
Hypoglycemia is an anticipated 
undesirable effect related to the 
pharmacological mechanism of 
insulin.   
Frequent blood glucose 
measurements will be made 
throughout drug exposure and will 
prevent worsening of hypoglycaemia 
by early detection and administration 
of carbohydrates and medical 
treatment, if necessary.  
The risk of hypoglycaemia is 
addressed in the SI-IC and IB. 
Patients are provided with a 
guidance on hypoglycaemia 
awareness and rescue actions. 
Identified risk:  
Injection site reactions 
Injection site reactions may occur 
with all injectable drugs. Injection 
site reactions were reported in trials 
NN1436-4422, NN1436-4383, 
NN1436-4465, NN1436-4466, 
NN1436-4226. All were mild and 
resolved during continued treatment 
with insulin icodec. 
Subjects are instructed by the 
investigators on the most appropriate 
injection techniques. 
Recommendations on rotation of the 
site of injection are included in the 
trial protocol. Investigators and 
subjects will be asked to pay careful 
attention to injection site reactions. 
Investigators should ensure careful 
monitoring and medical evaluation 
in case of injection site reaction 
occurrence.  
For further information on injection 
site reactions, please refer to 
Appendix 3 (Section 10.3) 
Potential risk: Hypersensitivity 
Severe systemic hypersensitivity 
reactions may potentially occur 
following injection of therapeutic 
proteins. No systemic 
hypersensitivity reactions were 
observed in trials NN1436-4314, 
NN1436-4383, NN1436-4465, 
NN1436-4466, NN1436-4226 and 
NN1436-44422. 
Known of suspected hypersensitivity 
to trial product(s) or related products 
is an exclusion criterion in the 
clinical trial.  
Subjects and investigators will be 
instructed in signs and symptoms of 
hypersensitivity reactions and 
subjects will be instructed to contact 
the site immediately in case of signs 
of systemic hypersensitivity.  
Blood sampling for assessment of 
antibodies against insulin icodec, as 
well as other assessments will be 
conducted in the case of systemic 
hypersensitivity reaction. Confirmed 
anti-insulin icodec antibody positive 
samples will have an antibody titer 
value determined and will be further 
tested for cross-reactivity to 
endogenous insulin.  
The risk of hypersensitivity reactions 
is described in the IB and SI-IC. 
For further information on 
hypersensitivity reactions, please 
refer to Sections 8.9.2 and Appendix 
3 (Section 10.3.3). 
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Potential risks: Antibody formation 
leading to changes in clinical effects 
Antibodies to exogenously delivered 
insulins are common with insulin 
treatment but are not often clinically 
significant. In NN1436-4383 clinical 
trial, the proportion of subjects with 
anti-insulin antibodies was higher 
with insulin icodec (82.1%) than 
insulin glargine (35.0%). Maximum 
level of antibody response was 
higher against insulin icodec than 
insulin glargine. 
No apparent relationship between 
antibody titres and change in HbA1c 
or weekly insulin dose was observed.   
In case lack of clinical effect is 
observed, rescue actions will be 
initiated if deemed necessary.  
In the case of systemic 
hypersensitivity reaction blood 
sampling for assessment of 
antibodies against insulin icodec, as 
well as other assessments will be 
conducted. For more information 
please refer to Section 8.9.1 and 
Appendix 3 (Section 10.3) 
Trial treatment (Insulin Degludec & Insulin Aspart) 
For more information regarding the known and expected benefits and risks of insulin degludec, please refer to the 
insulin degludec IB10, EMA Summary of Product Characteristics (SmPC)11 and the US Prescribing Information 
(PI)12, or any locally approved label.  
For more information regarding the known and expected benefits and risks of insulin aspart, please refer to the 
insulin aspart IB13, the (NovoRapid) EMA SmPC14,  (NovoLog) US PI15 or any locally approved label.  
Trial procedures 
Potential risk: 
COVID-19 infection in relation to 
participation in trial 
 
Subjects may be exposed to the risk 
of COVID-19 transmission and 
infection in relation to site visits if 
an outbreak is ongoing in the given 
country. 
The risk of COVID-19 transmission 
in relation to site visits is overall 
considered to be low, however this 
may vary between geographical 
area. To minimize the risk as much 
as possible, the following measures 
have been taken: 
• Cautious subject recruitment 
planning ensures controlled subject 
enrolment in countries where the 
COVID-19 pandemic is evaluated to 
be sufficiently under control, and at 
sites where health care resources are 
evaluated to be adequate. 
• On-site visits will be well-prepared 
and as short as possible. Physical 
contact between subjects and site 
staff will be limited to the extent 
possible, and protective measures 
will be implemented (e.g. use of 
masks, sanitizers, no aerosol-
generating procedures etc. according 
to the local practice). 
• A COVID-19 mitigation plan has 
been developed for this trial which 
lists the additional actions to 
consider in case a site or country are 
locked down and subjects cannot 
attend on-site visits. 
 
2.3.2 
Benefit assessment 
Insulin icodec is currently in development for treatment of diabetes mellitus. In both clinical and 
non-clinical trials, insulin icodec has shown to have a long and stable PK and PD profile, supporting 
a once weekly treatment. Currently available long-acting basal insulin products need to be 
administered once or twice daily to provide 24-hour coverage. Market research has shown that 
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people with diabetes, put value in reducing the number of insulin injections16. Therefore, the 
treatment adherence and quality of life are expected to increase by introducing a once weekly basal 
insulin treatment. 
 
The trial population will consist of subjects with T1D. For all subjects participating in this 52-week 
trial, the anticipated benefits include improved glycaemic control. The titration algorithm 
(Appendix 8, Section 10.8), which specifies recommended adjustments of both basal and bolus 
insulin dose at different plasma glucose levels, will be used to ensure that subjects receive optimal 
treatment.  
2.3.3 
Overall benefit-risk conclusion 
Insulin icodec is efficacious at clinically relevant doses. Titration guidance for phase 3a trials aims 
to achieve good glycaemic control without increasing the risk of hypoglycaemic events.  
No new significant safety information that changes the current benefit-risk profile of insulin icodec 
emerged from the ongoing and completed clinical trials. The safety profile of insulin icodec remains 
in line with the cumulative experience.  
As an overall assessment, Novo Nordisk evaluates that the benefit-risk balance of insulin icodec 
remains favourable.  
Considering the measures taken to minimise risk to subjects participating in this trial, the risks 
identified in association with insulin icodec are justified by the anticipated benefits that may be 
afforded to subjects with diabetes mellitus.  
More detailed information about the known and expected benefits and risk of insulin icodec can be 
found in the IB9 and any updates hereof.   
3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objectives and estimand 
3.1.1 
Primary objective 
To confirm the effect on glycaemic control of once weekly insulin icodec in combination with 
insulin aspart, in subjects with T1D. This includes comparing the difference in change from 
baseline in HbA1c between once weekly insulin icodec and once daily insulin degludec both in 
combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%.  
3.1.2 
Secondary objective 
To compare the safety and patient reported outcomes of once weekly insulin icodec versus once 
daily insulin degludec, both in combination with insulin aspart, in subjects with T1D.  
Estimand 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec and insulin degludec of the change in HbA1c from baseline to week 26 for all randomised 
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subjects, irrespective of adherence to randomised treatment and changes to anti-diabetic background 
medication. The following intercurrent events will be handled by the treatment policy strategy: 
discontinuation of randomised insulin treatment, and withdrawal from the trial (measurements 
collected after these intercurrent events are used in the primary analysis).  
3.2 
Primary, secondary and exploratory endpoints 
3.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline (week 0) to week 26 
%-point 
 
3.2.2 
Secondary endpoints 
3.2.2.1 
Supportive secondary efficacy endpoints 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose 
(FPG)  
From baseline (week 0) to week 26 
mmol/L 
Time in range 3.9-10.0 mmol/L 
(70-180 mg/dL)* 
From week 22 to week 26  
% of readings  
Change in DTSQs (Diabetes 
Treatment Satisfaction 
Questionnaire) in total treatment 
satisfaction 
From baseline (week 0) to week 26 
Score 0-36 
6 items scored on a 
scale of 0 to 6. The 
higher the score the 
greater the satisfaction with 
treatment 
Change in HbA1c 
From baseline (week 0) to week 52 
%-point 
*using continuous glucose monitoring (CGM) system, Dexcom G6 
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3.2.2.2 
Secondary safety endpoints  
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter)   
From baseline (week 0) to week 26 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter)   
From baseline (week 0) to week 57 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Time spent < 3.0 mmol/L (54 
mg/dL)* 
From week 22 to week 26  
% of readings 
Time spent > 10 mmol/L (180 
mg/dL)* 
From week 22 to week 26  
% of readings 
Mean total weekly insulin dose 
From week 24 to week 26  
U 
Mean total weekly insulin dose 
From week 50 to week 52 
U 
Change in body weight 
From baseline (week 0) to week 26  
Kg 
*using continuous glucose monitoring (CGM) system, Dexcom G6 
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3.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter)   
From baseline (week 0) to week 52 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
 
4 
Trial design 
4.1 
Overall design 
This is a 26-week, randomised, multicentre, multinational, open-label, active-controlled, parallel 
group, two-armed, treat-to-target trial investigating the effect on glycaemic control and safety of 
treatment with once weekly insulin icodec compared to once daily insulin degludec, both in 
combination with insulin aspart in subjects with T1D, with a 26-week extension phase. The first 26 
weeks of the trial constitute the main phase, after which the primary analysis is planned. The focus 
of the 26-week extension phase is to evaluate long-term safety and provide long-term exposure 
data. 
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
an initial 26-week randomised treatment period, a 26-week extension phase and a 5-week follow-up 
period. Primary analysis is planned after the initial 26-week main phase.  
The overall trial design and visit schedule are outlined in Figure 4-1 and trial flowchart 
(Section 1.2), respectively.  
Subjects will be randomised (1:1) to a treat-to-target basal-bolus insulin regimen with either once 
weekly insulin icodec or once daily insulin degludec, both in combination with insulin aspart. The 
randomisation of subjects will be stratified by pre-trial basal insulin regimen (either twice daily/ 
insulin glargine U300 or once daily) and HbA1c (either <8% or ≥8%) at screening. During the 52-
week treatment period, subjects will have weekly contact with the site either at site visits or by 
phone contacts. The end of treatment visit (V54) will be one week after the last dose of insulin 
icodec and on the day of or day after the last dose of insulin degludec. The end of trial visit (V56) 
will be performed 5 weeks after end of treatment visit (V54). This will allow for appropriate wash-
out of trial drug, following at least 5 half-lives of insulin icodec. After the end of treatment subjects 
will be transferred to a marketed product at the discretion of the investigator (Section 6.7 and 
Appendix 8, Section 10.8). 
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Subjects will carry a continuous glucose monitoring (CGM) device for the entire trial duration 
including the follow-up period. Subjects wearing a personal CGM or flash glucose monitoring 
(FGM) device prior to entering the trial, will discontinue the use of the personal pre-trial CGM or 
FGM device and switch to a trial CGM. The trial CGM receiver will be unblinded for both subjects 
and investigators.  
Event adjudication will be performed for acute coronary syndrome events (acute myocardial 
infarction or unstable angina pectoris requiring hospitalisation), cerebrovascular events (stroke or 
transient ischemic attack), heart failure (requiring hospitalisation or urgent heart failure visit) and 
all-cause death.     
 
Figure 4-1 
Trial design 
4.2 
Scientific rationale for trial design 
The trial is designed to investigate the effect on glycaemic control and safety of once weekly insulin 
icodec versus once daily insulin degludec in combination with insulin aspart. A treatment duration 
of 26 weeks is evaluated as adequate for assessing effect on glycaemic control and safety; the 
extension of 26 weeks is included to provide long-term insulin icodec exposure for safety 
evaluation.  
Subjects included in the trial will be representative of a broad T1D population that may benefit from 
insulin titration using a treat-to-target titration algorithm. To safeguard the subjects, the inclusion 
and exclusion criteria defined in this trial will limit the population to subjects not suffering from 
advanced underlying diseases other than T1D. This is to avoid compromising the safety of the 
subjects participating in the trial and to strengthen conclusions regarding the effect and safety of 
once weekly insulin icodec. 
Currently, basal insulins are dosed once or twice daily. In order to compare to well established and 
widely used basal insulin analogues with once daily dosing, insulin degludec has been chosen as 
comparator.  
Treatment in both arms will be open label as it was not considered feasible to blind the two 
treatments; the dosing regimen is not the same between treatment groups and there is a risk of pen-
injector mix-up if a double-blind, double-dummy design was used as it would require the use of 
three different pen-injectors (two basal and one bolus pen-injector) in both treatment arms.  
The treat-to-target approach has been chosen in order to ensure optimal titration of insulin based on 
self-measured plasma glucose (SMPG) values with the aim of improving HbA1c. The initial 26 
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weeks will allow sufficient time for up-titrating of the basal and bolus insulins and sufficient time in 
maintenance period for HbA1c analysis. 
Titration of insulin icodec, insulin degludec and insulin aspart is outlined in the titration guidelines, 
Appendix 8, Section 10.8. Titration of insulin icodec and insulin degludec will be based on 
pre-breakfast SMPG values and adjusted once weekly in connection with the scheduled visits/phone 
contacts. Titration of insulin aspart will be adjusted once weekly in connection with the scheduled 
visit/phone contacts based on pre-prandial and bedtime SMPG values as outlined in the titration 
guidelines or based on carbohydrate counting per investigator's discretion.  
CGM will be used both to monitor subjects’ glycaemic control and to generate profiles for 
evaluating the effect on glycaemic control, as per section 3.1.2. CGM data from the receiver will be 
collected as specified in the flowchart (see Section 1.2). A minimum duration of 4 weeks data 
collection of CGM for the endpoint assessments has been chosen to accommodate evaluation of 
hypoglycaemia exposure.17 CGM values must not be used for hypoglycaemic episode reporting. If a 
hypoglycaemic episode is captured by the CGM, the subjects should use their BG meter to assess 
their PG level, and if hypoglycaemia is confirmed, it will be recorded in the eDiary, please refer to 
Appendix 7 (Section 10.7). 
A sufficient assay-sensitivity for the non-inferiority evaluation will be supported by the treat-to-
target trial design, the applied titration target/algorithm together with close titration surveillance and 
by having focus on adherence and discontinuation.  
4.2.1 
Subject input into design 
Not applicable for this trial  
4.3 
Justification for dose 
Subjects will be switched from pre-trial basal insulin analogues to insulin degludec according to 
local label, while insulin icodec will be initiated according to the principles outlined in the titration 
guideline in Appendix 8 (Section 10.8). A loading dose will be applied to avoid glycaemic slip 
during the first week of treatment. A 50% loading dose will be applied for subjects with an 
HbA1c < 8% at screening to reduce the risk of experiencing hypoglycaemic events at the beginning 
of the trial. While a 100% loading dose will be applied for subjects with an HbA1c ≥ 8% at 
screening to mitigate the occurrence of hyperglycaemic episodes in subjects entering the trial with 
poor glycaemic control. Subjects that prior to randomisation received insulin glargine U300 or basal 
insulin twice daily should receive a 50% loading dose regardless of their HbA1c at screening.   
One unit of insulin icodec has similar glucose lowering effect as one unit of insulin degludec, and 
therefore once weekly dosing corresponds to seven times the daily dose of the once daily 
comparator insulin degludec.  
The PK and PD properties of insulin icodec following five weeks of once weekly dosing in subjects 
with T2D (trial NN1436-4314) and T1D (trials NN1436-4225 & NN1436-4422) showed that 
insulin icodec exposure was well distributed across the dosing interval, with a PK and PD profile 
suitable for once weekly dosing.  
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After randomisation, subjects should start once weekly insulin icodec or once daily insulin degludec 
on the same day as randomisation. Due to the longer half-life of insulin icodec, the last dose of 
insulin icodec will be administered 51 weeks after randomisation, while once daily insulin degludec 
injections will continue until 52 weeks after randomisation. The follow up period for both insulin 
icodec and insulin degludec will be 5 weeks from end of treatment (V54) to end of trial (V56). 
Insulin aspart should also be initiated same day as randomisation and should be taken 2-4 times 
daily with meals throughout the 52 weeks treatment duration. Switch from other rapid-acting insulin 
analogues should be done unit-to-unit.  
Further details on dose adjustment can be found in Appendix 8 (Section 10.8).  
4.4 
End of trial definition 
A subject is considered to have completed the trial if he/she has completed all phases of the trial 
including the last visit. 
The end of the trial is defined as the date of the last visit of the last subject in the trial globally. 
5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
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 aged ≥18 years at the time of signing informed consent. 
3. Diagnosed with type 1 diabetes mellitus ≥ 1 year prior to the day of screening. 
4. Treated with multiple daily insulin injections (basal and bolus insulin analogue regimens) ≥ 1 
year prior to the day of screening. 
5. HbA1c <10% at screening visit measured by central laboratory. 
5.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
1. Known or suspected hypersensitivity to trial products or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice). 
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screeninga. 
5. Any disorder, except for conditions associated with T1D which in the investigator’s opinion 
might jeopardise subject’s safety or compliance with the protocol. 
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6. 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). 
7. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
8. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at 
screening. 
9. Planned coronary, carotid or peripheral artery revascularisation. 
10. Renal impairment with estimated Glomerular Filtration Rate (eGFR) value of 
<30 ml/min/1.73m2 at screening measured by central laboratory. 
11. Impaired liver function, defined as Alanine Aminotransferase (ALT) ≥2.5 times or 
Bilirubin >1.5 times upper normal limit at screening measured by central laboratory.   
12. Known hypoglycaemic unawareness as indicated by the investigator according to Clarke’s 
questionnaire question 8.18  
13. Recurrent severe hypoglycaemic episodes within the last year as judged by the investigator. 
14. Inadequately treated blood pressure defined as systolic ≥180 mmHg or diastolic ≥110 mmHg at 
screening. 
15. 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 randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination. 
16. Presence or history of malignant neoplasm (other than basal or squamous cell skin cancer, in-
situ carcinomas of the cervix, or in situ prostate cancer) within 5 years prior to the day of 
screening. 
17. 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. 
a Simultaneous participation in a trial with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is 
allowed, if the last dose of the investigational medicinal product has been received more than 30 days before 
screening. 
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
The subjects should be fasting when attending some of visits (Section 1.2). Fasting is defined as at 
least 8 hours without food and drink intake, except for water and other prescribed medication. Trial 
product and other glucose lowering agents should be withheld on the day of fasting visit until blood 
sampling has been performed. Any other prescribed medication should be taken as usual. If the 
subject attends a fasting visit in a non-fasting state, the blood sampling procedures should be 
re-scheduled.  
5.3.2 
Caffeine, alcohol and tobacco 
Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
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5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. 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 informed consent date, 
demography, screen failure details, and eligibility criteria. For UK: SAE is also included as minimal 
information (see Appendix 9, Section 10.9). 
A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria 
This section is not applicable for this trial. 
6 
Treatments 
6.1 
Treatments administered 
Investigational medicinal products (IMP) 
All investigational medical products (IMPs) are listed in Table 6-1. 
 
 
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Table 6-1 
Investigational medicinal product provided by Novo Nordisk A/S 
Trial product name and strength: 
 
Insulin icodec 
700 units/mL 
(IMP, test product) 
Insulin degludec, 
100 units/mL 
(IMP, reference therapy) 
 
Dosage form 
Solution for injection 
Solution for injection 
Route of administration  
Subcutaneous (into the thigh, 
upper arm or abdomen)   
Subcutaneous (into the thigh, 
upper arm or abdomen)   
Recommended initial dose 
Please refer to Appendix 8 
(Section 10.8) 
Please refer to Appendix 8 
(Section 10.8) 
Dosing instructions 
Administer insulin icodec once 
weekly, on the same day each 
week, at any time of the day. 
Rotation of injection site within 
the same area is recommended.  
Administer insulin degludec once 
daily at any time of the day, but 
preferably at the same time every 
day throughout the trial. Rotation 
of injection site within the same 
area is recommended. 
Packaging 
 
3 mL PDS290 pre-filled pen-
injector 
3 mL PDS290 pre-filled pen-
injector 
 
Insulin icodec and insulin degludec DFU will be provided electronically via the eDiary and 
available to the subjects throughout the trial. 
 
A pen differentiation guide will be provided  
 
At randomisation visit (V2) subjects should administer trial product at site. 
 
Subjects should be instructed to discard the needle after each injection and store the pen-
injector without a needle attached.  
Non-investigational medicinal products (NIMP) 
Table 6-2 
Non-investigational medicinal product  
Trial product name: 
 
Insulin aspart 
100 units/mL 
(NIMP, auxiliary therapy) 
Dosage form 
Solution for injection 
Route of administration  
Subcutaneous    
Recommended initial dose 
Please refer to Appendix 8 (Section 10.8) 
Dosing instructions 
Administer insulin aspart with meals, 2-4 times 
daily 
Packaging 
3 mL prefilled Flexpen 
Provider 
Novo Nordisk A/S 
 
Insulin aspart DFU will be provided electronically via the eDiary and available to the 
subjects throughout the trial. 
Auxiliary supplies 
Auxiliary supplies comprise supplies other than trial products. Auxiliary supplies will be provided 
in accordance with the trial materials manual (TMM), please see Table 6-3.  
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Table 6-3 
Auxiliary supplies 
Auxiliary supply  
Details 
Needles 
Needles for pre-filled pen injector. NovoFine needles no longer than 6 mm will be 
used for administration of trial product. Only needles approved by Novo Nordisk 
must be used for administration of trial product. 
Blood glucose meter 
Roche Accu Check 
At randomisation (V2) subjects must be instructed in how to use the BG meter and 
the BG meter should be linked to the eDiary as described in the eDiary site guide.  
Please refer to the Roche manufacturer’s guide provided  
Continuous Glucose 
Monitoring system  
Dexcom G6 
At randomisation (V2) subjects must be instructed in handling of the CGM. Please 
refer to the CGM manual for more information.  
eDiary  
Subject Mobile app, HCP Web Portal & Cloud service  
Please refer to the eDiary site guide.   
 
6.1.1 
Medical devices 
6.1.1.1 
Investigational medical device 
This section is not applicable for this trial 
6.1.1.2 
Non-investigational medical devices 
Non-investigational medical devices including needles for pre-filled pen injector, BG meter and 
CGM are listed as auxiliary supplies in Table 6-3. 
For countries where BG meter and CGM are not approved, please refer to Appendix 9, Section 10.9 
country-specific requirements for further information. 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply trial product. 
 
Acceptable temperature ranges and conditions for storage and handling of each trial product 
when not in use and when in use are described in the trial materials manual (TMM). 
 
Each site will be supplied with sufficient trial products for the trial on an ongoing basis. 
Trial product will be distributed to the sites according to screening and randomisation. 
 
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all trial products received, and that any discrepancies are 
reported and resolved before use of the trial products. 
 
All trial products must be stored in a secure, controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and delegated site staff. 
 
The investigator must inform Novo Nordisk immediately if any trial product has been 
stored outside specified conditions. The trial product must not be dispensed to any subject 
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before it has been evaluated and approved for further use by Novo Nordisk. Additional 
details regarding handling of temperature deviations can be found in the TMM. 
 
The investigator or designee is responsible for drug accountability and record maintenance 
(i.e. receipt, accountability and final disposition records). 
 
The investigator or designee must instruct the subject in what to return at next visit. 
 
Each single pen should be accounted for.  
 
Destruction of trial products can be performed on an ongoing basis and will be done 
according to local procedures after accountability is finalised by the site and reconciled by 
the monitor. 
 
All returned, un-used, expired or damaged trial products (for technical complaint samples, 
see Section 10.5) must be stored separately from non-allocated trial products. No 
temperature monitoring is required. 
 
Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
6.3 
Measures to minimise bias: Randomisation and blinding 
This is an open label trial; however, the specific treatment for a subject will be assigned using an 
IWRS. The site will access the IWRS before the start of trial product administration for each 
subject. Potential bias will be reduced by central randomisation and adjudication. 
All subjects will be centrally screened and randomised using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Randomisation will be stratified by pre-
trial basal insulin treatment (either twice daily/insulin glargine U300 or once daily) and HbA1c 
(either <8% or ≥ 8%) at screening. Within each stratum, each subject will be randomly allocated to 
receive once weekly insulin icodec once daily insulin degludec. Trial product will be 
dispensed/allocated at the trial visits summarised in the flowchart (Section 1.2).  
 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. 
When subjects self-administer trial product at home, compliance with trial product administration 
will be assessed by cross checking the following sources and comparing these to the expected use: 
 
Drug accountability information  
 
Review of eDiaries including SMPG profiles, insulin dose and hypoglycaemia reporting 
 
Evaluating glycaemic control and adherence to the visit schedule 
 
If any suspicion of non-compliance arises the site must enter into a dialogue with the 
subject, re-emphasizing the importance of compliance and uncover barriers to compliance. 
This dialogue must be documented in the medical record.  
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6.5 
Concomitant medication 
Any medication other than the trial product and anti-diabetic medication that the subject receives 
from screening (V1) until end of trial visit (V56) must be recorded along with: 
 
Generic name or trade name 
 
Indication 
 
Dates of administration including start and stop date. 
Concomitant medication (diabetes) 
Any anti-diabetic medication other than the trial product that the subject receives from screening 
(V1) until end of trial visit (V56) must be recorded in a separate concomitant medication (diabetes) 
form in the electronic case report form (eCRF).  
The following information must be recorded for any anti-diabetic drugs including pre-trial insulin 
and post-treatment insulin in the follow-up period: 
 Generic name or trade name (for insulin products: only trade name). 
 Dates of administration including start and stop date. 
 Doses and frequency (e.g. once daily, twice daily). 
Until end of treatment (V54) only randomised treatment are allowed, unless due to safety reasons at 
the discretion of the investigator. If the investigator chooses to initiate anti-diabetic medication prior 
to end of treatment (V54), this should be registered in the eCRF as change in concomitant 
medication (diabetes). 
Changes in concomitant medication including anti-diabetic medication and other indications must 
be recorded at each visit. If a change is due to an adverse event, then this must be reported 
according to Section 8.3. 
For information regarding concomitant medication collection including anti-diabetic medication 
and other indications for subjects who discontinue trial product, see Section 7. 
6.6 
Dose modification 
Doses are adjusted according to SMPG values as described in Appendix 8 (Section 10.8).  
6.7 
Treatment after end of trial 
When discontinuing trial products, the subject should be transferred to a suitable marketed product 
at the discretion of the investigator and according to local clinical practice. Please refer to the 
titration guideline in Appendix 8 (Section 10.8).  
7 
Discontinuation of trial treatment and subject 
discontinuation/withdrawal 
Treatment of a subject may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have the subjects who discontinue trial product attend the end of treatment 
visit (V54) as soon as possible to collect the required data for the analysis of the primary endpoint. 
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Two follow-up visits, V55 and V56, must be performed after discontinuation of the trial product. 
Visits V55 and V56 must be conducted 3 and 6 weeks respectively after discontinuation of once 
weekly insulin icodec and 2 and 5 weeks respectively after discontinuation of once daily insulin 
degludec. It is stressed that the visit window is plus 3 days for both visits V55 and V56. 
Further, it is important that discontinued subjects come in for discontinuation follow-up visit V28A, 
26 weeks after the randomisation visit and V54A, 52 weeks after the randomisation visit. V54A will 
be the last visit for discontinued subjects. 
Subjects who prematurely discontinue trial product should keep and use the eDiary, and return it at 
the V56.  
The investigator should change subject status in the healthcare professional (HCP) web portal to 
'Follow-up' at the end of treatment visit to ensure that the subject should no longer report insulin 
dose. 
Continue to collect, record and report AEs as described in Section 8.3.2. AEs and anti-diabetic 
medication should be collected and recorded in the eCRF until the discontinuation follow-up visit 
(V54A) for discontinued subjects, no other concomitant medication will be collected. Please, refer 
to Section 6.7 for treatment after end of trial. 
In case of any uncertainty regarding the scheduling of the visits after discontinuation or questions to 
said visits, the investigator should consult Novo Nordisk for further guidance. 
Only subjects who withdraw consent will be considered as withdrawn from the trial. Subjects must 
be educated about the continued scientific importance of their data, even if they discontinue trial 
product. Further, the site should stay in contact with discontinued subjects by phone and/or site 
visits to motivate subjects to attend the visits until the discontinuation follow-up visit (V54A). Site 
contact with discontinued subjects should be documented in the medical record 
7.1 
Discontinuation of trial treatment 
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern related to trial product or unacceptable intolerability 
2. Pregnancy 
3. Intention of becoming pregnant 
4. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical triala 
5. Lack of efficacy, defined as fulfilment of ALL 4 criteria below: 
a. No reduction in HbA1c measured by central laboratory from randomisation (V2) to 
V12, or to V20, or to V28 or to V38, or to V46 AND 
b. the pre-breakfast SMPG readings on 3 consecutive days higher than 240 mg/dL 
(13.3 mmol/L) within the last two weeks period despite appropriate dose 
adjustments, AND  
c. a confirmatory fasting plasma glucose exceeding 240 mg/dL (13.3 mmol/L) 
measured by central laboratory. The subject should come in for an unscheduled visit 
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as soon as possible (within one week), the next scheduled visit should not be 
awaited, AND  
d. no treatable intercurrent cause (e.g. non-compliance) for the hyperglycaemia at the 
investigator’s judgment. 
a Simultaneous participation in a trial with the primary objective of evaluating an approved or non-approved 
investigational medicinal product for prevention or treatment of COVID-19 disease or postinfectious conditions is 
allowed at the investigator discretion without discontinuing trial product. 
 
The primary reason for discontinuation of trial product must be specified in the end of treatment 
form in the eCRF, and final drug accountability must be performed. A treatment status session must 
be made in the IWRS. 
A subject, who does not fulfil the eligibility (inclusion/exclusion) criteria, must not be randomised. 
Randomisation in violation of any of the eligibility criteria is good clinical practice (GCP) non-
compliance and must be reported to the sponsor without delay. This will be handled as an important 
protocol deviation, and the independent ethics committee/institutional review board (IEC/IRB) and 
regulatory authorities must be notified according to local requirements.  
If a subject is randomised in violation of inclusion and exclusion criteria erroneously, the nature of 
the specific violation to in- or exclusion criteria will be evaluated carefully both by the principal 
investigator and Novo Nordisk medical specialist, independently. Subject can be allowed to 
continue in the trial and receive trial product if the violation is minimal or with no significant 
clinical relevance, and there are no safety concerns as evaluated by both the investigator and Novo 
Nordisk medical specialist (not applicable for UK, please see Appendix 9, Section 10.9). 
7.1.1 
Temporary discontinuation of trial treatment 
The subject should adhere to the treatment to the extent possible, with the exception of any adverse 
events such as hospitalisation or safety concerns, at the discretion of the investigator. Subjects who 
have temporarily discontinued trial product are allowed to restart trial product, unless any of the 
discontinuation criteria specified in Section 7.1 applies. Treatment status session must be made in 
the IWRS when the subject is temporarily discontinued and also when the subject resumes 
treatment. 
7.2 
Subject discontinuation/withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request. If a subject withdraws consent, 
the investigator must ask the subject if he/she is willing, as soon as possible, to have assessment 
performed according to V54. See the flowchart (Section 1.2) for data to be collected.  
Final drug accountability must be performed even if the subject is not able to come to the site. A 
treatment status session must be made in the IWRS. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
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Although a subject is not obliged to give his/her reason(s) for withdrawing, 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 withdrawal must be specified in the end of trial 
form in the CRF. 
7.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
trial. 
 
Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
 
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
8 
Trial assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart (see Section 1.2). 
 
Informed consent must be obtained before any trial related activity, see Section 10.1.3. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all inclusion criteria and none of the exclusion criteria. 
 
The investigator will maintain a screening log (e.g. electronic or paper) to record details of 
all subjects screened and to confirm eligibility or record reason for screen failure, as 
applicable. 
 
At screening, subjects will be provided with a card stating that they are participating in a 
trial and giving contact details of relevant site staff that can be contacted in case of 
emergency.  
 
Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
 
Assessments should be carried out according to the clinic’s standard of practice unless 
specified in the current section. Efforts should be made to limit the bias between the 
assessments. The suggested order of the assessments at randomisation visit (V2) is as 
follows: 
o Blood sample collection  
o Other assessments to confirm eligibility 
o Randomisation in IWRS 
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o Continuous glucose monitoring fitting and training 
o The investigator should create a subject profile and record administrative 
information (e.g. subject ID, year of birth and gender and treatment arm in the HCP 
web portal  
o Subjects should be provided with an eDiary and instructed in how to use it.  
o The BG meter should be connected with the eDiary  
o A fasting SMPG should be measured using the BG meter 
o Dosing of trial product 
 
For information regarding the eDiary and HCP web portal please refer to the site guide.  
 
Please refer to Section 6.4 for drug treatment compliance. 
 
All data entered in the eDiary is considered source data. The investigator should review all 
the data for the subjects through the HCP web portal, before or during each visit/phone 
contact. 
 
Review of eDiaries, PRO instruments, ECG, CGM data, laboratory reports, eye- and 
physical examinations must be documented either on the documents or in the subject's 
source documents. If clarification of entries or discrepancies in the eDiary is needed, the 
subject must be questioned, and a conclusion made in the subject's source documents, the 
eDiary should be updated retrospectively if applicable. Care must be taken not to bias the 
subject. 
 
Repeat samples may be taken for technical issues and unscheduled samples or assessments 
may be taken for safety reasons. Please refer to Appendix 2 (Section 10.2) for further 
details on laboratory samples. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2) 
8.1.1 
Self-measured plasma glucose  
Subjects will be provided with a BG meter including auxiliaries. 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. 
The BG meter provided by Novo Nordisk should be used for measurements required in the 
protocol, as described in the flowchart (see Section 1.2). 
A baseline SMPG value, in fasting condition, should be collected using the BG meter at V2. 
Subjects must be instructed in how to transfer the results of the SMPG values daily into the eDiary. 
4-point daily SMPG 
Subjects should be instructed to measure their pre-prandial and bedtime SMPGs daily from week 0 
(V2) to end of trial (V56) at the following time points: pre-breakfast, pre-lunch, pre-dinner, and at 
bedtime. The subject should transfer the measured SMPG values into the eDiary. 
Selected titration data (e.g. certain SMPGs and dose data) from the eDiary will be used during the 
trial for central titration surveillance, to ensure compliance with the titration guideline in 
Appendix 8 (Section 10.8) and will not be reported in the clinical trial report. All data will be stored 
by Novo Nordisk (see Appendix 1, Section 10.1). 
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8.1.2 
Continuous glucose monitoring  
Subjects will be equipped with a CGM device during the entire duration of the trial (i.e. from week 
0 (V2) to week 57 (V56)). 
The CGM system used in this trial will be the Dexcom G6®. 
The CGM readings will be open to both the subject and the investigator. 
If a subject withdraws consent during the trial, a site visit should be scheduled in order to remove 
the CGM sensor and upload the data from the receiver. 
CGM fitting and training  
The site staff will closely supervise and assist on fitting of the sensor and transmitter on the subject 
during the site visits. Training in the CGM is the responsibility of the investigator or site staff at the 
relevant visits. For information on fitting, and changing of the CGM parts, please refer to the CGM 
manual and subject guide provided. 
CGM Sensor Check  
The site staff should ensure that the subject has fitted the sensor correctly and that the CGM 
receiver is working. This will be done in person during the clinic visit, as specified in the flowchart 
(see Section 1.2). The site should ensure the subject can change the sensor at home weekly during 
trial periods when the subject will not attend site visits. 
CGM Upload 
Data stored on the CGM receiver must be uploaded at the site by the site staff to the CGM software 
following the instruction provided to the sites. Data upload will occur at each site visit, see 
flowchart (Section 1.2). Data upload will occur every week from V2 (week 0) to V8 (week 6), from 
V24 (week 22) to V28 (week 26), and from V50 (week 48) to V54 (week 52). Outside the specified 
periods, upload will occur every second or forth week in conjunction with site visit, and at the 
follow-up visits 1 and 2. The upload will be documented by the system directly. 
The serial number of the CGM receiver must be recorded in the eCRF at the randomisation visit 
(V2). In case the CGM receiver is replaced, the new receiver serial number should be entered in the 
eCRF as well. 
8.1.3 
Clinical outcome assessments 
The patient reported outcome questionnaires are to be completed by the subject without assistance 
of the site personnel and should preferably be completed after all fasting-related activities are 
completed, but before any other visit related procedures are conducted. It takes approximately five 
minutes to complete the questionnaires.  
The following patient reported outcome questionnaires will be supplied in linguistically validated 
versions in all languages relevant for this trial: 
 Diabetes Treatment Satisfaction Questionnaire (DTSQs)  
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o The questionnaire has been designed to measure satisfaction with diabetes treatment 
regimens in people with diabetes. The DTSQs questionnaire will be measured at 
baseline (V2), week 26 (V28), and end of treatment visit (V54).  
 International Physical Activity Questionnaire  
o The questionnaire has been designed to measure physical activity. It will be 
measured at baseline (V2) only. The questionnaire is for all subjects 18-69 years of 
age. 
8.1.4 
Clinical efficacy laboratory assessments  
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart.  
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product.  
Medical history is a medical event that the subject experienced prior to the time point from which 
AEs are collected. Only relevant medical history as judged by the investigator will be recorded in 
the eCRF.  
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form.  
Information on hypoglycaemia unawareness will be recorded according to Clarke's questionnaire, 
question 8. 18 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?" Subjects answering 'never, rarely or 
sometimes' are considered to have impaired awareness of hypoglycaemia, whereas those answering 
“often or always” are not. 
8.2.1 
Insulin dose 
The prescribed insulin doses will be determined by the investigator in accordance with the titration 
guideline (see Appendix 8, Section 10.8). 
During the trial, starting at randomisation (V2), subjects must be instructed to report date, dose and 
time of once weekly insulin or once daily insulin, and of bolus insulin in the eDiary. In the 
follow-up period if the subject switches to a new basal insulin and a new bolus insulin, the subject 
should also report date, dose and time of the new basal and bolus insulin in the eDiary. 
Please refer to Appendix 8 (Section 10.8) for more information. 
The investigator must record the following in the eCRF 
 
First and last date on trial product 
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 
First and last dose of trial product 
For dosing of anti-diabetic medication prescribed in the follow-up period please see Sections 6.5 
and 6.7 
8.2.2 
Physical examinations 
A physical examination will include assessments of: 
 
Head, ears, eyes, nose, throat, neck 
 
Cardiovascular system 
 
Respiratory system 
 
Gastrointestinal system 
 
Central and Peripheral Nervous System 
 
Musculoskeletal system 
 
Skin. 
 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
 
The physical examination will be recorded in the eCRF as either ‘normal’ or ‘abnormal’. If 
‘abnormal’, a comment must be given together with an assessment of clinical significance (yes/no).  
Abnormal, clinically significant findings at screening should be recorded as concomitant illness in 
the eCRF. At the following visits, any new abnormal, clinically significant findings or clinically 
significant deteriorations from baseline should be reported as an adverse event (see 
Appendix 3, Section 10.3). 
Body measurements (height and weight) will also be measured and recorded. Height will be 
measured and recorded at screening visit (V1). Weight will be measured and recorded throughout 
the trial as specified in the flowchart (Section 1.2). 
 
Body weight should be measured in kilogram (kg) or pounds (lb) without coat and shoes 
wearing only light clothing. Body weight will be recorded to one decimal.  
 
Body weight should be assessed with the same equipment throughout the trial, if possible. 
 
Height should be measured in centimetres (cm) or inches (in) without shoes. Height will be 
recorded to the nearest whole number. 
 
From the body weight and height, the BMI will be calculated in the eCRF 
8.2.3 
Vital signs 
 
Pulse rate, as well as systolic and diastolic blood pressure will be assessed. 
 
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of 
rest for the subject in a quiet setting without distractions (e.g. no use of television, mobile 
phones). 
 
Blood pressure and pulse rate measurements will be assessed sitting with a completely 
automated device. Manual techniques must be used only if an automated device is not 
available. 
 
Blood pressure and pulse rate will consist of 3 systolic and diastolic blood pressure 
measurements with intervals of at least 1-2 minutes. An additional fourth blood pressure 
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measurement must be performed if the first two readings on systolic or diastolic blood 
pressure differ by >10 mmHg. Systolic blood pressure will be calculated as the mean of the 
last 2 systolic blood pressure readings, and diastolic blood pressure as the mean of the last 2 
diastolic blood pressure readings. Only the last 2 systolic and last 2 diastolic blood pressure 
readings must be recorded in the eCRF.  
 
Pulse rate will be measured in connection to the blood pressure measurements. Record the 
pulse rate for the last 2 blood pressure measurements in the eCRF. The pulse rate will be 
calculated as the mean of the last 2 measurements 
8.2.4 
Electrocardiograms 
 
A 12-lead ECG must be performed by the investigator or delegated staff as outlined in the 
flowchart (Section 1.2). 
 
The ECG should be preceded by at least 5 minutes of rest for the subject in a supine/sitting 
position in a quiet setting without distractions (e.g. no use of television, mobile phones). 
 
The ECG must be interpreted, signed and dated by the investigator to verify that the data 
has been reviewed. 
 
The ECG required at screening can be obtained within 2 weeks prior to V2 but at the latest 
at V2. The results must be interpreted by the investigator prior to randomisation in order to 
determine the eligibility of the subject. 
 
The ECG required at the end of treatment visit can be obtained within 2 weeks prior to the 
end of treatment visit. The results must be available for evaluation at the end of treatment 
visit. 
 
Abnormal, clinically significant findings at screening should be recorded as concomitant 
illness in the eCRF. At the following visits, any new abnormal, clinically significant 
findings or clinically significant deteriorations from baseline should be reported as an 
adverse event (see Appendix 3, Section 10.3). 
8.2.5 
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 another suitably qualified health 
care provider (e.g. optometrist) must be available and evaluated by the investigator before 
randomisation to assess eligibility. 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). Pharmacological pupil-
dilation is a requirement 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 his/her evaluation upon the results of that examination. The examination must 
be repeated before randomisation if the subject has experienced worsening of visual function since 
the last examination. Eye examinations performed prior to randomisation visit (V2) are acceptable 
if results are available for evaluation before randomisation. If the applicable eye examination was 
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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. 
Eye examinations required at the end of treatment visit (V54) can be performed within 2 weeks 
prior to the visit, if results are available for evaluation at the visit. For discontinued subjects, eye 
examination can be performed up to 2 weeks after the end of treatment visit. The investigator 
should indicate the outcome of each eye examination. Relevant findings prior to randomisation 
must be recorded as concomitant illness/medical history. While relevant findings occurring after 
randomisation should be reported as an adverse event, please refer to Section 8.3. 
8.2.6 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the protocol flowchart (Section 1.2). 
8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.  
Some AEs require additional data collection on a specific event form. This always includes 
medication error, misuse and abuse of IMP. The relevant events are in Table 8-1, together with 
events for adjudication. 
The definition of AEs and SAEs can be found in Appendix 3 (Section 10.3), along with a 
description of events for adjudication and AEs requiring additional data collection.    
Hypoglycaemic episodes 
Hypoglycaemic episodes require data collection on a hypoglycaemic episode form in the eDiary. 
Non-serious hypoglycaemic episodes do not require an AE form to be completed in the eCRF. If the 
hypoglycaemic episode fulfils the criteria for an SAE, then, in addition to the hypoglycaemic 
episodes form, an AE form and a safety information form must be filled in the eCRF, please refer to 
Appendix 3 (Section 10.3). For more information on hypoglycaemic episodes, please refer to 
Appendix 7 (Section 10.7) 
 
 
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Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs) and 
events for adjudication  
Event type  
AE requiring additional data 
collection 
Event for adjudication 
 
Medication error 
X 
 
Misuse and abuse 
X 
 
Acute coronary syndrome (acute myocardial 
infarction or unstable angina pectoris requiring 
hospitalisation) 
 
X 
Cerebrovascular events* (stroke or transient 
ischemic attack) 
 
X 
Heart failure (requiring hospitalisation or urgent 
heart failure visit) 
 
X 
Death 
 
X 
Hypersensitivity 
X 
 
Injection Site Reaction 
X 
 
*All cerebrovascular events (stroke and transient ischemic attack) are to be reported and sent for adjudication, however 
the event adjudication committee will only confirm strokes. 
A detailed description of the events mentioned in the above table can be found in Appendix 3 
(Section 10.3.3). 
Events for Adjudication 
Event adjudication will be performed in randomised subjects and will be evaluated by an 
independent external EAC in a blinded manner, please refer to Appendix 1, Section 10.1.6.4. 
There are four ways to identify events relevant for adjudication as described below:  
 
Investigator-reported events for adjudication: investigator selects the appropriate AE 
category relevant for adjudication (Appendix 3, Section 10.3.3). 
 
AEs reported with fatal outcome.  
 
AE search (standardised screening): All AEs not reported with an AE category relevant for 
adjudication will undergo screening to identify potential events for adjudication. 
Investigators will be notified of these events in the eCRF.  
 
EAC-identified events: Unreported events relevant for adjudication identified by the EAC 
during review of source documents provided for another event for adjudication.  
Investigators will be notified of these events in the eCRF and has the option to report the 
EAC-identified event. 
For each event relevant for adjudication an event type specific adjudication form should be 
completed in the eCRF within 14 days. 
Copies of source documents should be uploaded to the event adjudication system (EAS) as soon as 
possible and preferably within 4 weeks. In cases where the EAS is not accessible the investigator 
should ensure that the relevant source documents are collected and saved locally until the EAS is 
ready. If no, or insufficient source documents are provided to the adjudication supplier, the 
investigator can be asked to complete a clinical narrative to be uploaded to the EAS.  
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If new information becomes available for an event sent for adjudication, it is the responsibility of 
the investigator to ensure the new information is uploaded to the EAS. 
An event adjudication site manual will be provided to each site detailing which source documents 
are relevant and how these should be provided to the adjudication supplier. The anonymization and 
labelling requirements are also described in the event adjudication site manual. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs must be collected from the randomisation visit and until the end of trial visit at 
the time points specified in the flowchart. For subjects discontinuing trial product prematurely AEs 
must be collected from the end of trial visit until the discontinuation follow-up visit (V54A). For 
AE reporting in UK, please refer to the UK specific requirements in Appendix 9 (Section 10.9). 
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3 (Section 10.3). All SAEs must be recorded and reported to Novo 
Nordisk within 24 hours, and the investigator must submit any updated SAE data to Novo Nordisk 
within 24 hours of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3) 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, should be followed until final outcome of the event or the 
subject is lost to follow-up as described in Section 7.3. Further information on follow-up and final 
outcome of events is given in Appendix 3 (Section 10.3) 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
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regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected serious 
adverse reactions (SUSAR). 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it along 
with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
Details of pregnancies in female subjects will be collected from first exposure to trial product and 
until the infant is one month of age. 
If a female subject becomes pregnant, the investigator should inform Novo Nordisk within 14 
calendar days of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3. 
8.3.7 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5 (Section 10.5). 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
8.4 
Treatment of overdose 
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.3 and Appendix 3 (Section 10.3) for further details. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities until the blood glucose is normalised and/or signs/symptoms 
have been relieved. 
A specific overdose for insulin icodec cannot be defined; however, hypoglycaemia may develop 
over sequential stages if the doses administered are too high relative to the subject’s requirements.  
 
Mild hypoglycaemia can be treated by oral administration of glucose or sugary products.  
 
Severe hypoglycaemia, where the subject is not able to treat him/herself, can be treated by 
glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or by 
glucose given intravenously by a medical professional. Glucose must also be given 
intravenously, if the subject dose not respond to glucagon within 10-15 minutes. If the 
subject has been unconscious, administration of oral carbohydrates is recommended for the 
subject upon regaining consciousness, in order to prevent a relapse. 
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Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject. 
For more information on overdose consult the current version of the insulin icodec investigator's 
brochure9. 
For more information on overdose for insulin degludec or insulin aspart, consult the relevant IB, 
EMA SmPC, US PI or locally approved label.  
8.5 
Pharmacokinetics 
Blood samples will be used to evaluate the pharmacokinetics (PK) of insulin icodec. PK samples 
will be collected at the visits outlined in the flowchart (Section 1.2) for subjects randomised to 
insulin icodec. The date and exact clock time for blood sampling must be recorded. 
Bioanalysis of insulin icodec samples will be performed at a special laboratory using a validated 
luminescent oxygen channelling immunoassay. The exact method will be described in a 
bioanalytical report. 
Residual PK samples may be used for exploratory metabolite analysis. Potential metabolite analysis 
will be reported separately from the clinical trial report.  
Genetic analyses will not be performed on these plasma/serum/whole blood samples. Subject 
confidentiality will be maintained.  
Procedures for sampling, handling, storage, labelling and shipments of the specimens must be 
performed in accordance with the laboratory manual. A randomisation list will be provided to the 
special laboratory. Samples from randomised subjects will be analysed for insulin icodec 
concentration. 
Subjects should be instructed to report dosing information in the eDiary as per Section 8.2.1.  
8.6 
Pharmacodynamics 
Not applicable for this trial.  
8.7 
Genetics 
Not applicable for this trial. 
8.8 
Biomarkers 
Not applicable for this trial.  
8.9 
Immunogenicity assessments 
8.9.1 
Anti-drug antibodies  
Anti-drug antibody samples will be collected according to the flowchart (Section 1.2) for subjects 
randomised to insulin icodec. All samples must be drawn prior to trial product administration if trial 
product administration is planned on the sampling day. Assessment of antibodies against insulin 
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icodec (anti-drug antibodies) in serum will be performed at a Novo Nordisk appointed laboratory. 
For details on blood sampling, serum preparation and storage, please refer to the laboratory manual.  
Analysis for anti-drug antibody will be done as listed in flowchart with a binding anti-drug antibody 
assay. Positive samples will be further characterised for titre, and cross-reactivity to endogenous 
human insulin. 
Detailed description of the assay methods will be included in an analytical report. Antibody assays 
will be validated according to international guidelines and recommendations.  
At the end of the trial, the following data will be electronically transferred to the Novo Nordisk 
database: Anti-insulin icodec binding antibodies (pos/neg) and titre of anti-drug antibody positive 
samples, and anti-insulin icodec binding antibodies cross-reacting with endogenous human insulin 
status (pos/neg). 
The investigator will not be able to review the results of antibody measurements in relation to AEs 
as the samples are often analysed after last subject last visit. Results from the binding anti-drug 
antibody analyses will be available after the completion of the trial. 
8.9.2 
Hypersensitivity 
Subjects and investigators will be instructed to detect signs and symptoms of systemic 
hypersensitivity.  
For subjects randomised to insulin icodec: In the event of a systemic hypersensitivity (not locally at 
the injection site), the subject should be called in as soon as possible to have additional blood 
samples taken in order to analyse the following parameters: 
 
Tryptase (optimal 0.5-2 hours post the hypersensitivity reaction) 
 
Total immunoglobulin E (IgE) antibodies 
 
Anti-insulin icodec IgE antibodies 
 
Anti-insulin icodec binding antibodies 
 
Anti-human insulin IgE antibodies. 
The blood sampling should be repeated 2-4 weeks following onset of the systemic hypersensitivity 
reaction. If possible, the tests should also be performed on samples drawn prior to first 
administration of trial drug. 
For details related to blood sampling, plasma preparation and storage, please refer to the laboratory 
manual. 
Analysis will be performed by Novo Nordisk or a Novo Nordisk appointed special laboratory 
(please refer to Attachment I). The results will be reported in a separate report and attached to the 
clinical trial report. 
For retention of residual hypersensitivity samples, please refer to Appendix 6, Section 10.6. 
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Digital pictures  
The investigator or the subject must take digital pictures of the affected area at time of 
identification, using any device available (mobile phone, camera etc.) and thereafter as often as 
judged necessary by the investigator. The pictures should include subject identification number, 
date and time, time after dosing and a ruler for scaling. All pictures must be stored as part of source 
documentation at site. 
8.10 
Health economics  
Not applicable for this trial.  
9 
Statistical considerations  
9.1 
Statistical hypotheses 
The primary hypothesis to be tested is that insulin icodec is non-inferior to insulin degludec in terms 
of change from baseline to week 26 in HbA1c. 
Formally, let D be the treatment difference ‘insulin icodec’ minus ‘insulin degludec’ of the change 
in HbA1c from baseline to week 26. The null-hypothesis will be tested against the alternative 
hypothesis of non-inferiority as given by   
H0: D ≥0.30% against HA: D <0.30%  
The non-inferiority margin of 0.3%-point is chosen based on the recommendation of health 
authority guidance for industry on developing drugs for treatment of diabetes.19, 20 Furthermore: 
 The margin does not represent an unacceptable loss of efficacy with insulin icodec relative 
to treatment with a basal insulin analogue 
 It represents less than 30% of a suitably conservative estimate of insulin degludec´s 
treatment effect on HbA1c in a placebo-controlled trial in a T1D population; The treatment 
effect of degludec versus placebo in a T1D population is unknown but in a progressed T2D 
population of subjects already treated with liraglutide, degludec was shown to be superior to 
placebo ( ETD: -0.92%-point [-1.00; -0.75] 95%CI). 
9.2 
Sample size determination  
The sample size is determined in order to have 90% power for declaring non-inferiority (NI) with a 
NI margin of 0.3%-point with respect to change in HbA1c for the specified estimand and the full 
analysis set (primary analysis set). All available data points for the primary endpoint will be used in 
the primary analysis and this has guided the treatment effect assumptions below.  
 
In studies with insulin degludec 100 units/mL in T1D subjects (NN1250-3583, NN1250-3770, and 
NN1250-3995) the percent withdrawing from treatment and/or trial during the initial 26 weeks was 
approximately 9%, 12% and 15%. Considering the increased focus on retention, 10% are expected 
to experience any of the specified intercurrent events before week 26 in this trial.  
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It is assumed that there is no difference in HbA1c between the treatment arms for subjects 
completing randomised treatment and a treatment difference of 0.3%-point in favour of the 
comparator for subjects either discontinuing treatment prematurely or withdrawing from trial. Thus, 
with 10% expected to experience any of the specified intercurrent events before week 26, this leads 
to an assumption of a mean treatment difference of 0.03%-point for the specified estimand in the 
overall population.   
The standard deviation (SD) is assumed to be 1.0%-point based on results from studies with insulin 
degludec in subjects with T1D (NN1250-3583, NN1250-3770 and NN1250-3995), where the SD 
was found to be 0.9, 0.9 and 0.93 respectively.   
From the above assumptions and requirements, 580 subjects will be randomised to trial product.  
This will ensure sufficient power (90%) of confirming non-inferiority.  
With an expected screening failure rate of 25%, approximately 774 subjects will be screened to 
achieve 580 subjects randomly assigned to trial product. 
This sample size appears to be reasonable also under deviations from the assumed treatment 
difference as illustrated in the table below (Table 9-1) displaying power for various alternative 
treatment differences and standard deviations.  
Table 9-1 
Power for various treatment differences and standard deviations 
SD 
(%-point) 
 
 
 
0.0/0.015 
True treatment 
difference/adjusted 
treatment difference 
(%-point) 
0.0/0.03 
 
 
 
0.0/0.045 
 
 
 
0.05/0.08 
0.9 
97% 
95% 
93% 
84% 
1.0 
93% 
90% 
87% 
75% 
1.1 
88% 
84% 
80% 
67% 
SD: standard deviation. Power is computed for 1:1 randomisation and 580 subjects randomised. 
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised.  
Full analysis set 
All subjects randomised. Subjects will be analysed according to the randomised 
treatment. 
Safety analysis set 
All subjects randomly assigned to trial treatment and who take at least one dose 
of trial product. Subjects are analysed according to the treatment they actually 
received.  
In exceptional cases, subjects or observations may be eliminated from the full analysis set. In such 
case the reasons for their exclusion will be documented before unblinding. 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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The following periods will be considered for the data collected:  
 
In-trial period  
The in-trial period starts at randomisation and ends at the date of:  
 
The last direct subject-site contact  
 
Withdrawal for subjects who withdraw their informed consent 
 
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up (i.e. possibly an unscheduled phone visit)  
 
Death for subjects who die before any of the above.  
 
Baseline assessments are always included in the in-trial observation period. 
 
On-treatment period  
The on-treatment period starts at the date of first dose of trial product as recorded on the eCRF, and 
ends at the first date of any of the following: 
 
The end of trial visit (V56)  
 
The last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once 
weekly insulin (corresponding to 5 weeks after the end of the dosing interval for both 
treatment arms) 
 
The end-date for the in-trial observation period.  
 
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product.  
 
Main-on-treatment period  
The main-on-treatment period starts at the date of first dose of trial product as recorded on the 
eCRF, and ends at the first date of any of the following:  
 
The end date of the on-treatment period  
 
Week 26 (V28).  
 
Baseline assessments are always included in the on-treatment observation periods. 
All efficacy endpoints will be summarised and analysed using the full analysis set and the ‘in-trial’ 
period. Safety endpoints will be evaluated using both the main-on-treatment and the on-treatment 
period with descriptive statistics being based on the safety analysis set and statistical analyses being 
based on the full analysis set unless otherwise specified.  
9.4 
Statistical analyses 
The statistical analysis plan (SAP) will be finalised prior to first subject first visit (FSFV), and it 
will include a more technical and detailed description of the statistical analyses described in this 
section.  
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9.4.1 
General considerations 
Presentation of results from a statistical analysis will include the estimated mean treatment 
difference (or ratio) presented together with the two-sided 95% confidence interval and the 
corresponding two-sided p-value. 
 
In the statistical models, explanatory factors will be coded as follows: 
 
Treatment: Once weekly insulin icodec, insulin degludec 
 
Screening HbA1c < 8%: yes, no   
 
Pre-trial basal insulin treatment: twice daily or insulin glargine U300: yes or no 
 
Region: Asia, Europe, North America 
 
The regions will be defined as follows: 
o Asia: India, Japan 
o Europe: Austria, Netherlands, Germany, Turkey, Italy, Russia, Spain, United 
Kingdom 
o North America: United States, Canada 
o  
The last available assessment made prior to the first dose will be used as the baseline value. All 
endpoints based on CGM measurements will be derived the following way. The percentage of time 
spent in a given glycaemic range will be calculated as 100 times the number of recorded 
measurements in the given glycaemic range, divided by the total number of recorded measurements. 
Following international consensus criteria it will be required that at least 70% of the planned CGM 
measurements during the last four weeks of treatment are available for endpoint data to be included 
in the analysis. 
9.4.2 
Primary endpoint 
The primary endpoint is change in HbA1c from baseline to week 26. 
The ‘treatment policy’ estimand, will be estimated based on the Full Analysis Set (FAS) using all 
HbA1c measurements obtained at the week 26 visit, especially including measurements from 
subjects discontinuing their randomised treatment. Missing HbA1c at the week 26 visit (regardless 
of treatment completion status) will be imputed from trial participants, who have discontinued their 
randomised treatment prior to the week 26 visit and have a measurement at the week 26 visit in the 
following way:   
 First, one thousand (1000) copies of the dataset will be generated for HbA1c.   
 Second, for subjects having discontinued their randomised treatment prior to the week 
26 visit and have a HbA1c visit measurement at the week 26 visit, the change in HbA1c 
from last available planned on-treatment (LAOT) value to the week 26 visit will be 
analysed for each dataset copy using an ANCOVA model with randomised treatment as 
fixed factor and LAOT value and the time point (study day) of this assessment as 
covariates. The estimated parameters, and their variances, from the model will be used to 
impute missing HbA1c values for the change from LAOT to the week 26 visit and 
subsequently the missing HbA1c value at the week 26 visit.  
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 For each of the complete data sets, the primary endpoint will be analysed using an 
ANCOVA model with region, screening HbA1c < 8% (yes/no) pre-trial basal insulin 
treatment and randomised treatment as fixed factors, and baseline HbA1c as covariate. 
The estimates and standard deviations for the 1000 data sets will be pooled to one 
estimate and associated standard deviation using Rubin’s rule.   
Explanatory factors will be coded as follows:  
 
Treatment: Once weekly insulin icodec, insulin degludec  
 
Region: Asia, Europe, North America 
 
Screening HbA1c < 8%: yes, no 
 
Pre-trial basal insulin treatment: twice daily or insulin glargine U300: yes or no 
 
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinues randomised treatment.  
The following sensitivity analysis evaluating the robustness of the assumptions about the missing 
data will be carried out:  
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
subjects having imputed HbA1c measurement at the week 26 visit are assumed to have a worse 
outcome in the insulin icodec arm and a better outcome in the insulin degludec arm compared to 
what was imputed in the primary analysis. This is done by adding or subtracting values Δi to the 
imputed HbA1c values before analysing the data. The value of Δi will be varied independently in the 
two treatment arms. The non-inferiority margin of 0.3% will be among the Δi values investigated. 
The plausibility of the values of Δi where the conclusion of the primary analysis change will be 
evaluated to assess the robustness of the primary analysis result. 
9.4.3 
Secondary endpoints 
9.4.3.1 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
Efficacy endpoints 
Change in fasting plasma glucose (FPG) from baseline week 0 (V2) to week 26 (V28) 
Missing FPG values at the week 26 visit (regardless of treatment completion status) for both 
treatment arms will be imputed with baseline value adding a random error term. The random error 
term is normally distributed with a standard deviation set equal to the estimated residual standard 
deviation of an ANCOVA analysis on the LAOT values. Specifically, the imputations and analyses 
will be carried out as follows: 
 
First, an ANCOVA model with region, screening HbA1c < 8% (yes/no), pre-trial basal 
insulin treatment and randomised treatment as fixed factors, and a baseline value as a 
covariate will be fitted to the LAOT value. 
 
Second, the estimated residual standard deviation, s, from this model will be used to impute 
missing values by the baseline value, adding a random normally distributed term with mean 
0 and standard deviation s. This will be done 1000 times. 
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 
For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and 
randomised treatment as fixed factors, and a baseline value as a covariate.  
 
The estimates and SDs for the 1000 data sets will be pooled to one estimate and associated 
SD using Rubin’s rule. 
 
Time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL) from week 22 (V24) to week 26 (V28) 
Missing time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL) (TIR) from week 22 to week 26 
will be imputed from trial participants who are from the insulin degludec group, and who have 
completed and adhered to their randomised insulin treatment - i.e., data will be imputed based on 
the assumption that, subjects with missing endpoint data will behave like subjects completing 
insulin degludec treatment. Specifically, the imputations and analyses will be carried out as follows: 
 
First, one thousand (1000) copies of the dataset will be generated for TIR. 
 
Second, for each dataset copy, an ANCOVA model will be fitted to TIR values for subjects 
who completed their randomised treatment in the insulin degludec group. The estimated 
mean, and variances, from the model will be used to impute missing values in both 
treatment groups. 
 
For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and 
randomised treatment as fixed factors. The estimates and SDs for the 1000 data sets will be 
pooled to one estimate and associated SD using Rubin’s rule. 
 
Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment 
satisfaction from baseline week 0 (V2) to week 26 (V28) 
The change in DTSQs in total treatment satisfaction from baseline to week 26 will be analysed 
using the same model as specified for change in FPG, but the corresponding baseline value will be 
used as a covariate. 
Change in HbA1c from baseline week 0 (V2) to week 52 (V54) 
The change in HbA1c from baseline to week 52 will be analysed similar to the primary endpoint 
specified above. 
Safety endpoints 
Hypoglycaemic episodes 
The following hypoglycaemic endpoints will be analysed separately using the method described 
below: 
 
Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 
26 (V28).  
 
Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 26 (V28). 
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 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3) from baseline week 0 (V2) to week 26 (V28). 
 
Number of nocturnal clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3) from baseline week 0 (V2) to week 26 (V28). 
 
For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 visit (V56) to planned end of the main-on-treatment period) will be 
imputed using a multiple imputation technique, assuming that the event rate pre-follow-up 2 visit 
(V56) follows the respective treatment groups rate whilst post-follow-up 2 visit (V56) event rate is 
the rate of the comparator group. The imputation will be done as follows: 
 
First, a Bayes negative binomial model with log-link function will be fitted to the event rate 
data to obtain the posterior distribution of model parameters. The model will include 
region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and randomised 
treatment as fixed factors and the logarithm of the main-on-treatment period as offset. 
 
Second, based on the estimated parameters for the comparator group in this model, the 
number of episodes in the missing period will be imputed for subjects who discontinued 
their randomised treatment. Multiple copies (1000 copies) of a complete data set will be 
generated by sampling from the estimated distribution. 
 
For each of the complete data sets, the number of episodes will be analysed using a 
negative binomial model with log-link, fixed factors and offset as described in step 1. The 
estimates and SDs for the 1000 data sets will be pooled to one estimate and associated SD 
using Rubin’s rule. 
 
The following hypoglycaemic endpoints will be analysed separately using the method described 
above, substituting the main-on-treatment period with the on-treatment period: 
 
Number of severe hypoglycaemic episodes (level 3), from baseline week 0 (V2) to week 
57 (V56). 
 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL) confirmed by BG meter), from baseline week 0 (V2) to week 57 
(V56). 
 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3), from baseline week 0 (V2) to week 57 (V56). 
 
Number of nocturnal clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3), from baseline week 0 (V2) to week 57 (V56). Nocturnal hypoglycaemic episodes 
are hypoglycaemic episodes occurring between 00:01 and 05:59 both inclusive.  
For the definition and classification of hypoglycaemic episodes refer to Appendix 7 (Section 10.7). 
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Time spent < 3.0 mmol/L (54 mg/dL) and time spent > 10 mmol/L (180 mg/dL) from week 22 
(V24) to week 26 (V28)  
Time spent < 3.0 mmol/L (54 mg/dL) (below range) and time spent > 10 mmol/L (180 mg/dL) 
(above range) from week 22 to week 26 will be analysed separately in a similar manner as ‘time in 
target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ if deemed appropriate, i.e. if data can be 
considered normally distributed. However, if a large number of subjects have 0 % time spent, then 
an alternative analysis will be performed where time spent below or above range will be analysed 
separately using a negative binomial model on the number of recorded measurements below and 
above range, respectively, with a log-link function and the logarithm of the total number of 
recorded measurements as offset. The model will include randomised treatment and region as 
factors. Further details will be provided in the SAP. 
Mean total weekly insulin dose from week 24 (V26) to week 26 (V28) and mean total weekly 
insulin dose from week 50 (V52) to week 52 (V54) 
Mean weekly insulin dose during the last 2 weeks of treatment (from week 50 to week 52) and 
during the last 2 weeks in the main part (from week 24 to 26) will be log-transformed and analysed 
separately using the same statistical model as specified for change in FPG. Pre-trial (baseline) total 
weekly insulin dose will be log-transformed and included as a covariate in the model. 
Change in body weight from baseline week 0 (V2) to week 26 (V28)  
Change in body weight from week 0 to week 26 will be analysed using the same statistical model as 
specified for the primary endpoint, but with the corresponding baseline value as a covariate.  
9.4.4 
Exploratory endpoints 
For details on analyses of exploratory endpoints, please refer to the SAP. 
9.4.5 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (SAEs, 
AEs, safety laboratory parameters, vital signs, etc.) will be reported descriptively based on both the 
main-on-treatment and the on-treatment period, including any notable changes of clinical interest in 
laboratory parameters. In addition, SAEs will be reported descriptively based on the in-trial period. 
9.4.6 
Other analyses  
For other analyses, please refer to the SAP.  
9.4.6.1 
Pharmacokinetic modelling 
Insulin icodec serum concentration data will be used for population PK analysis. The objective of 
the population PK analysis is to evaluate the effects of pre-specified covariates on serum 
concentrations of insulin icodec. 
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo 
Nordisk. A more technical and detailed elaboration of the population PK analysis will be given in a 
modelling analysis plan, which will be prepared before database lock. In brief, a previously 
developed PK model for insulin icodec will be applied. The absorption rate constant (Ka) in the 
model will be fixed, and the apparent clearance (CL/F) and the apparent volume of distribution 
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(V/F) will be re-estimated. The covariates of interest will be incorporated into the PK model using 
criteria which will be specified in the modelling analysis plan. 
The population PK analysis will be reported in a separate modelling report, which will not be part 
of the clinical trial report. The individual insulin icodec serum concentration data will be tabulated 
in the bioanalytical report. 
9.5 
Interim analyses  
The trial does not include a formal interim analysis. However, the reporting will be split into a 
main phase and an extension phase, where the results of the main phase can be reported possibly 
before LPLV. Subjects will provide consent for the full length of the trial. To preserve trial integrity 
during the extension phase, dissemination of results from the main phase will, during the extension 
phase, initially be limited to communication internally and with regulatory authorities. 
9.6 
Data monitoring committee  
This section is not applicable for this trial.  
9.7 
Reporting of the main part of the trial 
A database lock is planned shortly after last subject last visit of the main part of the trial. The results 
from this main part will thereafter be reported. The complete trial will be reported after database 
lock of the extension part. 
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki21 and applicable ICH Good Clinical Practice (GCP) Guideline22 
 
Applicable laws and regulations 
 
The protocol, informed consent form, investigator’s brochure (as applicable) and other 
relevant documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed 
and approved by the IRB/IEC before the trial is initiated. 
 
Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the CTR according to national requirements. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
safety hazard to trial subjects. 
 
Before a site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received. 
 
The investigator will be responsible for: 
o providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the 
IRB/IEC and/or regulatory authorities 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of the conduct of the trial at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
o ensuring submission of the CTR synopsis to the IRB/IEC 
o reporting any potential serious breaches to the sponsor immediately after discovery 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
10.1.3 
Informed consent process 
 
The investigator or his/her representative will explain the nature of the trial to the subject 
and answer all questions regarding the trial.  
 
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
 
Subjects must be informed that their participation is voluntary. 
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 
Subjects must be informed about their privacy rights.  
 
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines22, Declaration of Helsinki21 and the 
IRB/IEC or site. 
 
The medical record must include a statement that written informed consent was obtained 
before any trial related activity and the date when the written consent was obtained. The 
authorised person obtaining the informed consent must also sign and date the informed 
consent form before any trial related activity. 
 
The responsibility of 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. 
 
Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial. 
 
A copy of the informed consent form(s) must be provided to the subject.  
10.1.4 
Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further, the subject may receive other written information 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. 
10.1.5 
 Data protection 
 
Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records 
or datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the subject are transferred to Novo Nordisk. 
 
The subject and any biological material obtained from the subject will be identified by 
subject number, visit number and trial ID. Appropriate measures such as encryption or 
leaving out certain identifiers will be enforced to protect the identity of subjects as required 
by local, regional and national requirements.  
 
The subject must be informed about his/her privacy rights, including that his/her personal 
trial related data will be used by Novo Nordisk in accordance with local data protection 
law. The disclosure of the data must also be explained to the subject.  
 
The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 
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10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal trial independent ad hoc 
group will be established in order to maintain the blinding of the trial personnel. 
10.1.6.2 
Trial safety group 
This section is not applicable for this trial.  
10.1.6.3 
Data monitoring committee 
This section is not applicable for this trial. 
10.1.6.4 
Event adjudication committee 
An independent external EAC is established to perform ongoing blinded adjudication of selected 
AEs and deaths (see Table 8-1). 
The EAC will evaluate events sent for adjudication using pre-defined definitions and guidelines in 
accordance with the EAC charter. The evaluation is based on review of pre-defined clinical data 
collected by the sites. The EAC is composed of permanent members covering all required medical 
specialities. EAC members must disclose any potential conflicts of interest and must be independent 
of Novo Nordisk. The EAC will have no authority to impact trial conduct, trial protocol or 
amendments. The assessments made by both the event adjudication committee and the investigator 
will be evaluated and included in the CTR.  
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements, such as those of the International 
Committee of Medical Journal Editors (ICMJE)23, the Food and Drug Administration Amendment 
Act (FDAAA)24, European Commission Requirements1, 25, 26 and other relevant recommendations or 
regulations. If a subject requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint, and is for this 
trial last subject first treatment (LSFT) + 26 weeks corresponding to visit 28. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed 
visit 28. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
FDAAA. 
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10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
 
Novo Nordisk or designee is responsible for the data management of this trial including 
quality checking of the data. 
 
All subject data relating to the trial will be recorded on electronic CRFs (eCRFs) unless 
transmitted electronically to Novo Nordisk or designee (e.g. laboratory and eDiary data) or 
when applicable on paper CRF. The investigator is responsible for verifying that data 
entries are accurate and correct by physically or electronically signing the CRF.  
 
The following will be provided as paper CRFs:  
 
Pregnancy forms 
 
The following will be provided as paper CRFs to be used when access to the CRF is revoked or the 
CRF is temporarily unavailable:  
 
AE forms  
 
Safety information forms  
 
Technical complaint forms (also to be used to report complaints on trial product not yet 
allocated to a subject)  
Corrections to the CRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the CRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction. If corrections are made by the investigator’s delegated staff after the date when the 
investigator signed the CRF, the CRF must be signed and dated again by the investigator. 
The investigator must ensure that data is recorded in the CRF as soon as possible, preferably within 
5 working days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.  
10.1.8.2 
Monitoring 
 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data 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 site staff 
should be available for discussions at monitoring visits and between monitoring visits (e.g. 
by telephone).  
 
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is 
being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
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 
Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
 
Monitors will review the subject’s medical records and other source data to ensure 
consistency and/or identify omissions compared to the CRF.  
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay 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 CRF or via listings from the trial database.  
10.1.9 
Source documents 
All data entered in the eCRF must be verifiable in source documentation, except for the following 
data that has been recorded directly into the eCRFs and will be considered source data. 
 
Data in the service providers’ database is considered source data e.g. eDiaries, CGM and 
laboratory. 
 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
 
Data reported on the paper CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records. Also, current medical records must be available.  
 
It must be possible to verify subject’s medical history in source documents, such as 
subject’s medical record.  
 
The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested, and who was contacted. 
 
Definition of what constitutes source data can be found in a source document agreement at 
each site. There will only be one source document defined at any time for any data element. 
10.1.10 Retention of clinical trial documentation 
 
Records and documents, including signed informed consent forms, pertaining to the 
conduct of this trial must be retained by the investigator for 15 years after end of trial unless 
local regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of Novo Nordisk. No 
records may be transferred to another location or party without written notification to Novo 
Nordisk.  
 
The investigator must be able to access his/her trial documents without involving Novo 
Nordisk in any way. If applicable, electronic CRF (eCRF) and other subject data will be 
provided in an electronic readable format to the investigator before access is revoked to the 
systems supplied by Novo Nordisk. Site-specific CRFs and other subject data (in an 
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electronic readable format or as paper copies or prints) must be retained by the site. A copy 
of all data will be stored by Novo Nordisk. 
 
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
10.1.11 Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or 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. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
 
failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, Novo Nordisk procedures or GCP guidelines 
 
inadequate recruitment of subjects by the investigator 
 
discontinuation of further trial product development. 
10.1.12 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 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 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 that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
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must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
10.1.13 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.  
10.1.14 Publication policy 
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 investigators 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 investigators will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators.  
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
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The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. 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. 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. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.27 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre 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. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
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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10.2 
Appendix 2: Clinical laboratory tests 
 
The tests detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory. 
 
Additional tests may be performed at any time during the trial as determined necessary by 
the investigator or required by local regulations. Only laboratory samples specified in the 
protocol should be sent to the central laboratory for analysis; if additional laboratory 
sampling is needed, e.g. to follow up on AEs, this must be done at a local laboratory. 
 
The central lab will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab SOPs. These data will not be transferred to the trial database. The 
investigator should review such values for AEs and report these according to this protocol. 
 
The investigator must review all laboratory results for concomitant illnesses and AEs. 
 
Laboratory samples will be destroyed no later than at finalisation of the CTR.  
 
For haematology samples (differential count) where the test result is not normal, then a part 
of the sample may be kept for up to two years or according to local regulations.  
 
Human biosamples for retention will be stored as described in Appendix 6, Section 10.6. 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Glucose metabolism  
(V1*, V2, V12, V20, V28, 
V38, V46*, V54, V28A*, 
V54A*) 
*HbA1c only 
 Fasting plasma glucose (FPG)1  
 HbA1c  
NOTE: 
1A FPG result <3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a 
hypoglycaemic episode but as an AE at the discretion of the investigator (Appendix 3, Section 10.3). 
A FPG result >16.7 mmol/L (300 mg/dL) should not be reported as a hyperglycaemic episode but as an AE at the 
discretion of the investigator (Appendix 3, Section 10.3). 
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Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory 
 assessments 
Parameters 
Haematology 
(V1, V12, V28, V38, V54) 
 Erythrocytes 
 Haematocrit 
 Haemoglobin 
 Leucocytes 
 Thrombocytes 
Biochemistry1 
(V1, V12, V28, V38, V54) 
 Alanine Aminotransferase (ALT)  
 Albumin 
 Alkaline phosphatase 
 Aspartate Aminotransferase (AST) 
 Creatinine 
 Potassium 
 Sodium 
 Bilirubin 
Lipids 
(V2, V12, V28, V38, V54) 
 Cholesterol 
 High density lipoprotein (HDL) cholesterol 
 Low density lipoprotein (LDL) cholesterol 
 or IRB/IECTriglycerides 
Pregnancy Testing (V2, 
V56) 
 Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test2 
Other tests 
 eGFR calculated by the central laboratory based on the creatinine value using the CKD-
EPI equation, eGRF is for screening purposes only. 
 In case of systemic hypersensitivity (Section 8.9.2): Tryptase (optimal 0.5-2 hours post 
the hypersensitivity reaction), total IgE antibodies, anti-insulin icodec IgE antibodies, 
anti-insulin icodec binding antibodies, anti-human insulin IgE antibodies. 
 Anti-insulin icodec antibodies (V2, V4, V8, V12, V20, V28, V38, V54, V56) 
 Insulin-icodec serum concentration (V4, V8, V12, V20, V28, V38, V54, V56) 
Notes: 
1Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Section 10.3 (Hy’s Law) and Section 7.1. 
2Local urine testing will be standard unless serum testing is required by local regulation . 
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10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting 
10.3.1 
Definition of AE 
AE definition 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated 
with the use of an investigational medicinal product (IMP), whether or not considered related to 
the IMP. 
An AE can therefore be any unfavorable and unintended sign, including an abnormal laboratory 
finding, symptom or disease (new or exacerbated) temporally associated with the use of an IMP. 
 
Events meeting the AE definition 
 Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgment of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected 
 Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected  
 Exacerbation/worsening of a chronic or intermittent condition including either an increase in 
frequency and/or intensity of the condition 
 Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction 
 Signs, symptoms or the clinical sequelae of a suspected overdose of IMP regardless of intent 
 
A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfil the definition. 
Events NOT meeting the AE definition  
 Conditions present prior to the time point from which AEs are collected and anticipated day-to-
day fluctuations of these conditions, including those identified during screening or other trial 
procedures performed before exposure to IMP.  
 Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
 Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads to the 
procedure is the AE. 
 Medical or surgical procedures not preceded by an AE or worsening of a known condition. 
10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' 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 were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the physician’s office 
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or outpatient setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfils any other seriousness criteria, the event is serious. When in 
doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
 Hospitalisation for elective treatment (e.g. elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note:  
 Hospitalisations for administrative, trial related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs.  
 Hospital admissions for medical or surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs.  
d. Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 This definition is not intended to include experience of relatively minor medical significance, 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g. sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the subject 
or may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious and reported as SAEs 
using the important medical event criterion. 
 The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable: 
 Suspicion of transmission of infectious agents via the IMP  
 Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x UNL and total bilirubin >2 x UNL where no alternative aetiology exists (Hy's 
law) 
 
10.3.3 
Description of events for adjudication and AEs requiring additional data collection  
Description of events for adjudication and AEs requiring additional data collection (on 
specific event form)  
Events for adjudication 
An event for adjudication is a selected AE or death evaluated by an independent external EAC in 
a blinded manner, please refer to Table 8-1, Appendix 1 (Section 10.1.6.4) and Figure 10-1. 
Source data should be in accordance with Section 8.3. 
 Death 
 All cause death 
 Acute coronary syndrome 
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 All types of acute myocardial infarction and unstable angina pectoris requiring 
hospitalisation 
 Cerebrovascular event (stroke or transient ischemic attack) 
 Episode of focal or global neurological dysfunction that could be caused by brain, spinal 
cord, or retinal vascular injury as a result of haemorrhage or ischemia, with or without 
infarction 
 Heart failure (requiring hospitalisation or urgent heart failure visit) 
 New episode or worsening of existing heart failure leading to an urgent, unscheduled hospital 
admission or clinic/office/emergency department visit 
Adverse events requiring additional data collection 
AEs requiring additional data collection on a specific event form.  
Injection site reaction 
If an event of injection site reaction is observed, additional information must be obtained if 
available on a separate form. 
Hypersensitivity 
Systemic hypersensitivity can be manifested as isolated symptoms such as urticaria, angioedema, 
conjunctivitis, rhinitis, bronchospasm, gastrointestinal symptoms (nausea, vomiting, diarrhoea, 
abdominal pain), or as anaphylaxis or anaphylactic shock. 
 
Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden 
release of mast cell- and basophil-derived mediators into the circulation28. It most often results 
from immunologic reactions to foods, medications, and insect stings, although it can also be 
induced through nonimmunologic mechanisms by any agent capable of producing a sudden, 
systemic degranulation of mast cells or basophils29. Characteristic symptoms and signs, occurring 
minutes to a few hours after exposure to potential triggering agents or events may include: 
flushing, urticaria, angioedema, hoarseness, throat tightness, stridor, wheezing, coughing, 
shortness of breath, abdominal pain, vomiting, and/or hypotension, dizziness or collapse. 
Local hypersensitivity reactions, including rash, redness, pruritus and oedema, may occur at the 
site of investigational drug injection. 
Drug hypersensitivity reactions (DHRs) are the adverse effects of pharmaceutical formulations 
(including active drugs and excipients) that clinically resemble allergy30. They can be allergic and 
non-allergic. 
If a hypersensitivity event is suspected, the subjects must contact the site staff as soon as possible 
for further guidance. All events must be reported, and in case of systemic hypersensitivity, 
additional information must be provided on a separate form. 
Medication error 
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the subject, such as:  
 administration of wrong drug or use of wrong device 
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.  
 wrong route of administration, such as intramuscular instead of subcutaneous  
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 accidental administration of a lower or higher dose than intended. The administered dose must 
deviate from the intended dose to an extent where clinical consequences for the trial subject 
were likely to happen as judged by the investigator, although they did not necessarily occur. 
 missed doses or drug pauses are not to be reported as a medication error. 
 
Misuse and abuse  
 Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g. overdose to maximise effect) 
 Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm) 
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence (e.g. hypoglycaemia or other), this must be reported on an additional AE 
form. 
 
10.3.4 
Recording and follow-up of AE and/or SAE 
AE and SAE recording 
 The investigator will record all relevant AE/SAE information in the CRF. 
 The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) related to the 
event. 
 There may be instances when copies of source documents (e.g. medical records) for certain 
cases are requested by Novo Nordisk. In such cases, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the source documents before 
submission to Novo Nordisk. 
 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. For sign-off of SAE related forms, refer to “AE and SAE 
reporting via paper CRF” later in this section. 
 Novo Nordisk products used as concomitant medication or NIMP: if an AE is considered to 
have a causal relationship with a Novo Nordisk marketed product used as NIMP (insulin 
aspart) or concomitant medication in the trial, it is important that the suspected relationship is 
reported to Novo Nordisk, e.g. in the alternative aetiology section on the safety information 
form. Novo Nordisk may need to report this adverse event to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess severity for each event reported during the trial and assign it to one of 
the following categories:  
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
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 Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with a SAE. Both AEs and 
SAEs can be assessed as severe.  
 
Assessment of causality 
 The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. 
 Relationship between an AE/SAE and the relevant IMP(s) should be assessed as:  
 Probable - Good reason and sufficient documentation to assume a causal relationship. 
 Possible - A causal relationship is conceivable and cannot be dismissed. 
 Unlikely - The event is most likely related to aetiology other than the IMP. 
 Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
 The investigator should use the investigator’s brochure and/or product information, for 
marketed products, for the assessment. For each AE/SAE, the investigator must document in 
the medical records that he/she has reviewed the AE/SAE and has provided an assessment of 
causality. 
 There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator 
always makes an assessment of causality for every event before the initial transmission of 
the SAE data. 
 The investigator may change his/her opinion of causality, in light of follow-up information, 
and update the causality assessment in the CRF. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
 Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented 
 Recovering/resolving: The condition is improving, and the subject is expected to recover from 
the event. This term may be applicable in cases of chronic conditions, cancer or AEs ongoing 
at time of death (where death is due to another AE).  
 Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
 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.  
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE).  
 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 a fatal outcome must be reported as an SAE. 
 Unknown: This term is only applicable if the subject is lost to follow-up. 
 
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Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions). 
This may include additional laboratory tests (e.g. skin prick test) or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a subject dies during participation in the trial or during a recognised follow-up period, the 
investigator should provide Novo Nordisk with a copy of autopsy report including 
histopathology. 
New or updated information will be recorded in the CRF. 
 
10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
 Relevant forms (AE and safety information form) must be completed in the CRF.  
 For reporting and sign-off timelines, see Figure 10-1 below. Source data should be in 
accordance with Section 8.3. 
  If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form, and 
if the CRF is unavailable for more than 5 calendar days, then the site will use the safety 
information form (see box below). 
 The site will enter the SAE data into the CRF as soon as it becomes available. 
 After the trial is completed, the trial database will be locked, and the CRF will be 
decommissioned to prevent the entry of new data or changes to existing data. If a site receives 
a report of a new SAE from a subject or receives updated data on a previously reported SAE 
after CRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone. 
 
AE and SAE reporting via paper CRF 
 Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk in 
accordance with Section 10.1.5. 
 For SAEs, initial notification via telephone is acceptable, although it does not replace the need 
for the investigator to complete the AE and safety information form within the designated 
reporting timelines (as illustrated in the figure below): 
 AE form within 24 hours 
 Safety information form within 5 calendar days 
 Both forms must be signed within 7 calendar days after first knowledge by the investigator. 
 The specific event form for AEs requiring additional data collection within 14 calendar days  
 
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Source data should be in accordance with Section 8.3 
Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
Contact details for SAE reporting can be found in the investigator trial master file. 
Reporting of AEs for non-Novo Nordisk medical devices provided by Novo Nordisk for use 
in the trial 
Reporting of AEs on Roche Accu check and Dexcom G6: 
All complaints (including AEs) should be reported directly to the manufacturer. 
 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
If fertility is unclear (e.g. amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of trial treatment, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
 
Documented total hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
Females with permanent infertility due to an alternate medical cause other than the above (e.g. 
Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in determining 
trial enrolment. 
3. Postmenopausal female: 
 A postmenopausal state is defined as amenorrhoea for 12 months without an 
alternative medical cause.  
 Females ≥ 50 years of age can be considered postmenopausal (irrespective of 
treatment with a hormonal contraception or hormone replacement therapy (HRT)) 
if they have both: 
o Amenorrhoea and 
o Documentation of 2 high follicle stimulating hormone (FSH) measurements in the 
postmenopausal range and one of these was observed ≥1 year prior to screening. 
 Females ≥ 60 years of age can be considered postmenopausal. 
Females on HRT and whose menopausal status is in doubt are considered of childbearing potential 
and will be required to use at least an effective contraception method.  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of subject’s 
medical records, medical examination or medical history interview. 
Contraception guidance 
Male subjects  
No contraception measures are required as the risk of teratogenicity/fetotoxicity caused by transfer 
of insulin icodec or insulin degludec or insulin aspart in seminal fluid is unlikely31 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use at least an 
acceptable effective method of contraception consistently and correctly as described in Table 10-3 . 
As a minimum, contraception should be maintained until treatment discontinuation32. 
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Table 10-3 
Acceptable contraceptive methods 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
ACCEPTABLE METHODSb 
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action 
 Male or female condom with or without spermicidec 
 Cervical cap, diaphragm, or sponge with spermicide 
 A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods). 
NOTES 
a) Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical trials. 
b) Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. 
c) Male condom and female condom should not be used together (due to risk of failure with 
friction). 
 
Pregnancy testing 
 
Additional pregnancy testing should be performed during the treatment period, if required 
locally. Please refer to the Appendix 9 (Section 10.9). 
 
WOCBP should only be included after a negative highly sensitive urine pregnancy test 
(refer to Appendix 2 (Section 10.2) and the trial flowchart (Section 1.2). 
 
As a minimum, pregnancy test should be performed at the end of relevant systemic 
exposure (refer to Appendix 2, Section 10.2 and the trial flowchart, Section 1.2).Pregnancy 
testing should be performed whenever a menstruation is missed or when pregnancy is 
otherwise suspected. 
Collection of pregnancy information  
Female subjects who become pregnant  
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this trial. 
 
Information will be recorded on the appropriate form and submitted to Novo Nordisk 
within 14 calendar days of learning of a subject's pregnancy (see Figure 10-2). 
 
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate which will be forwarded to Novo 
Nordisk within 14 calendar days. Generally, follow-up will not be required for longer than 
1 month beyond the delivery date. 
 
Any termination of pregnancy will be reported, regardless of foetal status (presence or 
absence of anomalies) or indication for procedure. 
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 
While pregnancy itself is not considered to be an AE or SAE, any adverse event in 
connection with pregnancy or elective termination of a pregnancy for medical reasons will 
be reported as an AE or SAE. If relevant, consider adding ‘gestational’, ‘pregnancy related’ 
or a similar term when reporting the AE/SAE. 
 
Pregnancy outcome should be documented in the subject's medical record. Abnormal 
pregnancy outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies 
and ectopic pregnancy) is considered an SAE. 
 
Any SAE occurring as a result of a post-trial pregnancy which is considered 
possibly/probably related to the IMP by the investigator will be reported to Novo Nordisk 
as described in Section 10.3. While the investigator is not obligated to actively seek this 
information in former subjects, he or she may learn of an SAE through spontaneous 
reporting.  
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product.  
Maternal form 1b 
  14 calendar days after birth
Maternal form 1a
  14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2   14 calendar days
Paternal form*1   14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
Figure 10-2 Decision tree for determining the forms to complete with associated timelines 
for pregnancy.  
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10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.5.1 
Definition of technical complaint 
Technical complaint definition  
 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: 
 
Problems with the physical or chemical appearance of trial products (e.g. discoloration, 
particles or contamination) 
 
Problems with packaging material including labelling 
 
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and the needle) 
Time period for detecting technical complaints  
All technical complaints which occur from the time of receipt of the product at site until the time 
of the last usage of the product must be collected for products predefined on the technical 
complaint form.  
 
10.5.2 
Recording and follow-up of technical complaints 
Contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN. 
2. 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 CRF within: 
 5 days calendar for all technical complaints  
If the CRF is unavailable, or when reporting a technical complaint on a trial product that is not 
yet allocated to subject , the information must be provided on a paper form to Customer 
Complaint Center, Novo Nordisk, within the same timelines as stated above. When the CRF 
becomes available again, the investigator must enter the information on the technical complaint 
form in the CRF. 
 
Follow-up of technical complaints  
The investigator is responsible for ensuring that new or updated information will be recorded on 
the originally completed form. 
 
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Collection, storage and shipment of technical complaint samples 
The investigator must collect the technical complaint sample and all associated parts that were 
packed in the same DUN and notify the monitor within 5 calendar days of obtaining the sample at 
site. The sample and all associated parts must be sent as soon as possible to Customer Complaint 
Center, Novo Nordisk, together with a copy of the completed technical complaint form. The 
technical complaint sample should contain the batch, code or lot number and, if available, the 
DUN. If the technical complaint sample is unobtainable, the reason must be stated on the 
technical complaint form. If several samples are shipped in one shipment, the sample and the 
corresponding technical complaint form should be kept together. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
 
10.5.3 
Reporting of technical complaints 
Reporting of technical complaints for Novo Nordisk products not included in technical 
complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form 
should be reported to local Novo Nordisk. 
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10.6 
Appendix 6: Retention of human biosamples 
Hypersensitivity reaction samples 
In case of a systemic hypersensitivity reaction, the additional blood samples taken in relation to the 
reaction (Section 8.9.2) may be retained to follow-up on the hypersensitivity reaction. If deemed 
relevant by Novo Nordisk, relevant exploratory tests may be performed, e.g. histamine release 
(basophil activation). If measured, such data will be reported in a separate report. 
The samples will be stored at Novo Nordisk or a Novo Nordisk designated referral central 
bio-repository. The samples might be transferred to other countries, if not prohibited by local 
regulations. Only Novo Nordisk staff and bio-repository personnel will have access to the stored 
samples. The samples may be shipped to a contract research organisation (CRO) for analysis. 
The samples will be anonymised (identified only by a unique sample ID, visit number, trial 
identification number and sampling date). Confidentiality and personal data protection will be 
ensured during storage after the end of trial and no direct identification of the subject will be stored 
together with the samples.  
Potential further analyses of the samples will not have any consequences for the subject and their 
relatives. Subjects can contact the investigator if they wish to be informed about results derived 
from stored antibody samples obtained from their own body. 
The samples will be stored after end of trial and until marketing authorisation approval or until the 
research project terminates, but no longer than 15 years from end of trial after which they will be 
destroyed. 
Antibody samples 
Antibody samples may be retained for further characterisation of antibody responses towards drug, 
if required by health authorities or for safety reasons. The samples may also be used for further 
development of anti-insulin antibody assays, or for exploratory investigation of antibodies. 
The antibody samples will be stored after end of trial and until marketing authorisation approval or 
until the research project terminates, but no longer than 15 years from end of trial after which they 
will be destroyed. 
Metabolism samples (PK samples) 
Samples for metabolism analysis may be retained for later analysis of metabolites if needed. If 
samples are selected for metabolite analysis, they will be stored at Novo Nordisk after end of trial 
and until marketing authorisation approval or until the research project terminates, but no longer 
than 15 years from end of trial after which they will be destroyed 
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10.7 
Appendix 7: Hypoglycaemic episodes 
Table 10-4 
Classification of hypoglycaemia 
Classification of hypoglycaemia 
Level 
Glycaemic criteria 
Description 
Hypoglycaemia alert value 
(level 1) 
< 3.9 mmol/L (70 mg/dL) and  
≥ 3.0 mmol/L (54 mg/dL) 
Sufficiently low for treatment with fast-acting 
carbohydrate and dose adjustment of glucose-lowering 
therapy 
Clinically significant 
hypoglycaemia (level 2) 
< 3.0 mmol/L (54 mg/dL) 
Sufficiently low to indicate serious, clinically 
important hypoglycaemia 
Severe hypoglycaemia 
(level 3) 
No specific glucose threshold 
1Hypoglycaemia associated with severe cognitive 
impairment requiring external assistance for recovery 
Notes: The Novo Nordisk terms are adapted from IHSG33, ADA34, ISPAD35 type 1 diabetes outcomes program36, 
ATTD37. Severe hypoglycaemia as defined by Seaquist38 and ISPAD35. 
 
Severe hypoglycaemia 
1Severe hypoglycaemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be 
available during an event, but neurological recovery following the return of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.38 
In case of recurrent severe hypoglycaemia, the treatment of the subject is the responsibility of the 
investigator and the titration guidelines can be overruled at his/her discretion34 
Nocturnal hypoglycaemia 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive. 
Reporting of hypoglycaemic episodes in the eDiary  
Plasma glucose (PG) should always be measured by the trial BG meter and hypoglycaemic episodes 
should be recorded in the eDiary.  
The following should be reported in the eDiary as hypoglycaemic events: 
- PG values < 3.9 mmol/L (70 mg/dL) 
- Severe hypoglycaemic episodes without confirmed PG values  
The investigator should ensure correct reporting of the hypoglycaemic episode. Confirmation of the 
hypoglycaemic episode review must be documented in the web portal. In case a subject is not able 
to fill in the eDiary (e.g. in case of hospitalisation) at time of episode, the subject can report the 
episode in the eDiary retrospectively. 
If the hypoglycaemic episode fulfils the criteria for an SAE then in addition to the above patient 
reported data, an eCRF AE form and a safety information form must also be filled in. One AE form 
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and safety information form can cover several hypoglycaemic values, if the subject has not 
recovered between them and has reported them as one episode in the eDiary. 
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the PG value is ≥ 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance with current guidelines38. 
Repeated low PG measurements can be reported by the subject as one hypoglycaemic episode until 
a succeeding PG value is ≥ 3.9 mmol/L (70 mg/dL). In case of several low PG values within the 
hypoglycaemic episode, the lowest value is the one that will be reported as the PG value for the 
hypoglycaemic episode, but the start time of the episode will remain as the time for the first low PG 
value. The remaining values will be kept as source data. 
If the severity of a hypoglycaemic episode changes, only one hypoglycaemic episode will be 
reported, reflecting the most severe degree of hypoglycaemia. 
Regarding the question: “To feel better, did you need help to get a sugary drink, food, or 
medicine?” the investigator must instruct the subjects to answer “Yes”, if the episode was an event 
that required 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 concentration38. 
eDiary review 
At each contact the investigator should review the eDiary data for correct reporting of PG values 
and hypoglycaemic episodes. In case of incomplete or incorrect data in the eDiary, the subject must 
be questioned whether there have been any severe hypoglycaemic episodes since the last visit. The 
subject shall update the reported data in the eDiary accordingly. 
Re-training of subjects 
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low PG values not reported as hypoglycaemic episodes. The training should be documented by the 
investigator in source documents. 
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10.8 
Appendix 8: Titration guideline 
Titration guidelines have been developed, providing recommended dose adjustments at different PG 
levels to ensure that subjects receive an optimal treatment. However, it is recognised that insulin 
treatment should be individualised, and the specific titration algorithms may not be applicable in 
certain clinical situations. Hence, 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 is responsible for the treatment of the subjects and 
can therefore overrule the guidelines to avoid safety hazards. 
Initiation of trial products 
At randomisation eligible subjects will be randomised to receive insulin icodec or insulin degludec, 
both in combination with mealtime insulin aspart.  
 Insulin icodec should be taken once weekly on the same day of the week. 
o At randomisation (V2) 
▪ Subjects that prior to randomisation received insulin glargine U300 or 
received basal insulin twice daily should receive a dose which consists of 
total daily basal insulin dose before randomisation x7 + 50% (Table 10-5) 
regardless of their HbA1c at screening. 
▪ Subjects with HbA1c <8% (64 mmol/mol) at screening should receive a dose 
which consists of total daily basal insulin dose before randomisation 
x7 + 50% (Table 10-5) 
▪ Subjects with HbA1c ≥ 8% (64 mmol/mol) at screening should receive a dose 
which consists of total daily basal insulin dose before randomisation 
x7 + 100% (Table 10-6)  
The following weekly dose (V3) for all subjects should be the total daily dose x7. In the following 
table the weekly V2 and V3 doses for subjects receiving from 10 U to 100 U per day have been 
calculated. Please note that the displayed values are rounded off to the nearest dose divisible by 10. 
Table 10-5 
V2 and V3 doses for subjects that prior to randomisation received insulin 
glargine U300 or received basal insulin twice daily, or subjects with HbA1c <8% 
(64 mmol/mol) at screening 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
10 
110 
70 
56 
590 
390 
11 
120 
80 
57 
600 
400 
12 
130 
80 
58 
610 
410 
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13 
140 
90 
59 
620 
410 
14 
150 
100 
60 
630 
420 
15 
160 
110 
61 
640 
430 
16 
170 
110 
62 
650 
430 
17 
180 
120 
63 
660 
440 
18 
190 
130 
64 
670 
450 
19 
200 
130 
65 
682 
460 
20 
210 
140 
66 
690 
460 
21 
220 
150 
67 
700 
470 
22 
230 
150 
68 
710 
480 
23 
240 
160 
69 
720 
480 
24 
250 
170 
70 
740 
490 
25 
260 
180 
71 
750 
500 
26 
270 
180 
72 
760 
500 
27 
280 
190 
73 
770 
510 
28 
290 
200 
74 
780 
520 
29 
300 
200 
75 
790 
530 
30 
320 
210 
76 
800 
530 
31 
330 
220 
77 
810 
540 
32 
340 
220 
78 
820 
550 
33 
350 
230 
79 
830 
550 
34 
360 
240 
80 
840 
560 
35 
370 
250 
81 
850 
570 
36 
380 
250 
82 
860 
570 
37 
390 
260 
83 
870 
580 
38 
400 
270 
84 
880 
590 
39 
410 
270 
85 
890 
600 
40 
420 
280 
86 
900 
600 
41 
430 
290 
87 
910 
610 
42 
440 
290 
88 
920 
620 
43 
450 
300 
89 
930 
620 
44 
460 
310 
90 
950 
630 
45 
470 
320 
91 
960 
640 
46 
480 
320 
92 
970 
640 
47 
490 
330 
93 
980 
650 
48 
500 
340 
94 
990 
660 
49 
510 
340 
95 
1000 
670 
50 
530 
350 
96 
1010 
670 
51 
540 
360 
97 
1020 
680 
52 
550 
360 
98 
1030 
690 
53 
560 
370 
99 
1040 
690 
54 
570 
380 
100 
1050 
700 
55 
580 
390 
 
 
 
 
Table 10-6 
V2 and V3 doses for subjects with HbA1c ≥ 8% (64 mmol/mol) at screening 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
Total daily dose 
before randomisation 
V2 insulin icodec dose 
V3 insulin icodec dose 
10 
140 
70 
56 
780 
390 
11 
150 
80 
57 
800 
400 
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12 
170 
80 
58 
810 
410 
13 
180 
90 
59 
830 
410 
14 
200 
100 
60 
840 
420 
15 
210 
110 
61 
850 
430 
16 
220 
110 
62 
870 
430 
17 
240 
120 
63 
880 
440 
18 
250 
130 
64 
900 
450 
19 
270 
130 
65 
910 
460 
20 
280 
140 
66 
920 
460 
21 
300 
150 
67 
940 
470 
22 
310 
150 
68 
950 
480 
23 
320 
160 
69 
970 
480 
24 
340 
170 
70 
980 
490 
25 
350 
180 
71 
990 
500 
26 
360 
180 
72 
1010 
500 
27 
380 
190 
73 
1020 
510 
28 
390 
200 
74 
1040 
520 
29 
410 
200 
75 
1050 
530 
30 
420 
210 
76 
1060 
530 
31 
430 
220 
77 
1080 
540 
32 
450 
220 
78 
1090 
550 
33 
460 
230 
79 
1110 
550 
34 
480 
240 
80 
1120 
560 
35 
490 
250 
81 
1130 
570 
36 
500 
250 
82 
1150 
570 
37 
520 
260 
83 
1160 
580 
38 
530 
270 
84 
1180 
590 
39 
550 
270 
85 
1190 
600 
40 
560 
280 
86 
1200 
600 
41 
570 
290 
87 
1220 
610 
42 
590 
290 
88 
1230 
620 
43 
600 
300 
89 
1250 
620 
44 
620 
310 
90 
1260 
630 
45 
630 
320 
91 
1270 
640 
46 
640 
320 
92 
1290 
640 
47 
660 
330 
93 
1300 
650 
48 
670 
340 
94 
1320 
660 
49 
690 
340 
95 
1330 
670 
50 
700 
350 
96 
1340 
670 
51 
710 
360 
97 
1360 
680 
52 
730 
360 
98 
1370 
690 
53 
740 
370 
99 
1390 
690 
54 
760 
380 
100 
1400 
700 
55 
770 
390 
 
 
 
 
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 Insulin degludec should be taken once daily, at any time of the day but preferably at the 
same time every day. Switching from previous basal insulin should be in accordance with 
local label. 
 Insulin aspart should be taken with main meals 2-4 times per day. Switch from previous 
bolus insulin should be done unit-to-unit per meal. 
The treat-to-target approach will be applied to both treatment arms to optimise glycaemic control 
throughout the trial. 
There are no maximum or minimum insulin doses.  
Dose adjustment of trial products during the trial 
After randomisation the investigator should adjust the trial products once weekly in connection with 
the scheduled visits/phone contacts as described below: 
 The dose adjustment of insulin icodec and insulin degludec will be based on the three pre-
breakfast SMPG values measured on two days prior to titration and on the day of the 
contact. 
 If one or more pre-breakfast SMPG values are missing, the dose adjustment should be 
performed on the remaining SMPG value(s). 
 The prescribed dose should be determined by the investigator and recorded in the HCP web 
portal. 
Adjustment of insulin icodec and degludec will be done in accordance with the table below 
(Table 10-7).  
Table 10-7 
Adjustment of insulin icodec and insulin degludec 
Pre-breakfast SMPG 
Icodec 
adjustment 
Degludec 
adjustment 
Value to use 
mmol/L 
mg/dL 
U 
U 
Lowest of the 
SMPG values 
<4.4 
<80 
–20 
-3 
4.4–7.2 
80–130 
0 
0 
>7.2 
>130 
+20 
+3 
Titration of insulin aspart 
Titration of insulin aspart can either be adjusted weekly based on pre-prandial and bedtime SMPG 
values using the algorithm below or based on carbohydrate counting at the investigator’s discretion.  
Algorithm use: 
 
In the first 8 weeks after randomisation insulin aspart should be only be adjusted for safety 
reasons. Thereafter the doses should be considered adjusted weekly by the investigator. 
 
Dose adjustment will be based on the lowest pre-prandial or bedtime SMPG values 
measured in the week prior to titration in accordance with Table 10-8. 
o Breakfast dose will be adjusted based on the pre-lunch SMPG values 
o Lunch dose will be adjusted based on the pre-dinner SMPG values 
o Dinner dose will be adjusted based on the bedtime SMPG values. 
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If the patient eats more than four times a day the fourth dose will be adjusted in agreement with the 
investigator. 
Table 10-8 
Insulin aspart 
Lowest pre-prandial and bedtime SMPG 
Insulin aspart adjustment 
mmol/L 
mg/dL 
U 
<4.4 
<80 
-1 
4.4-7.2 
80-130 
0 
>7.2 
>130 
+1 
 
The subjects can take correction bolus doses in collaboration with the investigator. The investigator 
should consider using the “100 rule” (for mmol/L) or “1,800 rule” (for mg/dL) to estimate the 
correction bolus doses.  
Carbohydrate counting:  
 
This method should be reserved to subjects that are willing and able to do so. The subject 
needs to have prior hands-on experience using this method of determining bolus insulin 
doses. It is the investigator’s responsibility to ensure that the subject is adequately trained. 
If more training is needed, this should be done in accordance with local practice.  
 
Insulin aspart should be adjusted daily in accordance with the immediate pre-meal SMPG 
and carbohydrate content in the meal that the subject is about to eat. To use this method, the 
investigator needs to determine the insulin-to-carbohydrate ration (I:CHO ratio) and the 
insulin sensitivity factor (ISF) for each meal and adjust, when needed.  
 
I:CHO ratio expresses the amount of carbohydrates (in grams) for which IU of bolus insulin 
that would effectively minimise the postprandial glucose excursion. ISF expresses the 
expected reduction in plasma glucose concentration, when IU is administered.  
 
example: A subject has pre-prandial plasma glucose of 10.0 mmol/L (180 mg/dL) and 
intends to eat a meal containing 60 g of carbohydrates. For the given meal the I:CHO ratio 
has been estimated to 1U:10g and the ISF to be 2.0 mmol/L per 1U (36 mg/dL per 1U) and 
the target plasma glucose is 7.2 mmol/L (130 mg/dL) in this trial. The bolus dose for this 
meal can be calculated as follows: 
o To cover the meal carbohydrates: multiply grams of carbohydrates by I:CHO: 
o 60 g x 1U/10 g = 6U 
o To bring the pre-prandial glucose value to target: Subtract the target glucose value 
from the current pre-prandial glucose value and divide by ISF for this meal: 
o (10.0 mmol/L – 7.2 mmol/L)/2.0 mmol/L/U ~ 1U. 
o Thus, the bolus dose for this meal is 6U + 1U = 7U. 
Deviations from the algorithm 
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust insulin doses is based on all relevant information. A reason for deviating from the algorithm 
should be entered the into the HCP web portal by the investigator as applicable. 
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Missing insulin icodec dose guidance 
If an insulin icodec dose is missed for ≤ 3 days after the planned dosing day, subjects should inject 
the planned dose as soon as possible and perform control SMPG measurements and adjust bolus 
doses if needed. If the missing dose is missed for > 3 days, the subject should await the next 
planned day of injection. Subjects should perform frequent SMPG measurements to closely monitor 
their glycaemic control and adjust bolus doses, if needed.  
Dose recommendation from end of treatment and during follow up (insulin icodec) 
It is recommended that the subject is switched from insulin icodec to any available basal insulin at 
the discretion of the investigator. Regarding the switch from insulin icodec to post-trial basal insulin 
the following should be considered: 
 Calculate the new daily basal insulin dose by dividing the latest insulin icodec 
dose by 7. For subjects completing the trial the dose taken at V53 will be the latest 
dose. 
 Initiate basal insulin, when pre-breakfast SMPG daily in the follow up-period 
(after V54) exceeds 10.0 mmol/l (180 mg/dL). It is important that the investigator 
and the subjects are in close contact to prevent any misunderstanding. 
 Consider titrating the basal insulin once or twice weekly according to the 
pre-breakfast SMPG values and the local label of the chosen insulin. 
Data collection 
The subject should be instructed to report the following in the eDiary: 
 Date, dose and time of insulin icodec and insulin degludec or insulin aspart 
injections 
 Ensure transfer of SMPG values with an indication of “pre-breakfast”, “pre-
lunch”, “pre-dinner”, “bedtime” or “other” (Section 8.2.1). 
 Hypoglycaemic episodes as described in Appendix 7 (Section 10.7). 
While using the HCP web portal for titration the following will be entered by investigator: 
 Insulin degludec or insulin icodec and insulin aspart doses prescribed at this 
contact. 
 Reasons for deviation from the insulin icodec or insulin degludec titration 
algorithms, if applicable. 
Data surveillance 
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased or, if 
possible, a blinded manner. The data will be reviewed and significant deviations from the titration 
algorithm will be followed up.  
It is important that data regarding dose titration is entered into the eDiary and the HCP web portal. 
Timely registration is crucial in order to take appropriate actions 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. 
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The titration data should be reviewed by Novo Nordisk within 24 hours (on workdays). The 
reviewer may contact the investigator by e-mail or phone to clarify reasons 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 workdays). 
In addition, Novo Nordisk will monitor changes in HbA1c. Novo Nordisk may visit or phone sites to 
discuss progress in glycaemic control and titration of individual subjects. 
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10.9 
Appendix 9: Country-specific requirements  
For Austria: 
 
Contraceptive guidance: A monthly pregnancy test is mandatory for female subjects of 
childbearing potential. 
For Canada 
 
Retention of clinical trial documentation: Part C, Division 5 of the Food and Drug 
Regulations [C.05.012] requires a 25-year retention period  
For Germany 
 
Demography: Subject’s full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF.  
 Exclusion criteria 4: the footnote, “Simultaneous participation in a trial with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the 
last dose of the investigational medicinal product has been received more than 30 days 
before screening”, is not applicable for Germany. 
 
Discontinuation criteria 4, Section 7.1: the footnote, “Simultaneous participation in a trial 
with the primary objective of evaluating an approved or non-approved investigational 
medicinal product for prevention or treatment of COVID-19 disease or postinfectious 
conditions is allowed at the investigator discretion without discontinuing trial product”, is 
not applicable for Germany. 
For Japan: 
 
Inclusion criteria 3: age ≥ 20 years at the time of signing informed consent 
 
Preparation/Handling/Storage/Accountability: The head of the trial site or the trial product 
storage manager assigned by the head of the trial site (a pharmacist in principle) is 
responsible for control and accountability of the trial products. 
 Trial governance consideration: A seal is accepted as signature. 
 Exclusion criteria 4: the footnote, “Simultaneous participation in a trial with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the 
last dose of the investigational medicinal product has been received more than 30 days 
before screening”, is not applicable for Japan. 
 Discontinuation criteria 4, Section 7.1: the footnote, “Simultaneous participation in a trial 
with the primary objective of evaluating an approved or non-approved investigational 
medicinal product for prevention or treatment of COVID-19 disease or postinfectious 
conditions is allowed at the investigator discretion without discontinuing trial product”, is 
not applicable for Japan. 
 Drug(s) used in the clinical trial except for IMP(s) include the following Insulin aspart. 
Please refer to Insulin aspart local package insert, summary of product characteristics, US 
prescribing information or investigator’s brochure for the latest information.  
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For Russia: 
 Trial governance considerations: The trial should be conducted in compliance with the 
protocol, Ministry of Healthcare of Russian Federation’ order #200H from April, 01, 2016 
“Approval of rules of good clinical practice” and legal requirements of the Russian 
Federation regulating circulation of medicines. 
For Spain: 
 Retention of clinical trial documentation: 25 years according to the new Spanish Royal 
Decree 1090/2015. 
For Turkey  
 
Blood samples from Turkey will be analysed by a central lab. 
  This trial is a phase 3 trial. 
For USA: 
 Financial disclosure: Verification under disclosures per Code of Federal Regulations (CFR) 
of Financial Conflict of Interest. 
For Russia where BG meter is not approved at the time of the final protocol version 2.0:  
 The BG meter is regarded as investigational devices and will be labelled to indicate for 
investigational use only. This BG meter has been selected in order to have automatic 
transfer of SMPG data to the eDiary and thereby increase the accuracy of SMPG values. It is 
expected that the better accuracy in SMPG data will facilitate an improvement in the insulin 
titration efforts during the trial.  
Technical complaints on the BG meter, strips, lancets or control solutions, including 
technical complaints related to AEs and SAEs, must be reported to Roche on a special 
technical complaint paper form.  
Timelines for reporting, from the trial site obtaining knowledge of the technical complaint:  
o Technical complaint assessed as related to a SAE within 24 hours  
o  All other technical complaints within 5 calendar days  
AEs and SAEs related to the technical complaint must be reported both on the special 
technical complaint paper form and in the eCRF. In addition they must be reported in 
accordance with the standard protocol requirements for AE and SAE reporting as described 
in Section 8.3. At the end of the trial the BG meter must be collected by the investigator. 
If BG meter is approved during trial conduct, the procedures above are not applicable anymore and 
technical complaints reporting should follow the standard vigilance procedures. 
For UK: 
 Screen failures: Minimal information includes informed consent date, demography, screen 
failure details, eligibility criteria, and serious adverse event (SAE).   
 Discontinuation of trial treatment: Subjects that are randomised in violation of inclusion 
and exclusion criteria should be discontinued from the trial treatment. 
 Time period and frequency for collecting AE and SAE information: All AEs and SAEs 
must be collected from the time of informed consent and until the end of trial visit as 
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specified in the flowchart. For subjects discontinuing trial product prematurely SAEs must 
be collected from the end of trial visit until the discontinuation follow-up 2 visit (V54A). 
For India and Russia where CGM is not approved at the time of the final protocol version 2.0: 
 
The CGM is regarded as an investigational device and will be labelled to indicate for 
investigational use only.  
The CGM has been selected in order to provide the best data accuracy and to be consistent 
in the global clinical programme. Technical complaints on the CGM must be reported to 
 on a special technical complaint paper form. 
Timelines for reporting, from the trial site obtaining knowledge of the technical complaint: 
o Technical complaint assessed as related to a SAE within 24 hours 
o All other technical complaints within 5 calendar days  
AEs and SAEs related to the technical complaint must be reported both on the special technical 
complaint paper form and in the eCRF. In addition they must be reported in accordance with the 
standard protocol requirements for AE and SAE reporting as described in Section 8.3. At the end of 
the trial CGM must be collected by the investigator. 
If the CGM is approved in any of the countries during the trial conduct, the procedures above are 
not applicable any more in the said country and technical complaints reporting should follow the 
standard vigilance procedures. 
 
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10.10 Appendix 10: Abbreviations  
 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BG 
blood glucose 
CGM 
continous glucose monitor 
CRF 
case report form 
CTR 
clinical trial report 
CRO 
contract research organisation 
DTSQs 
Diabetes Treatment Satisfaction Questionnaire 
DFU 
directions for use 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FGM 
flash glucose monitor 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
HbA1c 
glycated haemoglobin 
HCP 
health care professional  
HRT 
hormone replacement therapy 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgE 
immunoglobulin E 
IMP 
investigational medicinal product 
INN 
international non-proprietary name 
ISPAD 
International Society for Pediatric and Adolescent Diabetes 
IRB 
institutional review board 
IWRS 
interactive web response system 
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LDL 
low-density lipoprotein 
LSLV 
last subject last visit 
NIMP 
non-investigational medical product 
PCD 
primary completion date 
PG 
plasma glucose 
PRO 
patient reported outcomes 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMPG 
self-measured plasma glucose 
SUSAR 
suspected unexpected serious adverse reaction 
TMM 
trial materials manual 
WOCBP 
woman of child bearing potential 
 
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10.11 Appendix 11: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version 4.0 (14 April 2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union1, because it neither significantly impacts the safety nor physical/mental integrity of 
subjects nor the scientific value of the trial. 
Overall rationale for preparing protocol, version 4.0: 
The protocol has been amended to correct typos and exclude Germany from co-participation in 
clinical trials evaluating medicinal products for prevention or treatment of COVID-19 disease or 
postinfectious conditions as per local health authority request. 
Section # and name 
Description of change 
Brief rationale 
2.3.1 Risk assessment 
“section 8.9.2.” is deleted from the 
sentence “For further information on 
injection site reactions, please refer to 
section 8.9.2 and Appendix 3 (Section 
10.3)”. 
Correction of reference. 
5.1 Inclusion criteria 
“basal and bolus insulin analogue 
regimes” is corrected to “basal and 
bolus insulin analogue regimens” 
Correction of typo 
10.1.7 Dissemination of clinical trial 
data 
The primary completion date (PCD) is 
corrected to last subject first treatment 
(LSFT) + 26 weeks corresponding to 
visit 28. 
Correction of typo, since the primary 
endpoint will be assessed at week 26 
(visit 28). 
10.1.9 Source documents 
“ePROs” is deleted. 
Correction due to no ePROs in this 
trial. 
10.8 Appendix 8 Titration guideline 
Table for V2 and V3 weekly dose: 
For “Total daily dose before 
randomisation (U): 82 “ 
“V2 insulin icodec dose (U)”: 960 is 
corrected to 860 
Correction of typo 
10.9 Appendix 9: Country/Region-
specific requirements 
Footnotes related to co-participation 
in clinical trial for COVID-19 in 
exclusion criteria 4 and 
discontinuation criteria 4 are not 
applicable for Germany 
To meet local Health Authority 
request. 
 
 
10.11 Appendix 11 Protocol 
amendment history  
Amendment history is updated by 
moving protocol v3.0 history to 
appendix 11 
Due to the new protocol v4.0 
11 References 
Reference 32 to CTFG guidance is 
added in appendix 4. 
Reference update 
 
 
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implementation of good clinical practice in the conduct of clinical trials on medicinal 
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Alatorre C, Fernández Landó L, Yu M, Brown K, Montejano L, Juneau P, et al. Treatment 
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U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
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The European Parliament and the Council of the European Council. Regulation (EC) No 
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37. 
Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International 
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40. 
38. 
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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16.1.01 
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. 
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Insulin icodec
Trial ID: NN1436-4625 ONWARDS 6
Clinical Trial Report (ext-1)
Appendix 16.1.1
17 March 2023
1.0
Final
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04848480 
Sponsor trial ID: 
NN1436-4625 
Official title of study: 
Efficacy and Safety of Once Weekly Insulin Icodec Compared 
to Once Daily Insulin Degludec 100 Units/mL, Both in 
Combination With Insulin Aspart, in Adults With Type 1 
Diabetes. A 26-week, Randomised, Multicentre, Open-label, 
Active-controlled, Parallel Group, Two Armed, Treat-to-target 
Trial Investigating the Effect on Glycaemic Control and Safety 
of Treatment With Once Weekly Insulin Icodec Compared to 
Once Daily Insulin Degludec, Both in Combination With 
Insulin Aspart in Adults With Type 1 Diabetes, With a 26-
week Extension Investigating Long Term Safety 
Document date* 
15 April 2021 
*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.


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Insulin icodec
Trial ID: NN1436-4625 ONWARDS 6 
Clinical Trial Report (ext-1)
Appendix 16.1.9
17 March 2023
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
1 of 29 
 
Statistical Analysis Plan 
NN1436-4625 
 
Efficacy and safety of once weekly insulin icodec compared to once 
daily insulin degludec 100 units/mL, both in combination with insulin 
aspart, in adults with type 1 diabetes. 
ONWARDS 6 
 
 
Author 
 
Insulin & Devices 
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Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
2 of 29 
 
Table of contents 
 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 3 
Table of tables ................................................................................................................................................... 3 
Version history .................................................................................................................................................. 4 
1 Introduction ................................................................................................................................................. 5 
1.1 
Objectives and endpoints .................................................................................................................... 5 
1.1.1 
Primary, secondary and exploratory objective and estimand .............................................. 5 
1.1.1.1 
Primary objective ............................................................................................. 5 
1.1.1.2 
Secondary objective ......................................................................................... 5 
1.1.1.3 
Estimand........................................................................................................... 5 
1.1.2 
Primary, secondary and exploratory endpoints ................................................................... 5 
1.1.2.1 
Primary endpoint .............................................................................................. 5 
1.1.2.2 
Secondary endpoints ........................................................................................ 5 
1.1.2.2.1 
Confirmatory secondary endpoints .......................................................... 5 
1.1.2.2.2 
Supportive secondary endpoints .............................................................. 6 
1.1.2.3 
Exploratory endpoints ...................................................................................... 7 
1.2 
Trial design ......................................................................................................................................... 7 
2 Statistical hypotheses .................................................................................................................................. 8 
3 Sample size determination .......................................................................................................................... 8 
4 Analysis sets ................................................................................................................................................. 8 
5 Statistical analyses ..................................................................................................................................... 10 
5.1 
General considerations ...................................................................................................................... 10 
5.2 
Subject disposition ............................................................................................................................ 10 
5.3 
Primary endpoint analysis ................................................................................................................. 10 
5.3.1 
Definition of endpoints ...................................................................................................... 10 
5.3.2 
Main analytical approach................................................................................................... 11 
5.3.3 
Sensitivity analysis ............................................................................................................ 11 
5.4 
Secondary endpoints analysis ........................................................................................................... 12 
5.4.1 
Supportive secondary endpoints ........................................................................................ 12 
5.4.1.1 
Efficacy endpoints .......................................................................................... 12 
5.4.1.2 
Safety endpoints ............................................................................................. 13 
5.5 
Exploratory endpoints analysis ......................................................................................................... 15 
5.6 
Other safety analyses ........................................................................................................................ 15 
5.6.1 
Nocturnal hypoglycaemic episodes ................................................................................... 15 
5.6.2 
Anti-insulin icodec antibodies ........................................................................................... 16 
5.6.3 
Record selection ................................................................................................................ 16 
5.7 
Other analyses ................................................................................................................................... 17 
5.7.1 
Other derivations and assessments .................................................................................... 17 
5.7.1.1 
Achievement of HbA1c target ....................................................................... 17 
5.7.1.2 
Self-measured plasma glucose (SMPG) ......................................................... 17 
5.7.1.3 
Insulin dose .................................................................................................... 17 
5.7.2 
Pharmacokinetic modelling ............................................................................................... 18 
5.7.3 
Assessments collected at week 52 ..................................................................................... 18 
5.8 
Interim analyses ................................................................................................................................ 18 
5.8.1 
Data monitoring committee ............................................................................................... 18 
5.9 
Reporting of the main part of the trial ............................................................................................... 18 
6 Supporting documentation ....................................................................................................................... 19 
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Date: 
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Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
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6.1 
Appendix 1: List of abbreviations ..................................................................................................... 19 
6.2 
Appendix 2: Changes to protocol-planned analyses ......................................................................... 20 
6.3 
Appendix 3: Definition and calculation of endpoints, assessments and derivations ........................ 21 
7 References .................................................................................................................................................. 29 
 
Table of figures 
 
Page 
Figure 1 
Trial design .................................................................................................................................. 8 
 
Table of tables 
 
Page 
Table 1 
SAP Version History Summary ................................................................................................... 4 
 
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Statistical Analysis Plan 
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Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
4 of 29 
 
Version history 
This Statistical Analysis Plan (SAP) for trial NN1436-4625 is based on the protocol version 4.0 
dated 14-APR-2021. 
Table 1 
SAP Version History Summary 
SAP 
Version 
Approval Date 
Change 
Rationale 
1.0 
See approval date in 
the electronic 
document 
management system 
Not Applicable 
Original version 
 
 
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Statistical Analysis Plan 
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Date: 
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Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
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1 
Introduction 
This statistical analysis plan (SAP) is based on the protocol: Efficacy and safety of once weekly 
insulin icodec compared to once daily insulin degludec 100 units/mL, both in combination with 
insulin aspart, in adults with type 1 diabetes, version 4.0 (dated 14-APR-2021). Most of the 
statistical analyses and derivations of endpoints presented in this SAP are identical to those 
described in the protocol, but some have been updated or added for technical or clinical reasons. 
The SAP also contains specifications of additional derivations and analyses. The changes to the 
protocol-planned statistical analyses and the reasons for these changes are described in Appendix 2, 
section 6.2. 
1.1 
Objectives and endpoints 
1.1.1 
Primary, secondary and exploratory objective and estimand 
1.1.1.1 
Primary objective 
To confirm the effect on glycaemic control of once weekly insulin icodec in combination with 
insulin aspart, in subjects with T1D. This includes comparing the difference in change from 
baseline in HbA1c between once weekly insulin icodec and once daily insulin degludec both in 
combination with insulin aspart after 26 weeks of treatment to a non-inferiority limit of 0.3%. 
1.1.1.2 
Secondary objective 
To compare the safety and patient reported outcomes of once weekly insulin icodec versus once 
daily insulin degludec, both in combination with insulin aspart, in subjects with T1D. 
1.1.1.3 
Estimand 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec and insulin degludec of the change in HbA1c from baseline to week 26 for all randomised 
subjects, irrespective of adherence to randomised treatment and changes to anti-diabetic background 
medication. The following intercurrent events will be handled by the treatment policy strategy: 
discontinuation of randomised insulin treatment, and withdrawal from the trial (measurements 
collected after these intercurrent events are used in the primary analysis). 
1.1.2 
Primary, secondary and exploratory endpoints 
1.1.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline (week 0) to week 26 
%-point 
1.1.2.2 
Secondary endpoints 
1.1.2.2.1 
Confirmatory secondary endpoints 
Not applicable for this trial. 
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Version: 
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1.1.2.2.2 
Supportive secondary endpoints 
Secondary efficacy endpoint 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose 
(FPG)  
From baseline (week 0) to week 26 
mmol/L 
Time in range 3.9-10.0 mmol/L (70-
180 mg/dL)* 
From week 22 to week 26  
% of readings  
Change in DTSQs (Diabetes 
Treatment Satisfaction 
Questionnaire) in total treatment 
satisfaction 
From baseline (week 0) to week 26 
Score 0-36 
6 items scored on a 
scale of 0 to 6. The 
higher the score the 
greater the satisfaction with 
treatment 
Change in HbA1c 
From baseline (week 0) to week 52 
%-point 
* using continuous glucose monitoring (CGM) system, Dexcom G6 
Secondary safety endpoints  
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed 
by BG meter)   
From baseline (week 0) to week 26 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed 
by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed 
by BG meter)   
From baseline (week 0) to week 57 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed 
by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 26 
Number of episodes 
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Version: 
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Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 57 
Number of episodes 
Time spent < 3.0 mmol/L (54 
mg/dL)* 
From week 22 to week 26  
% of readings 
Time spent > 10 mmol/L (180 
mg/dL)* 
From week 22 to week 26  
% of readings 
Mean total weekly insulin dose 
From week 24 to week 26  
U 
Mean total weekly insulin dose 
From week 50 to week 52 
U 
Change in body weight 
From baseline (week 0) to week 26  
Kg 
* using continuous glucose monitoring (CGM) system, Dexcom G6  
1.1.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed 
by BG meter)   
From baseline (week 0) to week 52 
Number of episodes 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed 
by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
Number of nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
From baseline (week 0) to week 52 
Number of episodes 
1.2 
Trial design 
This is a 26-week, randomised, multicentre, multinational, open-label, active-controlled, parallel 
group, two-armed, treat-to-target trial investigating the effect on glycaemic control and safety of 
treatment with once weekly insulin icodec compared to once daily insulin degludec, both in 
combination with insulin aspart in subjects with T1D, with a 26-week extension phase. The first 26 
weeks of the trial constitute the main phase, after which the primary analysis is planned. The focus 
of the 26-week extension phase is to evaluate long-term safety and provide long-term exposure 
data. 
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
an initial 26-week randomised treatment period, a 26-week extension phase and a 5-week follow-up 
period. Primary analysis is planned after the initial 26-week main phase. The overall trial design 
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Date: 
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Version: 
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and visit schedule are outlined in Figure 1 and trial flowchart (see protocol section 1.2), 
respectively. 
Figure 1 
Trial design 
 
For further details see protocol section 4.1.  
2 
Statistical hypotheses 
The primary hypothesis to be tested is that insulin icodec is non-inferior to insulin degludec in terms 
of change from baseline to week 26 in HbA1c. 
Formally, let D be the treatment difference ‘insulin icodec’ minus ‘insulin degludec’ of the change 
in HbA1c from baseline to week 26. The null-hypothesis will be tested against the alternative 
hypothesis of non-inferiority as given by   
H0: D ≥0.30% against HA: D <0.30%  
The non-inferiority margin of 0.3%-point is chosen based on the recommendation of health 
authority guidance for industry on developing drugs for treatment of diabetes.1,2 Furthermore: 
• The margin does not represent an unacceptable loss of efficacy with insulin icodec relative 
to treatment with a basal insulin analogue 
• It represents less than 30% of a suitably conservative estimate of insulin degludec´s 
treatment effect on HbA1c in a placebo-controlled trial in a T1D population; The treatment 
effect of degludec versus placebo in a T1D population is unknown but in a progressed T2D 
population of subjects already treated with liraglutide, degludec was shown to be superior to 
placebo (estimated treatment difference: -0.92%-point [-1.00; -0.75] 95%CI). 
3 
Sample size determination 
See protocol section 9.2.  
4 
Analysis sets 
The following populations are defined: 
Population 
Description 
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Version: 
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Status: 
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Randomised 
All subjects randomised 
Full analysis set 
Full analysis set: All subjects randomised. Subjects will be analysed according to 
the randomised treatment.  
Safety analysis set 
All subjects randomly assigned to trial treatment and who take at least one dose of 
trial product. Subjects are analysed according to the treatment they actually 
received.  
In exceptional cases, subjects or observations may be eliminated from the full analysis set. In such 
case the reasons for their exclusion will be documented before unblinding. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report. 
The following periods will be considered for the data collected: 
In-trial period 
The in-trial period starts at randomisation and ends at the date of: 
• The last direct subject-site contact. 
• Withdrawal for subjects who withdraw their informed consent. 
• The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up (i.e. possibly an unscheduled phone visit). 
• Death for subjects who die before any of the above. 
For subjects not randomised but exposed to trial product the in-trial period starts at the date of first 
dose of trial product. The end date is as defined as above. 
Baseline assessments are always included in the in-trial observation period. 
On-treatment period 
The on-treatment period starts at the date of first dose of trial product as recorded on the eCRF, and 
ends at the first date of any of the following: 
• The end of trial visit (V56). 
• The last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once 
weekly insulin (corresponding to 5 weeks after the end of the dosing interval for both 
treatment arms). 
• The end-date for the in-trial observation period. 
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product. 
Main-on-treatment period  
The main-on-treatment period starts at the date of first dose of trial product as recorded on the 
eCRF, and ends at the first date of any of the following:  
• The end date of the on-treatment period  
• Week 26 (V28).  
Baseline assessments are always included in the on-treatment observation periods. 
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Version: 
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Status: 
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All efficacy endpoints will be summarised and analysed using the full analysis set and the ‘in-trial’ 
period. Safety endpoints will be evaluated using both the main-on-treatment and the on-treatment 
period with descriptive statistics being based on the safety analysis set and statistical analyses being 
based on the full analysis set unless otherwise specified. 
5 
Statistical analyses 
5.1 
General considerations 
Presentation of results from a statistical analysis will include the estimated mean treatment 
difference (or ratio) presented together with the two-sided 95% confidence interval and the 
corresponding two-sided p-value. 
In the statistical models, explanatory factors will be coded as follows: 
• Treatment: Once weekly insulin icodec, insulin degludec 
• Screening HbA1c < 8%: yes, no   
• Pre-trial basal insulin treatment: twice daily or insulin glargine U300: yes or no 
• Region: Asia, Europe, North America 
The regions will be defined as follows: 
• Asia: India, Japan 
• Europe: Austria, Netherlands, Germany, Turkey, Italy, Russia, Spain, United Kingdom 
• North America: United States, Canada 
Baseline is defined as information collected at week 0 (V2). In case a measurement is not available 
at week 0 (V2) the most recent measurement prior to week 0 (V2) will be used as baseline. 
All endpoints based on CGM measurements will be summarised and analysed using the full 
analysis set and the ‘in-trial’ period and will be derived the following way. The percentage of time 
spent in a given glycaemic range will be calculated as 100 times the number of recorded 
measurements in the given glycaemic range, divided by the total number of recorded measurements. 
Following international consensus criteria it will be required that at least 70% of the planned CGM 
measurements during the last four weeks of treatment are available for endpoint data to be included 
in the analysis.3 
The number 541024 will be used as the seed for all imputations. 
5.2 
Subject disposition 
Subject disposition will be summarised descriptively.  
5.3 
Primary endpoint analysis 
5.3.1 
Definition of endpoints 
The primary endpoint is change in HbA1c from baseline to week 26. See also Appendix 3, section 
6.3. 
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Version: 
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UTN: U1111-1251-7315 
Status: 
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5.3.2 
Main analytical approach 
The ‘treatment policy’ estimand, will be estimated based on the Full Analysis Set (FAS) using all 
HbA1c measurements obtained at the week 26 visit, especially including measurements from 
subjects discontinuing their randomised treatment. Missing HbA1c at the week 26 visit (regardless 
of treatment completion status) will be imputed from trial participants, who have discontinued their 
randomised treatment prior to the week 26 visit and have a measurement at the week 26 visit in the 
following way: 
• First, one thousand (1000) copies of the dataset will be generated for HbA1c.   
• Second, for subjects having discontinued their randomised treatment prior to the week 26 
visit and have a HbA1c visit measurement at the week 26 visit, the change in HbA1c from last 
available planned on-treatment (LAOT) value to the week 26 visit will be analysed for each 
dataset copy using an ANCOVA model with randomised treatment as fixed factor and 
LAOT value and the time point (study day) of this assessment as covariates. The estimated 
parameters, and their variances, from the model will be used to impute missing HbA1c 
values for the change from LAOT to the week 26 visit and subsequently the missing HbA1c 
value at the week 26 visit. 
• For each of the complete data sets, the primary endpoint will be analysed using an 
ANCOVA model with region, screening HbA1c < 8% (yes/no), pre-trial basal insulin 
treatment and randomised treatment as fixed factors, and baseline HbA1c as covariate. The 
estimates and standard deviations for the 1000 data sets will be pooled to one estimate and 
associated standard deviation using Rubin’s rule.4 
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinue randomised treatment. 
In case the amount of data for the described imputation model (see second step above) is 
insufficient for meaningful imputation, the first alternative will be the following: 
• to simplify the imputation model by removing the following two covariates from the model: 
LAOT value and the time point (study day) of this assessment.  
If the amount of data for this reduced model is still insufficient for meaningful imputation, the 
following imputation strategy will be applied instead: 
• missing values at week 26 will be imputed with baseline value adding a random error term. 
This imputation method also includes measurements collected after intercurrent events, but 
is otherwise similar to the imputation method for endpoints where there is no data 
collection after premature treatment discontinuation as described for change in FPG (see 
section 5.4.1.1). 
Missing HbA1c at week 26 will be summarised by subject’s treatment completion status. 
5.3.3 
Sensitivity analysis 
The following sensitivity analysis evaluating the robustness of the assumptions about the missing 
data will be carried out: 
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
subjects having imputed HbA1c measurement at the week 26 visit are assumed to have a worse 
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outcome in the insulin icodec arm and a better outcome in the insulin degludec arm compared to 
what was imputed in the primary analysis. This is done by adding or subtracting values Δi to the 
imputed HbA1c values before analysing the data. The value of Δi will be varied independently in the 
two treatment arms. The non-inferiority margin of 0.3% will be among the Δi values investigated. 
The plausibility of the values of Δi where the conclusion of the primary analysis change will be 
evaluated to assess the robustness of the primary analysis result. 
5.4 
Secondary endpoints analysis 
5.4.1 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
5.4.1.1 
Efficacy endpoints 
Change in fasting plasma glucose (FPG) from baseline week 0 (V2) to week 26 (V28) 
Missing FPG values at the week 26 visit (regardless of treatment completion status) for both 
treatment arms will be imputed with baseline value adding a random error term. The random error 
term is normally distributed with a standard deviation set equal to the estimated residual standard 
deviation of an ANCOVA analysis on the LAOT values. Specifically, the imputations and analyses 
will be carried out as follows: 
• First, an ANCOVA model with region, screening HbA1c < 8% (yes/no), pre-trial basal 
insulin treatment and randomised treatment as fixed factors, and a baseline value as a 
covariate will be fitted to the LAOT value. 
• Second, the estimated residual standard deviation, s, from this model will be used to impute 
missing values by the baseline value, adding a random normally distributed term with mean 
0 and standard deviation s. This will be done 1000 times. 
• For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and 
randomised treatment as fixed factors, and a baseline value as a covariate.  
• The estimates and SDs for the 1000 data sets will be pooled to one estimate and associated 
SD using Rubin’s rule. 
Time in target range 3.9-10.0 mmol/L (70-180 mg/dL) from week 22 (V24) to week 26 (V28) 
Missing time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL) (TIR) from week 22 to week 26 
will be imputed from trial participants who are from the insulin degludec group, and who have 
completed and adhered to their randomised insulin treatment - i.e., data will be imputed based on 
the assumption that, subjects with missing endpoint data will behave like subjects completing 
insulin degludec treatment. Specifically, the imputations and analyses will be carried out as follows: 
• First, one thousand (1000) copies of the dataset will be generated for TIR. 
• Second, for each dataset copy, an ANCOVA model will be fitted to TIR values for subjects 
who completed their randomised treatment in the insulin degludec group. The estimated 
mean, and variances, from the model will be used to impute missing values in both 
treatment groups. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
13 of 29 
 
• For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and 
randomised treatment as fixed factors. The estimates and SDs for the 1000 data sets will be 
pooled to one estimate and associated SD using Rubin’s rule. 
Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment 
satisfaction from baseline week 0 (V2) to week 26 (V28) 
The change in DTSQs in total treatment satisfaction from baseline to week 26 will be analysed 
using the same model as specified for change in FPG, but the corresponding baseline value will be 
used as a covariate. 
Change in HbA1c from baseline week 0 (V2) to week 52 (V54) 
The change in HbA1c from baseline to week 52 will be analysed similar to the primary endpoint 
specified above. 
5.4.1.2 
Safety endpoints 
Hypoglycaemic episodes 
The following hypoglycaemic endpoints will be analysed separately using the method described 
below: 
• 
Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 
26 (V28).  
• 
Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 26 (V28). 
• 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3) from baseline week 0 (V2) to week 26 (V28). 
• 
Number of nocturnal clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3) from baseline week 0 (V2) to week 26 (V28). 
For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 visit (V56) to planned end of the main-on-treatment period) will be 
imputed using a multiple imputation technique, assuming that the event rate pre-follow-up 2 visit 
(V56) follows the respective treatment groups rate whilst post-follow-up 2 visit (V56) event rate is 
the rate of the comparator group. The imputation will be done as follows: 
• 
First, a Bayes negative binomial model with log-link function will be fitted to the event rate 
data to obtain the posterior distribution of model parameters. The model will include 
region, screening HbA1c < 8% (yes/no), pre-trial basal insulin treatment and randomised 
treatment as fixed factors and the logarithm of the main-on-treatment period as offset. 
• 
Second, based on the estimated parameters for the comparator group in this model, the 
number of episodes in the missing period will be imputed for subjects who discontinued 
their randomised treatment. Multiple copies (1000 copies) of a complete data set will be 
generated by sampling from the estimated distribution. 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
14 of 29 
 
• 
For each of the complete data sets, the number of episodes will be analysed using a 
negative binomial model with log-link, fixed factors and offset as described in step 1. The 
estimates and SDs for the 1000 data sets will be pooled to one estimate and associated SD 
using Rubin’s rule. 
The following hypoglycaemic endpoints will be analysed separately using the method described 
above, substituting the main-on-treatment period with the on-treatment period: 
• 
Number of severe hypoglycaemic episodes (level 3), from baseline week 0 (V2) to week 
57 (V56). 
• 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL) confirmed by BG meter), from baseline week 0 (V2) to week 57 
(V56). 
• 
Number of clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3), from baseline week 0 (V2) to week 57 (V56). 
• 
Number of nocturnal clinically significant hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes 
(level 3), from baseline week 0 (V2) to week 57 (V56). Nocturnal hypoglycaemic episodes 
are hypoglycaemic episodes occurring between 00:01 and 05:59 both inclusive.  
For the definition and classification of hypoglycaemic episodes refer to the protocol Appendix 7 
(protocol section 10.7). 
Time spent < 3.0 mmol/L (54 mg/dL) and time spent > 10 mmol/L (180 mg/dL) from week 22 
(V24) to week 26 (V28) 
Time spent < 3.0 mmol/L (54 mg/dL) (below range) and time spent > 10 mmol/L (180 mg/dL) 
(above range) from week 22 to week 26 will be analysed separately in a similar manner as ‘time in 
target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ if deemed appropriate, i.e. if data can be 
considered normally distributed. However, if a large number of subjects have 0 % time spent, then 
an alternative analysis will be performed where time spent below or above range will be analysed 
separately using a negative binomial model on the number of recorded measurements below and 
above range, respectively, with a log-link function and the logarithm of the total number of 
recorded measurements as offset. The model will include region, screening HbA1c < 8% (yes/no), 
pre-trial basal insulin treatment and randomised treatment as factors. 
Mean total weekly insulin dose from week 24 (V26) to week 26 (V28) and mean total weekly 
insulin dose from week 50 (V52) to week 52 (V54) 
Mean weekly insulin dose during the last 2 weeks of treatment (from week 50 to week 52) and 
during the last 2 weeks in the main part (from week 24 to 26) will be log-transformed and analysed 
separately using the same statistical model as specified for change in FPG. Pre-trial (baseline) total 
weekly insulin dose will be log-transformed and included as a covariate in the model. The 
imputation will also be done on log-transformed values, i.e., missing values will be imputed by the 
log-transformed baseline value adding a random error term. The random error term will be normally 
distributed with a standard deviation set equal to the estimated residual standard deviation of an 
ANCOVA analysis on the log-transformed LAOT values. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
15 of 29 
 
Change in body weight from baseline week 0 (V2) to week 26 (V28) 
Change in body weight from week 0 to week 26 will be analysed based on the in-trial period using 
the same statistical model as specified for the primary endpoint, but with the corresponding baseline 
value as a covariate. 
5.5 
Exploratory endpoints analysis 
Hypoglycaemic episodes 
The following hypoglycaemic endpoints will be analysed separately using the same method as 
described for supportive secondary hypoglycaemic endpoints (see section 5.4.1.2), substituting the 
main-on-treatment period with the period from week 0 to week 52 and the follow-up 2 (V56) with 
time of discontinuation: 
• Number of severe hypoglycaemic episodes (level 3) from week 0 (V2) to week 52 (V54) 
• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 
mg/dL), confirmed by BG meter) from week 0 (V2) to week 52 (V54) 
• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 
mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) from week 0 
(V2) to week 52 (V54) 
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) from week 
0 (V2) to week 52 (V54). 
5.6 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (SAEs, 
AEs, safety laboratory parameters, vital signs, etc.) will be reported descriptively based on the 
main-on-treatment and the on-treatment period, including any notable changes of clinical interest in 
laboratory parameters. In addition, SAEs will be reported descriptively based on the in-trial period. 
5.6.1 
Nocturnal hypoglycaemic episodes 
Nocturnal hypoglycaemic episodes are hypoglycaemic episodes occurring between 00:01 and 05:59 
both inclusive. The following nocturnal hypoglycaemic derivations will each be analysed separately 
using the same method as described for the corresponding supportive secondary hypoglycaemic 
endpoint (see section 5.4.1.2).  
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 26 (V28) 
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 26 (V28) 
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 57 (V56) 
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 57 (V56) 
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 52 (V54) 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
16 of 29 
 
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 52 (V54) 
5.6.2 
Anti-insulin icodec antibodies  
Antibodies will be evaluated based on the in-trial period. The following will be summarised by 
visit: 
• Anti-insulin icodec antibodies status (positive / negative) 
• Anti-insulin icodec antibodies cross-reactivity to endogenous insulin status (positive / 
negative)  
• Anti-insulin icodec antibodies titres and change from baseline in anti-insulin icodec antibody 
titres  
The correlation between anti-insulin icodec antibodies titres and actual weekly basal insulin dose, 
HbA1c, and change from baseline in HbA1c, respectively, will be illustrated using mean plots by 
treatment week for quartiles of peak post baseline to week 57 titre values.  
 
The Spearman’s rank correlation coefficient between change in anti-insulin icodec antibodies titres 
at follow-up and each of the following assessments: 
• actual weekly basal insulin dose from week 50 to 52 
• HbA1c at week 52 
• change from baseline in HbA1c at week 52 
• level 2 and level 3 combined hypoglycaemic episodes during the on-treatment period 
will be derived with the corresponding p-value for test of no correlation.  
A shift table from baseline to week 52 and week 57 for cross-reactivity anti-insulin antibody status 
will be prepared. 
Number and percentage of subjects with “treatment-induced” and “treatment-boosted” anti-insulin 
icodec antibodies will also be summarised. “Treatment-induced” anti-insulin icodec antibodies is 
defined as cases in which subjects switch from negative anti-insulin icodec antibodies at baseline to 
positive anti-insulin icodec antibodies during trial. “Treatment-boosted” anti-insulin icodec 
antibodies is defined as cases in which subjects, who have positive anti-insulin icodec antibodies at 
baseline, experience that anti-insulin icodec antibodies titres increase by at least two 2-fold dilution 
steps during trial. 
5.6.3 
Record selection 
A re-test at any visit is defined as repeating the same laboratory assessment using new sample 
material. A re-test may be taken if a subject shows up in a non-fasting state for a laboratory 
assessment that is to be taken in a fasting condition or when sample material is lost or damaged. 
In case of multiple eligible assessments at same planned time point (where only one was planned) 
only the first value will be selected. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
17 of 29 
 
5.7 
Other analyses 
5.7.1 
Other derivations and assessments 
5.7.1.1 
Achievement of HbA1c target 
The following derivations will be analysed separately using the method described below: 
• Achievement of HbA1c<7.0% after 26 weeks (yes/no)  
• Achievement of HbA1c<7.0% after 26 weeks without severe (level 3) or clinically significant 
hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) during 
the prior 12 weeks (yes/no) 
• Achievement of HbA1c<7.0% after 26 weeks without severe hypoglycaemic episodes (level 
3) during the prior 12 weeks (yes/no) 
• Achievement of HbA1c≤6.5% after 26 weeks (yes/no)  
• Achievement of HbA1c≤6.5% after 26 weeks without severe (level 3) or clinically significant 
hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) during 
the prior 12 weeks (yes/no) 
• Achievement of HbA1c≤6.5% after 26 weeks without severe hypoglycaemic episodes (level 
3) during the prior 12 weeks (yes/no) 
See Appendix 3, section 6.3, for further details. 
Missing HbA1c data at 26 weeks will be imputed in the same way as for the primary analysis (step 1 
and 2 in section 5.3.2) before deriving the dichotomous outcome. Subjects who discontinue 
randomised treatment prematurely will have the dichotomous outcome also evaluating 
hypoglycaemia set to ‘no’. For each of the 1000 complete data sets, the endpoint will be analysed 
using a logistic regression model with region, personal CGM device use (yes/no) and randomised 
treatment as fixed factors, and baseline HbA1c value as a covariate. The estimates and standard 
deviations for the 1000 data sets will be pooled to one estimate and associated standard deviation 
using Rubin’s rule. 
5.7.1.2 
Self-measured plasma glucose (SMPG) 
Mean fasting SMPG used for dose adjustment will be summarised by visit and treatment. 
Furthermore number and percentage of subjects achieving mean fasting SMPG used for dose 
adjustment within range (4.4–7.2 mmol/l) will be presented by visit and treatment. 
5.7.1.3 
Insulin dose 
Total weekly insulin dose, as well as weekly basal dose and weekly bolus dose will be summarised 
separately by treatment and week. 
Mean weekly basal insulin dose from week 24 to week 26, and mean weekly bolus insulin dose 
from week 24 to week 26 will be summarised and analysed separately using the same model as 
specified for the mean total weekly insulin dose, but with the corresponding log-transformed 
weekly insulin dose as a covariate. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
18 of 29 
 
5.7.2 
Pharmacokinetic modelling 
Insulin icodec serum concentration data will be used for population PK analysis. The objective of 
the population PK analysis is to evaluate the effects of pre-specified covariates on serum 
concentrations of insulin icodec. 
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo 
Nordisk. A more technical and detailed elaboration of the population PK analysis will be given in a 
modelling analysis plan, which will be prepared before database lock. In brief, a previously 
developed PK model for insulin icodec will be applied. The absorption rate constant (Ka) in the 
model will be fixed, and the apparent clearance (CL/F) and the apparent volume of distribution 
(V/F) will be re-estimated. The covariates of interest will be incorporated into the PK model using 
criteria which will be specified in the modelling analysis plan. 
The population PK analysis will be reported in a separate modelling report, which will not be part 
of the clinical trial report. The individual insulin icodec serum concentration data will be tabulated 
in the bioanalytical report. 
5.7.3 
Assessments collected at week 52 
Assessments collected at week 52, if not already described, will be summarised and analysed in the 
similar way as at week 26. 
5.8 
Interim analyses 
The trial does not include a formal interim analysis. However, the reporting will be split into a 
main phase and an extension phase, where the results of the main phase can be reported possibly 
before LPLV. Subjects will provide consent for the full length of the trial. To preserve trial integrity 
during the extension phase, dissemination of results from the main phase will, during the extension 
phase, initially be limited to communication internally and with regulatory authorities. 
5.8.1 
Data monitoring committee 
Not applicable for this trial. 
5.9 
Reporting of the main part of the trial 
A database lock is planned shortly after last subject last visit of the main part of the trial. The results 
from this main part will thereafter be reported. The complete trial will be reported after database 
lock of the extension part. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
19 of 29 
 
6 
Supporting documentation 
6.1 
Appendix 1: List of abbreviations 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BG 
Blood glucose 
CGM 
Continuous glucose monitoring 
CI 
Confidence interval 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
PK 
Pharmacokinetics 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMPG 
Self-measured plasma glucose 
T1D 
Type 1 Diabetes 
T2D 
Type 2 Diabetes 
TIR 
Time in range 
 
 
 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
20 of 29 
 
6.2 
Appendix 2: Changes to protocol-planned analyses 
In section 4 the sentence about subjects not randomised but exposed to trial product was added. 
In section 5.1 the baseline definition has been updated to clarify that week 0 (V2) is considered as 
baseline and if not available the most recent measurement prior to week 0 (V2) will be used as 
baseline. In this section, the seed number for the imputations has also been included. 
In section 5.3.2 description of alternative imputation strategies in case of insufficient amount of data 
for imputation has been added. 
In section 5.4.1.2 the description of the alternative analysis for time spent < 3.0 mmol/L and time 
spent > 10.0 mmol/L has been corrected because stratification factors were missing. Clarifying 
information was added to the description of the analysis of total weekly insulin dose and body 
weight. 
In section 5.5 description of analyses of exploratory endpoints has been added. 
Besides that, additional derivations and assessments have been added to section 5.6 and 5.7 along 
with further details on data reporting and presentation. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
21 of 29 
 
6.3 
Appendix 3: Definition and calculation of endpoints, assessments and derivations 
Type 
Title 
Time 
frame 
Unit 
Details 
Primary endpoint 
Change in HbA1c 
From baseline 
(week 0) to 
week 26 
%-point 
The HbA1c value at baseline week 
0 subtracted from the HbA1c value 
at week 26. 
Supportive 
secondary 
endpoint 
Change in fasting 
plasma glucose (FPG)  
From baseline 
(week 0) to 
week 26 
mmol/L 
The FPG value at baseline week 0 
subtracted from the FPG value at 
week 26. 
Supportive 
secondary 
endpoint 
Time in target-range 
3.9–10.0 
mmol/L (70-180 
mg/dL) 
From week 22 
to week 26 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements in the 
given glycaemic range, divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Supportive 
secondary 
endpoint 
Change in DTSQs 
(Diabetes Treatment 
Satisfaction 
Questionnaire) in total 
treatment satisfaction 
From baseline 
(week 0) to 
week 26 
Score 0-36 
6 items 
scored on a 
scale of 0 to 
6. The 
higher the 
score the 
greater the 
satisfaction 
with 
treatment  
The DTSQs score in total treatment 
satisfaction at baseline week 0 
subtracted from the DTSQs score 
in total treatment satisfaction at 
week 26. 
Supportive 
secondary 
endpoint 
Change in HbA1c 
From baseline 
(week 0) to 
week 52 
%-point 
The HbA1c value at baseline week 
0 subtracted from the HbA1c value 
at week 52. 
Supportive 
secondary 
endpoint 
Number of severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 26 
Number of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Supportive 
secondary 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) 
From baseline 
(week 0) to 
week 26 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
Supportive 
secondary 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) or severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 26 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Supportive 
secondary 
endpoint 
Number of severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 57 
Number of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
22 of 29 
 
Type 
Title 
Time 
frame 
Unit 
Details 
Supportive 
secondary 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) 
From baseline 
(week 0) to 
week 57 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
Supportive 
secondary 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) or severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 57 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Supportive 
secondary 
endpoint 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) or severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 26 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Supportive 
secondary 
endpoint 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) or severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 57 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Supportive 
secondary 
endpoint 
Time spent < 3.0 
mmol/L (54 mg/dL) 
From week 22 
to week 26 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements below 
3.0 mmol/L (54 mg/dL) divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
23 of 29 
 
Type 
Title 
Time 
frame 
Unit 
Details 
Supportive 
secondary 
endpoint 
Time spent > 10 
mmol/L (180 mg/dL) 
From week 22 
to week 26 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements above 
10 mmol/L (180 mg/dL) divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Supportive 
secondary 
endpoint 
Mean weekly insulin 
dose 
From week 24 
to week 26 
U 
The mean of weekly insulin doses 
during the two weeks. 
Supportive 
secondary 
endpoint 
Mean weekly insulin 
dose 
From week 50 
to week 52 
U 
The mean of weekly insulin doses 
during the two weeks. 
Supportive 
secondary 
endpoint 
Change in body 
weight 
From baseline 
(week 0) to 
week 26 
Kg 
The body weight value at baseline 
week 0 subtracted from the body 
weight value at week 26. 
Exploratory 
endpoint 
Number of severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 52 
Number of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Exploratory 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) 
From baseline 
(week 0) to 
week 52 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
Exploratory 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) or severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 52 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Exploratory 
endpoint 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) or severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
(week 0) to 
week 52 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
severe hypoglycaemic 
episodes (level 3)  
From baseline 
(week 0) to 
week 26 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
24 of 29 
 
Type 
Title 
Time 
frame 
Unit 
Details 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter)  
From baseline 
(week 0) to 
week 26 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
severe hypoglycaemic 
episodes (level 3)  
From baseline 
(week 0) to 
week 57 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter)  
From baseline 
(week 0) to 
week 57 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
severe hypoglycaemic 
episodes (level 3)  
From baseline 
(week 0) to 
week 52 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter)  
From baseline 
(week 0) to 
week 52 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Achievement of 
HbA1c<7.0% after 26 
weeks (yes/no)  
Week 26 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved 
HbA1c < 7.0% after 26 weeks 
 
No: subject did not achieve HbA1c 
< 7.0% after 26 weeks 
Derivation 
Achievement of 
HbA1c<7.0% after 26 
weeks without severe 
(level 3) or clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) during the prior 
12 weeks (yes/no) 
Week 26 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved 
HbA1c < 7.0% after 26 weeks 
without severe or clinically 
significant hypoglycaemic episodes 
during the prior 12 weeks 
 
No: subject did not achieve 
HbA1c < 7.0% after 26 weeks or 
subject had a severe or clinically 
significant hypoglycaemic episode 
during the prior 12 weeks or 
subject discontinued randomised 
treatment prematurely 
Derivation 
Achievement of 
HbA1c<7.0% after 26 
weeks without severe 
hypoglycaemic 
episodes (level 3) 
during the prior 12 
weeks (yes/no) 
Week 26 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved 
HbA1c < 7.0% after 26 weeks 
without severe hypoglycaemic 
episodes during the prior 12 weeks 
 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
25 of 29 
 
Type 
Title 
Time 
frame 
Unit 
Details 
No: subject did not achieve 
HbA1c < 7.0% after 26 weeks or 
subject had a severe 
hypoglycaemic episode during the 
prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Derivation 
Achievement of 
HbA1c≤6.5% after 26 
weeks (yes/no)  
Week 26 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 26 weeks 
 
No: subject did not achieve HbA1c 
≤6.5% after 26 weeks 
Derivation 
Achievement of 
HbA1c≤6.5% after 26 
weeks without severe 
(level 3) or clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) during the prior 
12 weeks (yes/no) 
Week 26 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 26 weeks without severe or 
clinically significant 
hypoglycaemic episodes during the 
prior 12 weeks 
 
No: subject did not achieve 
HbA1c ≤6.5% after 26 weeks or 
subject had a severe or clinically 
significant hypoglycaemic episode 
during the prior 12 weeks or 
subject discontinued randomised 
treatment prematurely 
Derivation 
Achievement of 
HbA1c≤6.5% after 26 
weeks without severe 
hypoglycaemic 
episodes (level 3) 
during the prior 12 
weeks (yes/no) 
Week 26 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 26 weeks without severe 
hypoglycaemic episodes during the 
prior 12 weeks 
 
No: subject did not achieve 
HbA1c ≤6.5% after 26 weeks or 
subject had a severe 
hypoglycaemic episode during the 
prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Assessment 
Mean weekly basal 
insulin dose 
From week 24 
to week 26 
U 
The mean of weekly insulin doses 
during the two weeks. 
Assessment 
Mean weekly bolus 
insulin dose 
From week 24 
to week 26 
U 
The mean of weekly insulin doses 
during the two weeks. 
Assessment 
Change in fasting 
plasma glucose (FPG)  
From baseline 
(week 0) to 
week 52 
mmol/L 
The FPG value at baseline week 0 
subtracted from the FPG value at 
week 52 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
26 of 29 
 
Type 
Title 
Time 
frame 
Unit 
Details 
Assessment 
Time in target-range 
3.9–10.0 
mmol/L (70-180 
mg/dL) 
From week 48 
to week 52 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements in the 
given glycaemic range, divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Assessment 
Change in DTSQs 
(Diabetes Treatment 
Satisfaction 
Questionnaire) in total 
treatment satisfaction 
From baseline 
(week 0) to 
week 52 
Score 0-36 
6 items 
scored on a 
scale of 0 to 
6. The 
higher the 
score the 
greater the 
satisfaction 
with 
treatment  
The DTSQs score in total treatment 
satisfaction at baseline week 0 
subtracted from the DTSQs score 
in total treatment satisfaction at 
week 52. 
Assessment 
Time spent < 3.0 
mmol/L (54 mg/dL) 
From week 48 
to week 52 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements below 
3.0 mmol/L (54 mg/dL) divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Assessment 
Time spent > 10 
mmol/L (180 mg/dL) 
From week 48 
to week 52 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements above 
10 mmol/L (180 mg/dL) divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Assessment 
Change in body 
weight 
From baseline 
(week 0) to 
week 52 
Kg 
The body weight value at baseline 
week 0 subtracted from the body 
weight value at week 52. 
Assessment 
Mean weekly basal 
insulin dose 
From week 50 
to week 52 
U 
The mean of weekly insulin doses 
during the two weeks. 
Assessment 
Mean weekly bolus 
insulin dose 
From week 50 
to week 52 
U 
The mean of weekly insulin doses 
during the two weeks. 
Derivation 
Achievement of 
HbA1c<7.0% after 52 
weeks (yes/no)  
Week 52 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved 
HbA1c < 7.0% after 52 weeks 
 
No: subject did not achieve HbA1c 
< 7.0% after 52 weeks 
 SAP  4625
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VV-TMF-4407188
29
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26
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1
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
27 of 29 
 
Type 
Title 
Time 
frame 
Unit 
Details 
Derivation 
Achievement of 
HbA1c<7.0% after 52 
weeks without severe 
(level 3) or clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) during the prior 
12 weeks (yes/no) 
Week 52 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved 
HbA1c < 7.0% after 52 weeks 
without severe or clinically 
significant hypoglycaemic episodes 
during the prior 12 weeks 
 
No: subject did not achieve 
HbA1c < 7.0% after 52 weeks or 
subject had a severe or clinically 
significant hypoglycaemic episode 
during the prior 12 weeks or 
subject discontinued randomised 
treatment prematurely 
Derivation 
Achievement of 
HbA1c<7.0% after 52 
weeks without severe 
hypoglycaemic 
episodes (level 3) 
during the prior 12 
weeks (yes/no) 
Week 52 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved 
HbA1c < 7.0% after 52 weeks 
without severe hypoglycaemic 
episodes during the prior 12 weeks 
 
No: subject did not achieve 
HbA1c < 7.0% after 52 weeks or 
subject had a severe 
hypoglycaemic episode during the 
prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Derivation 
Achievement of 
HbA1c≤6.5% after 52 
weeks (yes/no)  
Week 52 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 52 weeks 
 
No: subject did not achieve HbA1c 
≤6.5% after 52 weeks 
Derivation 
Achievement of 
HbA1c≤6.5% after 52 
weeks without severe 
(level 3) or clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) during the prior 
12 weeks (yes/no) 
Week 52 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 52 weeks without severe or 
clinically significant 
hypoglycaemic episodes during the 
prior 12 weeks 
 
No: subject did not achieve 
HbA1c ≤6.5% after 52 weeks or 
subject had a severe or clinically 
significant hypoglycaemic episode 
during the prior 12 weeks or 
subject discontinued randomised 
treatment prematurely 
Derivation 
Achievement of 
HbA1c≤6.5% after 52 
weeks without severe 
hypoglycaemic 
episodes (level 3) 
during the prior 12 
weeks (yes/no) 
Week 52 
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 52 weeks without severe 
hypoglycaemic episodes during the 
prior 12 weeks 
 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
28 of 29 
 
Type 
Title 
Time 
frame 
Unit 
Details 
No: subject did not achieve 
HbA1c ≤6.5% after 52 weeks or 
subject had a severe 
hypoglycaemic episode during the 
prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
15 April 2021 Novo Nordisk 
Trial ID: NN1436-4625 
Version: 
1.0 
UTN: U1111-1251-7315 
Status: 
Final 
EudraCT No: 2020-002374-27 
Page: 
29 of 29 
7 
References 
1.
Food and Drug Administration, CDER. Guidance for Industry. Diabetes Mellitus:
Developing Drugs and Therapeutic Biologics for Treatment and Prevention, Draft Guidance.
February 2008.
2.
European Medicines Agency. Guideline on clinical investigation of medicinal products in
the treatment or prevention of diabetes mellitus (CPMP/EWP/1080/00 Rev. 2). 29 Jan 2018.
3.
Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40.
4.
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John
Wiley & Sons. 1987.
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CONFIDENTIAL