Conditions: Diabetes Mellitus, Type 2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 588
Healthy volunteers: no

Brief summary:
This study compares insulin icodec (a new insulin taken once a week) to insulin degludec (an insulin taken once daily which is already available on the market) in people with type 2 diabetes.

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

Participants will get their study medicine in an injection pen. Participants will get a pen for weekly injection and one for daily injection. One will be icodec or degludec and the other will be dummy medicine. The treatment participants get is decided by chance. Participants and the study staff will not know which active medicine they get.

The insulin is injected with a needle in a skin fold in the thigh. The study could last for about 8 months. Participants will have 13 clinic visits and 17 phone calls with the study doctor. At 8 clinic visits participants will have blood samples taken. At 4 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit.

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

Detailed description:

Arms:
arm 1: Participants will get once daily and once weekly injections arm 2: Participants will get once daily and once weekly injections

Interventions: intervention 1: Insulin icodec intervention 2: Placebo insulin icodec intervention 3: Insulin degludec intervention 4: Placebo insulin degludec
Intervention descriptions: intervention 1: You will get a pen for weekly injection and one for daily injection. One will be icodec 700 units/mL and the other will be placebo.

Subcutaneously (under the skin) injections intervention 2: You will get a pen for weekly injection and one for daily injection. One will be insulin degludec 100 units/mL and the other will be placebo.

Subcutaneously (under the skin) injections intervention 3: You will get a pen for weekly injection and one for daily injection. One will be degludec 100 units/mL and the other will be placebo.

Subcutaneously (under the skin) injections intervention 4: You will get a pen for weekly injection and one for daily injection. One will be icodec 700 units/mL and the other will be placebo.

Subcutaneously (under the skin) injections

Protocol document:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04795531 
Sponsor trial ID: 
NN1436-4479 
Official title of study: 
A 26-week double blinded, multiregional, trial comparing the 
effect and safety of once weekly insulin icodec and once daily 
insulin degludec 100 units/mL, both in combination with non-
insulin anti-diabetic drugs, in insulin naïve subjects with type 2 
diabetes (ONWARDS 3) 
Document date*: 
30 November 2020 
 
*Document date refers to the date on which the document was most recently updated. 
 


Protocol 
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Date: 
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Trial ID: NN1436-4479  
Version: 
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Status: 
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Page: 
1 of 102 
 
Protocol 
 
Protocol title:  
A 26-week double blinded, multiregional, trial comparing the effect and safety of once 
weekly insulin icodec and once daily insulin degludec 100 units/mL, both in combination 
with non-insulin anti-diabetic drugs, in insulin naïve subjects with type 2 diabetes. 
ONWARDS 3 
 
Substance: Insulin icodec 
Universal Trial Number: U1111-1247-5218  
EudraCT Number: 2020-000472-37  
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. 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
 
 
 
Redacted 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 2.0 
30 November 2020 
All countries 
Original protocol version 1.0 
09 June 2020 
All countries 
 
Protocol version 2.0 (30 November 2020) 
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 2.0: 
The protocol has been amended to allow subjects to 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. 
1.2 Flowchart 
Deleted randomisation visit ”X” for 
hypo-reporting.  
Correction of error (hypo-reporting 
should follow AE reporting). 
2.3.1 Risk assessment 
Added a further COVID-19 related 
mitigation strategy. 
To provide guidance in case of 
COVID-19 related lock down of a site 
or country. 
5.2 Exclusion criteria 
A clarifying footnote has been added 
to exclusion criteria 4. 
To allow subjects to co-participate in 
clinical trials evaluating medicinal 
products for prevention or treatment 
of COVID-19 disease or 
postinfectious conditions. 
7.1 Discontinuation of trial treatment 
A clarifying footnote has been added 
to discontinuation criteria 4.  
To allow subjects to co-participate in 
clinical trials evaluating medicinal 
products for prevention or treatment 
of COVID-19 disease or 
postinfectious conditions without 
discontinuing trial product. 
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Section # and name 
Description of change 
Brief rationale 
6.3 Measures to minimise bias: 
Randomisation and blinding 
 
7.1 Discontinuation of trial treatment 
 
7.2 Subject 
discontinuation/withdrawal from the 
trial 
Updated wording to “treatment status 
session”. 
Correction of error. 
8.2 Safety assessments 
Deleted a sentence describing a 
disease specific form in the eCRF. 
The eCRF for medical history has 
changed to include the diagnosis of 
diabetes, thus the information is not 
applicable anymore. 
8.3 Adverse events (AEs) and serious 
adverse events (SAE) 
Footnote to table 8-1 inserted. 
To clarify that investigators should 
collect all cerebrovascular events even 
though the EAC will only be 
confirming stroke. 
8.3.1 Time period and frequency for 
collecting AE and SAE information 
Rephrasing a sentence in the first 
paragraph.  
Correction of an error and 
clarification. 
8.3.8 Adverse event of special interest A clarifying footnote has been added. To clarify Novo Nordisk definitions 
and processes about AE of special 
interest. 
8.5 Pharmacokinetics 
Rephrasing to: The date and exact 
clock time for blood sampling must be 
recorded. 
The date and exact clock time of the 
sampling must be recorded in the lab 
requisition form, not in the eCRF. 
8.5 Pharmacokinetics 
Sentence added in the first paragraph: 
“Samples from subjects in the insulin 
degludec arm will not be analysed”. 
Clarification. 
8.9.1 Anti-drug antibodies  
Sentence added in the first paragraph: 
“Samples from subjects in the insulin 
degludec arm will not be analysed”. 
Clarification. 
10.1.8.2 Monitoring 
Deleted “HCP web portal” and 
“eDiaries”. 
Monitors are not requested to perform 
source data verification in the HCP 
web portal. 
10.9 Appendix 9: Country/Region-
specific requirements 
Described that the footnotes to 
exclusion criteria 4 and to 
discontinuation criteria 4 are not 
applicable for China.  
To meet local Chinese Health 
Authority requirement. 
 
 
10.9 Appendix 9: Country/Region-
specific requirements 
Deleted China specific exclusion 
criteria 3 requirement. 
China will follow the global 
requirements on contraceptive 
methods in appendix 4. 
10.9 Appendix 9: Country/Region-
specific requirements 
Deleted USA specific eye 
examination requirement. 
USA will follow the global 
requirements for eye examination in 
section 8.2.5. 
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Section # and name 
Description of change 
Brief rationale 
10.11 Appendix 11: Protocol 
amendment history 
New appendix added. 
Log amendments and version history. 
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Table of Contents 
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 5 
1 
Protocol summary ..................................................................................................................................... 9 
1.1 
Synopsis ........................................................................................................................................... 9 
1.2 
Flowchart ....................................................................................................................................... 12 
1.3 
Flowchart – phone contacts ........................................................................................................... 15 
2 
Introduction ............................................................................................................................................. 16 
2.1 
Trial rationale ................................................................................................................................. 16 
2.2 
Background .................................................................................................................................... 17 
2.3 
Benefit-risk assessment .................................................................................................................. 18 
2.3.1 
Risk assessment ............................................................................................................... 18 
2.3.2 
Benefit assessment ........................................................................................................... 21 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 21 
3 
Objectives and endpoints ........................................................................................................................ 22 
3.1 
Primary, secondary and exploratory objective and estimand......................................................... 22 
3.1.1 
Primary objective ............................................................................................................. 22 
3.1.2 
Secondary objective ......................................................................................................... 22 
3.1.3 
Estimand .......................................................................................................................... 22 
3.2 
Primary, secondary and exploratory endpoints .............................................................................. 22 
3.2.1 
Primary endpoint ............................................................................................................. 22 
3.2.2 
Secondary endpoints ........................................................................................................ 22 
3.2.2.1 
Confirmatory secondary endpoints ................................................................. 22 
3.2.2.2 
Supportive secondary endpoints ..................................................................... 23 
3.2.3 
Exploratory endpoints ..................................................................................................... 23 
4 
Trial design .............................................................................................................................................. 23 
4.1 
Overall design ................................................................................................................................ 23 
4.2 
Scientific rationale for trial design ................................................................................................. 26 
4.2.1 
Subject input into design ................................................................................................. 27 
4.3 
Justification for dose ...................................................................................................................... 27 
4.4 
End of trial definition ..................................................................................................................... 28 
5 
Trial population ....................................................................................................................................... 28 
5.1 
Inclusion criteria ............................................................................................................................ 28 
5.2 
Exclusion criteria ........................................................................................................................... 29 
5.3 
Lifestyle considerations ................................................................................................................. 30 
5.3.1 
Meals and dietary restrictions .......................................................................................... 30 
5.3.2 
Caffeine, alcohol and tobacco ......................................................................................... 30 
5.3.3 
Physical activity............................................................................................................... 30 
5.4 
Screen failures ................................................................................................................................ 31 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria...................................................... 31 
6 
Treatments ............................................................................................................................................... 31 
6.1 
Treatments administered ................................................................................................................ 31 
6.1.1 
Medical devices ............................................................................................................... 33 
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6.1.1.1 
Investigational medical device ........................................................................ 33 
6.1.1.2 
Non-investigational medical devices .............................................................. 33 
6.2 
Preparation/handling/storage/accountability .................................................................................. 33 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 34 
6.4 
Treatment compliance .................................................................................................................... 35 
6.5 
Concomitant medication ................................................................................................................ 35 
6.5.1 
Rescue medication or Rescue therapy ............................................................................. 36 
6.6 
Dose modification .......................................................................................................................... 36 
6.6.1 
Dose escalation trials ....................................................................................................... 36 
6.7 
Treatment after end of trial ............................................................................................................ 36 
7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 37 
7.1 
Discontinuation of trial treatment .................................................................................................. 37 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 38 
7.1.2 
Rescue criteria ................................................................................................................. 38 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 39 
7.2.1 
Replacement of subjects .................................................................................................. 39 
7.3 
Lost to follow-up ........................................................................................................................... 39 
8 
Trial assessments and procedures ......................................................................................................... 40 
8.1 
Efficacy assessments ...................................................................................................................... 41 
8.1.1 
Self-measured plasma glucose (SMPG) .......................................................................... 41 
8.1.2 
Clinical efficacy laboratory assessments ......................................................................... 41 
8.2 
Safety assessments ......................................................................................................................... 41 
8.2.1 
Insulin dose ...................................................................................................................... 42 
8.2.2 
Physical examinations ..................................................................................................... 42 
8.2.3 
Vital signs ........................................................................................................................ 43 
8.2.4 
Electrocardiograms .......................................................................................................... 43 
8.2.5 
Eye examination .............................................................................................................. 44 
8.2.6 
Clinical safety laboratory assessments ............................................................................ 44 
8.3 
Adverse events and serious adverse events .................................................................................... 45 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 46 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 47 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 47 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 47 
8.3.5 
Pregnancy ........................................................................................................................ 47 
8.3.6 
Cardiovascular and death events ..................................................................................... 48 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE ................................................................................................................................. 48 
8.3.8 
Adverse event of special interesta .................................................................................... 48 
8.3.9 
Technical complaints ....................................................................................................... 48 
8.4 
Treatment of overdose ................................................................................................................... 48 
8.5 
Pharmacokinetics ........................................................................................................................... 49 
8.6 
Pharmacodynamics ........................................................................................................................ 49 
8.7 
Genetics ......................................................................................................................................... 49 
8.8 
Biomarkers ..................................................................................................................................... 49 
8.9 
Immunogenicity assessments ......................................................................................................... 50 
8.9.1 
Anti-drug antibodies ........................................................................................................ 50 
8.9.2 
Hypersensitivity ............................................................................................................... 50 
8.10 
Health economics ........................................................................................................................... 51 
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9 
Statistical considerations ........................................................................................................................ 51 
9.1 
Statistical hypotheses ..................................................................................................................... 51 
9.2 
Sample size determination ............................................................................................................. 52 
9.3 
Populations for analyses ................................................................................................................ 53 
9.4 
Statistical analyses ......................................................................................................................... 55 
9.4.1 
General considerations .................................................................................................... 55 
9.4.2 
Primary endpoint ............................................................................................................. 55 
9.4.3 
Secondary endpoints ........................................................................................................ 56 
9.4.3.1 
Confirmatory secondary endpoint ................................................................... 56 
9.4.3.2 
Supportive secondary endpoints ..................................................................... 56 
9.4.4 
Exploratory endpoints ..................................................................................................... 58 
9.4.5 
Other safety analyses ....................................................................................................... 58 
9.4.6 
Other analyses ................................................................................................................. 59 
9.4.6.1 
Pharmacokinetic modelling ............................................................................. 59 
9.5 
Interim analyses ............................................................................................................................. 59 
9.6 
Data monitoring committee ........................................................................................................... 60 
9.7 
Reporting of the main part of the trial............................................................................................ 60 
10 Supporting documentation and operational considerations ............................................................... 61 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 61 
10.1.1 
Regulatory and ethical considerations ............................................................................. 61 
10.1.2 
Financial disclosure ......................................................................................................... 61 
10.1.3 
Informed consent process ................................................................................................ 62 
10.1.4 
Information to subjects during trial ................................................................................. 62 
10.1.5 
Data protection ................................................................................................................ 62 
10.1.6 
Committees structure ....................................................................................................... 63 
10.1.6.1 Novo Nordisk safety committee...................................................................... 63 
10.1.6.2 Trial safety group ............................................................................................ 63 
10.1.6.3 Data monitoring committee............................................................................. 63 
10.1.6.4 Event adjudication committee ......................................................................... 63 
10.1.7 
Dissemination of clinical trial data .................................................................................. 63 
10.1.8 
Data quality assurance ..................................................................................................... 64 
10.1.8.1 Case report forms ............................................................................................ 64 
10.1.8.2 Monitoring ...................................................................................................... 65 
10.1.8.3 Protocol compliance ........................................................................................ 65 
10.1.9 
Source documents ............................................................................................................ 65 
10.1.10 Retention of clinical trial documentation ........................................................................ 66 
10.1.11 Trial and site closure ....................................................................................................... 66 
10.1.12 Responsibilities................................................................................................................ 67 
10.1.13 Indemnity statement ........................................................................................................ 68 
10.1.14 Publication policy ............................................................................................................ 68 
10.1.14.1 Communication of results ............................................................................... 68 
10.1.14.2 Authorship ....................................................................................................... 69 
10.1.14.3 Site-specific publication(s) by investigator(s)................................................. 69 
10.1.14.4 Investigator access to data and review of results ............................................ 69 
10.2 
Appendix 2: Clinical laboratory tests ............................................................................................ 70 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting ............................................................................................................................ 72 
10.3.1 
Definition of AE .............................................................................................................. 72 
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10.3.2 
Definition of an SAE ....................................................................................................... 73 
10.3.3 
Description of events for adjudication and AEs requiring additional data collection ..... 74 
10.3.4 
Recording and follow-up of AE and/or SAE ................................................................... 76 
10.3.5 
Reporting of SAEs ........................................................................................................... 78 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ............................ 80 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ................................................................................................................. 83 
10.5.1 
Definition of technical complaint .................................................................................... 83 
10.5.2 
Recording and follow-up of technical complaints ........................................................... 83 
10.5.3 
Reporting of technical complaints ................................................................................... 84 
10.6 
Appendix 6: Retention of human biosamples ................................................................................ 85 
10.7 
Appendix 7: Hypoglycaemic episodes ........................................................................................... 86 
10.8 
Appendix 8: Titration guideline ..................................................................................................... 88 
10.9 
Appendix 9: Country/Region-specific requirements ..................................................................... 92 
10.10 Appendix 10: Abbreviations .......................................................................................................... 97 
10.11 Appendix 11: Protocol amendment history ................................................................................... 99 
11 References .............................................................................................................................................. 100 
 
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 s.c. injection. 
The present trial is a 26-week trial designed to investigate the effect and safety of once weekly 
insulin icodec in comparison to once daily insulin degludec, both in combination with non-insulin 
anti-diabetic drugs in insulin-naïve subjects with type 2 diabetes (T2D). A double blinded, double 
dummy design is used in this trial to ensure collection of blinded safety data for insulin icodec in 
comparison to insulin degludec as well as to allow for an extension part should recruitment in China 
not meet its target in due time. 
Objectives and endpoints: 
Primary objective 
The objective of this trial is to demonstrate the effect on glycaemic control of once weekly insulin 
icodec in combination with non-insulin anti-diabetic drugs in insulin-naïve subjects with T2D. This 
includes comparing the difference in change from baseline in HbA1c between insulin icodec and 
insulin degludec after 26 weeks of treatment to a non-inferiority limit of 0.3%. 
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: 
initiation of bolus insulin treatment for more than 2 weeks, discontinuation of randomised insulin 
treatment, and withdrawal from the trial (measurements collected after these intercurrent events are 
used in the primary analysis). 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline week 0 (V2) to week 26 (V28) 
%-point 
 
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Overall design: 
This is a 26-week randomised, stratified, double blinded, double dummy, active-controlled, parallel-
group, multicentre, multiregional, treat-to-target trial with two treatment arms. 
Subjects will be randomised (1:1) to receive once weekly insulin icodec and once daily placebo or 
once weekly placebo and once daily insulin degludec. Randomisation will be stratified according to 
region (Asia, North America, South America, Europe) and treatment with Sulfonylureas or glinides 
(yes/no). 
Key inclusion criteria: 
1. Male or female aged above or equal to 18 years at the time of signing informed consent. 
2. Diagnosed with T2D ≥ 180 days prior to the day of screening. 
3. HbA1c from 7.0-11.0% (53.0-96.7 mmol/mol) both inclusive at screening confirmed by central 
laboratory analysis. 
4. Insulin naïve. However, short term insulin treatment for a maximum of 14 days prior to the day 
of screening is allowed, as is prior insulin treatment for gestational diabetes. 
5. Stable daily dose(s) ≥ 90 days prior to the day of screening of any of the following anti-diabetic 
drug(s) or combination regimen(s): 
a. Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose. 
b. Any metformin combination formulations ≥ 1500 mg or maximum tolerated or 
effective dose. 
c. Any of the following oral anti-diabetic drug classes including combinations (≥ half 
of the maximum approved dose according to local label or maximum tolerated or 
effective dose). 
• Sulfonylureas 
• Meglitinides (glinides) 
• DPP-4 inhibitors 
• SGLT2 inhibitors 
• Thiazolidinediones 
• Alpha-glucosidase inhibitors 
• Oral combination products (for the allowed individual Oral Anti-diabetic 
Drugs (OADs)) 
• Oral or injectable GLP-1-receptor agonists 
6. Body mass index (BMI) ≤ 40.0 kg/m2. 
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Key exclusion criteria: 
1. Any episodesa of diabetic ketoacidosis within 90 days prior to the day of screening. 
2. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
3. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at 
screening. 
4. 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). 
5. 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. 
a as declared by the subject or in the medical records.  
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 33 weeks, consisting of a 2-week screening period, followed by 
a 26-week randomised treatment period and a 5-week follow-up period. All subject will be centrally 
randomised in a 1:1 manner and assigned to receive once weekly insulin icodec and once daily 
placebo or once weekly placebo and once daily insulin degludec throughout the 26-week. 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/placebo, s.c., solution for injection, 3 mL PDS290 pre-filled pen-
injector 
• Insulin degludec 100 units/mL/placebo, s.c., solution for injection 3 mL PDS290 pre-filled pen-
injector. 
Data monitoring committee: No 
 
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1.2 
Flowchart 
Procedure 
Protocol 
section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Discontinuation 
Follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V8 
V12 
V16 
V20 
V24 
V28 
V29 
V30 
V28A 
Weekly Phone Contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
P6 
P7 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
 
 
 
 
Timing of visit (weeks) 
<-2 
0 
1 
2 
3 
6 
10 
14 
18 
22 
26 
28 
31 
26 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
+3 
±3 
Informed consent and 
demography 
10.1.3 
and 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 
 
 
 
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 
Vital signs 
8.2.3 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Physical examination 
8.2.2 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Body measurements 
8.2.2 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
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Procedure 
Protocol 
section 
Screening 
Randomisation 
Treatment 
Follow-up 1 
Follow-up 2 
Discontinuation 
Follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V8 
V12 
V16 
V20 
V24 
V28 
V29 
V30 
V28A 
Weekly Phone Contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
P6 
P7 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
 
 
 
 
Timing of visit (weeks) 
<-2 
0 
1 
2 
3 
6 
10 
14 
18 
22 
26 
28 
31 
26 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
+3 
±3 
Eye examination 
8.2.5 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECG 
8.2.4 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pregnancy test 
8.3.5 
App.4; 
10.4 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
Laboratory assessments 
App.2; 
10.2 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
  HbA1c  
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
Pop-PK 
8.5 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Antibodies 
8.9.1 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Self-measured plasma 
glucose 
8.1.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event 
8.3 
App. 3; 
10.3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypoglycaemic episodes 
App. 7; 
10.7 
 
 
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 
Discontinuation 
Follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V8 
V12 
V16 
V20 
V24 
V28 
V29 
V30 
V28A 
Weekly Phone Contact 
number (P) (For details see 
separate flow chart below) 
 
 
 
 
P6 
P7 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
 
 
 
 
Timing of visit (weeks) 
<-2 
0 
1 
2 
3 
6 
10 
14 
18 
22 
26 
28 
31 
26 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
+3 
±3 
Training in trial Product, Pen-
handling 
6.1 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
Drug dispensing 
6 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Hand out and instruct in 
devices 
6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
End of trial 
4.4 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
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1.3 
Flowchart – phone contacts  
Phone contacts during the treatment period (P) 
Time shown in site visit flow chart 
Protocol 
section 
P6-P27 
Visit window (days) 
 
±3 
Concomitant medication 
6.5 
X 
Self-measured plasma glucose 
8.1.1 
X 
Adverse event 
8.3 
App. 3; 
10.3 
X 
Hypoglycaemic episodes 
App. 7; 
10.7 
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.1 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.2  
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 persistence3 
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 a 26-week trial designed to investigate the effect and safety of once weekly 
insulin icodec in comparison to once daily insulin degludec 100 units/mL (referred to as insulin 
degludec in this document), both in combination with non-insulin anti-diabetic drugs in insulin-
naïve subjects with T2D. The double blinded, double dummy design is used in this trial to ensure 
collection of blinded safety data for insulin icodec in comparison to insulin degludec. 
This trial design also allows for an extension part, if recruitment in China does not meet its target of 
minimum 100 subjects in due time. Continued recruitment in China will lead to an extension for 
this trial. All the randomised subjects will be reported in the extension report (see Section 9.5). 
The long-acting basal insulin products currently approved for treatment of diabetes are usually 
administered once or twice daily. Development of compounds with prolonged action has in several 
treatment areas been demonstrated to improve subject compliance and treatment outcomes. The 
once weekly insulin icodec would be a more convenient basal insulin, with significantly fewer 
injections over time, which could improve treatment adherence3 and overcome insulin initiation 
barriers as compared to once or twice daily basal insulin for subjects with T2D. 
Overall, the results of the present trial will be important for evaluating the effect and safety 
parameters of insulin icodec in insulin naïve subjects and will be used to support the marketing 
authorisation approval of insulin icodec. The trial will also generate data on dosing flexibility. 
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2.2 
Background 
Diabetes mellitus  
T2D is characterised by insulin resistance, impaired insulin secretion, increased hepatic glucose 
output due to glucagon dysregulation resulting in chronic hyperglycaemia.4 The pathogenesis is not 
fully understood but seems to be heterogeneous, involving environmental, lifestyle, and genetic 
factors leading to chronic hyperglycaemia caused by peripheral tissue insulin resistance, impaired 
insulin secretion due to abnormal beta-cell function and abnormal glucose metabolism in the liver.5 
The current treatment cascade follows a stepwise approach comprising lifestyle changes in 
combination with pharmacological intervention. In many countries, metformin is recommended as 
initial pharmacological therapy, followed by combination therapy with other oral anti-diabetic drugs 
(OADs), glucagon-like peptide 1 receptor agonists (GLP-1 RA) and/or insulin as the disease 
progresses.6 On average, after failure of diet and exercise alone, patients require a new intervention 
with glucose-lowering agents every 3-4 years in order to obtain/retain good glycaemic control.7 
Clinical inertia, often resulting from a resistance to insulin initiation and intensification, is a major 
contributing factor to patients with T2D who are not achieving recommended glycaemic targets.8, 9 
Increased convenience is believed to support timely insulin initiation in the treatment for T2D and 
thereby overcoming the clinical inertia associated with insulin initiation. 
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 (s.c.) 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 
proteolytical 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 clinical pharmacology 
trials, NN1436-4314 [T2D], NN1436-4226 [renal impaired] and NN1436-4422 [T1D] have been 
completed. No unexpected safety concerns were identified. Two clinical pharmacology trials 
(NN1436-4462 [T2D] and NN1436-4225 [T1D]) are ongoing. 
Three phase 2 trials in subjects with T2D have recently been completed (NN1436-4465, NN1436-
4383 and NN1436-4466). Once weekly insulin icodec was shown to provide comparable glucose 
lowering effects and similar safety profile to insulin glargine in subjects with T2D. Results from 
these trials 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)10 and any updates hereof. 
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Insulin degludec  
For further details on insulin degludec, please refer to the current insulin degludec Investigator’s 
Brochure11, the current EMA summary of product characteristics (SmPC) for insulin degludec 
(Tresiba®)12, the U.S Prescribing Information (US PI)13, or any locally approved label. 
Trial population 
The trial population will consist of insulin naïve subjects with T2D. This population has been 
chosen to ensure that a broad T2D patient group is represented across the clinical development 
programme. 
Subjects with T1D are excluded from this trial. Subjects with T1D will be addressed in a dedicated 
trial. 
For more information on the trial population, see Sections 4.2, or the inclusion and exclusion 
criteria, Sections 5.1 and 5.2, respectively. 
2.3 
Benefit-risk assessment 
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 IB10. 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 
and SI-IC.  
Investigators and subjects will be instructed 
to monitor for injection site reactions at the 
place of injection for early detection. 
Investigators should ensure careful 
monitoring and medical evaluation in case 
of injection site reaction occurrence. The 
risk of injection site reactions is described in 
the IB10 and the SI-IC. 
For further information on injection site 
reactions, please refer to Section 8.9.2 and 
Appendix 3 (Section 10.3.3). 
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 
NN1436-4422.  
Known or suspected hypersensitivity to trial 
products 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 IB10 and SI-IC.   
For further information on hypersensitivity 
reactions, please refer to Sections 8.9.2 and 
10.3.3. 
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Potential risks:  
Antibody formation leading to 
changes in clinical effect 
Antibodies to exogenously 
delivered insulin 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. 
Blood samples will be taken for analysis of 
serum antibodies against insulin icodec at 
pre-first dose time point. Then at appropriate 
time points during the trial and at the end of 
trial visit. 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. There will be a close 
monitoring of the glycemic control on 
subject level during the trial. In case lack of 
clinical effect is observed, rescue medication 
will be provided 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 Sections 
8.9.2 and 10.3.3. 
Trial procedures 
Potential risk:  
COVID-19 infection in relation 
to participation in trial 
Patients 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 patient recruitment planning 
ensures controlled patient 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 patients 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. 
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Other 
For more information regarding 
the known and expected 
benefits and risk of insulin 
degludec, please refer to the 
insulin degludec IB11, the EMA 
SmPC12, the US PI13, or any 
locally approved label. 
 
 
 
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 daily to provide 24-hour coverage. Market research has shown that people with 
diabetes, put value in reducing the number of insulin injections14. 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 insulin naïve subjects with T2D. For all subjects participating in 
this 26-week trial, the anticipated benefits include improved glycaemic control. The titration 
algorithm Appendix 8 (Section 10.8), which specifies recommended adjustments of basal insulin 
dose at different plasma glucose levels, will be used to ensure that subjects receive optimal 
treatment. Subjects will receive intense medical care by means of contact with the sites weekly. 
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 potential 
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 IB10 and any updates hereof.  
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3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objective and estimand 
3.1.1 
Primary objective 
To demonstrate the effect on glycaemic control of once weekly insulin icodec in combination with 
non-insulin anti-diabetic drugs in insulin-naïve subjects with T2D. This includes comparing the 
difference in change from baseline in HbA1c between insulin icodec and insulin degludec after 26 
weeks of treatment to a non-inferiority limit of 0.3%. 
3.1.2 
Secondary objective 
To compare parameters of safety with once weekly insulin icodec versus once daily insulin 
degludec, both in combination with non-insulin anti-diabetic drugs in insulin-naïve subjects with 
T2D. 
3.1.3 
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: 
initiation of bolus insulin treatment for more than 2 weeks, 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 (V2) to week 26 (V28) 
%-point 
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoints 
Not applicable for this trial. 
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3.2.2.2 
Supportive secondary endpoints 
Secondary efficacy endpoint 
Endpoint title 
Time frame 
Unit 
Change in fasting plasma glucose 
(FPG)  
From baseline week 0 (V2) to week 26 (V28) 
mmol/L 
Secondary safety endpoints  
Endpoint title  
Time frame 
Unit 
Number of severe hypoglycaemic episodes (level 3) 
From baseline week 0 (V2) to week 31 (V30) 
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 (V2) to week 31 (V30) 
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 (V2) to week 31 (V30) 
Number of 
episodes 
Number of severe hypoglycaemic episodes (level 3) 
From baseline week 0 (V2) to week 26 (V28) 
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 (V2) to week 26 (V28) 
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 (V2) to week 26 (V28) 
Number of 
episodes 
Change in body weight 
From baseline week 0 (V2) to week 26 (V28) 
Kg 
Mean weekly insulin dose 
From week 24 (P26) to week 26 (V28) 
U 
3.2.3 
Exploratory endpoints 
Not applicable for this trial. 
4 
Trial design 
4.1 
Overall design 
This is a 26-week randomised, stratified, double blinded, double dummy, active-controlled, parallel-
group, multicentre, multiregional, treat-to-target trial with two treatment arms. The trial investigates 
the effect on glycaemic control and safety of treatment with once weekly insulin icodec compared 
to once daily insulin degludec, both in combination with non-insulin anti diabetic drugs, in insulin 
naïve subjects with inadequately controlled T2D on non-insulin anti-diabetic drugs in need for 
insulin initiation.   
The trial duration is approximately 33 weeks, consisting of a 2-week screening period, followed by 
a 26-week randomised treatment period and a 5-week follow-up period. 
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The overall trial design and visit schedule are outlined in Figure 4-1 and trial flowchart (see 
Section 1.2), respectively. 
 
Figure 4-1 
Trial design 
Subjects will be randomised (1:1) to receive once weekly insulin icodec + once daily placebo or 
once weekly placebo + once daily insulin degludec. The dose and dosing frequency of any pre-trial 
non-insulin anti-diabetic treatment should not be changed during the trial unless due to safety 
concerns; except for treatment with sulfonylureas (SU) and glinides that must be reduced by 
approximately 50% at randomisation at the discretion of the investigator. Randomisation will be 
stratified according to region (Asia, North America, South America, Europe) and treatment with SU 
or glinides (yes/no). During the 26-week treatment period, subjects will have contact with the site 
weekly either at site visits or by phone. The end of treatment visit (V28) will be one week after the 
last dose of insulin icodec/weekly placebo and on the day of or the day after the last dose of insulin 
degludec/daily placebo. Two follow-up visits (V29 and V30) will be performed 2 and 5 weeks, 
respectively, after the end of treatment visit. 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. 
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. 
All participating countries should recruit the subjects within the planned recruitment period. If 
China reaches the recruitment target of 100 Chinese subjects within the planned recruitment period 
the trial will have database lock (DBL) when global last subject last visit (LSLV) has been reached, 
thus all subjects will contribute to the primary endpoint analysis (Figure 4-2). 
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Figure 4-2 
If China reaches the recruitment target within the planned recruitment period 
all subjects contribute to the primary endpoint analysis 
An extension design will be applied to accommodate any recruitment delays in China beyond the 
planned recruitment target period. For this reason, the recruitment process in China will be 
monitored closely. If signs of delayed recruitment are identified, additional subjects will be 
recruited from other regions to ensure that a minimum of 580 subjects have been randomised at the 
end of the planned recruitment period. Chinese subjects that have been randomised within the 
planned recruitment period will contribute to the primary endpoint analysis (main reporting in 
Figure 4-3).  
The recruitment process will continue in China until a minimum of 100 Chinese subjects have been 
randomised. With the extension design the trial could include up to 680 subjects in total, if no 
Chinese subjects were randomised within the planned recruitment period. Chinese subjects 
randomised after the end of the planned recruitment period will not contribute to the primary 
endpoint analysis, but will be part of the extension reporting (Figure 4-3 and Section 9.4). 
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Figure 4-3 
Extension design to accommodate if China misses the recruitment target of 100 
subjects within the planned recruitment period 
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 during 26 weeks of treatment. 
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. 
To minimise bias a double blinded, double dummy design has been chosen. Subjects in the active 
arm will thus receive one insulin icodec and seven placebo injections each week, while subjects in 
the comparator arm will receive one placebo and seven insulin degludec injections each week. 
Stratification according to region and SU or glinide use will be performed to ensure equal 
distribution in the two treatment arms. 
During the 26 weeks long treatment period, the subjects will have weekly contact with the site, 
either as site visits or phone contacts. The treatment duration of 26 weeks is evaluated to be 
adequate time for assessing effect on glycaemic control and safety. This duration will also allow for 
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up-titrating the basal insulin. 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 in the period. 
The end of trial visit is planned six weeks after the last weekly dose of insulin icodec/placebo, 
allowing enough time for wash-out of trial drug, following at least five half-lives of insulin icodec. 
The primary target population for treatment with once weekly insulin icodec is expected to be 
subjects with T2D. Once weekly treatment with insulin icodec may facilitate earlier initiation of 
insulin treatment in subjects who need treatment intensification and hence insulin-naïve T2D 
subjects with non-insulin anti-diabetic drugs are the target population for this trail. The HbA1c limits 
of 7.0-11.0% (53.0-96.7 mmol/mol) have been chosen to include subjects needing intensification of 
their anti-diabetic treatment. The defined inclusion and exclusion criteria will limit the trial 
population to subjects not suffering from advanced underlying diseases other than T2D and related 
diseases. This is to avoid compromising the safety of the subjects participating in the trial and to 
strengthen conclusions regarding the effect and safety properties of once weekly insulin icodec. 
Overall, the eligibility criteria will allow for enrolment of a representative broad trial population 
resembling the primary target population. 
A sufficient assay-sensitivity for the non-inferiority evaluation will be ensured 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 
At randomisation eligible subjects are randomised to receive either: 
• once weekly insulin icodec + once daily placebo 
  OR 
• once weekly placebo + once daily insulin degludec 
Insulin degludec will be initiated at 10 units daily, while insulin icodec will be initiated at 70 units 
once weekly. One unit of insulin icodec has similar glucose lowering effect to one unit of insulin 
degludec, and therefore once weekly dosing corresponds to seven times the daily dose of the once 
daily comparator. 
The PK/PD properties of insulin icodec following five weeks of once weekly dosing in subjects 
with T2D (trial NN1436-4314) showed that insulin icodec exposure was well distributed across the 
dosing interval, with a PK profile suitable for once weekly dosing. Insulin icodec was well tolerated 
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in subjects with T2D and no unexpected safety concerns were identified after multiple once weekly 
dosing in the dose range of 12−24 nmol/kg (2-4 units/Kg). 
After randomisation, subjects should start once daily and once weekly injections on the same day. 
Due to the longer half-life of insulin icodec, the last dose of once weekly insulin/placebo will be 
administered 25 weeks after randomisation while the last dose of once daily insulin/placebo will be 
administered 26 weeks after randomisation. The follow-up period will be the 5 weeks from end of 
treatment (V28) until end of trial (V30). 
The treat-to-target approach is applied in both treatment arms to optimise titration and glycaemic 
control throughout the trial. After randomisation the insulin and placebo doses will be adjusted once 
weekly by the investigator in connection with the scheduled visit/phone contacts. 
Further details on dose adjustment can be found in the titration guideline 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 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. 
3. Age above or equal to 18 years at the time of signing informed consent. 
4. Diagnosed with T2D ≥ 180 days prior to the day of screening. 
5. HbA1c from 7.0-11.0% (53.0-96.7 mmol/mol) both inclusive at screening confirmed by 
central laboratory analysis. 
6. Insulin naïve. However, short term insulin treatment for a maximum of 14 days prior to the 
day of screening is allowed, as is prior insulin treatment for gestational diabetes. 
7. Stable daily dose(s) ≥ 90 days prior to the day of screening of any of the following anti-
diabetic drug(s) or combination regimen(s): 
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a. Any metformin formulations ≥ 1500 mg or maximum tolerated or effective dose. 
b. Any metformin combination formulations ≥ 1500 mg or maximum tolerated or 
effective dose. 
c. Any of the following oral anti-diabetic drug classes including combinations (≥ half 
of the maximum approved dose according to local label or maximum tolerated or 
effective dose): 
• Sulfonylureas 
• Meglitinides (glinides) 
• DPP-4 inhibitors 
• SGLT2 inhibitors 
• Thiazolidinediones 
• Alpha-glucosidase inhibitors 
• Oral combination products (for the allowed individual Oral Anti-diabetic 
Drugs (OADs)) 
• Oral or injectable GLP-1-receptor agonists 
8. Body mass index (BMI) ≤ 40.0 kg/m2. 
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 type 2 diabetes mellitus, which in the 
investigator’s opinion might jeopardise subject’s safety or compliance with the protocol. 
6. Any episodesb of diabetic ketoacidosis within 90 days prior to the day of screening. 
7. Myocardial infarction, stroke, hospitalisation 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 eGFR < 30 
ml/min/1.73m2 at screening15 by central laboratory analysis. 
11. Impaired liver function, defined as Alanine Aminotransferase (ALT) ≥ 2.5 times or 
Bilirubin >1.5 times upper normal limit at screening by central laboratory analysis. 
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12. Inadequately treated blood pressure defined as systolic ≥180 mmHg or diastolic ≥110 
mmHg at screening. 
13. Treatment with any medication for the indication of diabetes or obesity other than stated in 
the inclusion criteria within 90 days prior to the day of screening. However, short term 
insulin treatment for a maximum of 14 days and prior insulin treatment for gestational 
diabetes are allowed. 
14. Anticipated initiation or change in concomitant medications (for more than 14 consecutive 
days) known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid 
hormones, or corticosteroids). 
15. 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. Anticipated change in lifestyle affecting glucose control. 
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. 
b as declared by the subject or in the medical records.  
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
The subjects should be fasting when attending some of the visits, see flowchart (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 the fasting visit until blood sampling have 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 rescheduled. 
5.3.2 
Caffeine, alcohol and tobacco 
Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
5.3.3 
Physical activity 
Not applicable for this trial. 
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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. 
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 
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: 
Insulin icodec  
700 units/mL 
(IMP, test product) 
Weekly placebo  
Insulin degludec 
100 units/mL 
(IMP, reference 
therapy) 
Daily placebo  
Dosage form 
Solution for injection 
Solution for injection Solution for injection 
Solution for injection 
Route of 
administration  
Subcutaneous (into 
the left thigh) 
Subcutaneous (into 
the left thigh) 
Subcutaneous (into the 
right thigh)   
Subcutaneous (into the 
right thigh)   
Recommended 
initial dose 
Initial dose 70 units 
Please refer to 
Appendix 8, 10.8 
Initial dose 70 units 
Please refer to 
Appendix 8, 10.8 
Initial dose 10 units.  
Please refer to 
Appendix 8, 10.8 
Initial dose 10 units. 
Please refer to 
Appendix 8, 10.8 
Dosing 
instructions 
Administer insulin 
icodec once weekly, 
on the same day each 
week, at any time of 
the day. The day of 
the weekly 
administration can be 
changed if necessary, 
by up to 3 days. A 
minimum of 4 days 
between injections 
should always be 
ensured. Rotation of 
injection site on the 
left thigh is 
recommended.  
Administer placebo 
once weekly, on the 
same day of the week, 
at any time of the 
day. The day of 
weekly administration 
can be changed if 
necessary, by up to 3 
days. A minimum of 
4 days between 
injections should 
always be ensured. 
Rotation of injection 
site on the left thigh is 
recommended.  
 
Administer insulin 
degludec once daily at 
any time of the day, but 
at the same time every 
day throughout the trial. 
Rotation of injection site 
on the right thigh is 
recommended.  
Administer placebo 
once daily at any time 
of the day, but at the 
same time every day 
throughout the trial. 
Rotation of injection 
site on the right thigh is 
recommended.  
Packaging 
 
3 mL PDS290 
pre-filled pen-injector 
 
3 mL PDS290 
pre-filled pen-injector 
3 mL PDS290 pre-filled 
pen-injector 
3 mL PDS290 pre-filled 
pen-injector 
• At randomisation visit (V2) subjects should administer trial drug 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) 
After randomisation subjects should continue their pre-trial non-insulin anti-diabetic background 
medication throughout the entire trial except for sulfonylureas and glinides, which should be 
reduced at randomisation by approximately 50% at the discretion of the investigator. The 
background medication should be maintained at the stable, pre-trial dose and at the same frequency 
during the entire treatment period unless due to safety concerns.  
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In addition, the background medication: 
• is considered to be non-investigational medicinal product (NIMP) 
• will not be provided by Novo Nordisk A/S and should be purchased or otherwise delivered 
to subjects in accordance with local health plans 
• should be used in accordance with standard of care or local label in the individual country at 
the discretion of the investigator. 
Auxiliary supplies 
Auxiliary supplies comprise supplies other than trial products. Auxiliary supplies will be provided 
in accordance with the trial materials manual, please see Table 6-2. 
Table 6-2 
Auxiliary supplies 
Auxiliary supply 
Details  
Needles 
Needles for pre-filled pen injectors.   
Only needles provided and approved by Novo Nordisk must be used for administration 
of trial product. 
Blood glucose (BG) 
meter  
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 Accu-Chek® Guide  
eDiary 
Subject Mobile App, HCP Web Portal, & Cloud Service 
Please refer to the eDiary site guide.  
• Information about the PDS290 pre-filled pen-injector can be found in the directions for use 
(DFU) provided in the eDiary. 
• A pen differentiation guide will be provided. 
• Training in the pen-injectors is the responsibility of the investigator or a delegate and must be 
repeated during the trial at regular intervals, as specified in the flowchart (Section 1.2) in order 
to ensure correct use of the pen-injector. 
6.1.1 
Medical devices 
6.1.1.1 
Investigational medical device 
Not applicable for this trial. 
6.1.1.2 
Non-investigational medical devices 
Non-investigational medical devices are listed in Section 6.1 as auxiliary supplies (Table 6-2). 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply trial product. 
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• 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 Material Manual (TMM) and trial 
product label. 
• Each site will be supplied with sufficient trial product 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 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. 
• 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 a double dummy, double blinded trial 
• The following trial products will be packed blinded and are visually identical: 
o Once weekly insulin icodec or once weekly placebo, 3 mL PDS290 pre-filled 
pen-injector 
o Once daily insulin degludec or once daily placebo, 3 mL PDS290 pre-filled 
pen-injector 
• All subjects will be centrally screened and randomised using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Trial product will be 
dispensed/allocated at the trial visits summarised in the flowchart (see Section 1.2). 
• Randomisation will be stratified according to region (Asia, North America, South America, 
Europe) and treatment with Sulfonylureas (SU) or glinides (yes/no) 
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• The IWRS is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a subjects’ treatment is warranted. Subject 
safety must always be the first consideration in making such a determination. 
• If the investigator decides that unblinding is warranted, the investigator should make every 
effort to contact Novo Nordisk prior to unblinding a subjects’ treatment unless this could delay 
emergency treatment of the subject. If a subject’s treatment is unblinded, Novo Nordisk 
(Global Safety department) must be notified within 24 hours after breaking the blind. 
• The date and reason that the blind was broken must be recorded in the source documentation. 
The person breaking the blind must print the “code break confirmation” notification generated 
by the IWRS, sign and date the document. If IWRS is not accessible at the time of blind break, 
the IWRS helpdesk should be contacted. Contact details are listed in Attachment I. 
• The subject must discontinue treatment with trial product, and a treatment status session must 
be completed in IWRS. 
• The laboratory responsible for pharmacokinetics and antibody analysis and the responsible 
development bioanalysis scientist in Novo Nordisk will have access to the treatment 
allocation. 
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 patient, 
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 (V30) must be recorded along with: 
• Generic name or trade name 
• Indication 
• Dates of administration including start and stop date. 
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Concomitant medication (diabetes) 
Any anti-diabetic medication other than the trial product that the subject receives from screening 
(V1) until end of trial visit (V30) must be recorded in a separate concomitant medication (diabetes) 
form in the eCRF. 
The following information must be recorded for oral antidiabetic drug (OADs), GLP-1 RAs, and 
insulin products including 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 (V28) only randomised treatment (trial products and pre-trial non-insulin 
anti-diabetic background medication) are allowed, unless due to safety reasons at the discretion of 
the investigator. If the investigator chooses to initiate anti-diabetic medication or change dose of 
pre-trial anti-diabetic background medication prior to end of treatment (V28), 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 AE, 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. 
6.5.1 
Rescue medication or Rescue therapy 
Not applicable for this trial. 
6.6 
Dose modification 
Doses are adjusted according to blood/plasma glucose values as described in Appendix 8 
(Section 10.8). 
6.6.1 
Dose escalation trials  
Not applicable for this trial. 
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. If the switch to post-trial treatment includes a new insulin 
treatment, please refer to the titration guideline in Appendix 8 (Section 10.8). 
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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 (V28) as soon as possible to collect the required data for the analysis of the primary endpoint. 
Two follow-up visits, V29 and V30, must be performed after discontinuation of the trial product. 
Visits V29 and V30 must be conducted 3 and 6 weeks respectively after discontinuation of once 
weekly insulin icodec/weekly placebo. It is stressed that the visit window is plus 3 days for both 
visits V29 and V30. 
Further, it is important that discontinued subjects come in for discontinuation follow-up visit V28A, 
26 weeks after the randomisation visit. V28A will be the last visit for discontinued subjects. 
The investigator should change subject status in the HCP web portal to ‘Follow-up’ at the end of 
treatment visit to ensure that the subject should no longer report insulin dose.  
Subjects who prematurely discontinue trial product should keep and use the eDiary, and return it at 
the follow-up 2 visit (V30). 
Continue to collect, record and report AEs as described in Section 8.3. AEs and anti-diabetic 
medication should be collected and recorded in the eCRF until the discontinuation follow-up visit 
(V28A) 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 (V28A). 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 
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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 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 (FPG) 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. 
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. 
Subjects that are randomised in violation of inclusion and exclusion criteria can be allowed to 
continue in the trial and receive trial product if there are no safety concerns as evaluated by the 
investigator and Novo Nordisk medical specialist. 
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. 
7.1.2 
Rescue criteria 
Not applicable for this trial. 
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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 the end of treatment visit (V28). 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 eCRF. 
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’. 
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8 
Trial assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart (Section 1.2). 
• Informed consent must be obtained before any trial related activity, see 
Appendix 1 (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 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 The Investigator should create a subject profile and record administrative 
information (e.g. subject ID, year of birth and gender 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 eDiary, ECG, 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. 
• Source data of clinical assessments performed and recorded in the eCRF must be available and 
will usually be in the subject’s medical records. Additional recording to be considered source 
data includes, but is not limited to; laboratory reports, BG meter. 
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• 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 (SMPG) 
Subjects will be provided with a blood glucose 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 the plasma glucose measurements 
required in the protocol, as described in the flowchart (Section 1.2). 
A baseline SMPG value, in fasting condition, should be collected using the BG meter at V2. 
Pre-breakfast daily SMPG  
Subjects should be instructed to measure their pre-breakfast SMPG daily from week 0 (V2) to end 
of trial (V30) and to 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 (CTR). All data will be 
stored by Novo Nordisk (see Appendix 1, Section 10.1). 
8.1.2 
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 (Section 1.2) and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart (Section 1.2). 
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. 
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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. 
8.2.1 
Insulin dose  
The prescribed insulin doses will be determined by the investigator in accordance with the titration 
guideline (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/placebo and once daily insulin/placebo in the eDiary. In the follow-up 
period if the subject switches to a new basal insulin, the subject should also report date, dose and 
time of the new basal 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 
• 
First and last dose of trial product 
For dosing of anti-diabetic medication prescribed in the follow-up period please see Section 6.5. 
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 AE (Appendix 4, Section 10.4). 
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Body measurements (e.g. height and weight) will also be measured and recorded 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) at screening visit (V1) 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, cell 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 at screening (V1), V16 and end of treatment (V28) 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, cell 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. 
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• 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 AE 
(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 
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 (V28) 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 AE, 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 flowchart (Section 1.2) and laboratory manual. 
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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. 
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. 
Some AEs require additional data collection on a specific event form. This always includes 
medication, misuse and abuse of IMP. The relevant events are listed below in Table 8-1, together 
with events for adjudication. 
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 filled in. 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 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). 
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 (MI) or unstable angina pectoris 
requiring hospitalisation) 
 
X 
Cerebrovascular eventsa (stroke or transient 
ischemic attack) 
 
X 
Heart failure (requiring hospitalisation or urgent 
heart failure visit) 
 
X 
Death 
 
X 
Hypersensitivity 
X 
 
Injection Site Reaction 
X 
 
a All cerebrovascular events are to be reported and sent for adjudication, however the EAC 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). 
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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 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.  
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 anonymisation 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 (Section 1.2). For subjects discontinuing trial product 
prematurely AEs must be collected until the discontinuation follow-up visit (V28A). 
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 
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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 
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 IB 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 new-born infant is one month of age. 
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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 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE 
Not applicable for this trial. 
8.3.8 
Adverse event of special interesta 
Not applicable for this trial. 
a Adverse events of special interest are, as per Novo Nordisk definitions and processes, required to have expedited 
reporting by the investigators. Only adverse events fulfilling the seriousness criteria are considered for expedited 
reporting in this trial. 
8.3.9 
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 s.c. by a trained person, or by glucose 
given i.v. by a medical professional. Glucose must also be given i.v., if the patient dose not 
respond to glucagon within 10-15 minutes. If the patient has been unconscious, 
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administration of oral carbohydrates is recommended for the subject upon regaining 
consciousness, in order to prevent a relapse. 
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, also consult the current version of the insulin icodec IB10 or 
insulin degludec IB11. 
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). The date and exact clock time 
for blood sampling must be recorded. Samples from subjects in the insulin degludec arm will not be 
analysed. 
Bioanalysis of insulin icodec samples will be performed at a special laboratory using a validated 
Luminescent Oxygen Channelling Immunoassay (LOCI). 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 CTR.  
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. 
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8.9 
Immunogenicity assessments 
8.9.1 
Anti-drug antibodies 
Anti-drug antibody (ADA) samples will be collected according to the flowchart (Section 1.2). 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 icodec (anti-drug antibodies) in 
serum will be performed at a Novo Nordisk A/S appointed laboratory. Samples from subjects in the 
insulin degludec arm will not be analysed. For details on blood sampling, serum preparation and 
storage, please refer to the laboratory manual.  
Analysis for ADA will be done as listed in flowchart with a binding ADA 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 ADA 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 (LSLV). Results from the binding ADA 
analyses from visit randomisation (V2), V4, V8, V12, V20, end of treatment (V28) and end of trial 
visit (V30) 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. In the event of a systemic hypersensitivity (not locally at the injection site), the 
patient 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. 
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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 
CTR. 
If the reaction is classified as a SAE, the results from the hypersensitivity tests will also be reported 
to Novo Nordisk Safety Operations for inclusion in the ARGUS database and included in the 
narratives of the CTR. 
For retention of residual hypersensitivity samples, please refer to Section 10.6. 
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 in the FDA 
guidance for industry on developing drugs for treatment of diabetes.16 Also, this margin is 
considered to provide sufficient assay sensitivity based on the below considerations: 
• The margin does not represent an unacceptable loss of efficacy with insulin icodec relative to 
treatment with a basal insulin analogue 
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• It represents less than 50% of a suitably conservative estimate of insulin glargine’s treatment 
effect on HbA1c in a placebo-controlled trial (-0.85%-point [-1.04; -0.66]95%CI versus placebo) 
in insulin-naïve subjects, which demonstrated insulin glargine’s superiority.17 
• Other basal insulin analogues have previously been shown to yield similar reductions in HbA1c 
compared to insulin glargine. As only insulin glargine (not insulin degludec) has been 
compared to placebo in previous trials, the above-mentioned insulin glargine results are used 
as reference for consideration of the margin. 
The following describe the secondary confirmatory hypothesis. In order to control the overall Type 
I error at a 5% level, two sided, a hierarchical testing procedure will be used. If non-inferiority (NI) 
in glycaemic control is concluded in the primary analysis, confirmatory testing proceeds to the 
following hypothesis: 
• Insulin icodec is superior to insulin degludec in terms of change from baseline to week 26 in 
HbA1c 
Formally, let D be the mean treatment difference ‘insulin icodec’ minus ‘insulin degludec’ of the 
change in HbA1c from baseline to week 26. The null-hypothesis of insulin icodec not superior will 
be tested against the alternative hypothesis of superiority as given by 
H0: D≥0% against HA: D<0% 
9.2 
Sample size determination  
The sample size is determined in order to have 90% power for declaring non-inferiority 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). 
Based on a recent double blinded study with basal insulin analogues in subjects with T2D 
(NN1250-3998) the percent experiencing any of the intercurrent events specified during 6 months is 
expected to be 10%. 
It is assumed that there is no difference in HbA1c between the treatment arms for subjects 
completing randomised treatment without initiation of bolus insulin treatment for more than 2 
weeks and a treatment difference of 0.3%-point in favour of the comparator for subjects either 
discontinuing treatment prematurely, initiating bolus insulin for more than 2 weeks 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 insulin naïve T2D subjects (trials NN1250-3579, NN1250-3643 and NN1250-3672). 
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From the above assumptions and requirements, 580 subjects will be randomly assigned 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. If the trial is extended with 100 Chinese 
subjects, then a maximum of approximately 904 subjects need to be screened. 
This sample size appears to be reasonable also under deviations from the assumed treatment 
difference as illustrated in the table below displaying power for various alternative treatment 
differences and standard deviations. 
For the hypothesis of superiority of insulin icodec compared to insulin degludec in terms of change 
from baseline to week 26 in HbA1c there will be 50% marginal power and also 50% combined 
power to detect if the true treatment difference in HbA1c is 0.18%-point with the sample size of 580. 
Table 9-1 
Power for various treatment differences and standard deviations. 
SD  
(%-point) 
 
 
0.015 
Treatment difference 
(%-point) 
0.03 
 
 
0.045 
0.9 
97% 
95% 
93% 
1.0 
93% 
90% 
87% 
1.1 
88% 
84% 
80% 
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  
Full analysis set (FAS): All subjects randomised excluding the Chinese 
extension cohort. Subjects will be analysed according to the randomised 
treatment.  
Safety analysis set 
All subjects randomly assigned to trial treatment excluding the Chinese 
extension cohort and who take at least 1 dose of trial product. Subjects are 
analysed according to the treatment they actually received.  
Chinese extension cohort 
All Chinese subjects randomised after the respective planned recruitment period. 
Extended full analysis set 
Extended full analysis set (EFAS): All subjects randomised including the 
Chinese extension cohort.  Subjects will be analysed according to the 
randomised treatment.  
Extended safety analysis set 
Extended safety analysis set (ESAS): All subjects randomly assigned to trial 
treatment including the Chinese extension cohort and who take at least 1 dose of 
trial product. Subjects are analysed according to the treatment they actually 
received.  
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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 (CTR). 
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. 
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 (V30) 
• 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. 
All efficacy endpoints will be summarised and analysed using the full analysis set (FAS) and the 
‘in-trial’ period. Safety endpoints will be evaluated using the on-treatment period with descriptive 
statistics being based on the safety analysis set (SAS) and statistical analyses being based on the 
FAS unless otherwise specified. 
If China does not reach recruitment target of 100 Chinese subjects within the planned recruitment 
period all efficacy endpoints will in addition be summarised and analysed using the extended full 
analysis set (EFAS) and the ‘in-trial’ period, and safety endpoints will be evaluated using the on-
treatment period with descriptive statistics being based on the extended safety analysis set (ESAS) 
and statistical analyses being based on the EFAS unless otherwise specified. These results will be 
presented in the extension part report. 
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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. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and secondary endpoints. 
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  
• Region: Asia, Europe, North America, South America, 
• SU or glinide use: yes, no 
The regions will be defined as follows:  
• Asia: China, Taiwan 
• Europe: Austria, Denmark, France, Czech Republic 
• North America: Canada, United States 
• South America: Argentina, Brazil, Mexico 
The last available assessment made prior to the first dose will be used as the baseline value. 
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 or initiating bolus insulin treatment for more than 
2 weeks. Missing HbA1c at the week 26 visit (regardless of treatment completion status) will be 
imputed from trial participants, who have discontinued their randomised treatment or initiated bolus 
insulin treatment for more than 2 weeks 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 who discontinued their randomised treatment or initiated bolus insulin 
treatment for more than 2 weeks at any time prior to the week 26 visit and have an HbA1c 
measurement at the week 26 visit, the change in HbA1c from last available planned on-
treatment without initiation of more than 2 weeks bolus insulin treatment (LAOT-WOB) value 
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to the week 26 visit will be analysed for each dataset copy using an analysis of covariance 
(ANCOVA) model with randomised treatment as fixed factor and LAOT-WOB 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-WOB 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, SU or glinide use (yes/no), and randomised treatment as fixed factors, and 
baseline HbA1c 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.18 
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinue randomised treatment or initiate bolus insulin treatment for more than 2 
weeks. 
If non-inferiority is confirmed, i.e. if the 95% CI is strictly below 0.3%, then the primary endpoint 
will further be tested for superiority. Superiority for change in HbA1c will be considered confirmed 
if the 95% CI is strictly below zero. 
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 
Confirmatory secondary endpoint 
Not applicable for this trial. 
9.4.3.2 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
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Efficacy endpoint 
Change in fasting plasma glucose (FPG) from week 0 (V2) to week 26 (V28) 
Missing FPG values at the week 26 visit (regardless of treatment completion status) will be imputed 
from trial participants who are from the insulin degludec group, and who have completed and 
adhered to their randomised insulin treatment without  initiation of bolus insulin treatment for more 
than 2 weeks at any time prior to the week 26 visit – i.e., data will be imputed based on the 
assumption that subjects with missing endpoint data will behave like subjects completing insulin 
degludec treatment without initiation of bolus insulin treatment for more than 2 weeks at any time 
prior to the week 26 visit. Specifically, the imputations and analyses will be carried out as follows: 
• First, one thousand (1000) copies of the dataset will be generated for FPG. 
• Second, for each dataset copy, an analysis of covariance (ANCOVA) model with a baseline 
value as a covariate will be fitted to FPG values for subjects who completed their randomised 
treatment without initiation of bolus insulin treatment for more than 2 weeks at any time prior 
to the week 26 visit 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, SU or glinide use (yes/no), and randomised treatment as fixed factors, and a 
baseline 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. 
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 week 0 (V2) to week 31 (V30) 
• 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 31 (V30) 
• 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 31 (V30) 
• Number of severe hypoglycaemic episodes (level 3) from 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 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 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 discontinuation to planned end of the on-treatment period) will be imputed using a 
multiple imputation technique, assuming that the event rate pre discontinuation follows the 
respective treatment groups rate whilst post discontinuation event rate is the rate of the insulin 
degludec 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, 
SU or glinide use (yes/no), and randomised treatment as fixed factors and the logarithm of the 
on-treatment period as offset. 
• Second, based on the estimated parameters for the insulin degludec 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 
standard deviations for the 1000 data sets will be pooled to one estimate and associated 
standard deviation using Rubin’s rule. 
For the definition and classification of hypoglycaemic episodes refer to Appendix 7 (Section 10.7). 
Mean weekly insulin dose from week 24 (P26) to week 26 (V28) 
Mean weekly insulin dose during the last 2 weeks of treatment (from week 24 to 26) will be log-
transformed and analysed without a baseline value as a covariate, but otherwise using the same 
statistical model as specified for change in FPG.  
Change in body weight from 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. 
For details on analyses of additional supportive secondary endpoints, please refer to the SAP. 
9.4.4 
Exploratory endpoints 
Not applicable for this trial. 
9.4.5 
Other safety analyses 
All safety analyses will be made on the safety analysis set and the extension safety analysis set 
(ESAS), if applicable. The standard safety assessments (SAEs, AEs, safety laboratory parameters, 
vital signs, etc.) will be reported descriptively based on 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. 
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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/S. A more technical and detailed elaboration of the population PK analysis will be given 
in a modelling analysis plan (MAP), which will be prepared before DBL. 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 MAP. 
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 potential split of the trial into a 
main and an extension part offers the opportunity of reporting results before LSLV. Main part is 
defined to end at time of LSLV for subjects recruited within the planned recruitment period. The 
main part analysis will include a minimum of 580 randomised subjects and will include data from 
all non-Chinese subjects and data from Chinese subjects that have been recruited within the planned 
recruitment period and have achieved end of trial. No data from the remaining Chinese subjects will 
be included in the main part evaluation and the randomisation code for these subjects will not be 
revealed at time of DBL for the main part. So, blinding of randomised treatment for these subjects 
will be maintained ensuring that trial integrity is preserved. 
If 100 Chinese subjects cannot be recruited within the planned recruitment period, there will also be 
an extension part of the trial. The extension part will include all randomised subjects and is defined 
to end at the time of LSLV for the entire Chinese cohort. A second reporting of the trial based on 
the extension part will take place when LSLV for the entire Chinese cohort has been reached.  
Confirmation of glycaemic control of insulin icodec will be based on the results from the analysis of 
the main part of the trial. The data from the extension part will be considered supportive only and is 
intended for the Chinese NDA. 
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The type 1 error rate will be maintained at 5%, as no statistical inference from the entire trial 
population will be drawn at the time of the extension part analysis. 
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. In case 100 Chinese subjects cannot be recruited 
within the planned recruitment period 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 
Helsinki19 and applicable ICH Good Clinical Practice (GCP) Guideline20. 
• Applicable laws and regulations. 
• The protocol, informed consent form, IB (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. 
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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. 
• 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 guidelines20, Declaration of Helsinki19 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 
Novo Nordisk offers a communication package for the subject during the conduct of the trial. The 
communication package contains written information which 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. 
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• 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. 
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 
Not applicable for this trial. 
10.1.6.3 
Data monitoring committee 
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)21, the Food and Drug Administration Amendment 
Act (FDAAA)22, European Commission Requirements23-25 and other relevant recommendations or 
regulations. If a subject request 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 
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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 + 26 weeks corresponding to visit V28. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed visit 
V28. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
FDAAA. 
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 (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: 
o Pregnancy forms 
• The following will be provided as paper CRFs to be used when access to the eCRF is revoked 
or the eCRF is temporarily unavailable: 
o AE forms 
o Safety information forms 
o 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. 
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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 eCRF 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. 
• 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 eCRF. 
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 eCRF 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 transferred directly into the database and will be considered source 
data: 
• For e.g. eDiary, data in the service providers’ database is considered source data. 
• 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. 
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• 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 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. 
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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 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
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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. 
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. 
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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.26 
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, except the 
following:  
o 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.  
o 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  
(V2, V12, V20, V28) 
• Fasting plasma glucose (FPG)1  
• HbA1c (also at V1 and V28A) 
NOTE: 
1An 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) 
• Erythrocytes  
• Haematocrit  
• Haemoglobin  
• Leucocytes  
• Thrombocytes  
• Basophils   
• Eosinophils  
• Lymphocytes  
• Monocytes 
• Neutrophils 
Biochemistry1  
(V1, V12, V28) 
• Alanine Aminotransferase (ALT) 
• Albumin 
• Alkaline phosphatase 
• Aspartate Aminotransferase (AST) 
• Creatinine 
• Potassium 
• Sodium 
• Total bilirubin 
Lipids 
(V2, V12, V28) 
• Cholesterol 
• High density lipoprotein (HDL) cholesterol 
• Low density lipoprotein (LDL) cholesterol 
• Triglycerides 
• Free fatty acids 
Pregnancy Testing 
(V2, V28, V30) 
• Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2 
Other tests 
 
• eGFR calculated by the central laboratory based on the creatinine value using the 
CKD-EPI equation, eGFR 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, V30) 
• insulin-icodec serum concentration (V4, V8, V12, V20, V28, V30) 
Notes: 
1Details of required actions for increased liver parameters are given in Section 10.3 (Hy’s Law). 
2Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
Laboratory/analyte results that could unblind the trial (e.g. antibodies) will not be reported to the 
sites until the trial has been unblinded.  
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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 unfavourable 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. 
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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 
a) 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. 
b) 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 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.  
c) 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 
d) 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) 
 
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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. 
• Death 
• 
All cause death 
• Acute coronary syndrome 
• 
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, diarrhea, 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 circulation27. 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 basophils28. 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 allergy29. 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. 
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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.  
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  
• 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, this must be reported on an additional 
AE form. 
 
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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 or NIMP 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. 
• 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 Brochures for insulin icodec and insulin degludec 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. 
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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. 
 
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, Novo Nordisk may request a 
copy of the autopsy report including histopathology. 
New or updated information will be recorded in the CRF. 
 
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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. 
• 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 paper 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. 
 
Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
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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: 
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 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 acceptable effective contraception methods as described in 
Table 10-3. 
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 in seminal fluid is unlikely30. 
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Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use at least an 
acceptable effective methods of contraception consistently and correctly as described in Table 10-3 
below. As a minimum, contraception should be maintained until treatment discontinuation. 
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 
e) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical trials. 
f) 
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. 
g) 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 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). 
• 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 subject’s pregnancy (see Figure 10-2). 
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• Subject will be followed to determine the outcome of the pregnancy. The investigators 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 the foetal status (presence or 
absence of anomalies) or indication for procedure. 
• 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 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 possible/probably 
related to the IMP by the investigator will be reported to Novo Nordisk as described in 
Appendix 3 (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. 
 
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.  
Any female subject who becomes pregnant while participating in the trial will discontinue IMP.  
 
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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 
Reporting of technical complaints to Novo Nordisk 
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. 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
• 24 hours if related to an SAE  
• 5 days calendar for all other 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 systematic 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 patient 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 IHSG31, ADA32, ISPAD33, type 1 diabetes outcomes program34, 
ATTD35. Severe hypoglycaemia as defined by Seaquist36 and ISPAD33. 
 
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.36 
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 discretion.32 
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. 
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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 
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 guidelines.36 
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 concentration.36  
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  
Introduction 
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 + insulin degludec-
placebo or insulin degludec + insulin icodec-placebo. 
• Insulin icodec/placebo should be taken once weekly on the same day of the week. The starting 
dose will be 70U. 
• Insulin degludec/placebo should be taken once daily anytime of the day the same time every 
day. The starting dose will be 10U. 
• The treat-to-target approach will be applied 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 will be based on the three pre-breakfast SMPG values measured on the 
two days prior to titration and on the day of contact. 
• If one or more 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. 
For practical purposes the calculation of the recommended doses will be based on the actual insulin 
icodec/placebo dose taken by the patient in accordance with table 1. The recommended insulin 
degludec/placebo dose will be calculated dividing the recommended insulin icodec dose/placebo by 
7 and round off in accordance with table 2. The insulin degludec/placebo will be adjusted by 
increments of approximately ± 3U. Example: If the weekly insulin icodec/placebo dose is 510U, the 
daily insulin degludec/placebo dose is 73U. 
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Table 10-5 
Insulin icodec/placebo 
Pre breakfast SMPG 
Dose adjustment 
Value to use 
mmol/L 
mg/dL 
U 
Lowest of the SMPG values <4.4 
<80 
–20 
Mean of the SMPG values 
4.4–7.2 
80–130 
0 
>7.2 
>130 
+20 
Table 10-6 
Insulin degludec/placebo 
Once-weekly dose (U) 
Once-daily dose (U) 
Once-weekly dose (U) 
Once-daily dose (U) 
Once-weekly dose (U) 
Once-daily dose (U) 
10 
1 
510 
73 
1010 
144 
20 
3 
520 
74 
1020 
146 
30 
4 
530 
76 
1030 
147 
40 
6 
540 
77 
1040 
149 
50 
7 
550 
79 
1050 
150 
60 
9 
560 
80 
1060 
151 
70 
10 
570 
81 
1070 
153 
80 
11 
580 
83 
1080 
154 
90 
13 
590 
84 
1090 
156 
100 
14 
600 
86 
1100 
157 
110 
16 
610 
87 
1110 
159 
120 
17 
620 
89 
1120 
160 
130 
19 
630 
90 
1130 
161 
140 
20 
640 
91 
1140 
163 
150 
21 
650 
93 
1150 
164 
160 
23 
660 
94 
1160 
166 
170 
24 
670 
96 
1170 
167 
180 
26 
680 
97 
1180 
169 
190 
27 
690 
99 
1190 
170 
200 
29 
700 
100 
1200 
171 
210 
30 
710 
101 
1210 
173 
220 
31 
720 
103 
1220 
174 
230 
33 
730 
104 
1230 
176 
240 
34 
740 
106 
1240 
177 
250 
36 
750 
107 
1250 
179 
260 
37 
760 
109 
1260 
180 
270 
39 
770 
110 
1270 
181 
280 
40 
780 
111 
1280 
183 
290 
41 
790 
113 
1290 
184 
300 
43 
800 
114 
1300 
186 
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310 
44 
810 
116 
1310 
187 
320 
46 
820 
117 
1320 
189 
330 
47 
830 
119 
1330 
190 
340 
49 
840 
120 
1340 
191 
350 
50 
850 
121 
1350 
193 
360 
51 
860 
123 
1360 
194 
370 
53 
870 
124 
1370 
196 
380 
54 
880 
126 
1380 
197 
390 
56 
890 
127 
1390 
199 
400 
57 
900 
129 
1400 
200 
410 
59 
910 
130 
1410 
201 
420 
60 
920 
131 
1420 
203 
430 
61 
930 
133 
1430 
204 
440 
63 
940 
134 
1440 
206 
450 
64 
950 
136 
1450 
207 
460 
66 
960 
137 
1460 
209 
470 
67 
970 
139 
1470 
210 
480 
69 
980 
140 
1480 
211 
490 
70 
990 
141 
1490 
213 
500 
71 
1000 
143 
1500 
214 
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. 
Missing insulin icodec/placebo dose guidance 
If an insulin icodec/placebo 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 measurement. If the 
missing dose is missed for > 3 days, the subject should await the next planned day-of-injection. 
Dose recommendation from end of treatment and during follow-up (insulin icodec/placebo) 
If it is decided that the individual subject should continue basal insulin after end of treatment, it is 
recommended that the subject is switched from insulin icodec/placebo to any available basal insulin 
at the discretion of the investigator. The investigator should instruct the subject in how to switch at 
the “end of treatment” visit (V28).  
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Regarding the switch from insulin icodec to post-trial basal insulin the following should be 
considered: 
• Calculate the new daily basal insulin dose dividing the latest insulin icodec dose by 7 
• Continue to measure pre-breakfast SMPG daily in the follow-up period. If pre-breakfast SMPG 
exceeds 10.0 mmol/L (180 mg/dL), it should be considered to initiate the daily basal insulin 
dose  
• 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 degludec/placebo and insulin icodec/placebo  
• Ensure transfer of SMPG values with an indication of “pre-breakfast” or “other” (Section 8.1.1) 
• 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/placebo or insulin icodec/placebo doses prescribed at this contact. 
• Reasons for deviation from the 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 into 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. 
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/Region-specific requirements 
For Argentina: 
• In reference to exclusion criteria 3 and Appendix 4 (see 10.4, Table 10-3): The 
contraceptive methods and pregnancy tests will be reimbursed by the sponsor. Monthly 
testing with highly sensitive urine pregnancy tests is required for woman of childbearing 
potential (WOCBP). Use of double contraceptive method is required for WOCBP. 
• In reference to Protocol section Treatment after end of trial products: The sponsor 
commits to comply with what is stated in point 6.8 of the current local regulation, 
disposition 6677/10. According to it, commits to comply with the following: “For 
Argentina, after the conclusion of subjects participation in the study, trial doctor will discuss 
with subjects the best alternatives for future treatment. If trial doctor, based on his/her 
adequately justified medical analysis, decides that the Sponsor’s study drug is the best 
available treatment option for the subject, trial doctor will prescribe the study drug, which 
must be approved by the Ethics Committee. The Sponsor (Novo Nordisk Pharma Argentina 
S.A.) will provide access to the Sponsor’s study drug to the subject for the time the Ethics 
Committee decides or until access is ensured by any other means and in accordance with the 
applicable provisions in Argentina. Subjects must visit trial doctor to receive the Sponsor’s 
study drug and will have to provide information about health status and any possible side 
effects that may have been experienced since last visit. 
For Austria: 
• Contraceptive guidance: A monthly pregnancy test is mandatory for female subjects of 
childbearing potential. 
For Brazil:  
• Exclusion criteria: Participation in other trials within one year prior to screening visit 
unless there is a direct benefit to the subject at the investigator’s discretion. 
• Treatment after the end of the trial: At the end of the trial, all participant subjects should 
be assured the access to the best proved prophylactic, diagnostic and therapeutic methods 
identified during the study. 
• Clinical laboratory results: All laboratory results will be communicated to the 
investigators. 
• Contraceptive guidance: For women who expressively declare free of the risk pregnancy, 
either by not engaging in sexual activity or by having sexual activity with no birth potential 
risk (e.g. sex with a same sex partner), use of contraceptive method will not be mandatory.  
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• Retention of human biosamples: Biological samples from Brazil will not be stored but 
destroyed after completion of the trial.  
For China: 
• 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 China. 
• 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 China. 
• Clinical laboratory tests: All lab assessments will be analysed in a central laboratory or 
special laboratory located in China. There will be no exploratory tests/exploratory 
endpoints/investigations for Chinese subjects. In case of systematic hypersensitivity 
reaction, the samples required in Section 8.9.2 should be taken and stored at the central 
laboratory before further analysis in the special laboratory. 
• Retention of human biosamples: All laboratory samples for Chinese subjects will be 
destroyed according to local regulatory requirement. No sample will be stored after the final 
CTR. 
• Trial governance consideration: Information of the trial will be disclosed at 
clinicaltrials.gov, chinadrugtrials.org.cn and novonordisk-trials.com. 
• Regulatory and ethical considerations: Regulatory authorities will receive the clinical trial 
application, protocol amendments, reports on SAEs, and the CTR according to national 
requirements.  
• For China, an international cooperative relevant report of related China’s Human Genetic 
Resources will be submitted based on local regulation requirement. 
• Any trial procedure conducted in China mainland should comply with “Regulations on 
management of Human Genetic Resources of People’s Republic of China” and relative 
guideline. http://www.gov.cn/zhengce/content/2019-06/10/content_5398829.htm 
• 10.1.10 Retention of clinical trial documentation: 
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• About site specific data storage, sites have the equal right with sponsor. 
• Long term preservation of Chinese Patients’ Trial Data is Prohibited in any other entities.  
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For Czech Republic: 
• Date of Birth: Patient’s full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth. 
For Denmark: 
• Contraceptive guidance: Contraceptive measures considered adequate include intrauterine 
devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, 
vaginal rings or long-acting injections). 
For France: 
• Indemnity statement: French Public Health Code article L 1121-10 (law n° 2004-806 of 9 
August 2004 art. 88 I,IX, Journal Official of 11 August 2004. “The sponsor is responsible 
for identification of the harmful consequences of the biomedical research for the person 
lending himself thereto and for indemnification of his beneficiaries, except in case of proof, 
incumbent on it, that the prejudice is not attributable to his fault of or the fault of any 
intervening party, without the sponsor’s being entitled to call on acts by a third party or the 
voluntary withdrawal of the person who had initially consented to cooperating in the 
research”. 
• Demography: Subject’s full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF. Collection of race and ethnicity are not allowed in the 
CRF.  
For Mexico: 
• Withdrawal from the trial: should the subject his/her family members parents or legal 
representative decide to withdraw the consent for participation in the trial, the subject will 
be entitled to receive appropriate, free of charge medical care and/or trial drug during the 
follow-up period of the protocol when it will be established with certainty that no untoward 
medical consequences of the subject´s participation in the research occurred. 
• Trial governance considerations: In the case of Mexico, the above will include the 
following responsibilities for the head of the Institution/Health Care Establishment, Ethics, 
Research and, when applicable, Biosafety Committees and sponsor within their scope of 
responsibility: a) Investigation follow-up; b) Damages to health arising from the 
investigation development; as well as those arising from interruption or advanced 
suspension of treatment due to non-attributable reasons to the Subject; c) Timely compliance 
of the terms in which the authorization of a research for health in human beings had been 
issued; d) To present in a timely manner the information required by the Health Authority. 
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• Indemnity statement: 
a) 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, including 
those applicable provisions on the Mexican United States. If the subject feels that something 
goes wrong during the course of this trial, the subject should contact the trial staff in the first 
instance. 
b) If during their participation in the trial the subject experiences a disease or injury that, 
according to the trial doctor and the sponsor, is directly caused by the study medication 
and/or a study procedure that otherwise would not have been part of his/her regular medical 
care, the subject will receive from the institution or medical care establishment and free of 
charge, the appropriate medical treatment as required. In this case, the costs resulting from 
such treatment as well as the costs of any indemnification established by law will be covered 
by the trial sponsor in accordance with the terms provided by all applicable regulations; 
even if the subject discontinues his/her participation in the study by his own will or by a 
decision from the investigator. 
c) By signing the informed consent, the subject will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur any additional 
expense as a result of his/her participation in the trial; any additional expense resulting from 
the subject’s participation in the trial will be covered by the trial sponsor. 
For Taiwan: 
• Inclusion criteria 3: age ≥ 20 years at the time of signing informed consent. 
For USA: 
• Financial disclosure: Verification under disclosures per Code of Federal Regulations 
(CFR) of Financial Conflict of Interest. 
 
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10.10 Appendix 10: Abbreviations  
ADA 
anti-drug antibody 
AE 
adverse event 
ANCOVA 
analysis of covariance  
ANOVA 
analysis of variance  
BG 
blood glucose 
CGM 
continuous glucose monitoring  
CI 
confidence interval  
CRF 
case report form 
CTR 
clinical trial report 
DBL 
database lock  
DUN 
dispensing unit number 
EAC 
event adjudication committee 
EAS 
event adjudication system 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EFAS  
extended full analysis set 
EMA SmPC 
European Medicinal Agency summary of product characteristics  
ESAS 
extended safety analysis set 
ETD 
estimated treatment difference 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
U.S. Food and Drug Administration Amendments Act 
FPG 
fasting plasma glucose 
FSFV 
first subject first visit 
GCP 
Good Clinical Practice 
GLP-1 RA 
glucagon-like peptide 1 receptor agonists 
HbA1c 
glycated haemoglobin 
HCP 
healthcare professional 
HRT 
hormone replacement therapy 
IB 
Investigator’s brochure 
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ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
INN 
international nonproprietary name 
IRB 
institutional review board 
IWRS 
interactive web response system 
LAOT-WOB 
last available planned on-treatment without initiation of more than 2 weeks bolus insulin treatment  
LSLV 
last subject last visit 
MAP 
modelling analysis plan  
NI 
non-inferiority  
NIMP 
non-investigational medical product 
OAD 
oral anti-diabetic drug 
PCD 
primary completion date 
PD 
pharmacodynamic 
PI 
prescribing information 
PK 
pharmacokinetics 
PG 
plasma glucose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation  
SI-IC 
subject information-informed consent 
SMPG 
self-measured plasma glucose 
SU 
sulfonylureas  
T1D 
type 1 diabetes 
T2D 
type 2 diabetes 
TMM 
trial materials manual 
V 
visit 
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. 
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11 References 
1. 
American Diabetes Association. 2. Classification and Diagnosis of Diabetes:. Diabetes Care. 
2019;42(Suppl 1):S13-S28. 
2. 
International Diabetes Federation. IDF Diabetes Atlas, 9th Edition. 2019. 
3. 
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. 
4. 
Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res. 2005;36(3):197-209. 
5. 
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 
2004;88(4):787-835, ix. 
6. 
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. 
Update to a position statement of the American Diabetes Association and the European 
Association for the Study of Diabetes. Diabetologia. 2015;58(3):429-42. 
7. 
European Medicines Agency. Guideline on clinical investigation of medicinal products in 
the treatment or prevention of diabetes mellitus (CPMP/EWP/1080/00 Rev. 1). 14 May 
2012. 
8. 
Halimi S, Balkau B. Better analyze the determinants of therapeutic inertia to overcome it. 
Diabetes Metab. 2012;38 Suppl 3:S27-8. 
9. 
Khunti K, Millar-Jones D. Clinical inertia to insulin initiation and intensification in the UK: 
A focused literature review. Prim Care Diabetes. 2017;11(1):3-12. 
10. 
Novo Nordisk A/S. Investigator's Brochure, insulin icodec, project NN1436, (edition 6). 5 
Jun 2020. 
11. 
Novo Nordisk A/S. Investigator's Brochure, Insulin Degludec (Tresiba®), project : NN1250 
IDeg, (edition 15). 2018. 
12. 
Novo Nordisk A/S. Tresiba® (insulin degludec) EU Summary of Product Characteristics 
(SmPC). 12 Nov 2018. 
13. 
Novo Nordisk A/S. Tresiba® (insulin degludec), US Prescribing Information (PI). Mar 2018. 
14. 
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. 
15. 
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease. http://www.kidney-international.org. 2013 2013. 
16. 
Food and Drug Administration, CDER. Guidance for Industry. Diabetes Mellitus: 
Developing Drugs and Therapeutic Biologics for Treatment and Prevention, Draft Guidance. 
February 2008. 
17. 
Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs 
insulin glargine and placebo in combination with metformin and sulfonylurea therapy in 
type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 
2009;52(10):2046-55. 
18. 
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987. 
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19. 
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. 
20. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
21. 
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. 
22. 
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. 
23. 
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. 
24. 
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. 
25. 
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. 
26. 
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. 
27. 
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. 
28. 
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin 
Immunol. 2002;110(3):341-8. 
29. 
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. 
30. 
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. 
31. 
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. 
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32. 
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64. 
33. 
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. 
34. 
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. 
35. 
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. 
36. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95. 
 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04795531 
Sponsor trial ID: 
NN1436-4479 
Official title of study: 
A 26-week double blinded, multiregional, trial comparing the 
effect and safety of once weekly insulin icodec and once daily 
insulin degludec 100 units/mL, both in combination with non-
insulin anti-diabetic drugs, in insulin naïve subjects with type 2 
diabetes (ONWARDS 3) 
Document date*: 
20 January 2021 
 
*Document date refers to the date on which the document was most recently updated. 
 


Statistical Analysis Plan 
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Trial ID: NN1436-4479 
Version: 
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Statistical Analysis Plan 
NN1436-4479 
 
A 26-week double blinded, multiregional, trial comparing the effect 
and safety of once weekly insulin icodec and once daily insulin 
degludec 100 units/mL, both in combination with non-insulin anti-
diabetic drugs, in insulin naïve subjects with type 2 diabetes. 
 
ONWARDS 3 
 
Author 
 
Biostatistics Aalborg 1 
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Includes redaction of personal identifiable information only. 
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Statistical Analysis Plan 
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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 ...................................................................................... 6 
1.2 
Trial design ......................................................................................................................................... 6 
2 Statistical hypotheses .................................................................................................................................. 7 
3 Sample size determination .......................................................................................................................... 8 
4 Analysis sets ................................................................................................................................................. 8 
5 Statistical analyses ....................................................................................................................................... 9 
5.1 
General considerations ........................................................................................................................ 9 
5.2 
Subject disposition ............................................................................................................................ 10 
5.3 
Primary endpoint analysis ................................................................................................................. 10 
5.3.1 
Definition of endpoints ...................................................................................................... 10 
5.3.2 
Main analytical approach................................................................................................... 10 
5.3.3 
Sensitivity analysis ............................................................................................................ 11 
5.4 
Secondary endpoints analysis ........................................................................................................... 11 
5.4.1 
Supportive secondary endpoints ........................................................................................ 11 
5.4.1.1 
Efficacy endpoints .......................................................................................... 11 
5.4.1.2 
Safety endpoints ............................................................................................. 12 
5.5 
Exploratory endpoints analysis ......................................................................................................... 14 
5.6 
Other safety analyses ........................................................................................................................ 14 
5.6.1 
Nocturnal hypoglycaemic episodes ................................................................................... 14 
5.6.2 
Anti-insulin icodec antibodies ........................................................................................... 14 
5.6.3 
Record selection ................................................................................................................ 15 
5.7 
Other analyses ................................................................................................................................... 15 
5.7.1 
Other derivations and assessments .................................................................................... 15 
5.7.1.1 
Achievement of HbA1c target ....................................................................... 15 
5.7.1.2 
Self-measured plasma glucose (SMPG) ......................................................... 16 
5.7.1.3 
Antidiabetic background medication ............................................................. 16 
5.7.1.4 
Insulin dose .................................................................................................... 16 
5.7.2 
Pharmacokinetic modelling ............................................................................................... 16 
5.8 
Interim analyses ................................................................................................................................ 17 
5.8.1 
Data monitoring committee ............................................................................................... 17 
5.9 
Reporting of the main part of the trial ............................................................................................... 17 
6 Supporting documentation ....................................................................................................................... 18 
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6.1 
Appendix 1: List of abbreviations ..................................................................................................... 18 
6.2 
Appendix 2: Changes to protocol-planned analyses ......................................................................... 19 
6.3 
Appendix 3: Definition and calculation of endpoints, assessments and derivations ........................ 21 
7 References .................................................................................................................................................. 24 
 
Table of figures 
 
Page 
Figure 1-1 
Trial design .................................................................................................................................. 7 
 
Table of tables 
 
Page 
Table 1 
SAP Version History Summary ................................................................................................ 4 
 
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Version history 
This Statistical Analysis Plan (SAP) for trial NN1436-4479 is based on the protocol version 2.0 
dated 30-NOV-2020.  
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 
2.0 
See approval date in 
the electronic 
document 
management system 
Method for imputing missing 
data using completing 
comparator subjects changed 
to imputing from baseline 
values within own arm when 
baseline values are available 
Based on FDA 
recommendation 
 
 
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Statistical Analysis Plan 
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1 
Introduction 
This statistical analysis plan (SAP) is based on the protocol: A 26-week double blinded, 
multiregional, trial comparing the effect and safety of once weekly insulin icodec and once daily 
insulin degludec 100 units/mL, both in combination with non-insulin anti-diabetic drugs, in insulin 
naïve subjects with type 2 diabetes, version 2.0 (dated 30-NOV-2020). 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 demonstrate the effect on glycaemic control of once weekly insulin icodec in combination with 
non-insulin anti-diabetic drugs in insulin-naïve subjects with T2D. This includes comparing the 
difference in change from baseline in HbA1c between insulin icodec and insulin degludec after 26 
weeks of treatment to a non-inferiority limit of 0.3%. 
1.1.1.2 
Secondary objective 
To compare parameters of safety with once weekly insulin icodec versus once daily insulin 
degludec, both in combination with non-insulin anti-diabetic drugs in insulin-naïve subjects with 
T2D. 
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: 
initiation of bolus insulin treatment for more than 2 weeks, 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 (V2) to week 26 (V28) 
%-point 
1.1.2.2 
Secondary endpoints 
1.1.2.2.1 
Confirmatory secondary endpoints 
Not applicable for this trial. 
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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 (V2) to week 26 (V28) 
mmol/L 
Secondary safety endpoints  
Endpoint title  
Time frame 
Unit 
Number of severe hypoglycaemic episodes (level 3) 
From baseline week 0 (V2) to week 31 (V30) 
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 (V2) to week 31 (V30) 
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 (V2) to week 31 (V30) 
Number of 
episodes 
Number of severe hypoglycaemic episodes (level 3) 
From baseline week 0 (V2) to week 26 (V28) 
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 (V2) to week 26 (V28) 
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 (V2) to week 26 (V28) 
Number of 
episodes 
Change in body weight 
From baseline week 0 (V2) to week 26 (V28) 
Kg 
Mean weekly insulin dose 
From week 24 (P26) to week 26 (V28) 
U 
1.1.2.3 
Exploratory endpoints 
Not applicable for this trial. 
1.2 
Trial design 
This is a 26-week randomised, stratified, double blinded, double dummy, active-controlled, parallel-
group, multicentre, multiregional, treat-to-target trial with two treatment arms. The trial investigates 
the effect on glycaemic control and safety of treatment with once weekly insulin icodec compared 
to once daily insulin degludec, both in combination with non-insulin anti diabetic drugs, in insulin 
naïve subjects with inadequately controlled T2D on non-insulin anti-diabetic drugs in need for 
insulin initiation.   
The trial duration is approximately 33 weeks, consisting of a 2-week screening period, followed by 
a 26-week randomised treatment period and a 5-week follow-up period. 
The overall trial design and visit schedule are outlined in Figure 1-1 and trial flowchart (see 
protocol section 1.2), respectively. 
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Figure 1-1 
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 in the FDA 
guidance for industry on developing drugs for treatment of diabetes.1 Also, this margin is 
considered to provide sufficient assay sensitivity based on the below considerations: 
• 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 50% of a suitably conservative estimate of insulin glargine’s treatment 
effect on HbA1c in a placebo-controlled trial (-0.85%-point [-1.04; -0.66]95%CI versus 
placebo) in insulin-naïve subjects, which demonstrated insulin glargine’s superiority.2 
• Other basal insulin analogues have previously been shown to yield similar reductions in 
HbA1c compared to insulin glargine. As only insulin glargine (not insulin degludec) has 
been compared to placebo in previous trials, the above-mentioned insulin glargine results 
are used as reference for consideration of the margin. 
The following describe the secondary confirmatory hypothesis. In order to control the overall Type 
I error at a 5% level, two sided, a hierarchical testing procedure will be used. If non-inferiority in 
glycaemic control is concluded in the primary analysis, confirmatory testing proceeds to the 
following hypothesis: 
• Insulin icodec is superior to insulin degludec in terms of change from baseline to week 26 in 
HbA1c 
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Formally, let D be the mean treatment difference ‘insulin icodec’ minus ‘insulin degludec’ of the 
change in HbA1c from baseline to week 26. The null-hypothesis of insulin icodec not superior will 
be tested against the alternative hypothesis of superiority as given by 
H0: D≥0% against HA: D<0% 
3 
Sample size determination 
See protocol section 9.2.  
4 
Analysis sets 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised. 
Full analysis set  
Full analysis set (FAS): All subjects randomised excluding the Chinese 
extension cohort. Subjects will be analysed according to the randomised 
treatment.  
Safety analysis set 
All subjects randomly assigned to trial treatment excluding the Chinese 
extension cohort and who take at least 1 dose of trial product. Subjects are 
analysed according to the treatment they actually received.  
Chinese extension cohort 
All Chinese subjects randomised after the respective planned recruitment period. 
Extended full analysis set 
Extended full analysis set (EFAS): All subjects randomised including the 
Chinese extension cohort.  Subjects will be analysed according to the 
randomised treatment.  
Extended safety analysis set 
Extended safety analysis set (ESAS): All subjects randomly assigned to trial 
treatment including the Chinese extension cohort and who take at least 1 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 
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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 (V30) 
• 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. 
Baseline assessments are always included in the on-treatment observation period. 
All efficacy endpoints will be summarised and analysed using the full analysis set (FAS) and the 
‘in-trial’ period. Safety endpoints will be evaluated using the on-treatment period with descriptive 
statistics being based on the safety analysis set (SAS) and statistical analyses being based on the 
FAS unless otherwise specified. 
If China does not reach recruitment target of 100 Chinese subjects within the planned recruitment 
period all efficacy endpoints will in addition be summarised and analysed using the extended full 
analysis set (EFAS) and the ‘in-trial’ period, and safety endpoints will be evaluated using the on-
treatment period with descriptive statistics being based on the extended safety analysis set (ESAS) 
and statistical analyses being based on the EFAS unless otherwise specified. These results will be 
presented in the extension part report. 
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. For the extension part analyses p-values will not be included (see 
also section 5.8). 
In the statistical models, explanatory factors will be coded as follows: 
• Treatment: Once weekly insulin icodec, insulin degludec  
• Region: Asia, Europe, North America, South America, 
• SU or glinide use: yes, no 
The regions will be defined as follows:  
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• Asia: China, Taiwan 
• Europe: Austria, Denmark, France, Czech Republic 
• North America: Canada, United States 
• South America: Argentina, Brazil, Mexico 
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. 
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. 
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 or initiating bolus insulin treatment for more than 
2 weeks. Missing HbA1c at the week 26 visit (regardless of treatment completion status) will be 
imputed from trial participants, who have discontinued their randomised treatment or initiated bolus 
insulin treatment for more than 2 weeks 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 who discontinued their randomised treatment or initiated bolus insulin 
treatment for more than 2 weeks at any time prior to the week 26 visit and have an HbA1c 
measurement at the week 26 visit, the change in HbA1c from last available planned on-
treatment without initiation of more than 2 weeks bolus insulin treatment (LAOT-WOB) 
value to the week 26 visit will be analysed for each dataset copy using an analysis of 
covariance (ANCOVA) model with randomised treatment as fixed factor and LAOT-WOB 
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-WOB 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, SU or glinide use (yes/no), and randomised treatment as fixed 
factors, and baseline HbA1c 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.3 
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This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinue randomised treatment or initiate bolus insulin treatment for more than 2 
weeks. 
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-WOB 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. 
The baseline value will be included as a covariate. 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).     
If non-inferiority is confirmed, i.e. if the 95% CI is strictly below 0.3%, then the primary endpoint 
will further be tested for superiority. Superiority for change in HbA1c will be considered confirmed 
if the 95% CI is strictly below zero. 
Missing HbA1c at week 26 will be summarised by subject 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 
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 non-inferiority or superiority change 
will be evaluated to assess the robustness of the results. 
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) 
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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-WOB values. Specifically, the imputations and 
analyses will be carried out as follows: 
• First, an ANCOVA model with region, SU or glinide use (yes/no), and randomised 
treatment as fixed factors, and a baseline value as a covariate will be fitted to the LAOT-
WOB values. 
• 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 a 1000 times. 
• For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region, SU or glinide use (yes/no), and randomised treatment as fixed factors, and a 
baseline 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. 
 
5.4.1.2 
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 31 
(V30) 
• 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 31 (V30) 
• 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 31 (V30) 
 
For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 visit (V30) to planned end of the on-treatment period) will be imputed 
using a multiple imputation technique, assuming that the event rate pre follow-up 2 visit (V30) 
follows the respective treatment groups rate whilst post follow-up 2 visit (V30) event rate is the rate 
of the insulin degludec 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, 
SU or glinide use (yes/no), and randomised treatment as fixed factors and the logarithm of 
the on-treatment period as offset. 
• Second, based on the estimated parameters for the insulin degludec 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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• 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 standard deviations for the 1000 data sets will be pooled to one estimate and associated 
standard deviation using Rubin’s rule. 
 
The following hypoglycaemic endpoints will be analysed separately using the method described 
above, substituting the on-treatment period with the period from week 0 to week 26, and 
substituting ‘follow up 2 visit (V30)’ with ‘discontinuation of treatment’: 
• 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). 
 
For the definition and classification of hypoglycaemic episodes refer to the protocol Appendix 7 
(protocol section 10.7). 
Mean weekly insulin dose from week 24 (P26) to week 26 (V28) 
Missing mean weekly insulin dose during the last 2 weeks of treatment (from week 24 to 26) will be 
analysed log-transformed. Missing mean weekly insulin doses during the last 2 weeks of treatment 
(from week 24 to 26) (regardless of treatment completion status) will be imputed from trial 
participants who are from the insulin degludec group, and who have completed and adhered to their 
randomised insulin treatment without  initiation of bolus insulin treatment for more than 2 weeks at 
any time prior to the week 26 visit – i.e., data will be imputed based on the assumption that subjects 
with missing endpoint data will behave like subjects completing insulin degludec treatment without 
initiation of bolus insulin treatment for more than 2 weeks at any time prior to the week 26 visit. 
Specifically, the imputations and analyses will be carried out as follows: 
• First, one thousand (1000) copies of the dataset will be generated for mean weekly insulin 
dose. 
• Second, for each dataset copy, an analysis of variance (ANOVA) model will be fitted to 
mean weekly insulin dose values for subjects who completed their randomised treatment 
without initiation of bolus insulin treatment for more than 2 weeks at any time prior to the 
week 26 visit 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 ANOVA model 
with region, SU or glinide use (yes/no), and randomised treatment as fixed factors. The 
estimates and standard deviations for the 1000 data sets will be pooled to one estimate and 
associated standard deviation using Rubin’s rule. 
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. 
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5.5 
Exploratory endpoints analysis 
Not applicable for this trial. 
5.6 
Other safety analyses 
All safety analyses will be made on the safety analysis set and the extension safety analysis set 
(ESAS), if applicable. The standard safety assessments (SAEs, AEs, safety laboratory parameters, 
vital signs, etc.) will be reported descriptively based on 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 31 (V30) 
• 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 31 (V30) 
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) or severe nocturnal hypoglycaemic episodes (level 3) 
from baseline week 0 (V2) to week 31 (V30) 
• 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 clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) or severe nocturnal hypoglycaemic episodes (level 3) 
from baseline week 0 (V2) to week 26 (V28). 
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 31 titre values.  
 
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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 24 to week 26 
• HbA1c at week 26 
• change from baseline in HbA1c at week 26 
• 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 26 and week 31 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. 
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) 
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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, SU or glinide 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 
Antidiabetic background medication 
Subjects experiencing changes to antidiabetic background medication during the trial lasting more 
than 2 weeks will be summarised descriptively by treatment including number and proportion of 
subjects. Subjects will be further divided into two subgroups: 
• subjects with changes to bolus treatment for more than 2 weeks  
• subjects with changes to other antidiabetic background medication for more than 2 weeks  
 
Changes to antidiabetic background medication are considered to be both initiation / discontinuation 
of antidiabetic background medication and increase / decrease in dose level of antidiabetic 
background medication. 
5.7.1.4 
Insulin dose 
Weekly actual insulin doses will be summarised by treatment and week. 
Flexibility of up to +/-3 days is allowed for the dosing of the weekly trial drug. Number of subjects 
utilizing this flexibility together with the number of times they have utilized it and the number of 
days they have deviated from the weekly dosing will be summarised.  
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/S. A more technical and detailed elaboration of the population PK analysis will be given 
in a modelling analysis plan (MAP), which will be prepared before DBL. 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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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
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Trial ID: NN1436-4479 
Version: 
2.0 
UTN: U1111-1247-5218 
Status: 
Final 
EudraCT No: 2020-000472-37 
Page: 
17 of 24 
 
(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 MAP. 
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. 
5.8 
Interim analyses 
The trial does not include a formal interim analysis. However, the potential split of the trial into a 
main and an extension part offers the opportunity of reporting results before LSLV. Main part is 
defined to end at time of LSLV for subjects recruited within the planned recruitment period. The 
main part analysis will include a minimum of 580 randomised subjects and will include data from 
all non-Chinese subjects and data from Chinese subjects that have been recruited within the planned 
recruitment period and have achieved end of trial. No data from the remaining Chinese subjects will 
be included in the main part evaluation and the randomisation code for these subjects will not be 
revealed at time of DBL for the main part. So, blinding of randomised treatment for these subjects 
will be maintained ensuring that trial integrity is preserved. 
If 100 Chinese subjects cannot be recruited within the planned recruitment period, there will also be 
an extension part of the trial. The extension part will include all randomised subjects and is defined 
to end at the time of LSLV for the entire Chinese cohort. A second reporting of the trial based on 
the extension part will take place when LSLV for the entire Chinese cohort has been reached.  
Confirmation of glycaemic control of insulin icodec will be based on the results from the analysis of 
the main part of the trial. The data from the extension part will be considered supportive only and is 
intended for the Chinese NDA. 
The type 1 error rate will be maintained at 5%, as no statistical inference from the entire trial 
population will be drawn at the time of the extension part analysis. For the extension part similar 
analyses and data presentations as for the main part will be conducted and reported. Confidence 
intervals will be presented if relevant, but no p-values will be included in the extension part 
analyses.   
5.8.1 
Data monitoring committee 
This section is 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. In case 100 Chinese subjects cannot be recruited 
within the planned recruitment period the complete trial will be reported after database lock of the 
extension part. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
20 January 2021 Novo Nordisk 
Trial ID: NN1436-4479 
Version: 
2.0 
UTN: U1111-1247-5218 
Status: 
Final 
EudraCT No: 2020-000472-37 
Page: 
18 of 24 
 
6 
Supporting documentation 
6.1 
Appendix 1: List of abbreviations 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
BG 
Blood glucose 
CI 
Confidence interval 
EFAS 
Extended full analysis set 
ESAS 
Extended safety analysis set 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
MAP 
Modelling analysis plan 
PK 
Pharmacokinetics 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SMPG 
Self-measured plasma glucose 
SU 
Sulfonylureas 
T2D 
Type 2 Diabetes 
 
 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
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Trial ID: NN1436-4479 
Version: 
2.0 
UTN: U1111-1247-5218 
Status: 
Final 
EudraCT No: 2020-000472-37 
Page: 
19 of 24 
 
6.2 
Appendix 2: Changes to protocol-planned analyses 
In section 4 the sentence “Baseline assessments are always included in the in-trial observation 
period.” has been added to the definition of the in-trial period, and the sentence “Baseline 
assessments are always included in the on-treatment observation period.” has been added to the 
definition of the on-treatment period to clarify that the baseline assessments should always be 
included. 
In section 5.4.1.2 the following changes have been made: 
1. In the described analysis method “discontinuation” has been replaced with “follow-up 2 
visit (V30)”. For subjects who discontinue their randomised treatment, hypoglycaemic 
episodes are collected until follow-up 2 visit (V30), and this data should be included as 
supportive secondary endpoints will be evaluated in the framework of the primary 
estimand.  
2. For the 3 hypoglycaemic endpoints based on the period week 0 (V2) to week 26 (V28) 
further specifications for the analysis method were needed:  
o the on-treatment period in the described analysis method should be replaced with 
the period from week 0 to week 26. 
o ‘follow-up 2 visit (V30)’ should be replaced with ‘discontinuation of treatment’, 
since the analysis of these endpoints should consider only hypoglycaemic episodes 
occurring while subjects are being treated with icodec or degludec, and hence 
hypoglycaemic episodes occurring during follow-up should not be included. 
3. For supportive secondary endpoints with time frame starting at week 0 (V2) the word 
“baseline” has been added in front of week 0 (V2) in the headers to align with section 3.2 
in the protocol. 
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 additional information on the extension part analyses and the seed number 
for the imputations have 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 5.3.3 it has been added that the sensitivity analysis will also be done for the superiority 
evaluation. 
In sections 5.4.1.1 and 5.4.1.2, based on recommendations from FDA, the method for imputing 
missing data has been changed from imputing missing data using completing comparator subjects to 
imputing from baseline values within own arm. The following analyses are affected: 
• second alternative approach for endpoints with data collection after premature treatment 
discontinuation (change in HbA1c and body weight), 
• change in FPG. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
20 January 2021 Novo Nordisk 
Trial ID: NN1436-4479 
Version: 
2.0 
UTN: U1111-1247-5218 
Status: 
Final 
EudraCT No: 2020-000472-37 
Page: 
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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. Also further elaborations on extension part 
reporting have been added to section 5.8. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
20 January 2021 Novo Nordisk 
Trial ID: NN1436-4479 
Version: 
2.0 
UTN: U1111-1247-5218 
Status: 
Final 
EudraCT No: 2020-000472-37 
Page: 
21 of 24 
 
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 (V2) to 
week 26 (V28) 
%-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 (V2) to 
week 26 (V28) 
mmol/L 
The FPG value at baseline week 0 
subtracted from the FPG value at 
week 26. 
Supportive 
secondary 
endpoint 
Number of severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 31 (V30) 
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 (V2) to 
week 31 (V30) 
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 (V2) to 
week 31 (V30) 
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 (V2) to 
week 26 (V28) 
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 (V2) to 
week 26 (V28) 
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 (V2) to 
week 26 (V28)  
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 
Change in body weight 
From baseline 
week 0 (V2) to 
week 26 (V28) 
Kg 
The body weight value at baseline 
week 0 subtracted from the body 
weight value at week 26. 
Supportive 
secondary 
endpoint 
Mean weekly insulin 
dose 
From week 24 
(P26) to week 
26 (V28) 
U 
The mean of weekly insulin doses 
during the two weeks. 
Derivation 
Number of nocturnal 
severe hypoglycaemic 
episodes (level 3)  
From baseline 
week 0 (V2) to 
week 31 (V30)  
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
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Statistical Analysis Plan 
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Date: 
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Trial ID: NN1436-4479 
Version: 
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UTN: U1111-1247-5218 
Status: 
Final 
EudraCT No: 2020-000472-37 
Page: 
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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 (V2) to 
week 31 (V30)  
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) or nocturnal 
severe hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 31 (V30)  
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 (V2) to 
week 26 (V28) 
end of 
treatment visit 
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 (V2) to 
week 26 (V28) 
end of 
treatment visit 
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) or nocturnal 
severe hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 26 (V28) 
end of 
treatment visit 
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 (V28)  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 (V28)  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 
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Statistical Analysis Plan 
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Date: 
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Trial ID: NN1436-4479 
Version: 
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UTN: U1111-1247-5218 
Status: 
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EudraCT No: 2020-000472-37 
Page: 
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Type 
Title 
Time frame 
Unit 
Details 
Derivation 
Achievement of 
HbA1c<7.0% after 26 
weeks without severe 
hypoglycaemic 
episodes (level 3) 
during the prior 12 
weeks (yes/no) 
Week 26 (V28)  Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c < 7.0% 
after 26 weeks without severe 
hypoglycaemic episodes during the 
prior 12 weeks 
 
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 (V28)  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 (V28)  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 (V28)  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 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
20 January 2021 Novo Nordisk 
Trial ID: NN1436-4479 
Version: 
2.0 
UTN: U1111-1247-5218 
Status: 
Final 
EudraCT No: 2020-000472-37 
Page: 
24 of 24 
 
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. 
Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs 
insulin glargine and placebo in combination with metformin and sulfonylurea therapy in 
type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 
2009;52(10):2046-55. 
3. 
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987. 
 
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