Clinical trial NCT04460885
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2020-11-25; Completion date: 2022-12-01
Enrollment: 984 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares insulin icodec (a new insulin taken once a week) to insulin glargine (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 glargine taken daily. Participants will either get insulin icodec that participants will have to inject once a week on the same day of the week or insulin glargine that participants will have to inject once a day at the same time every day. Which treatment participants get is decided by chance.

The insulin is injected with a needle in a skin fold in the thigh, upper arm or stomach. The study will last for about 1 ½ years. Participants will have 37 clinic visits and 26 phone calls with the study doctor. At 11 clinic visits participant will have blood samples taken. At 8 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit.

Participants will be asked to wear a sensor that measures the blood sugar all the time in 5 periods of about one month during the study (about 5 months in total). Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.

Detailed description:

Arms: arm 1: Insulin icodec + non-insulin anti-diabetic drugs. The pre-trial non-insulin anti-diabetic background medication should be maintained at the stable, pre-trial dose and at the same frequency during the entire treatment period arm 2: Insulin glargine + non-insulin anti-diabetic drugs. The pre-trial non-insulin anti-diabetic background medication should be maintained at the stable, pre-trial dose and at the same frequency during the entire treatment period
Interventions: intervention 1: Insulin icodec intervention 2: Insulin glargine
Intervention descriptions: intervention 1: Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 78 weeks. intervention 2: Participants will receive subcutaneous (s.c.) injections of insulin glargine once daily for 78 weeks

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04460885 
Sponsor trial ID: 
NN1436-4477 
Official title of study: 
A 78-week Trial Comparing the Effect and Safety of Once 
Weekly Insulin Icodec and Once Daily Insulin Glargine 100 
units/mL, Both in Combination With Non-insulin Anti-
diabetic Treatment, in Insulin Naïve Subjects With Type 2 
Diabetes (ONWARDS 1) 
Document date: 
30-November-2020 
*Document date refers to the date on which the document was most recently updated. 


Protocol 
CONFIDENTIAL 
Date: 
30 November 2020 
Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
4.0 
Status: 
Final 
Page: 
1 of 94 
Protocol
Protocol title: A 78-week trial comparing the effect and safety of once weekly insulin icodec 
and once daily insulin glargine 100 units/mL, both in combination with non-
insulin anti-diabetic treatment, in insulin naïve subjects with type 2 diabetes. 
ONWARDS 1 
Substance: Insulin icodec 
Universal Trial Number: U1111-1247-3878 
EudraCT Number: 2020-000442-34 
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. 
. 


Protocol 
CONFIDENTIAL 
Date: 
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Trial ID: NN1436-4477 
Version: 
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Status: 
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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s)  
Protocol version 4.0 
30 November 2020 
All countries 
Protocol version 3.0 
03 November 2020 
Italy only 
Protocol version 2.0 
21 August 2020 
UK only 
Original protocol version 1.0 
19 June 2020 
All countries except UK and Italy 
 
Protocol version 4.0 (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 4.0: 
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 
1.1 Synopsis 
Correcting a week number. 
Correction of error 
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. 
3.1.3 Estimand 
Correcting a week number. 
Correction of error. 
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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Trial ID: NN1436-4477 
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Section # and name 
Description of change 
Brief rationale 
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. 
8.9.2 Hypersensitivity 
The sentence “For the subjects 
randomised to insulin icodec” has 
been added in the first paragraph. 
To clarify that the additional blood 
sampling is only taken in the insulin 
icodec arm. 
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-specific 
requirements 
UK specific BG meter instruction 
deleted. 
Specific UK instruction is not needed.  
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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Trial ID: NN1436-4477 
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Table of Contents    
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 4 
1 
Protocol summary ..................................................................................................................................... 8 
1.1 
Synopsis ........................................................................................................................................... 8 
1.2 
Flowchart ....................................................................................................................................... 11 
1.3 
Flowchart – phone contacts ........................................................................................................... 14 
2 
Introduction ............................................................................................................................................. 15 
2.1 
Trial rationale ................................................................................................................................. 15 
2.2 
Background .................................................................................................................................... 15 
2.3 
Benefit-risk assessment .................................................................................................................. 17 
2.3.1 
Risk assessment ............................................................................................................... 17 
2.3.2 
Benefit assessment ........................................................................................................... 20 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 20 
3 
Objectives and endpoints ........................................................................................................................ 21 
3.1 
Primary, secondary and exploratory objective and estimand......................................................... 21 
3.1.1 
Primary objective ............................................................................................................. 21 
3.1.2 
Secondary objective ......................................................................................................... 21 
3.1.3 
Estimand .......................................................................................................................... 21 
3.2 
Primary, secondary and exploratory endpoints .............................................................................. 21 
3.2.1 
Primary endpoint ............................................................................................................. 21 
3.2.2 
Secondary endpoints ........................................................................................................ 22 
3.2.2.1 
Confirmatory secondary endpoint ................................................................... 22 
3.2.2.2 
Supportive secondary endpoints ..................................................................... 22 
3.2.3 
Exploratory endpoints ..................................................................................................... 23 
4 
Trial design .............................................................................................................................................. 23 
4.1 
Overall design ................................................................................................................................ 23 
4.2 
Scientific rationale for trial design ................................................................................................. 24 
4.2.1 
Subject input into design ................................................................................................. 25 
4.3 
Justification for dose ...................................................................................................................... 25 
4.4 
End of trial definition ..................................................................................................................... 26 
5 
Trial population ....................................................................................................................................... 26 
5.1 
Inclusion criteria ............................................................................................................................ 26 
5.2 
Exclusion criteria ........................................................................................................................... 27 
5.3 
Lifestyle considerations ................................................................................................................. 28 
5.3.1 
Meals and dietary restrictions .......................................................................................... 28 
5.3.2 
Caffeine, alcohol and tobacco ......................................................................................... 28 
5.3.3 
Physical activity............................................................................................................... 28 
5.4 
Screen failures ................................................................................................................................ 28 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria...................................................... 28 
6 
Treatments ............................................................................................................................................... 28 
6.1 
Treatments administered ................................................................................................................ 28 
6.1.1 
Medical devices ............................................................................................................... 30 
6.1.1.1 
Investigational medical device ........................................................................ 30 
6.1.1.2 
Non-investigational medical devices .............................................................. 30 
6.2 
Preparation/handling/storage/accountability .................................................................................. 30 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 31 
6.4 
Treatment compliance .................................................................................................................... 31 
6.5 
Concomitant medication ................................................................................................................ 32 
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6.5.1 
Rescue medication or Rescue therapy ............................................................................. 32 
6.6 
Dose modification .......................................................................................................................... 32 
6.6.1 
Dose escalation trials ....................................................................................................... 32 
6.7 
Treatment after end of trial ............................................................................................................ 33 
7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 33 
7.1 
Discontinuation of trial treatment .................................................................................................. 34 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 34 
7.1.2 
Rescue criteria ................................................................................................................. 35 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 35 
7.2.1 
Replacement of subjects .................................................................................................. 35 
7.3 
Lost to follow-up ........................................................................................................................... 35 
8 
Trial assessments and procedures ......................................................................................................... 35 
8.1 
Efficacy assessments ...................................................................................................................... 36 
8.1.1 
Self-measured plasma glucose (SMPG) .......................................................................... 37 
8.1.2 
Continuous glucose monitoring (CGM) .......................................................................... 37 
8.1.3 
Clinical efficacy laboratory assessments ......................................................................... 38 
8.2 
Safety assessments ......................................................................................................................... 38 
8.2.1 
Insulin dose ...................................................................................................................... 38 
8.2.2 
Physical examinations ..................................................................................................... 39 
8.2.3 
Vital signs ........................................................................................................................ 39 
8.2.4 
Electrocardiograms .......................................................................................................... 40 
8.2.5 
Eye examination .............................................................................................................. 40 
8.2.6 
Clinical safety laboratory assessments ............................................................................ 41 
8.3 
Adverse events (AEs) and serious adverse events (SAE) .............................................................. 41 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 42 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 43 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 43 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 43 
8.3.5 
Pregnancy ........................................................................................................................ 43 
8.3.6 
Cardiovascular and death events ..................................................................................... 44 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE ................................................................................................................................. 44 
8.3.8 
Adverse event of special interesta .................................................................................... 44 
8.3.9 
Technical complaints ....................................................................................................... 44 
8.4 
Treatment of overdose ................................................................................................................... 44 
8.5 
Pharmacokinetics ........................................................................................................................... 45 
8.6 
Pharmacodynamics ........................................................................................................................ 45 
8.7 
Genetics ......................................................................................................................................... 45 
8.8 
Biomarkers ..................................................................................................................................... 45 
8.9 
Immunogenicity assessments ......................................................................................................... 45 
8.9.1 
Anti-drug antibodies ........................................................................................................ 45 
8.9.2 
Hypersensitivity ............................................................................................................... 45 
8.10 
Health economics ........................................................................................................................... 46 
9 
Statistical considerations ........................................................................................................................ 46 
9.1 
Statistical hypotheses ..................................................................................................................... 46 
9.2 
Sample size determination ............................................................................................................. 47 
9.3 
Populations for analyses ................................................................................................................ 48 
9.4 
Statistical analyses ......................................................................................................................... 49 
9.4.1 
General considerations .................................................................................................... 49 
9.4.2 
Primary endpoint ............................................................................................................. 50 
9.4.3 
Secondary endpoints ........................................................................................................ 51 
9.4.3.1 
Confirmatory secondary endpoint ................................................................... 51 
9.4.3.2 
Supportive secondary endpoints ..................................................................... 51 
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9.4.4 
Exploratory endpoints ..................................................................................................... 53 
9.4.5 
Other safety analyses ....................................................................................................... 53 
9.4.6 
Other analyses ................................................................................................................. 53 
9.4.6.1 
Pharmacokinetic modelling ............................................................................. 53 
9.5 
Interim analyses ............................................................................................................................. 53 
9.6 
Data monitoring committee ........................................................................................................... 54 
9.7 
Reporting of the main phase of the trial ......................................................................................... 54 
10 Supporting documentation and operational considerations ............................................................... 55 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 55 
10.1.1 
Regulatory and ethical considerations ............................................................................. 55 
10.1.2 
Financial disclosure ......................................................................................................... 55 
10.1.3 
Informed consent process ................................................................................................ 55 
10.1.4 
Information to subjects during trial ................................................................................. 56 
10.1.5 
Data protection ................................................................................................................ 56 
10.1.6 
Committees structure ....................................................................................................... 57 
10.1.6.1 Novo Nordisk safety committee...................................................................... 57 
10.1.6.2 Trial safety group ............................................................................................ 57 
10.1.6.3 Data monitoring committee............................................................................. 57 
10.1.6.4 Event adjudication committee ......................................................................... 57 
10.1.7 
Dissemination of clinical trial data .................................................................................. 57 
10.1.8 
Data quality assurance ..................................................................................................... 57 
10.1.8.1 Case report forms ............................................................................................ 57 
10.1.8.2 Monitoring ...................................................................................................... 58 
10.1.8.3 Protocol compliance ........................................................................................ 59 
10.1.9 
Source documents ............................................................................................................ 59 
10.1.10 Retention of clinical trial documentation ........................................................................ 59 
10.1.11 Trial and site closure ....................................................................................................... 60 
10.1.12 Responsibilities................................................................................................................ 60 
10.1.13 Indemnity statement ........................................................................................................ 61 
10.1.14 Publication policy ............................................................................................................ 61 
10.1.14.1 Communication of results ............................................................................... 61 
10.1.14.2 Authorship ....................................................................................................... 62 
10.1.14.3 Site-specific publication(s) by investigator(s)................................................. 62 
10.1.14.4 Investigator access to data and review of results ............................................ 62 
10.2 
Appendix 2: Clinical laboratory tests ............................................................................................ 63 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting ............................................................................................................................ 65 
10.3.1 
Definition of AE .............................................................................................................. 65 
10.3.2 
Definition of an SAE ....................................................................................................... 65 
10.3.3 
Description of event(s) for adjudication and AEs requiring additional data 
collection ......................................................................................................................... 66 
10.3.4 
Recording and follow-up of AE and/or SAE ................................................................... 68 
10.3.5 
Reporting of SAEs ........................................................................................................... 70 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ............................ 72 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ................................................................................................................. 75 
10.5.1 
Definition of technical complaint .................................................................................... 75 
10.5.2 
Recording and follow-up of technical complaints ........................................................... 75 
10.5.3 
Reporting of technical complaints ................................................................................... 76 
10.6 
Appendix 6: Retention of human biosamples ................................................................................ 77 
10.7 
Appendix 7: Hypoglycaemic episodes ........................................................................................... 78 
10.8 
Appendix 8: Titration guideline ..................................................................................................... 80 
10.9 
Appendix 9: Country-specific requirements .................................................................................. 83 
10.10 Appendix 10: Abbreviations .......................................................................................................... 87 
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10.11 Appendix 11: Protocol amendment history ................................................................................... 89 
11 References ................................................................................................................................................ 92 
 
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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Trial ID: NN1436-4477 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
Insulin icodec is a novel long-acting insulin analogue which is developed to safely cover the basal 
insulin requirements for a full week with a single subcutaneous injection. 
The present trial is designed to investigate the effect and long-term safety of once weekly insulin 
icodec in comparison to once daily insulin glargine 100 units/mL (referred to as insulin glargine in 
this document), both in combination with non-insulin anti-diabetic drugs in insulin naïve subjects 
with type 2 diabetes (T2D). The effect of insulin icodec is evaluated after a 52-week main phase, 
followed by a 26-week extension phase with the primary aim to assess long-term safety. 
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 glargine after 52 weeks of treatment to a non-inferiority limit of 0.3%. 
Key secondary objective 
To compare parameters of glycaemic control and safety of once weekly insulin icodec with once 
daily insulin glargine, both in combination with non-insulin anti-diabetic drugs, in insulin naïve 
subjects with T2D. 
Estimand 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec and insulin glargine of the change in HbA1c from baseline to week 52 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 52 
(V46) 
%-point 
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Confirmatory secondary endpoint 
Endpoint title 
Time frame 
Unit 
Time in target range 3.9-10.0 mmol/L 
(70-180 mg/dL)* 
From week 48 (V42) to week 52 (V46) 
% of readings 
* using continuous glucose monitoring (CGM) system, Dexcom G6 
Overall design: 
This is a 78-week randomised, open label, active-controlled, parallel-group, multicentre, 
multinational, treat-to-target trial with two treatment arms.  
The first 52 weeks of the trial constitute the main phase, after which the primary and confirmatory 
secondary endpoints are analysed. The focus of the 26 weeks extension phase is to evaluate long 
term safety. However, all endpoints will be analysed for the main phase and for the entire trial 
which includes both the main and the extension phase.  
Subjects will be randomised (1:1) to receive once weekly insulin icodec or once daily insulin 
glargine. 
Continuous glucose monitoring (CGM) profiles will be collected to evaluate the effect on 
glycaemic control. The CGM receiver will be blinded for both subjects and investigators. 
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) 
• 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 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 1293 subjects will be screened to achieve 970 subjects randomly assigned to trial 
product. 
Treatment groups and duration: 
The trial duration is approximately 85 weeks, consisting of a 2-week screening period, followed by 
a 78-week randomised treatment period and a 5-week follow-up period. All subjects will be 
centrally randomised in a 1:1 manner and assigned to receive once weekly insulin icodec or once 
daily insulin glargine throughout the 78-week treatment period. After end of treatment, subjects will 
be transferred to a marketed product at the discretion of the investigator.   
The following trial products will be supplied by Novo Nordisk for the duration of the trial: 
• Insulin icodec 700 units/mL, subcutaneous, solution for injection, 3 mL PDS290 pre-filled 
pen-injector 
• Insulin glargine 100 units/mL, subcutaneous, solution for injection, 3 mL SoloSTAR 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 1 
Discontinuation 
follow-up 2 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V36 
V38 
V40 
V42 
V43 
V44 
V45 
V46 
V47 
V49 
V51 
V53 
V55 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V46A 
V61A 
Phone contact 
number (P) (For 
details see separate 
flow chart in 1.3) 
 
 
 
 
 
 
P7 
  
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
 
P35 
 
 
P37 
 
 
P39 
 
 
P41 
 
 
 
 
 
 
 
P48 
 
 
P50 
 
 
P52 
 
 
P54 
 
 
P56  
 
 
 
 
 
 
 
 
 
Timing of visit 
(weeks) 
 
≤-2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
23 
24 
25 
26 
28 
32 
36 
40 
44 
48 
49 
50 
51 
52 
54 
58 
62 
66 
70 
74 
75 
76 
77 
78 
80 83 
52 
78 
Visit window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 +3 
±3 
±3 
Informed consent 
and demography 
10.1 
App. 
1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tobacco use 
5.3.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
5.1 
5.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Attend visit fasting 
5.3.1 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Concomitant 
illness/medical 
history 
8.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
Vital signs 
8.2.3 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Physical 
examination 
8.2.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Body measurements 8.2.2 
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 1 
Discontinuation 
follow-up 2 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V36 
V38 
V40 
V42 
V43 
V44 
V45 
V46 
V47 
V49 
V51 
V53 
V55 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V46A 
V61A 
Phone contact 
number (P) (For 
details see separate 
flow chart in 1.3) 
 
 
 
 
 
 
P7 
  
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
 
P35 
 
 
P37 
 
 
P39 
 
 
P41 
 
 
 
 
 
 
 
P48 
 
 
P50 
 
 
P52 
 
 
P54 
 
 
P56  
 
 
 
 
 
 
 
 
 
Timing of visit 
(weeks) 
 
≤-2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
23 
24 
25 
26 
28 
32 
36 
40 
44 
48 
49 
50 
51 
52 
54 
58 
62 
66 
70 
74 
75 
76 
77 
78 
80 83 
52 
78 
Visit window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 +3 
±3 
±3 
Eye examination 
8.2.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
ECG 
8.2.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pregnancy test 
8.3.5 
10.4 
App.4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Laboratory 
assessments 
10.2 
App.2 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
X 
HbA1c 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
 
 
CGM 
8.1.2 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X X 
 
 
Adverse event 
8.3 
10.3 
App. 
3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
Hypoglycaemic 
episodes 
8.3 
10.7 
App. 
7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
 
 


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Version: 
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Procedure 
Protocol section 
Screening 
Randomisation 
 
 
Treatment 
Follow-up 1 
Follow-up 2 
Discontinuation 
follow-up 1 
Discontinuation 
follow-up 2 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V8 
V12 
V16 
V20 
V24 
V25 
V26 
V27 
V28 
V30 
V34 
V36 
V38 
V40 
V42 
V43 
V44 
V45 
V46 
V47 
V49 
V51 
V53 
V55 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V46A 
V61A 
Phone contact 
number (P) (For 
details see separate 
flow chart in 1.3) 
 
 
 
 
 
 
P7 
  
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
 
 
 
 
P29 
P31 
P32 
P33 
 
P35 
 
 
P37 
 
 
P39 
 
 
P41 
 
 
 
 
 
 
 
P48 
 
 
P50 
 
 
P52 
 
 
P54 
 
 
P56  
 
 
 
 
 
 
 
 
 
Timing of visit 
(weeks) 
 
≤-2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
23 
24 
25 
26 
28 
32 
36 
40 
44 
48 
49 
50 
51 
52 
54 
58 
62 
66 
70 
74 
75 
76 
77 
78 
80 83 
52 
78 
Visit window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 +3 
±3 
±3 
Training in trial 
Product, Pen-
handling 
6.1 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Drug dispensing 
6 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
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  
Procedure 
Protocol section 
Treatment 
Visit 
 
P7 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P29 
P31 
P32 
P33 
P35 
P37 
P39 
P41 
P48 
P50 
P52 
P54 
P56 
Timing of visit 
(weeks) 
 
5 
7 
8 
9 
11 
12 
13 
15 
16 
17 
19 
20 
21 
27 
29 
30 
31 
34 
38 
42 
46 
56 
60 
64 
68 
72 
Visit window 
(days) 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Concomitant 
medication 
6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-measured 
plasma glucose 
8.1.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
8.3 10.3 
App. 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypoglycaemic 
episodes 
8.3 10.7 
App. 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol 
CONFIDENTIAL 
Date: 
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Trial ID: NN1436-4477 
Version: 
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Status: 
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2 
Introduction 
Diabetes mellitus is a metabolic disorder characterised by the presence of hyperglycaemia due to 
defective insulin secretion, insulin action or both. The chronic hyperglycaemia of diabetes mellitus 
is associated with significant long-term complications, particularly damage, dysfunction and failure 
of various tissues – especially the kidney, eye, nerves, heart and blood vessels.2 Diabetes is 
generally classified according to aetiological factors, where type 1 diabetes (T1D) and type 2 
diabetes (T2D) constitute the vast majority of cases. In the latest edition of the International 
Diabetes Federation’s Diabetes Atlas (2019), the estimated worldwide diabetes prevalence was 463 
million, with a prediction that by 2045, the number of people with diabetes will have increased to 
700 million.3 
Insulin icodec (proposed INN) is a novel long-acting insulin analogue which is developed to safely 
cover the basal insulin requirements for a full week with a single subcutaneous injection. Insulin 
icodec has a terminal elimination half-life of approximately 196 hours. For subjects with diabetes 
there is still an unmet medical need for products with the potential to improve clinical outcomes 
through reduced treatment burden and increased treatment adherence and persistence4 compared to 
once or twice daily basal insulin administration. The aim of the development programme for insulin 
icodec is to improve clinical outcomes for subjects with diabetes by limiting the burden associated 
with insulin treatment. 
2.1 
Trial rationale 
The present trial is designed to investigate the effect and long-term safety of once weekly insulin 
icodec in comparison to once daily insulin glargine 100 units/mL (referred to as insulin glargine in 
this document), both in combination with non-insulin anti-diabetic drugs in insulin naïve subjects 
with T2D. The effect of insulin icodec is evaluated after the 52-week main phase, followed by a 
26-week extension phase with the primary aim to assess long-term safety. 
The long-acting basal insulin products currently approved for the treatment of diabetes are usually 
administered once or twice daily. Once weekly insulin icodec would be a more convenient basal 
insulin, which could improve treatment adherence and overcome insulin initiation barriers as 
compared to once or twice daily basal insulin for insulin naïve T2D subjects.  
Overall the results of the present trial will be used to evaluate effect and long-term safety 
parameters of insulin icodec in insulin naïve T2D subjects and will support the marketing 
authorisation approval of insulin icodec. The trial will also generate data on dosing flexibility. 
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.5 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.6 
The current treatment cascade follows a stepwise approach comprising lifestyle changes in 
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Date: 
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Trial ID: NN1436-4477 
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Status: 
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combination with pharmacological intervention. In many countries, metformin is recommended as 
initial pharmacological therapy, followed by combination therapy with other oral anti-diabetic 
drugs, glucagon-like peptide 1 receptor agonists (GLP-1 RA) and/or insulin as the disease 
progresses.7 On average, after failure of diet and exercise alone, subjects require a new intervention 
with glucose-lowering agents every 3-4 years in order to obtain/retain good glycaemic control.8 
Clinical inertia, often resulting from a resistance to insulin initiation and intensification, is a major 
contributing factor to subjects with T2D who are not achieving recommended glycaemic targets.9, 10 
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 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 brochure11 and any updates hereof.  
Insulin glargine  
For further details on insulin glargine, please refer to the current EMA summary of product 
characteristics for insulin glargine (Lantus®)12, the US prescribing information for insulin glargine 
(Lantus®)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 subject 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. 
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For more information on the trial population, see Section 4.2, or the inclusion and exclusion criteria, 
Sections 5.1 and 5.2, respectively.  
2.3 
Benefit-risk assessment 
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 IB11. 
Subjects 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 IB11 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). 
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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 product(s) or related products 
is an exclusion criterion in the 
clinical trial.  
Subjects and investigators will be 
instructed in signs and symptoms of 
hypersensitivity reactions and 
subjects will be instructed to contact 
the site immediately in case of signs 
of systemic hypersensitivity. 
Blood sampling for assessment of 
antibodies against insulin icodec, as 
well as other assessments will be 
conducted in the case of systemic 
hypersensitivity reaction. Confirmed 
anti-insulin icodec antibody positive 
samples will have an antibody titer 
value determined and will be further 
tested for cross-reactivity to 
endogenous insulin. 
The risk of hypersensitivity reactions 
is described in the IB11 and SI-IC.   
For further information on 
hypersensitivity reactions, please 
refer to Sections 8.9.2 and 10.3.3. 
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 trial NN1436-4383, the proportion 
of subjects with anti-insulin 
antibodies was higher with insulin 
icodec (82.1%) than insulin glargine 
(35.0%). 
Maximum level of antibody response 
was higher against insulin icodec 
than insulin glargine.  
No apparent relationship between 
antibody titres and change in HbA1c 
or weekly insulin dose was observed.   
In 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 
Subjects may be exposed to the risk 
of COVID-19 transmission and 
infection in relation to site visits if an 
outbreak is ongoing in the given 
country.  
The risk of COVID-19 transmission 
in relation to site visits is overall 
considered to be low, however this 
may vary between geographical 
areas. To minimize the risk as much 
as possible, the following measures 
have been taken: 
• 
Cautious subject recruitment 
planning ensures controlled 
subject enrolment in countries 
where the COVID-19 pandemic 
is evaluated to be sufficiently 
under control, and at sites 
where health care resources are 
evaluated to be adequate. 
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• 
On-site visits will be well-
prepared and as short as 
possible. Physical contact 
between subjects and site staff 
will be limited to the extent 
possible, and protective 
measures will be implemented 
(e.g. use of masks, sanitizers, 
no aerosol-generating 
procedures etc. according to the 
local practice). 
• 
A COVID-19 mitigation plan 
has been developed for this trial 
which lists the additional 
actions to consider in case a site 
or country are locked down and 
subjects cannot attend on-site 
visits. 
Other 
For more information regarding the 
known and expected benefits and 
risk of insulin glargine, please refer 
to the insulin glargine EMA SmPC14, 
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 injections15. 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 78-week trial, the anticipated benefits include improved glycaemic control. The titration 
algorithm in 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 or 
every other week. 
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. 
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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 investigator’s brochure11 and any updates hereof.  
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 glargine after 52 
weeks of treatment to a non-inferiority limit of 0.3%. 
3.1.2 
Secondary objective 
To compare parameters of glycaemic control and safety of once weekly insulin icodec with once 
daily insulin glargine, 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 glargine of the change in HbA1c from baseline to week 52 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 52 (V46) 
%-point 
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3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoint 
Endpoint title 
Time frame 
Unit 
Time in target range 3.9-10.0 mmol/L 
(70-180 mg/dL)* 
From week 48 (V42) to week 52 (V46) 
% of readings 
* using continuous glucose monitoring (CGM) system, Dexcom G6 
 
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 52 (V46)  
mmol/L 
 
Secondary safety endpoints  
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline week 0 (V2) to week 52 (V46) 
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 52 (V46) 
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 52 (V46) 
Number of episodes 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline week 0 (V2) to week 83 (V63) 
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 83 (V63) 
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 83 (V63) 
Number of episodes 
Mean weekly insulin dose 
From week 50 (V44) to week 52 (V46) 
U 
Change in body weight 
From baseline week 0 (V2) to week 52 (V46) 
kg 
Time spent < 3.0 mmol/L (54 mg/dL)* 
From week 48 (V42) to week 52 (V46) 
% of readings 
Time spent > 10 mmol/L (180 mg/dL)* 
From week 48 (V42) to week 52 (V46) 
% of readings 
* using continuous glucose monitoring (CGM) system, Dexcom G6 
 
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3.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3)  
From baseline week 0 (V2) to week 78 (V61) 
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 78 (V61) 
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 78 (V61) 
Number of episodes 
 
4 
Trial design 
4.1 
Overall design 
This is a 78-week, randomised, open label, active-controlled, parallel-group, multicentre, 
multinational, treat-to-target trial with two treatment arms investigating the effect on glycaemic 
control and safety of treatment with once weekly insulin icodec compared to once daily insulin 
glargine, both in combination with non-insulin anti-diabetic drugs, in insulin naïve subjects with 
T2D inadequately controlled on non-insulin anti-diabetic drugs in need for insulin initiation.  
The trial duration is approximately 85 weeks, consisting of a 2-week screening period, followed by 
a 78-week randomised treatment period and a 5-week follow-up period. The first 52 weeks of the 
trial constitute the main phase, after which the primary and confirmatory secondary endpoints are 
analysed. The focus of the 26 weeks extension phase is to evaluate long term safety. However, all 
endpoints will be analysed for the main phase and for the entire trial including both the main and 
the extension phase.  
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 or once daily insulin 
glargine. The dose and dosing frequency of any pre-trial non-insulin anti-diabetic treatment should 
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not be changed during the trial unless due to safety concerns; except for treatment with 
sulfonylureas and glinides that must be discontinued at randomisation. During the 78-week 
treatment period, subjects will have contact with the site weekly or every other week either at site 
visits or by phone. The end of treatment visit (V61) will be one week after the last dose of insulin 
icodec and on the day of or the day after the last dose of insulin glargine. Two follow-up visits (V62 
and V63) 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. 
To evaluate the effect on glycaemic control, subjects will have continuous glucose monitoring 
(CGM) profiles collected, as specified in the flowchart (see Section 1.2). The CGM data will be 
blinded for both subjects and investigators. 
Event adjudication will be performed for acute coronary syndrome events (acute myocardial 
infarction or unstable angina pectoris requiring hospitalisation), cerebrovascular events (stroke or 
transient ischemic attack), heart failure (requiring hospitalisation or urgent heart failure visit) and 
all-cause death. 
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 glargine during 78 weeks of treatment. The trial duration and 
number of subjects were chosen to accommodate regulatory requirements for long-term insulin 
icodec exposure for safety evaluation. 
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 glargine has been chosen as 
comparator. 
The treatment arms will be open label as it was not considered feasible to blind the two treatments 
since it would increase the burden on the subjects, due to the high number of injections required for 
a double-blind, double dummy trial. 
The treat-to-target approach serves to ensure optimal titration of insulin to improve HbA1c. Insulin 
titration will be based on self-measured plasma glucose (SMPG) values. 
Titration of insulin icodec and insulin glargine will be based on pre-breakfast SMPG values and 
follow the principles outlined in the titration guideline, see Appendix 8 (Section 10.8). CGM values 
will be used during the reporting phase to generate profiles for evaluating the effect on glycaemic 
control during initiation of trial product, steady state and follow-up. To avoid influence on titration 
and the glycaemic control the CGM data will be blinded for both subjects and investigator. 
The trial population will be restricted to insulin naïve subjects on current treatment with non-
insulin, anti-diabetic drugs. This population was chosen to ensure representativeness for a broad 
type 2 diabetes subject group. Pre-trial treatment with all non-insulin anti-diabetic drugs is allowed, 
however, to decrease the risk of hypoglycaemia, sulfonylureas and glinides will be discontinued at 
randomisation. 
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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 of once weekly insulin icodec. 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.  
During the 78-week long treatment period, the subjects will be in contact with the site weekly or 
every other week, either by site visit or by phone. During the first 32 weeks the contact will be 
weekly including two CGM collection periods. From week 32 (V34) to end of treatment (V61), 
visits will be every other week except for weekly contact during CGM collection from week 
48 (V42) to week 52 (V46) and from week 74 (V57) to end of treatment week 78 (V61). The end of 
trial visit is planned six weeks after the last weekly dose of insulin icodec, allowing enough time for 
wash-out of trial drug, following at least five half-lives of insulin icodec. 
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 
Insulin glargine 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 
glargine, 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 
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 insulin glargine or once weekly insulin icodec 
injections on the same day. Due to the longer half-life of insulin icodec, the last dose of insulin 
icodec will be administered 77 weeks after randomisation, while the last dose of once daily insulin 
glargine will be administered 78 weeks after randomisation. The follow-up period for both insulin 
icodec and insulin glargine will be the 5 weeks from end of treatment (V61) until end of trial (V63). 
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. 
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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. 
For country-specific requirement to the inclusion and exclusion criteria, please refer to Appendix 9 
(Section 10.9) for further information. 
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): 
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) 
• Oral or injectable GLP-1 RAs 
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 product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
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3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
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 T2D, 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 Class IV at screening. 
9. Planned coronary, carotid or peripheral artery revascularisation. 
10. Renal impairment with estimated glomerular filtration rate value of < 30 ml/min/1.73m2 at 
screening16 by central laboratory analysis. 
11. Impaired liver function, defined as Alanine Aminotransferase ≥ 2.5 times or bilirubin >1.5 times 
upper normal limit at screening by central laboratory analysis. 
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 
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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 re-scheduled. 
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. 
5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes informed consent date, 
demography, screen failure details, and eligibility criteria. For UK: SAE is also included as minimal 
information. 
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 (IMPs) 
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 
Trial product name: 
Insulin icodec 700 units/mL 
(IMP, test product) 
Insulin glargine 100 units/mL 
(IMP, reference therapy) 
Dosage form 
Solution for injection 
Solution for injection 
Route of administration  
Subcutaneous (into the thigh, upper arm 
or abdomen) 
Subcutaneous (into the thigh, upper arm or 
abdomen) 
Recommended initial dose 
Please refer to Appendix 8  
Please refer to Appendix 8  
Dosing instructions 
Administer insulin icodec once weekly, 
on the same day each 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 is 
recommended. 
Administer insulin glargine once daily, at 
any time of the day but at the same time 
every day throughout the trial. Rotation of 
injection site is recommended. 
Packaging 
3 mL PDS290 pre-filled pen-injector 
3 mL SoloSTAR 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 from sulfonylureas and glinides, which must be 
discontinued at randomisation. 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.  
In addition, the background medication: 
• is considered to be non-investigational medicinal product (NIMP). 
• will not be provided by Novo Nordisk 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. 
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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 manufacturer’s guide.  
Continuous glucose 
monitoring (CGM) 
system 
At randomisation (V2) subjects must be instructed in handling of the CGM.  
Please refer to the Dexcom G6® manufacturer’s guide provided. 
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 
provided in the eDiary. 
• Information about the SoloSTAR pre-filled pen-injector can be found in the summary of 
product characteristics. 
• 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 (see 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 as auxiliary supplies (Table 6-2). 
For the countries where BG meter and CGM are not approved, please refer to the Appendix 9 
(Section 10.9) country-specific requirements for further information. 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply trial product. 
• Acceptable temperature ranges and conditions for storage and handling of each trial product 
when not in use and when in use are described in the trial material manual 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. 
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• 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 trial material manual. 
• 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-injector 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 an open label trial; however, the specific treatment for a subject will be assigned using 
an IWRS. The site will access the IWRS before the start of trial product administration for 
each subject. Potential bias will be reduced by central randomisation and adjudication. 
• All subjects will be centrally screened and randomised using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Trial product will be 
dispensed/allocated at the trial visits summarised in the flowchart (see Section 1.2). 
 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. 
When subjects self-administer trial product at home, compliance with trial product administration 
will be assessed by cross checking the following sources and comparing these to the expected use: 
• Drug accountability information.  
• Review of eDiaries including SMPG profiles, insulin dose and hypoglycaemia reporting. 
• Evaluating glycaemic control and adherence to the visit schedule. 
• If any suspicion of non-compliance arises the site must enter into a dialogue with the subject, 
re-emphasizing the importance of compliance and uncover barriers to compliance. This 
dialogue must be documented in the medical record.  
6.5 
Concomitant medication 
Any medication other than the trial product and anti-diabetic medication that the subject receives 
from screening (V1) until end of trial visit (V63) must be recorded along with: 
• Generic name or trade name  
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• Indication  
• Dates of administration including start and stop date. 
Concomitant medication (diabetes) 
Any anti-diabetic medication other than the trial product that the subject receives from screening 
(V1) until end of trial visit (V63) must be recorded in a separate concomitant medication (diabetes) 
form in the electronic case report form eCRF.  
The following information must be recorded for oral anti-diabetic drug, 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 (V61) only randomised treatment (trial products and pre-trial non-insulin 
anti-diabetic background medication except for sulfonylureas and glinides which must be 
discontinued at randomisation) is 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 (V61), this should be registered 
in the eCRF as change in concomitant medication (diabetes). 
Changes in concomitant medication including anti-diabetic medication and other indications must 
be recorded at each visit. If a change is due to an adverse event, then this must be reported 
according to Section 8.3. 
For information regarding concomitant medication collection including anti-diabetic medication 
and other indications for subjects who discontinue trial product see Section 7. 
6.5.1 
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 (V61) as soon as possible to collect the required data for the analysis of the primary endpoint. 
Two follow-up visits, V62 and V63, must be performed after discontinuation of the trial product. 
Visits V62 and V63 must be conducted 3 and 6 weeks respectively after discontinuation of once 
weekly insulin icodec and 2 and 5 weeks respectively after discontinuation of once daily insulin 
glargine. It is stressed that the visit window is plus 3 days for both visits V62 and V63.  
Further, it is important that discontinued subjects come in for discontinuation follow-up visits V46A 
and V61A, 52 and 78 weeks after the randomisation visit, respectively. V61A will be the last visit 
for discontinued subjects. 
Subjects who prematurely discontinue trial product should keep and use the eDiary, and return it at 
follow-up 2 visit (V63). 
If a subject discontinues the treatment prior to week 48 (V42), the subject should be asked to wear 
CGM from week 48 (V42) to week 52 (V46) in accordance with the flowchart (see Section 1.2).  
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.  
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 
(V61A) 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 (V61A). Site 
contact with discontinued subjects should be documented in the medical record.  
7.1 
Discontinuation of trial treatment 
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern related to trial product or unacceptable intolerability 
2. Pregnancy 
3. Intention of becoming pregnant 
4. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical triala 
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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, to V20, to V28, to V36, to V40, to V46, to V51, or to V55 AND 
b. the pre-breakfast SMPG readings on 3 consecutive days higher than 240 mg/dL 
(13.3 mmol/L) within the last two weeks period despite appropriate dose adjustments 
AND  
c. a confirmatory fasting plasma glucose exceeding 240 mg/dL (13.3 mmol/L) 
measured by central laboratory. The subject should come in for an unscheduled visit 
as soon as possible (within one week), the next scheduled visit should not be awaited 
AND  
d. no treatable intercurrent cause (e.g. non-compliance) for the hyperglycaemia at the 
investigator’s judgment.  
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 (not applicable for UK) . 
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. 
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 (V61). See the flowchart (Section 1.2) for data to 
be collected. 
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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/she repeatedly fails to return for scheduled visits 
and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the trial. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
8 
Trial assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart (see Section 1.2). 
• Informed consent must be obtained before any trial related activity, see 
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.  
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• 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: 
• 
Blood sample collection  
• 
Other assessments to confirm eligibility 
• 
Randomisation in IWRS 
• 
Continuous glucose monitoring fitting and training 
• 
The Investigator should create a subject profile and record administrative 
information (e.g. subject ID, year of birth and gender and treatment arm) in the 
HCP web portal  
• 
Subjects should be provided with an eDiary and instructed in how to use it  
• 
The BG meter should be connected with the eDiary  
• 
A fasting SMPG should be measured using the BG meter 
• 
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, CGM, pictures, and ECG 
recordings.  
• 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 (see Section 1.2). 
8.1.1 
Self-measured plasma glucose (SMPG) 
Subjects will be provided with a blood glucose (BG) meter including auxiliaries. The BG meters 
use test strips calibrated to plasma values. Therefore, all measurements performed with capillary 
blood are automatically calibrated to plasma equivalent glucose values, which will be shown on the 
display.  
The BG meter provided by Novo Nordisk should be used for the plasma glucose measurements 
required in the protocol, as described in the flowchart (see Section 1.2). 
A baseline SMPG value, in fasting condition, should be collected using the BG meter at V2.  
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Pre-breakfast daily SMPG  
Subjects should be instructed to measure their pre-breakfast SMPG daily from week 0 (V2) to end 
of trial (V63) 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. All data will be stored 
by Novo Nordisk (see Appendix 1, Section 10.1). 
8.1.2 
Continuous glucose monitoring (CGM) 
Subjects will be equipped with a CGM device during the treatment periods from week 0 (V2) to 
week 4 (V6) and from week 22 (V24) to week 26 (V28) and from week 48 (V42) to week 52 (V46), 
and from week 74 (V57) to week 78 (V61) and during the follow-up period from week 78 (V61) to 
week 83 (V63).  
The CGM system used in this trial will be the Dexcom G6®. 
The CGM readings will be blinded to both the subject and investigator and will not be used for any 
insulin dose titration or hypoglycaemic episode reporting. 
If a subject withdraws consent during the trial, a site visit should be scheduled in order to remove 
the CGM sensor and upload the data from the receiver. 
CGM fitting and training 
The site staff will closely supervise and assist on fitting of the sensor and transmitter on the subject 
during the site visits. Training in the CGM is the responsibility of the investigator or site staff at the 
relevant visits. For information on fitting, and changing of the CGM parts, please refer to the 
manufacturer’s manual and subject guide provided. 
CGM sensor check 
The site staff should ensure that the subject has fitted the sensor correctly and that the CGM 
receiver is working. This will be done in person during the site visit, as specified in the flowchart 
(see Section 1.2). At the end of treatment visit (V61), the site should ensure the subject can change 
the sensor at home weekly during the follow-up period.  
CGM upload 
Data stored on the CGM receiver must be uploaded at the site by the site staff to the CGM software 
following the instruction provided to the sites. The upload will be documented by the system 
directly. 
The serial number of the CGM receiver must be recorded in the eCRF at the start of each CGM 
period. In case the CGM receiver is being replaced, the serial number should be updated. 
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8.1.3 
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 (see Section 1.2) and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart (see 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. 
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 (see Appendix 8, Section 10.8). 
During the trial, starting at randomisation (V2), subjects must be instructed to report date, dose and 
time of once weekly insulin or once daily insulin 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 
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8.2.2 
Physical examinations 
A physical examination will include assessments of: 
• 
Head, ears, eyes, nose, throat, neck  
• 
Cardiovascular system  
• 
Respiratory system  
• 
Gastrointestinal system 
• 
Central and Peripheral Nervous System 
• 
Musculoskeletal system 
• 
Skin. 
Investigators should pay special attention to clinical signs related to previous serious illnesses.  
The physical examination will be recorded in the eCRF as either ‘normal’ or ‘abnormal’. If 
‘abnormal’, a comment must be given together with an assessment of clinical significance (yes/no).  
Abnormal, clinically significant findings at screening should be recorded as concomitant illness in 
the eCRF. At the following visits, any new abnormal, clinically significant findings or clinically 
significant deteriorations from baseline should be reported as an adverse event 
(Appendix 3, Section 10.4). 
Body measurements (height and weight) will also be measured and recorded. Height will be 
measured and recorded at screening visit (V1). Weight will be measured and recorded throughout 
the trial as specified in the flowchart (Section 1.2). 
• 
Body weight should be measured in kilogram (kg) or pounds (lb) without coat and shoes 
wearing only light clothing. Body weight will be recorded to one decimal.  
• 
Body weight should be assessed with the same equipment throughout the trial, if possible. 
• 
Height should be measured in centimetres (cm) or inches (in) without shoes. Height will be 
recorded to the nearest whole number. 
• 
From the body weight and height, the BMI will be calculated in the eCRF.  
8.2.3 
Vital signs 
• Pulse rate, as well as systolic and diastolic blood pressure will be assessed. 
• Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest for 
the subject in a quiet setting without distractions (e.g. no use of television, mobile phones). 
• Blood pressure and pulse rate measurements will be assessed sitting with a completely 
automated device. Manual techniques must be used only if an automated device is not 
available. 
• Blood pressure and pulse rate at screening (V1), V16, V28, V46, and end of treatment (V61) 
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.  
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• Pulse rate will be measured in connection to the blood pressure measurements. Record the pulse 
rate for the last 2 blood pressure measurements in the eCRF. The pulse rate will be calculated 
as the mean of the last 2 measurements. 
8.2.4 
Electrocardiograms 
• A 12-lead ECG must be performed by the investigator or delegated staff as outlined in the 
flowchart (Section 1.2). 
• The ECG should be preceded by at least 5 minutes of rest for the subject in a supine/sitting 
position in a quiet setting without distractions (e.g. no use of television, mobile phones). 
• The ECG must be interpreted, signed and dated by the investigator to verify that the data has 
been reviewed. 
• The ECG required at screening can be obtained within 2 weeks prior to V2 but at the latest at 
V2. The results must be interpreted by the investigator prior to randomisation in order to 
determine the eligibility of the subject. 
• The ECG required at visit V46 and at the end of treatment visit (V61) can be obtained within 2 
weeks prior to said visits. The results must be available for evaluation at visit V46 and at the 
end of treatment visit (V61), respectively. 
• Abnormal, clinically significant findings at screening should be recorded as concomitant illness 
in the eCRF. At the following visits, any new abnormal, clinically significant findings or 
clinically significant deteriorations from baseline should be reported as an adverse event 
(Appendix 3, Section 10.4).  
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 (V61) visit 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 
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should indicate the outcome of each eye examination. Relevant findings prior to randomisation 
must be recorded as concomitant illness/medical history. While relevant findings occurring after 
randomisation should be reported as an adverse event, please refer to Section 8.3 and Appendix 3 
(Section 10.4).  
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 (see Section 1.2) and laboratory manual. 
8.3 
Adverse events (AEs) and serious adverse events (SAE) 
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 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. 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 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. 
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A detailed description of the events mentioned in the above table can be found in 
Appendix 3 (Section 10.3.3). 
Events for Adjudication 
Event adjudication will be performed in randomised subjects and will be evaluated by an 
independent external EAC in a blinded manner, please refer to 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 (V2) and until the end of trial 
visit as specified in the flowchart (see Section 1.2). For subjects discontinuing trial product 
prematurely AEs must be collected until the discontinuation follow-up 2 visit (V61A). For AE 
reporting in UK, please refer to the UK specific requirements in Appendix 9 (Section 10.9). 
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3 (Section 10.3). All SAEs must be recorded and reported to Novo 
Nordisk within 24 hours, and the investigator must submit any updated SAE data to Novo Nordisk 
within 24 hours of it being available. 
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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 investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
Details of pregnancies in female subjects will be collected from first exposure to trial product and 
until the new-born infant is one month of age. 
If a female subject becomes pregnant, the investigator should inform Novo Nordisk within 14 
calendar days of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4 (Section 10.4). 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3. 
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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 subcutaneously by a trained person, or by 
glucose given intravenously by a medical professional. Glucose must also be given 
intravenously, if the subject dose not respond to glucagon within 10-15 minutes. If the 
subject has been unconscious, administration of oral carbohydrates is recommended for the 
subject upon regaining consciousness, in order to prevent a relapse. 
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 
investigator’s brochure11 or insulin glargine EMA summary of product characteristics14, US 
prescribing information13, or any locally approved label. 
8.5 
Pharmacokinetics 
Not applicable for this trial. 
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8.6 
Pharmacodynamics 
Not applicable for this trial. 
8.7 
Genetics 
Not applicable for this trial. 
8.8 
Biomarkers 
Not applicable for this trial. 
8.9 
Immunogenicity assessments 
8.9.1 
Anti-drug antibodies  
Not applicable for this trial. 
8.9.2 
Hypersensitivity  
Subjects and investigators will be instructed to detect signs and symptoms of systemic 
hypersensitivity.  
For subjects randomised to insulin icodec: In the event of a systemic hypersensitivity (not locally at 
the injection site), the subject should be called in as soon as possible to have additional blood 
samples taken in order to analyse the following parameters: 
• 
Tryptase (optimal 0.5-2 hours post the hypersensitivity reaction) 
• 
Total immunoglobulin E (IgE) antibodies 
• 
Anti-insulin icodec IgE antibodies 
• 
Anti-insulin icodec binding antibodies 
• 
Anti-human insulin IgE antibodies. 
The blood sampling should be repeated 2-4 weeks following onset of the systemic hypersensitivity 
reaction. If possible, the tests should also be performed on samples drawn prior to first 
administration of trial drug. 
For details related to blood sampling, plasma preparation and storage, please refer to the laboratory 
manual. 
Analysis will be performed by Novo Nordisk or a Novo Nordisk appointed special laboratory 
(please refer to Attachment I). The results will be reported in a separate report and attached to the 
clinical trial report. 
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 clinical trial report. 
For retention of residual hypersensitivity samples, please refer to Section 10.6. 
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Digital pictures 
The investigator or the subject must take digital pictures of the affected area at time of 
identification, using any device available (mobile phone, camera etc.) and thereafter as often as 
judged necessary by the investigator. The pictures should include subject identification number, 
date and time, time after dosing and a ruler for scaling. All pictures must be stored as part of source 
documentation at site. 
8.10 
Health economics  
Not applicable for this trial. 
9 
Statistical considerations  
9.1 
Statistical hypotheses 
The primary hypothesis to be tested is that insulin icodec is non-inferior to insulin glargine in terms 
of change from baseline to week 52 in HbA1c. 
Formally, let D be the treatment difference ‘insulin icodec’ minus ‘insulin glargine’ of the change in 
HbA1c from baseline to week 52. 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.17 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 suitable conservative estimate of insulin glargine’s 
treatment effect on HbA1c in a placebo-controlled trial in insulin naïve subjects (-0.85%-
point [-1.04; -0.66] 95% CI versus placebo), which demonstrated insulin glargine’s 
superiority.18 
The following sections detail the secondary confirmatory hypotheses. 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 
down the following hierarchy as long as the confirmatory secondary hypothesis at a given stage is 
confirmed:  
• 
Insulin icodec is superior to insulin glargine in terms of ‘time in target range 3.9 – 10.0 
mmol/L (70-180 mg/dL)’ from week 48 to week 52. 
• 
Insulin icodec is superior to insulin glargine in terms of change from baseline to week 52 in 
HbA1c. 
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Formally, let DT be the mean difference with respect to percent ‘time in target range 3.9 – 10.0 
mmol/L (70-180 mg/dL)’ from week 48 to week 52 for ‘insulin icodec’ minus ‘insulin glargine’. 
The null-hypothesis will be tested against the alternative hypothesis of superiority as given by: 
H0: DT≤0% against HA: DT >0% 
As above, let D be the mean treatment difference ‘insulin icodec’ minus ‘insulin glargine’ of the 
change in HbA1c from baseline to week 52. 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 to fulfil the FDA requirement to have at least 300 subjects 
completing 78 weeks treatment with insulin icodec as well as having sufficient marginal power for 
the confirmatory secondary hypotheses. In the recent open label study NN1250-4252 with 88 weeks 
of treatment with insulin degludec 200 units/mL and insulin glargine 300 units/mL, around 12% in 
total had discontinued treatment after 78 weeks. Assuming 85% will complete treatment in the 
present trial, 300/0.85 = 353 subjects starting treatment with insulin icodec is needed to obtain 300 
subjects completing treatment. With equal randomisation, a minimum of 706 randomised subjects 
in total is required.  
The sample size calculation also considers the power for declaring non-inferiority with a non-
inferiority margin of 0.3%-point with respect to the primary endpoint, change in HbA1c from 
baseline to week 52, for the specified estimand and the full analysis set (primary analysis set). 
Based on NN1250-4252, 10% is expected to experience an intercurrent event, as specified above, 
during the first 52 weeks of treatment. 
It is assumed that there is no difference in HbA1c between the treatment arms for subjects 
completing randomised treatment without treatment with bolus insulin for more than 2 weeks and a 
treatment difference of 0.3%-point in favour of the comparator for subjects either discontinuing 
treatment prematurely, has treatment with bolus insulin for more than 2 weeks, or withdraws from 
trial. Thus, with 10% expected to experience any of the specified intercurrent events before week 
52, this leads to an assumption of a mean treatment difference of 0.10*0.3=0.03%-point for the 
specified estimand in the overall population. 
In NN1250-4252, a standard deviation (SD) of 0.96%-points was observed in the glargine arm at 48 
weeks. In NN1250-3579, an open label study of insulin degludec 100 units/mL vs insulin glargine 
100 units/mL in insulin naïve subjects, a SD of 0.92%-points was observed in the glargine arm at 52 
weeks. Based on this, the SD is assumed to be 1.0%-point. In order to ensure a marginal power of 
80% to detect if the true treatment difference in HbA1c is 0.2%-point, 0.18%-point when adjusted 
for the 10% expected to experience any of the specified intercurrent events, 970 subjects are 
needed. With 970 subjects and the assumption of a mean treatment difference of 0.03%, there is 
sufficient power of 99% for declaring non-inferiority with a non-inferiority margin of 0.3%-point 
with respect to the primary endpoint. 
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From the above assumptions and requirements, a total of 970 subjects will be randomised 1:1. 
Assuming 25% screening failures, approximately 1293 subjects will be screened to achieve 485 
subjects randomly assigned to trial product and 485 subjects randomly assigned to the control 
group. This sample size appears to be reasonable also under deviations from the assumed treatment 
difference as illustrated in Table  9-1 displaying power for various alternative treatment differences 
and SDs. 
The confirmatory secondary endpoint is ‘time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ 
from week 48 to week 52. In a previous trial, NN1250-3874, the SD of the percent of time-in-range 
was 13.9. It is assumed that the SD is 15% and that 0.90*970=873 subjects will have time-in-range 
measurements at 52 weeks. With the assumptions above and a true difference of 4% in time-in-
target range, there is 98% power to confirm the confirmatory secondary hypothesis. 
Table  9-1 
Power for the HbA1c superiority hypothesis for various treatment differences 
and standard deviations. 
SD 
 
% intercurrent events/ 
Treatment difference 
 
8% / 0.184 
10% / 0.18 
12% / 0.176 
0.9 
88.9% 
87.5% 
86.0% 
1.0 
81.7% 
80.0% 
78.2% 
1.1 
74.0% 
72.1% 
70.2% 
SD: standard deviation. Power is computed for 1:1 randomisation and 970 subjects randomised.  
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised. 
Full analysis set  
Full analysis set: All subjects randomised. Subjects will be analysed according to 
the randomised treatment.  
Safety analysis set 
All subjects randomly assigned to trial treatment and who take at least one dose of 
trial product. Subjects are analysed according to the treatment they actually 
received.  
In exceptional cases, subjects or observations may be eliminated from the full analysis set. In such 
case the reasons for their exclusion will be documented before unblinding. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report. 
The following periods will be considered for the data collected: 
In-trial period 
The in-trial period starts at randomisation and ends at the date of: 
• The last direct subject-site contact 
• Withdrawal for subjects who withdraw their informed consent 
• The last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up (i.e. possibly an unscheduled phone visit) 
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• 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 (not applicable for UK). 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 (V63) 
• The last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly 
insulin (corresponding to 5 weeks after the end of the dosing interval for both treatment arms) 
• The end-date for the in-trial observation period. 
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product.  
Main-on-treatment period 
The main-on-treatment period starts at the date of first dose of trial product as recorded on the 
eCRF, and ends at the first date of any of the following: 
• The end date of the on-treatment period 
• Week 52 (V46). 
All efficacy endpoints will be summarised and analysed using the full analysis set and the ‘in-trial’ 
period. Safety endpoints will be evaluated using both the main-on-treatment and the on-treatment 
period with descriptive statistics being based on the safety analysis set and statistical analyses being 
based on the full analysis set unless otherwise specified. 
9.4 
Statistical analyses 
The statistical analysis plan (SAP) will be finalised prior to first subject first visit, 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 glargine 
• Region: Asia, Europe, North America, South America 
• The regions will be defined as follows:  
• Asia: India, Japan 
• Europe: Croatia, Italy, Israel, Poland, Russia, Slovakia, Spain, United Kingdom 
• North America: United States 
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• South America: Mexico 
The last available assessment made prior to the first dose will be used as the baseline value. 
All endpoints based on CGM measurements will be derived the following way. The percentage of 
time spent in a given glycaemic range will be calculated as 100 times the number of recorded 
measurements in the given glycaemic range, divided by the total number of recorded measurements. 
Following international consensus criteria it will be required that at least 70% of the planned CGM 
measurements during the last four weeks of treatment are available for endpoint data to be included 
in the analysis.19 
9.4.2 
Primary endpoint 
The primary endpoint is change in HbA1c from baseline to week 52. 
The ‘treatment policy’ estimand, will be estimated based on the full analysis set using all HbA1c 
measurements obtained at the week 52 visit, especially including measurements from subjects 
discontinuing their randomised treatment or initiating treatment with bolus insulin for more than 2 
weeks. Missing HbA1c values at the week 52 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 52 visit and have a measurement at 
the week 52 visit in the following way:  
1. First, one thousand (1000) copies of the dataset will be generated for HbA1c.  
2. Second, for subjects who discontinued their randomised treatment or initiated treatment with 
bolus insulin for more than 2 weeks at any time prior to the week 52 visit and have an HbA1c 
measurement at the week 52 visit, the change in HbA1c from last available planned on-
treatment without initiation of more than 2 weeks bolus treatment (LAOT-WOB) value to 
the week 52 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 52 visit and subsequently the missing HbA1c value at the 
week 52 visit. 
3. For each of the complete data sets, the primary endpoint will be analysed using an 
ANCOVA model with region and randomised treatment as fixed factors, and baseline HbA1c 
as a covariate. The estimates and SDs for the 1000 data sets will be pooled to one estimate 
and associated SD using Rubin’s rule.20  
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinue randomised treatment or initiate treatment with bolus insulin for more than 
2 weeks. 
The following sensitivity analysis evaluating the robustness of the assumptions about the missing 
data will be carried out: 
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For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
subjects having imputed HbA1c measurement at the week 52 visit are assumed to have a worse 
outcome in the insulin icodec arm and a better outcome in the insulin glargine 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 
The confirmatory secondary endpoint ‘time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ 
from week 48 to week 52 will be analysed similarly to the primary endpoint specified above 
without inclusion of a baseline covariate. 
The robustness of the assumptions about the missing data will be evaluated by performing a two-
dimensional tipping point analysis following the same principle as for the primary endpoint. 
The statistical analysis of the primary endpoint change in HbA1c from baseline to week 52 described 
for the primary analysis will be evaluated for superiority if the hierarchical testing is not stopped. 
9.4.3.2 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
Efficacy endpoint 
Change in fasting plasma glucose (FPG) from baseline week 0 (V2) to week 52 (V46) 
Missing FPG values at the week 52 visit (regardless of treatment completion status) will be imputed 
from trial participants who are from the insulin glargine 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 52 visit - i.e., data will be imputed based on the 
assumption that, subjects with missing endpoint data will behave like subjects completing insulin 
glargine treatment without initiation of bolus insulin treatment for more than 2 weeks at any time 
prior to the week 52 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 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 for more than 2 weeks at any time prior to the week 52 visit in the insulin 
glargine 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 and randomised treatment as fixed factors, and a baseline value as a covariate. The 
estimates and SDs for the 1000 data sets will be pooled to one estimate and associated SD 
using Rubin’s rule20. 
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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 52 
(V46). 
• 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 52 (V46). 
• 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 52 (V46). 
The following hypoglycaemic endpoints will be analysed separately using the method described 
below, substituting the main-on-treatment period with the on-treatment period: 
• Number of severe hypoglycaemic episodes (level 3), from baseline week 0 (V2) to week 83 
(V63). 
• 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 83 (V63). 
• 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 83 (V63). 
For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 visit (V63) to planned end of the main-on-treatment period) will be 
imputed using a multiple imputation technique, assuming that the event rate pre-follow-up 2 visit 
(V63) follows the respective treatment groups rate whilst post-follow-up 2 visit (V63) event rate is 
the rate of the comparator group. The imputation will be done as follows: 
1. 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 
and randomised treatment as fixed factors and the logarithm of the main-on-treatment period 
as offset.  
2. Second, based on the estimated parameters for the comparator group in this model, the 
number of episodes in the missing period will be imputed for subjects who discontinued 
their randomised treatment. Multiple copies (1000 copies) of a complete data set will be 
generated by sampling from the estimated distribution. 
3. For each of the complete data sets, the number of episodes will be analysed using a negative 
binomial model with log-link, fixed factors and offset as described in step 1. The estimates 
and SDs for the 1000 data sets will be pooled to one estimate and associated SD using 
Rubin’s rule20. 
For the definition and classification of hypoglycaemic episodes refer to Appendix 7 (Section 10.7). 
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Mean weekly insulin dose from week 50 (V44) to week 52 (V46) 
Mean weekly insulin dose during the last 2 weeks of treatment (from week 50 to 52) will be log-
transformed and analysed without using the baseline value as a covariate, but otherwise using the 
same statistical model as specified for change in FPG.  
Time spent < 3.0 mmol/L (54 mg/dL) and time spent > 10 mmol/L (180 mg/dL) from week 48 
(V42) to week 52 (V46) 
Time spent < 3.0 mmol/L (54 mg/dL) (below range) and time spent > 10 mmol/L (180 mg/dL) 
(above range) from week 48 to week 52 will be analysed separately in a similar manner as ‘time in 
target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ if deemed appropriate, i.e. if data can be 
considered normally distributed. However, if a large number of subjects have 0% time spent, then 
an alternative analysis will be performed either considering the endpoint as a dichotomous endpoint 
or by applying a censored analysis of the log-transformed values. Further details will be provided in 
the SAP. 
Change in body weight from baseline week 0 (V2) to week 52 (V46) 
Change in body weight from week 0 to week 52 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 including assessments 
collected at week 78 visit, please refer to the SAP. 
9.4.4 
Exploratory endpoints 
For details on analyses of exploratory endpoints, please refer to the SAP. 
9.4.5 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (SAEs, 
AEs, safety laboratory parameters, vital signs, etc.) will be reported descriptively based on both the 
main-on-treatment and the on-treatment period; including any notable changes of clinical interest in 
laboratory parameters. In addition, SAEs will be reported descriptively based on the in-trial period. 
9.4.6 
Other analyses  
For other analyses, please refer to the SAP. 
9.4.6.1 
Pharmacokinetic modelling  
Not applicable for this trial. 
9.5 
Interim analyses  
The trial does not include a formal interim analysis. However, the reporting will be split into a main 
phase and an extension phase, where the results of the main phase can be reported before last 
subject last visit. Subjects will provide consent for the full length of the trial. To preserve trial 
integrity during the extension phase, dissemination of results from the main phase will initially be 
limited to communication internally and with regulatory authorities. 
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9.6 
Data monitoring committee  
Not applicable for this trial.  
9.7 
Reporting of the main phase of the trial 
A database lock is planned shortly after last subject last visit of the main phase of the trial. The 
results from this main phase will thereafter be reported. The complete trial will be reported after 
database lock of the extension phase. 
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki21 and applicable ICH good clinical practice (GCP) Guideline22. 
• Applicable laws and regulations. 
• The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the clinical trial report 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 guidelines22, the IRB/IEC, and all other applicable local 
regulations 
o ensuring submission of the clinical trial report synopsis to the IRB/IEC 
o reporting any potential serious breaches to the sponsor immediately after discovery. 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
10.1.3 
Informed consent process 
• The investigator or his/her representative will explain the nature of the trial to the subject and 
answer all questions regarding the trial.  
• The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
• Subjects must be informed that their participation is voluntary. 
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• Subjects must be informed about their privacy rights.  
• Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines22, Declaration of Helsinki21 and the IRB/IEC 
or site. 
• The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form 
before any trial related activity. 
• The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
• Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial. 
• A copy of the informed consent form(s) must be provided to the subject.  
10.1.4 
Information to subjects during trial 
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.  
• 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.  
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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 EAC and the investigator will be evaluated and 
included in the clinical trial report.  
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements, such as those of the International 
Committee of Medical Journal Editors (ICMJE)23, the Food and Drug Administration Amendment 
Act (FDAAA)24, European Commission Requirements1, 25, 26 and other relevant recommendations or 
regulations. If a subject 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 
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 + 52 weeks corresponding to visit V46. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed visit 
V46. 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 
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• 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 Adverse event 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.  
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. 
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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.  
• 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). 
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.  
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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 clinical trial report for this trial. 
One or two investigators will be appointed by Novo Nordisk to review and sign the clinical trial 
report (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 clinical trial report is available. This 
includes the right not to release the results of interim analyses, because the release of such 
information may influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
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. 
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Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.27 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects’ data and will be provided with the 
randomisation code after results are available. 
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10.2 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory. 
• Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is 
needed, e.g. to follow-up on AEs, this must be done at a local laboratory. 
• The central lab will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab standard operating procedures (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 clinical trial report, 
except the following:  
• 
For haematology samples (differential count) where the test result is not normal, then a part 
of the sample may be kept for up to two years or according to local regulations.  
• 
Human biosamples for retention will be stored as described in Appendix 6 (Section 10.6). 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Glucose metabolism  
 
• Fasting plasma glucose (FPG)1 (V2, V12, V20, V28, V46, V61) 
• HbA1c (V1, V2, V12, V20, V28, V36, V40, V46, V51, V55, V61, V46A, V61A) 
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 adverse event 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, V36, 
V46, V51, V61) 
• Erythrocytes  
• Haematocrit  
• Haemoglobin  
• Leucocytes  
• Thrombocytes  
• Basophils   
• Eosinophils  
• Lymphocytes  
• Monocytes 
• Neutrophils 
Biochemistry1  
(V1, V12, V28, V36, 
V46, V51, V61) 
• Alanine Aminotransferase 
• Albumin 
• Alkaline phosphatase 
• Aspartate Aminotransferase 
• Creatinine 
• Potassium 
• Sodium 
• Total bilirubin 
Lipids 
(V2, V12, V28, V36, 
V46, V51, V61) 
• Cholesterol 
• High density lipoprotein (HDL) cholesterol 
• Low density lipoprotein (LDL) cholesterol 
• Triglycerides 
• Free fatty acids 
Pregnancy Testing 
(V2, V46, V61, V63) 
• Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for woman 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. 
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. 
 
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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. 
10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the physician’s office 
or outpatient setting. Complications that occur during hospitalisation are AEs. If a complication 
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prolongs hospitalisation or fulfils any other seriousness criteria, the event is serious. When in 
doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalisation for elective treatment (e.g. elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note:  
• Hospitalisations for administrative, trial related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs.  
• Hospital admissions for medical or surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs.  
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experience of relatively minor medical significance, 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g. sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the subject 
or may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious and reported as SAEs 
using the important medical event criterion. 
• The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable: 
• 
Suspicion of transmission of infectious agents via the IMP 
• 
Risk of liver injury defined as alanine aminotransferase or aspartate aminotransferase 
>3 x UNL and total bilirubin >2 x UNL where no alternative aetiology exists (Hy's law) 
 
10.3.3 
Description of event(s) for adjudication and AEs requiring additional data 
collection  
Description of event(s) 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) 
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• 
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 circulation28. It most often results 
from immunologic reactions to foods, medications, and insect stings, although it can also be 
induced through nonimmunologic mechanisms by any agent capable of producing a sudden, 
systemic degranulation of mast cells or basophils29. Characteristic symptoms and signs, occurring 
minutes to a few hours after exposure to potential triggering agents or events may include: 
flushing, urticaria, angioedema, hoarseness, throat tightness, stridor, wheezing, coughing, 
shortness of breath, abdominal pain, vomiting, and/or hypotension, dizziness or collapse. 
Local hypersensitivity reactions, including rash, redness, pruritus and oedema, may occur at the 
site of investigational drug injection. 
Drug hypersensitivity reactions (DHRs) are the adverse effects of pharmaceutical formulations 
(including active drugs and excipients) that clinically resemble allergy30. They can be allergic and 
non-allergic. 
If a hypersensitivity event is suspected, the subjects must contact the site staff as soon as possible 
for further guidance. All events must be reported, and in case of systemic hypersensitivity, 
additional information must be provided on a separate form. 
Medication error 
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the subject, such as:  
• administration of wrong drug.  
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. 
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• 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. 
 
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.  
 
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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 the summary 
of product characteristics for non-Novo Nordisk marketed products, for the assessment. For 
each AE/SAE, the investigator must document in the medical records that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator 
always makes an assessment of causality for every event before the initial transmission of 
the SAE data. 
• The investigator may change his/her opinion of causality, in light of follow-up information, 
and update the causality assessment in the CRF. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
• Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented. 
• Recovering/resolving: The condition is improving, and the subject is expected to recover from 
the event. This term may be applicable in cases of chronic conditions, cancer or AEs ongoing 
at time of death (where death is due to another AE).  
• Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
• Recovered/resolved with sequelae: The subject has recovered from the condition but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
• Not recovered/not resolved: The condition of the subject has not improved, and the symptoms 
are unchanged, or the outcome is not known.  
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE). 
• Fatal: This term is only applicable if the subject died from a condition related to the reported 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed as 
“recovered/resolved”, “recovering/resolving”, “recovered/resolved with sequelae” or “not 
recovered/not resolved”. An AE with a fatal outcome must be reported as an SAE. 
• Unknown: This term is only applicable if the subject is lost to follow-up. 
 
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Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions). 
This may include additional laboratory tests (e.g. skin prick test) or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a subject dies during participation in the trial or during a recognised follow-up period, Novo 
Nordisk may request a copy of the autopsy report including histopathology. 
New or updated information will be recorded in the CRF. 
 
10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
• Relevant forms (AE and safety information form) must be completed in the CRF.  
• For reporting and sign-off timelines, see Figure 10-1. 
• 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 figure Figure 10-1): 
• 
AE form within 24 hours 
• 
Safety information form within 5 calendar days 
• 
Both forms must be signed within 7 calendar days after first knowledge by the 
investigator. 
• The specific event form for AEs requiring additional data collection within 14 calendar days.  
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Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
Contact details for SAE reporting can be found in the investigator trial master file. 
Reporting of AEs for non-Novo Nordisk medical devices provided by Novo Nordisk for use 
in the trial 
Reporting of AEs on Roche Accu check and Dexcom G6: 
All complaints (including AEs) should be reported directly to the manufacturer.  
 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. If fertility is unclear 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 glargine in seminal fluid is unlikely31. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use at least an 
acceptable effective methods of contraception consistently and correctly as described in Table 10-3. 
As a minimum, contraception should be maintained until treatment discontinuation. 
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Table 10-3 
Acceptable contraceptive methods 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
ACCEPTABLE METHODSb 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action 
• Male or female condom with or without spermicidec 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods). 
NOTES 
a) Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical trials. 
b) Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. 
c) Male condom and female condom should not be used together (due to risk of failure with 
friction). 
 
Pregnancy testing 
• Additional pregnancy testing should be performed during the treatment period, if required 
locally. Please refer to the Appendix 9 (Section 10.9). 
• WOCBP should only be included after a negative highly sensitive urine pregnancy test (refer to 
Appendix 2, Section 10.2). 
• 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). 
• 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. 
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• While pregnancy itself is not considered to be an AE or SAE, any adverse event in connection 
with pregnancy or elective termination of a pregnancy for medical reasons will be reported as 
an AE or SAE. If relevant, consider adding “gestational”, “pregnancy related” or 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/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 subject will be stored 
together with the samples.  
Potential further analyses of the samples will not have any consequences for the subject and their 
relatives. Subjects can contact the investigator if they wish to be informed about results derived 
from stored antibody samples obtained from their own body. 
The samples will be stored after end of trial and until marketing authorisation approval or until the 
research project terminates, but no longer than 15 years from end of trial after which they will be 
destroyed. 
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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 IHSG32, ADA33, ISPAD34, type 1 diabetes outcomes program35, 
ATTD19. Severe hypoglycaemia as defined by Seaquist36 and ISPAD34. 
 
Severe hypoglycaemia 
1Severe hypoglycaemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose (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 concentration36. 
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 discretion33.  
Nocturnal hypoglycaemia 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive. 
Reporting of hypoglycaemic episodes in the eDiary 
PG should always be measured by the trial BG meter and hypoglycaemic episodes should be 
recorded in the eDiary.  
The following should be reported in the eDiary as hypoglycaemic events: 
- PG values < 3.9 mmol/L (70 mg/dL) 
- Severe hypoglycaemic episodes without confirmed PG values  
The investigator should ensure correct reporting of the hypoglycaemic episode. Confirmation of the 
hypoglycaemic episode review must be documented in the web portal. In case a subject is not able 
to fill in the eDiary (e.g. in case of hospitalisation) at time of episode, the subject can report the 
episode in the eDiary retrospectively. 
If the hypoglycaemic episode fulfils the criteria for an SAE then in addition to the above subject 
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. 
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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 guidelines36. 
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 concentration36.  
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 or insulin glargine. 
• Insulin icodec should be taken once weekly on the same day of the week. The starting dose will 
be 70U. 
• Insulin glargine should be taken once daily, at anytime of the day but at 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 or every other 
week 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 two 
days prior to titration and on the day of the 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. 
Titration of insulin glargine 
Adjustment of insulin glargine will be done in accordance with Table 10-5. 
Table 10-5 Insulin glargine 
 
Pre-breakfast SMPG 
Dose adjustment 
Value to use 
mmol/L 
mg/dL 
U 
Lowest of the SMPG 
values 
<4.4 
<80 
–3 
Mean of the SMPG 
values 
4.4–7.2 
80–130 
0 
>7.2 
>130 
+3 
Titration of insulin icodec 
Adjustment of insulin icodec will be done in accordance with Table 10-6. 
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Table 10-6 
Insulin icodec 
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 
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 into the HCP web portal by the investigator as applicable. 
Missing insulin icodec dose guidance 
If an insulin icodec dose is missed for ≤ 3 days after the planned dosing day, subjects should inject 
the planned dose as soon as possible and perform control SMPG 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) 
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 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 (V61).  
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 
• Initiate the new daily basal insulin two weeks after the last injection of insulin icodec 
• 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 earlier than two weeks after the last dose of insulin icodec 
• 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 glargine or insulin icodec injections. 
• SMPG values with an indication of “pre-breakfast” or “other” (see 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 glargine or insulin icodec doses prescribed at this contact. 
• Reasons for deviation from the titration algorithm, if applicable. 
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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-specific requirements 
For Italy: 
• Additional exclusion criteria:  
o 18. Known hypoglycaemic unawareness as indicated by the investigator according to 
Clarke’s questionnaire, question 8.37 
o 19. Recurrent severe hypoglycaemic episodes within the last year as judged by the 
investigator. 
o 20. Known severe diabetic autonomic neuropathy as judged by the investigator.  
 
With regard to exclusion criteria 18, information on hypoglycaemia unawareness will be 
recorded according to Clarke’s questionnaire, question 8.37 The investigator must ask the 
subject in the following way: “To what extent can you tell by your symptoms that your 
blood glucose is low?” Subjects answering “never, rarely or sometimes” are considered to 
have impaired awareness of hypoglycaemia, whereas those answering “often or always” are 
not. 
For Japan: 
• Inclusion criteria 3: age ≥ 20 years at the time of signing informed consent. 
• Preparation/Handling/Storage/Accountability: The head of the trial site or the trial 
product storage manager assigned by the head of the trial site (a pharmacist in principle) is 
responsible for control and accountability of the trial products. 
• Trial governance consideration: A seal is accepted as signature. 
For Mexico: 
• Withdrawal from the trial: should the subject, his/her family members, parents or legal 
representative decide to withdraw the consent from 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 following responsibilities will 
be included 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 
authorisation 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. 
 
• 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. 
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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 Russia: 
• Trial governance considerations: The trial should be conducted in compliance with the 
protocol, Ministry of Healthcare of Russian Federation’ order #200н from April, 01, 2016 
”Approval of rules of good clinical practice” and legal requirements of the Russian 
Federation regulating circulation of medicines.  
• BG meter and CGM: The BG meter and CGM are not approved at the time of the final 
protocol version 1.0, therefore are regarded as  investigational devices and will be labelled 
to indicate for investigational use only This BG meter has been selected in order to have 
automatic transfer of SMPG data to the eDiary and thereby increase the accuracy of SMPG 
values. It is expected that the better accuracy in SMPG data will facilitate an improvement 
in the insulin titration efforts during the trial. 
Technical complaints on the BG meter, strips, lancets or control solutions, including 
technical complaints related to AEs and SAEs, must be reported to Roche on a special 
technical complaint paper form. 
The CGM has been selected in order to provide the best data accuracy and to be consistent 
in the global clinical programme. Technical complaints on the CGM must be reported to 
 on a special technical complaint paper form. 
Timelines for reporting, from the trial site obtaining knowledge of the technical complaint: 
o Technical complaint assessed as related to a SAE within 24 hours 
o All other technical complaints within 5 calendar days  
AEs and SAEs related to the technical complaint must be reported both on the special 
technical complaint paper form and in the eCRF. In addition they must be reported in 
accordance with the standard protocol requirements for AE and SAE reporting as described 
in Section 8.3. 
At the end of the trial the BG meter and CGM must be collected by the investigator. 
If the CGM or BGM is approved in Russia during the trial conduct, the procedures above 
are not applicable anymore and technical complaints reporting should follow the standard 
vigilance procedures. 
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For Spain: 
• Retention of clinical trial documentation: 25 years according to the new Spanish Royal 
Decree 1090/2015. 
For Poland: 
• Indemnity statement: Novo Nordisk carries liability for the Trial exclusively in the scope 
defined by the applicable laws and in particular by the Civil Code and the Pharmaceutical 
Law dated 6 September 2001 (uniform version Journal of Laws of 2008 No. 45 item 271 
with amendments). In order to support potential claims for liability attributable to the Trial, 
Novo Nordisk and Investigator are covered by the Insurance Policy issued according to 
applicable Polish law. 
For UK: 
• Screen failures: Minimal information includes informed consent date, demography, screen 
failure details, eligibility criteria, and serious adverse event (SAE).   
 
• Discontinuation of trial treatment: Subjects that are randomised in violation of inclusion 
and exclusion criteria should be discontinued from the trial treatment.   
 
• Time period and frequency for collecting AE and SAE information: All AEs and SAEs 
must be collected from the time of informed consent (V1) and until the end of trial visit as 
specified in the flowchart. For subjects discontinuing trial product prematurely SAEs must 
be collected from the end of trial visit until the discontinuation follow-up 2 visit (V61A). 
 
Flowchart:  
 
• In-trial period: The subjects should not be exposed to trial product if they are not 
randomised beforehand. 
 
For US: 
• Financial disclosure: Verification under disclosures per Code of Federal Regulations 
(CFR) of Financial Conflict of Interest. 
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For India and Mexico where CGM is not approved at the time of the final protocol version 
1.0: 
• The CGM is regarded as an investigational device and will be labelled to indicate for 
investigational use only. The CGM has been selected in order to provide the best data 
accuracy and to be consistent in the global clinical programme.  
Technical complaints on the CGM must be reported to 
 on a special technical 
complaint paper form. 
Timelines for reporting, from the trial site obtaining knowledge of the technical complaint: 
o Technical complaint assessed as related to a SAE within 24 hours 
o All other technical complaints within 5 calendar days  
AEs and SAEs related to the technical complaint must be reported both on the special 
technical complaint paper form and in the eCRF. In addition they must be reported in 
accordance with the standard protocol requirements for AE and SAE reporting as described 
in Section 8.3. 
At the end of the trial CGM must be collected by the investigator. 
 
If the CGM is approved in any of the countries above during the trial conduct, the 
procedures above are not applicable any more in the said country and technical complaints 
reporting should follow the standard vigilance procedures. 
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10.10 Appendix 10: Abbreviations  
AE 
adverse event 
ANCOVA 
analysis of covariance  
BG 
blood glucose 
CGM 
continuous glucose monitoring  
CI 
confidence interval  
CRF 
case report form 
DPP-4 
dipeptidyl peptidase-4 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
EAS 
event adjudication system 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicinal Agency 
FDA 
U.S. Food and Drug Administration 
FDAAA 
U.S. Food and Drug Administration Amendments Act 
FPG 
fasting plasma glucose 
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 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgE 
immunoglobulin E 
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  
NIMP 
non-investigational medical product 
PCD 
primary completion date 
PD 
pharmacodynamic 
PI 
prescribing information 
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PK 
pharmacokinetics 
PG 
plasma glucose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI-IC 
subject information-informed consent 
SmPC 
summary of product characteristics 
SMPG 
self-measured plasma glucose 
T1D 
type 1 diabetes mellitus 
T2D 
type 2 diabetes mellitus 
V 
visit 
WOCBP 
woman of childbearing potential 
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10.11 Appendix 11: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version 3.0 (03 November 2020), Italy only 
This amendment is considered to be 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. 
Overall rationale for preparing protocol, version 3.0: 
The protocol has been amended to meet local Italian requirement.   
Section # and name 
Description of change 
Brief rationale 
5 Trial population 
The sentence: “For country specific 
requirement to the to the inclusion and 
exclusion criteria, please refer to 
Appendix 9 (Section 10.9) for further 
information.” has been added. 
To stress that country-specific 
requirements relevant for the 
eligibility criteria are described in 
appendix 9. 
10.9 Appendix 9: Country-specific 
requirements  
A new section describing Italian 
specific requirement has been added, 
in which three Italian specific 
additional exclusion criteria are 
described. 
To meet local Italian requirement. 
10.11 Appendix 11: Protocol 
amendment history 
Description of the changes included in 
version 2.0 has been added (was 
former described in section “Protocol 
amendment summary of changes 
table”). 
Log amendments and version history. 
11 References 
A reference has been added: “Clarke 
WL, Cox DJ, Gonder-Frederick LA, 
Julian D, Schlundt D, Polonsky W. 
Reduced awareness of hypoglycemia 
in adults with IDDM. A prospective 
study of hypoglycemic frequency and 
associated symptoms. Diabetes Care. 
1995;18(4):517-22”. 
Refence relevant for the added Italian 
exclusion criteria. 
 
Protocol version 2.0 (21 August 2020), UK only 
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. 
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Overall rationale for preparing protocol, version 2.0: 
The protocol has been amended to meet local UK requirement. 
Section # and name 
Description of change 
Brief rationale 
Protocol amendment summary of 
changes table 
New section added. 
Disclose version history 
5.4 Screen failures 
The sentence: “For UK: SAE is also 
included as minimal information” has 
been added at the end of the first 
paragraph. 
To meet local UK requirement 
7.1 Discontinuation of trial treatment 
The sentence ”not applicable for UK” 
has been added at the end of the last 
sentence in the section.  
To meet local UK requirement 
8.3.1 Time period and frequency for 
collecting AE and SAE information 
The following reference to UK 
specific requirements in appendix 9  
has been inserted at the end of the first 
paragraph: “For AE reporting in UK, 
please refer to the UK specific 
requirements in Appendix 9 (Section 
10.9).” 
To meet local UK requirement 
9.3 Populations for analyses  
The sentence ”not applicable for UK” 
has been added after the sentence “For 
subjects not randomised but exposed 
to trial product the in-trial period 
starts at the date of first dose of trial 
product”. 
To meet local UK requirement 
10.9 Appendix 9: Country-specific 
requirements  
The following sentences has been 
added to the list of UK specific 
requirements: 
“Screen failures: Minimal 
information includes informed 
consent date, demography, screen 
failure details, eligibility criteria, and 
serious adverse event (SAE).”  
“Discontinuation of trial treatment: 
Subjects that are randomised in 
violation of inclusion and exclusion 
criteria should be discontinued from 
the treatment”. 
“Time period and frequency for 
collecting AE and SAE information: 
All AEs and SAEs must be collected 
from the time of informed consent 
(V1) and until the end of trial visit as 
specified in the flowchart. For 
subjects discontinuing trial product 
prematurely SAEs must be collected 
from the end of trial visit until the 
discontinuation follow-up 2 visit 
(V61A).” 
To meet local UK requirement 
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Trial ID: NN1436-4477 
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Section # and name 
Description of change 
Brief rationale 
“In-trial period: The subjects should 
not be exposed to trial product if they 
are not randomised beforehand”. 
Further, a flowchart disclosing UK 
specific AE reporting has been 
inserted. 
10.11 Appendix 11: Protocol 
amendment history 
New appendix added. 
Log amendments and version history 
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Trial ID: NN1436-4477 
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11 References 
1. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
2. 
American Diabetes Association. 2. Classification and Diagnosis of Diabetes:. Diabetes Care. 
2019;42(Suppl 1):S13-S28. 
3. 
International Diabetes Federation. IDF Diabetes Atlas, 9th Edition. 2019. 
4. 
Alatorre C, Fernández Landó L, Yu M, Brown K, Montejano L, Juneau P, et al. Treatment 
patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 
receptor agonists: Higher adherence and persistence with dulaglutide compared with once-
weekly exenatide and liraglutide. Diabetes Obes Metab. 2017;19(7):953-61. 
5. 
Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res. 2005;36(3):197-209. 
6. 
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 
2004;88(4):787-835, ix. 
7. 
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. 
8. 
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. 
9. 
Halimi S, Balkau B. Better analyze the determinants of therapeutic inertia to overcome it. 
Diabetes Metab. 2012;38 Suppl 3:S27-8. 
10. 
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. 
11. 
Novo Nordisk A/S. Investigator's Brochure, insulin icodec, project NN1436, (edition 6). 5 
Jun 2020. 
12. 
Sanofi-Aventis Deutschland GmbH. Lantus®  (insulin glargine), EU Summary of Product 
Characteristics (SmPC). 2018. 
13. 
Food and Drug Administration. Lantus - U.S. Label information. 2015. 
14. 
Sanofi-Aventis Groupe. Lantus®  (insulin glargine), EU Summary of Product Characteristics 
(SmPC). 13 Jul 2018. 
15. 
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. 
16. 
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease. http://www.kidney-international.org. 2013. 
17. 
Food and Drug Administration, CDER. Guidance for Industry. Diabetes Mellitus: 
Developing Drugs and Therapeutic Biologics for Treatment and Prevention, Draft Guidance. 
February 2008. 
18. 
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. 
19. 
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. 
20. 
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987. 
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Date: 
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Trial ID: NN1436-4477 
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Page: 
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21. 
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013. 
22. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
23. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
24. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
25. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
26. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
27. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at  www.icmje.org. 
28. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et 
al. Second symposium on the definition and management of anaphylaxis: summary report--
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
29. 
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin 
Immunol. 2002;110(3):341-8. 
30. 
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised 
nomenclature for allergy for global use: Report of the Nomenclature Review Committee of 
the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-6. 
31. 
Scialli AR, Bailey G, Beyer BK, Bøgh IB, Breslin WJ, Chen CL, et al. Potential seminal 
transport of pharmaceuticals to the conceptus. Reprod Toxicol. 2015;58:213-21. 
32. 
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. 
33. 
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64. 
34. 
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. 
35. 
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 
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Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 
2017;40(12):1622-30. 
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. 
37. 
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22. 
 
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for SAP 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04460885 
Sponsor trial ID: 
NN1436-4477 
Official title of study: 
A 78-week Trial Comparing the Effect and Safety of Once 
Weekly Insulin Icodec and Once Daily Insulin Glargine 100 
units/mL, Both in Combination With Non-insulin Anti-
diabetic Treatment, in Insulin Naïve Subjects With Type 2 
Diabetes (ONWARDS 1) 
Document date* 
11-January-2021 
*Document date refers to the date on which the document was most recently updated. 
 


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
1 of 29 
Statistical Analysis Plan
NN1436-4477 
A 78-week trial comparing the effect and safety of once weekly 
insulin icodec and once daily insulin glargine 100 units/mL, 
both in combination with non-insulin anti-diabetic treatment, 
in insulin naïve subjects with type 2 diabetes. 
ONWARDS 1 
Trial Phase: 3a 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
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Table of contents 
 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 4 
Table of tables ................................................................................................................................................... 5 
Version history .................................................................................................................................................. 6 
1 Introduction ................................................................................................................................................. 7 
1.1 
Objectives and endpoints .................................................................................................................... 7 
1.1.1 
Primary, secondary and exploratory objective and estimand .............................................. 7 
1.1.1.1 
Primary objective ............................................................................................. 7 
1.1.1.2 
Secondary objective ......................................................................................... 7 
1.1.1.3 
Estimand........................................................................................................... 7 
1.1.2 
Primary, secondary and exploratory endpoints ................................................................... 7 
1.1.2.1 
Primary endpoint .............................................................................................. 7 
1.1.2.2 
Secondary endpoints ........................................................................................ 8 
1.1.2.2.1 
Confirmatory secondary endpoint............................................................ 8 
1.1.2.2.2 
Supportive secondary endpoints .............................................................. 8 
1.1.2.3 
Exploratory endpoints ...................................................................................... 8 
1.2 
Trial design ......................................................................................................................................... 9 
2 Statistical hypotheses ................................................................................................................................ 10 
3 Sample size determination ........................................................................................................................ 11 
4 Analysis sets ............................................................................................................................................... 11 
5 Statistical analyses ..................................................................................................................................... 12 
5.1 
General considerations ...................................................................................................................... 12 
5.2 
Subject disposition ............................................................................................................................ 13 
5.3 
Primary endpoint analysis ................................................................................................................. 13 
5.3.1 
Definition of endpoint ....................................................................................................... 13 
5.3.2 
Main analytical approach................................................................................................... 13 
5.3.3 
Sensitivity analysis ............................................................................................................ 14 
5.4 
Secondary endpoints analysis ........................................................................................................... 14 
5.4.1 
Confirmatory secondary endpoint ..................................................................................... 14 
5.4.1.1 
Definition of endpoint .................................................................................... 14 
5.4.1.2 
Main analytical approach ............................................................................... 14 
5.4.1.3 
Sensitivity analysis ......................................................................................... 15 
5.4.2 
Supportive secondary endpoints ........................................................................................ 15 
5.4.2.1 
Efficacy endpoint ........................................................................................... 15 
5.4.2.1.1 
Change in fasting plasma glucose (FPG) from baseline week 0 
(V2) to week 52 (V46) ........................................................................... 15 
5.4.2.2 
Safety endpoints ............................................................................................. 15 
5.4.2.2.1 
Hypoglycaemic episodes endpoints ....................................................... 15 
5.4.2.2.2 
Mean weekly insulin dose from week 50 (V44) to week 52 (V46) ....... 16 
5.4.2.2.3 
Time spent < 3.0 mmol/L (54 mg/dL) and time spent > 10 mmol/L 
(180 mg/dL) from week 48 (V42) to week 52 (V46) ............................ 17 
5.4.2.2.4 
Change in body weight from baseline week 0 (V2) to week 52 
(V46) ...................................................................................................... 17 
5.5 
Exploratory endpoints analysis ......................................................................................................... 17 
5.6 
Other safety analyses ........................................................................................................................ 17 
5.6.1 
Nocturnal hypoglycaemic episodes ................................................................................... 18 
5.6.2 
Record selection ................................................................................................................ 18 
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5.7 
Other analyses ................................................................................................................................... 18 
5.7.1 
Other derivations and assessments .................................................................................... 18 
5.7.1.1 
Achievement of HbA1c target ......................................................................... 18 
5.7.1.2 
Self-measured plasma glucose (SMPG) ......................................................... 19 
5.7.1.3 
Antidiabetic background medication ............................................................. 19 
5.7.1.4 
Insulin dose .................................................................................................... 19 
5.7.1.5 
Assessments collected at week 78.................................................................. 20 
5.8 
Interim analyses ................................................................................................................................ 20 
5.9 
Reporting of the main phase of the trial ............................................................................................ 20 
6 Supporting documentation ....................................................................................................................... 21 
6.1 
Appendix 1: List of abbreviations ..................................................................................................... 21 
6.2 
Appendix 2: Changes to protocol-planned analyses ......................................................................... 21 
6.2.1 
Changes prior to first patient first visit .............................................................................. 21 
6.2.2 
Changes after first patient first visit but before database lock for the main phase ............ 22 
6.3 
Appendix 3: Definition and calculation of endpoint, assessments and derivations .......................... 22 
7 References .................................................................................................................................................. 29 
 
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Version: 
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Table of figures 
 
Page 
Figure 1-1 
Trial design .................................................................................................................................. 9 
 
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Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
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EudraCT No: 2020-000442-34 
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Table of tables 
 
Page 
Table 1-1 
SAP Version History Summary ................................................................................................... 6 
 
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CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
6 of 29 
 
Version history 
This Statistical Analysis Plan (SAP) for trial NN1436-4477 is based on the protocol version 4.0 
dated 30Nov2020 including local amendments in the United Kingdom dated 21Aug2020 and Italy 
dated 03Nov2020. 
Table 1-1 
SAP Version History Summary 
SAP 
Version 
Approval Date Change 
Rational 
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 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
7 of 29 
 
1 
Introduction 
This Statistical Analysis Plan (SAP) is based on the protocol: A 78-week trial comparing the effect 
and safety of once weekly insulin icodec and once daily insulin glargine 100 units/mL, both in 
combination with non-insulin anti-diabetic treatment, in insulin naïve subjects with type 2 diabetes. 
ONWARDS 1, version 4.0 (dated 30Nov2020). 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 type 2 diabetes (T2D). This includes 
comparing the difference in change from baseline in HbA1c between insulin icodec and insulin 
glargine after 52 weeks of treatment to a non-inferiority limit of 0.3%. 
1.1.1.2 
Secondary objective 
To compare parameters of glycaemic control and safety of once weekly insulin icodec with once 
daily insulin glargine, 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 glargine of the change in HbA1c from baseline to week 52 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 52 (V46) 
%-point 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
8 of 29 
 
1.1.2.2 
Secondary endpoints 
1.1.2.2.1 
Confirmatory secondary endpoint 
Endpoint title 
Time frame 
Unit 
Time in target range 3.9-10.0 mmol/L 
(70-180 mg/dL)* 
From week 48 (V42) to week 52 (V46) 
% of readings 
* using continuous glucose monitoring (CGM) system, Dexcom G6 
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 52 (V46)  
mmol/L 
Secondary safety endpoints 
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline week 0 (V2) to week 52 (V46) 
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 52 (V46) 
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 52 (V46) 
Number of episodes 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline week 0 (V2) to week 83 (V63) 
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 83 (V63) 
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 83 (V63) 
Number of episodes 
Mean weekly insulin dose 
From week 50 (V44) to week 52 (V46) 
U 
Change in body weight 
From baseline week 0 (V2) to week 52 (V46) 
kg 
Time spent < 3.0 mmol/L (54 mg/dL)* 
From week 48 (V42) to week 52 (V46) 
% of readings 
Time spent > 10 mmol/L (180 mg/dL)* 
From week 48 (V42) to week 52 (V46) 
% of readings 
* using continuous glucose monitoring (CGM) system, Dexcom G6 
1.1.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3)  
From baseline week 0 (V2) to week 78 (V61) 
Number of episodes 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
9 of 29 
 
Endpoint title 
Time frame 
Unit 
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 78 (V61) 
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 78 (V61) 
Number of episodes 
 
1.2 
Trial design 
This is a 78-week, randomised, open label, active-controlled, parallel-group, multicentre, 
multinational, treat-to-target trial with two treatment arms investigating the effect on glycaemic 
control and safety of treatment with once weekly insulin icodec compared to once daily insulin 
glargine, both in combination with non-insulin anti-diabetic drugs, in insulin naïve subjects with 
T2D inadequately controlled on non-insulin anti-diabetic drugs in need for insulin initiation.  
The trial duration is approximately 85 weeks, consisting of a 2-week screening period, followed by 
a 78-week randomised treatment period and a 5-week follow-up period. The first 52 weeks of the 
trial constitute the main phase, after which the primary and confirmatory secondary endpoints are 
analysed. The focus of the 26 weeks extension phase is to evaluate long term safety.   
The overall trial design is outlined in Figure 1-1. 
Figure 1-1 
Trial design 
 
For further details see the trial protocol. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
10 of 29 
 
2 
Statistical hypotheses 
The primary hypothesis to be tested is that insulin icodec is non-inferior to insulin glargine in terms 
of change from baseline to week 52 in HbA1c. 
Formally, let D be the treatment difference ‘insulin icodec’ minus ‘insulin glargine’ of the change in 
HbA1c from baseline to week 52. 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 suitable conservative estimate of insulin glargine’s 
treatment effect on HbA1c in a placebo-controlled trial in insulin naïve subjects (-0.85%-
point [-1.04; -0.66] 95% CI versus placebo), which demonstrated insulin glargine’s 
superiority.2 
The following sections detail the secondary confirmatory hypotheses. 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 
down the following hierarchy as long as the confirmatory secondary hypothesis at a given stage is 
confirmed:  
• 
Insulin icodec is superior to insulin glargine in terms of ‘time in target range 3.9 – 10.0 
mmol/L (70-180 mg/dL)’ from week 48 to week 52. 
• 
Insulin icodec is superior to insulin glargine in terms of change from baseline to week 52 in 
HbA1c. 
Formally, let DT be the mean difference with respect to percent ‘time in target range 3.9 – 10.0 
mmol/L (70-180 mg/dL)’ from week 48 to week 52 for ‘insulin icodec’ minus ‘insulin glargine’. 
The null-hypothesis will be tested against the alternative hypothesis of superiority as given by: 
H0: DT≤0% against HA: DT >0% 
As above, let D be the mean treatment difference ‘insulin icodec’ minus ‘insulin glargine’ of the 
change in HbA1c from baseline to week 52. 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% 
 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
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3 
Sample size determination 
Please see the protocol section 9.2. 
4 
Analysis sets 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised. 
Full analysis set  
Full analysis set: All subjects randomised. Subjects will be analysed according to 
the randomised treatment.  
Safety analysis set 
All subjects randomly assigned to trial treatment and who take at least one dose of 
trial product. Subjects are analysed according to the treatment they actually 
received.  
In exceptional cases, subjects or observations may be eliminated from the full analysis set. In such 
case the reasons for their exclusion will be documented before unblinding. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report. 
The following periods will be considered for the data collected: 
In-trial period 
The in-trial period starts at randomisation and ends at the date of: 
• The last direct subject-site contact 
• Withdrawal for subjects who withdraw their informed consent 
• The last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up (i.e. possibly an unscheduled phone visit) 
• Death for subjects who die before any of the above. 
For subjects not randomised but exposed to trial product the in-trial period starts at the date of first 
dose of trial product. The end date is as defined as above. 
Baseline assessments are always included in the in-trial observation period.  
On-treatment period 
The on-treatment period starts at the date of first dose of trial product as recorded on the electronic 
case report form (eCRF), and ends at the first date of any of the following: 
• The end of trial visit (V63) 
• 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.  
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
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Baseline assessments are always included in the on-treatment observation period. 
Main-on-treatment period 
The main-on-treatment period starts at the date of first dose of trial product as recorded on the 
eCRF, and ends at the first date of any of the following: 
• The end date of the on-treatment period 
• Week 52 (V46). 
Baseline assessments are always included in the main-on-treatment period. 
All efficacy endpoints will be summarised and analysed using the full analysis set and the ‘in-trial’ 
period. Safety endpoints will be evaluated using both the main-on-treatment and the on-treatment 
period with descriptive statistics being based on the safety analysis set and statistical analyses being 
based on the full analysis set unless otherwise specified. The main-on-treatment period will be used 
to report the main phase of the trial and the on-treatment period will be used to report the complete 
trial. 
5 
Statistical analyses 
5.1 
General considerations 
Presentation of results from a statistical analysis will include the estimated mean treatment 
difference (or ratio) presented together with the two-sided 95% confidence interval and the 
corresponding two-sided p-value. 
In the statistical models, explanatory factors will be coded as follows: 
• Treatment: Once weekly insulin icodec, insulin glargine 
• Region: Asia, Europe, North America, South America 
• The regions will be defined as follows:  
• Asia: India, Japan 
• Europe: Croatia, Italy, Israel, Poland, Russia, Slovakia, Spain, United Kingdom 
• North America: United States 
• South America: 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. 
All endpoints based on CGM measurements will be summarised and analysed using the full 
analysis set and the ‘in-trial’ period and will be derived the following way. The percentage of time 
spent in a given glycaemic range will be calculated as 100 times the number of recorded 
measurements in the given glycaemic range, divided by the total number of recorded measurements. 
Following international consensus criteria it will be required that at least 70% of the planned CGM 
measurements during the last four weeks of treatment are available for endpoint data to be included 
in the analysis.3 
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CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
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5.2 
Subject disposition 
Subject disposition will summarised descriptively. 
5.3 
Primary endpoint analysis 
5.3.1 
Definition of endpoint 
The primary endpoint is change in HbA1c from baseline week 0 to week 52. 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 using all HbA1c 
measurements obtained at the week 52 visit, especially including measurements from subjects 
discontinuing their randomised treatment or initiating treatment with bolus insulin for more than 2 
weeks. Missing HbA1c values at the week 52 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 52 visit and have a measurement at 
the week 52 visit in the following way:  
1. First, one thousand (1000) copies of the dataset will be generated for HbA1c.  
2. Second, for subjects who discontinued their randomised treatment or initiated treatment with 
bolus insulin for more than 2 weeks at any time prior to the week 52 visit and have an HbA1c 
measurement at the week 52 visit, the change in HbA1c from last available planned on-treatment 
without initiation of more than 2 weeks bolus treatment (LAOT-WOB) value to the week 52 
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 52 
visit and subsequently the missing HbA1c value at the week 52 visit. 
3. For each of the complete data sets, the primary endpoint will be analysed using an ANCOVA 
model with region and randomised treatment as fixed factors, and baseline HbA1c as a covariate. 
The estimates and SDs for the 1000 data sets will be pooled to one estimate and associated 
standard deviation (SD) using Rubin’s rule.4  
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinue randomised treatment or initiate treatment with bolus insulin 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: 
1. 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.  
 
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CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
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If the amount of data for this reduced model is still insufficient for meaningful imputation, the 
following imputation strategy will be applied instead: 
2. missing values at week 52 will be imputed with baseline value adding a random error term. This 
imputation method also includes measurements collected after intercurrent events, but is 
otherwise similar to the imputation method for endpoints where there is no data collection after 
premature treatment discontinuation as described for change in FPG (see section 5.4.2.1.1).  
 
Provided that the hierarchical testing described in section 2 was not stopped the evaluation of 
superiority for the primary endpoint will be based on the same model as above. 
Missing HbA1c at week 52 will be summarised by subject treatment completion status. 
5.3.3 
Sensitivity analysis 
The following sensitivity analysis evaluating the robustness of the assumptions about the missing 
data will be carried out: 
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
subjects having imputed HbA1c measurement at the week 52 visit are assumed to have a worse 
outcome in the insulin icodec arm and a better outcome in the insulin glargine 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 non-inferiority or superiority change 
will be evaluated to assess the robustness of the primary analysis result.  
5.4 
Secondary endpoints analysis 
5.4.1 
Confirmatory secondary endpoint 
5.4.1.1 
Definition of endpoint 
The confirmatory secondary endpoint ‘time in range 3.9-10.0 mmol/L (70-180 mg/dL)’ from week 
48 to week 52 will be calculated as 100 times the number of recorded measurements in the given 
glycaemic range, divided by the total number of recorded measurements. Following international 
consensus criteria it will be required that at least 70% of the planned CGM measurements during 
the last four weeks of treatment are available for endpoint data to be included in the analysis.3 
5.4.1.2 
Main analytical approach 
The confirmatory secondary endpoint ‘time in target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ 
from week 48 to week 52 will be analysed similarly to the primary endpoint specified above 
without inclusion of a baseline covariate.  
In case the amount of data for the described imputation model is insufficient for meaningful 
imputation, the first alternative approach will be similar to that for the primary endpoint. However 
for the second alternative approach missing values will be imputed from trial participants in the 
insulin glargine arm who have completed their randomised insulin treatment. This imputation 
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Date: 
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Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
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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 and no baseline value is available as described for mean weekly insulin dose (see 
section 5.4.2.2.2).  
5.4.1.3 
Sensitivity analysis 
The robustness of the assumptions about the missing data will be evaluated by performing a two-
dimensional tipping point analysis following the same principle as for the primary endpoint. 
5.4.2 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
5.4.2.1 
Efficacy endpoint 
5.4.2.1.1 
Change in fasting plasma glucose (FPG) from baseline week 0 (V2) to week 52 
(V46) 
Missing FPG values at the week 52 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 and randomised treatment as fixed factors, and a baseline 
value as a covariate will be fitted to the LAOT-WOB value.  
• Second, the estimated residual standard deviation, s,  from this model will be used to impute 
missing values by the baseline value, adding a random normally distributed term with mean 0 
and standard deviation s. This will be done a 1000 times. 
• For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region and randomised treatment as fixed factors, and a baseline value as a covariate. The 
estimates and SDs for the 1000 data sets will be pooled to one estimate and associated SD using 
Rubin’s rule4. 
5.4.2.2 
Safety endpoints 
5.4.2.2.1 
Hypoglycaemic episodes endpoints 
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 52 
(V46). 
• 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 52 (V46). 
• 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 52 (V46). 
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Date: 
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Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
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The following hypoglycaemic endpoints will be analysed separately using the method described 
below, substituting the main-on-treatment period with the on-treatment period: 
• Number of severe hypoglycaemic episodes (level 3), from baseline week 0 (V2) to week 83 
(V63). 
• 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 83 (V63). 
• 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 83 (V63). 
For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 visit (V63) to planned end of the main-on-treatment period) will be 
imputed using a multiple imputation technique, assuming that the event rate pre-follow-up 2 visit 
(V63) follows the respective treatment groups rate whilst post-follow-up 2 visit (V63) event rate is 
the rate of the comparator group. The imputation will be done as follows: 
1. 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 and 
randomised treatment as fixed factors and the logarithm of the main-on-treatment period as 
offset.  
2. Second, based on the estimated parameters for the comparator group in this model, the number 
of episodes in the missing period will be imputed for subjects who discontinued their 
randomised treatment. Multiple copies (1000 copies) of a complete data set will be generated by 
sampling from the estimated distribution. 
3. For each of the complete data sets, the number of episodes will be analysed using a negative 
binomial model with log-link, fixed factors and offset as described in step 1. The estimates and 
SDs for the 1000 data sets will be pooled to one estimate and associated SD using Rubin’s rule4. 
For the definition and classification of hypoglycaemic episodes refer to Appendix 7 in the protocol. 
5.4.2.2.2 
Mean weekly insulin dose from week 50 (V44) to week 52 (V46) 
Mean weekly insulin dose during the last 2 weeks of treatment (from week 50 to 52) will be 
analysed log-transformed. Missing mean weekly insulin doses during the last 2 weeks of treatment 
(from week 50 to 52) (regardless of treatment completion status) will be imputed from trial 
participants who are from the insulin glargine 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 52 visit - i.e., data will be imputed based on the assumption that, subjects 
with missing endpoint data will behave like subjects completing insulin glargine treatment without 
initiation of bolus insulin treatment for more than 2 weeks at any time prior to the week 52 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 week insulin dose. 
• Second, for each dataset copy, an ANCOVA model will be fitted to mean weekly insulin dose 
values for subjects who completed their randomised treatment without initiation of bolus insulin 
for more than 2 weeks at any time prior to the week 52 visit in the insulin glargine group. The 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
17 of 29 
 
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 and randomised treatment as fixed factors. The estimates and SDs for the 1000 data sets 
will be pooled to one estimate and associated SD using Rubin’s rule4. 
 
5.4.2.2.3 
Time spent < 3.0 mmol/L (54 mg/dL) and time spent > 10 mmol/L (180 mg/dL) 
from week 48 (V42) to week 52 (V46) 
Time spent < 3.0 mmol/L (54 mg/dL) (below range) and time spent > 10 mmol/L (180 mg/dL) 
(above range) from week 48 to week 52 will be analysed separately in a similar manner as ‘time in 
target range 3.9 – 10.0 mmol/L (70-180 mg/dL)’ if deemed appropriate, i.e. if data can be 
considered normally distributed. However, if a large number of subjects have 0% time spent below 
range or above range, then an alternative analysis will be performed, where time spent below or 
above range will be analysed separately using a negative binomial model on the number of recorded 
measurements below and above range respectively with a log-link function and the logarithm of the 
total number of recorded measurements as offset. The model will include randomised treatment and 
region as factors.  
5.4.2.2.4 
Change in body weight from baseline week 0 (V2) to week 52 (V46) 
Change in body weight from week 0 to week 52 will be analysed based on the in-trial period using 
the same statistical model as specified for the primary endpoint, but with the corresponding baseline 
value as a covariate. 
5.5 
Exploratory endpoints analysis 
The following hypoglycaemic exploratory endpoints will be analysed separately using the method 
described in section 5.4.2.2.1, substituting the main-on-treatment period with the period from week 
0 to week 78, and substituting ‘follow-up 2 visit (V63)’ with ‘discontinuation of treatment’: 
• Number of severe hypoglycaemic episodes (level 3), from baseline week 0 (V2) to week 78 
(V61). 
• 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 78 (V61). 
• 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 78 (V61). 
5.6 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (serious 
adverse events (SAEs), adverse events (AEs), safety laboratory parameters, vital signs, etc.) will be 
reported descriptively based on both the main-on-treatment and the on-treatment period; including 
any notable changes of clinical interest in laboratory parameters. In addition, SAEs will be reported 
descriptively based on the in-trial period. 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
18 of 29 
 
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 5.4.2.2.1) or exploratory endpoint (see section 5.5). 
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 52 (V46) 
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 52 (V46) 
• 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 52 (V46) 
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 83 (V63) 
• 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 83 (V63) 
• 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 83 (V63). 
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 78 (V61) 
• 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 78 (V61) 
• 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 78 (V61). 
5.6.2 
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 52 weeks (yes/no)  
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
19 of 29 
 
• Achievement of HbA1c<7.0% after 52 weeks without severe (level 3) or clinically significant 
hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) during 
the prior 12 weeks  (yes/no) 
• Achievement of HbA1c<7.0% after 52 weeks without severe hypoglycaemic episodes (level 
3) during the prior 12 weeks (yes/no) 
• Achievement of HbA1c≤6.5% after 52 weeks (yes/no)  
• Achievement of HbA1c≤6.5% after 52 weeks without severe (level 3) or clinically significant 
hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter) during 
the prior 12 weeks  (yes/no) 
• Achievement of HbA1c≤6.5% after 52 weeks without severe hypoglycaemic episodes (level 
3) during the prior 12 weeks (yes/no) 
 
See Appendix 3 section 6.3 for further details. 
Missing HbA1c data at 52 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 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 
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. 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
20 of 29 
 
5.7.1.5 
Assessments collected at week 78 
Assessments collected at week 78 will be summarised and analysed in the similar way as at week 
52, however the hierarchical testing procedure will not be applied. 
5.8 
Interim analyses 
The trial does not include a formal interim analysis. However, the reporting will be split into a main 
phase and an extension phase, where the results of the main phase can be reported before last 
subject last visit. Subjects will provide consent for the full length of the trial. To preserve trial 
integrity during the extension phase, dissemination of results from the main phase will initially be 
limited to communication internally and with regulatory authorities. 
5.9 
Reporting of the main phase of the trial 
A database lock is planned shortly after last subject last visit of the main phase of the trial. The 
results from this main phase will thereafter be reported. The complete trial will be reported after 
database lock of the extension phase. 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
21 of 29 
 
6 
Supporting documentation 
6.1 
Appendix 1: List of abbreviations 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BG 
Blood glucose 
CGM 
Continuous glucose monitoring 
CI 
Confidence interval 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
LAOT-WOB 
Last available planned on-treatment without initiation of more than 2 weeks bolus treatment 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SMPG 
Self-measured plasma glucose 
T2D 
Type 2 diabetes 
 
6.2 
Appendix 2: Changes to protocol-planned analyses 
6.2.1 
Changes prior to first patient first visit 
In section 1.1.1.3 presenting the estimand the time frame for the endpoint has been changed from 
“from baseline to week 78” to “from baseline to week 52” to align with the primary endpoint and 
the primary analysis. 
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. It has also been clarified how the main-on-treatment and on-treatment periods will be 
used to report the main phase of the trial and the complete trial. 
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 how endpoints based on CGM measurements will 
be presented and the seed number for all 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 clarified that the sensitivity analysis will be performed to evaluate the 
conclusion of non-inferiority or superiority. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
22 of 29 
 
Besides that, additional derivations and assessments has been added to section 5.6 and 5.7 along 
with further details on data reporting and presentation. 
6.2.2 
Changes after first patient first visit but before database lock for the main phase 
Based on recommendations from FDA the method for imputing missing data for the second 
alternative approach for endpoints with data collection after premature treatment discontinuation 
(HbA1c and BW) and change in FPG has been changed from imputing missing data using 
completing comparator subjects to imputing from baseline values within own arm. 
6.3 
Appendix 3: Definition and calculation of endpoint, assessments and derivations 
Type 
Title 
Time frame 
Unit 
Details 
Primary 
endpoint 
Change in HbA1c 
From baseline 
week 0 (V2) to 
week 52 (V46) 
%-point 
The HbA1c value at baseline week 0 
week 52 subtracted from the HbA1c 
value week 52. 
Confirmatory 
secondary 
endpoint 
Time in target range 3.9-10.0 
mmol/L (70-180 mg/dL)* 
From week 48 
(V42) to week 52 
(V46) 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements in the 
given glycaemic range, divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Supportive 
secondary 
efficacy 
endpoint 
Change in fasting plasma 
glucose (FPG) 
From baseline 
week 0 (V2) to 
week 52 (V46)  
mmol/L 
The FPG value at baseline week 0 
subtracted from the FPG value at 
week 52. 
Supportive 
secondary safety 
endpoint 
Number of severe 
hypoglycaemic episodes 
(level 3) 
From baseline 
week 0 (V2) to 
week 52 (V46) 
Number 
of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Supportive 
secondary safety 
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 52 (V46) 
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 safety 
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 52 (V46) 
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 safety 
endpoint 
Number of severe 
hypoglycaemic episodes 
(level 3) 
From baseline 
week 0 (V2) to 
week 83 (V63) 
Number 
of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Supportive 
secondary safety 
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 83 (V63) 
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. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
23 of 29 
 
Type 
Title 
Time frame 
Unit 
Details 
Supportive 
secondary safety 
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 83 (V63) 
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 safety 
endpoint 
Mean weekly insulin dose 
From week 50 
(V44) to week 52 
(V46) 
U 
The mean of weekly insulin doses 
during the two weeks. 
Supportive 
secondary safety 
endpoint 
Change in body weight 
From baseline 
week 0 (V2) to 
week 52 (V46) 
kg 
The body weight value at baseline 
week 0 subtracted from the body 
weight value at week 52. 
Supportive 
secondary safety 
endpoint 
Time spent < 3.0 mmol/L (54 
mg/dL)* 
From week 48 
(V42) to week 52 
(V46) 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements below 3.0 
mmol/L (54 mg/dL) divided by the 
total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Supportive 
secondary safety 
endpoint 
Time spent > 10 mmol/L 
(180 mg/dL)* 
From week 48 
(V42) to week 52 
(V46) 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements above 10 
mmol/L (180 mg/dL) divided by the 
total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Exploratory 
endpoint 
Number of severe 
hypoglycaemic episodes 
(level 3)  
From baseline 
week 0 (V2) to 
week 78 (V61) 
Number 
of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Exploratory 
endpoint 
Number of clinically 
significant hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter)  
From baseline 
week 0 (V2) to 
week 78 (V61) 
Number 
of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
Exploratory 
endpoint 
Number of clinically 
significant hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or 
severe hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 78 (V61) 
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. 
Derivation 
Number of nocturnal severe 
hypoglycaemic episodes 
(level 3) 
From baseline 
week 0 (V2) to 
week 52 (V46) 
Number 
of 
episodes 
The count of all nocturnal severe 
hypoglycaemic episodes (level 3) 
within the time frame.  
Nocturnal hypoglycaemic episodes: 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
24 of 29 
 
Type 
Title 
Time frame 
Unit 
Details 
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 52 (V46) 
Number 
of 
episodes 
The count of all nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
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 52 (V46) 
Number 
of 
episodes 
The count of all 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) within the time 
frame. 
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 83 (V63) 
Number 
of 
episodes 
The count of all nocturnal severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
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 83 (V63) 
Number 
of 
episodes 
The count of all nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
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 83 (V63) 
Number 
of 
episodes 
The count of all 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) within the time 
frame. 
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 78 (V61) 
Number 
of 
episodes 
The count of all nocturnal severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
25 of 29 
 
Type 
Title 
Time frame 
Unit 
Details 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 
mg/dL), confirmed by BG 
meter)  
From baseline 
week 0 (V2) to 
week 78 (V61) 
Number 
of 
episodes 
The count of all nocturnal clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
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 78 (V61) 
Number 
of 
episodes 
The count of all 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) within the time 
frame. 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Achievement of HbA1c<7.0% 
(yes/no)  
At week 52 (V46) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c < 7.0% 
No: subject did not achieve HbA1c < 
7.0% 
Missing HbA1c data at 52 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c<7.0% 
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) 
At week 52 (V46) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c <7.0% 
without severe or clinically 
significant hypoglycaemic episodes 
during the prior 12 weeks 
No: subject did not achieve HbA1c 
<7.0% or subject had a severe or 
clinically significant hypoglycaemic 
episode during the prior 12 weeks 
or subject discontinued randomised 
treatment prematurely 
Missing HbA1c data at 52 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c<7.0% 
without severe 
hypoglycaemic episodes 
(level 3) during the prior 12 
weeks (yes/no) 
At week 52 (V46) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c <7.0% 
without severe hypoglycaemic 
episodes during the prior 12 weeks 
No: subject did not achieve HbA1c 
<7.0% or subject had 
a severe hypoglycaemic episode 
during the prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Missing HbA1c data at 52 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
26 of 29 
 
Type 
Title 
Time frame 
Unit 
Details 
Derivation 
Achievement of HbA1c≤6.5% 
(yes/no)  
At week 52 (V46) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
No: subject did not achieve HbA1c 
≤6.5% 
Missing HbA1c data at 52 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c≤6.5% 
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) 
At week 52 (V46) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5 
without severe or clinically 
significant hypoglycaemic episodes 
during the prior 12 weeks 
No: subject did not achieve HbA1c 
≤6.5% or subject had a severe or 
clinically significant hypoglycaemic 
episode during the prior 12 weeks 
or subject discontinued randomised 
treatment prematurely 
Missing HbA1c data at 52 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c≤6.5% 
without severe 
hypoglycaemic episodes 
(level 3) during the prior 12 
weeks (yes/no) 
At week 52 (V46) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
without severe hypoglycaemic 
episodes during the prior 12 weeks 
No: subject did not achieve HbA1c 
≤6.5% or subject had 
a severe hypoglycaemic episode 
during the prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Missing HbA1c data at 52 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Change in HbA1c 
From baseline 
week 0 (V2) to 
week 78 (V61) 
%-point 
The HbA1c value at baseline week 0 
subtracted from the HbA1c value at  
week 78. 
Derivation 
Time in target range 3.9-10.0 
mmol/L (70-180 mg/dL)* 
From week 74 
(V57) to week 78 
(V61) 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements in the 
given glycaemic range, divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Derivation 
Change in fasting plasma 
glucose (FPG) 
From baseline 
week 0 (V2) to 
week 78 (V61)  
mmol/L 
The FPG value at baseline week 0 
subtracted from the FPG value at 
week 78. 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
27 of 29 
 
Type 
Title 
Time frame 
Unit 
Details 
Derivation 
Mean weekly insulin dose 
From week 76 
(V59) to week 78 
(V61) 
U 
The sum of all actual insulin doses 
within the time frame divided by the 
actual number of days between the 
two visits multiplied by 7. 
Derivation 
Change in body weight 
From baseline 
week 0 (V2) to 
week 78 (V61) 
kg 
The body weight value at baseline 
week 0 subtracted from the body 
weight value at week 78. 
Derivation 
Time spent < 3.0 mmol/L (54 
mg/dL)* 
From week 74 
(V57) to week 78 
(V61) 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements below 3.0 
mmol/L (54 mg/dL) divided by the 
total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Derivation 
Time spent > 10 mmol/L 
(180 mg/dL)* 
From week 74 
(V57) to week 78 
(V61) 
% of 
readings 
Calculated as 100 times the number 
of recorded measurements above 10 
mmol/L (180 mg/dL) divided by the 
total number of recorded 
measurements. Following 
international consensus criteria, it 
will be required that at least 70% of 
the planned CGM measurements 
during the last four weeks of 
treatment are available for endpoint 
data to be included in the analysis. 
Derivation 
Achievement of HbA1c<7.0% 
(yes/no)  
At week 78 (V61) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c < 7.0% 
No: subject did not achieve HbA1c < 
7.0% 
Missing HbA1c data at 78 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c<7.0% 
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) 
At week 78 (V61) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c <7.0% 
without severe or clinically 
significant hypoglycaemic episodes 
during the prior 12 weeks 
No: subject did not achieve HbA1c 
<7.0% or subject had a severe or 
clinically significant hypoglycaemic 
episode during the prior 12 weeks 
or subject discontinued randomised 
treatment prematurely 
Missing HbA1c data at 78 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
28 of 29 
 
Type 
Title 
Time frame 
Unit 
Details 
Derivation 
Achievement of HbA1c<7.0% 
without severe 
hypoglycaemic episodes 
(level 3) during the prior 12 
weeks (yes/no) 
At week 78 (V61) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c <7.0% 
without severe hypoglycaemic 
episodes during the prior 12 weeks 
No: subject did not achieve HbA1c 
<7.0% or subject had 
a severe hypoglycaemic episode 
during the prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Missing HbA1c data at 78 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c≤6.5% 
(yes/no)  
At week 78 (V61) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
No: subject did not achieve HbA1c 
≤6.5% 
Missing HbA1c data at 78 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c≤6.5% 
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) 
At week 78 (V61) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5 
without severe or clinically 
significant hypoglycaemic episodes 
during the prior 12 weeks 
No: subject did not achieve HbA1c 
≤6.5% or subject had a severe or 
clinically significant hypoglycaemic 
episode during the prior 12 weeks 
or subject discontinued randomised 
treatment prematurely 
Missing HbA1c data at 78 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
Derivation 
Achievement of HbA1c≤6.5% 
without severe 
hypoglycaemic episodes 
(level 3) during the prior 12 
weeks (yes/no) 
At week 78 (V61) Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
without severe hypoglycaemic 
episodes during the prior 12 weeks 
No: subject did not achieve HbA1c 
≤6.5% or subject had 
a severe hypoglycaemic episode 
during the prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Missing HbA1c data at 78 weeks will 
be imputed in the same way as in 
the primary analysis before deriving 
the dichotomous outcome.  
* using continuous glucose monitoring (CGM) system, Dexcom G6 
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CONFIDENTIAL


Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
11 January 2021 Novo Nordisk 
Trial ID: NN1436-4477 
Version: 
2.0 
UTN: U1111-1247-3878 
Status: 
Final 
EudraCT No: 2020-000442-34 
Page: 
29 of 29 
 
7 
References 
1. 
Food and Drug Administration, CDER. Guidance for Industry. Diabetes Mellitus: 
Developing Drugs and Therapeutic Biologics for Treatment and Prevention, Draft Guidance. 
February 2008. 
2. 
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. 
Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International 
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40. 
4. 
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987. 
 
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