Clinical trial NCT04760626
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2021-03-01; Completion date: 2022-08-29
Enrollment: 1085 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares insulin icodec to different daily insulins in people with type 2 diabetes.

The study will look at how well insulin icodec taken once weekly controls blood sugar compared to the insulins taken once daily. Participants will either get insulin icodec, that participants will have to inject once a week on the same day of the week, or a marketed insulin, that participants will have to inject once a day. Which treatment participants get is decided at random.

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

Participants will measure their blood sugar every day. Participants will get a study phone to record safety data in the electronic diary (eDiary). If participants get a daily insulin they will record their insulin doses in the eDiary. If Participants get weekly insulin icodec, participants study phone will also have the DoseGuide App. The DoseGuide App gives dose recommendations based on their blood sugar and previous doses. Participants will record their insulin doses in the DoseGuide App.

The study will last for about 1 year and 2 months. Participants will have 8 planned clinic visits with the study doctor. More visits will be planned to meet individual needs. At 6 clinic visits participants will have blood samples taken.

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

Detailed description:

Arms: arm 1: Participants randomised to insulin icodec will use insulin icodec with the DoseGuide App to guide their titration. arm 2: Participants randomised to basal insulin analogue injections once daily
Interventions: intervention 1: Insulin icodec intervention 2: Insulin Glargine 100U/mL intervention 3: Insulin Degludec intervention 4: Insulin Glargine 300U/mL
Intervention descriptions: intervention 1: Participants will receive subcutaneous (s.c.) injections of insulin icodec once weekly for 52 weeks. intervention 2: Participants will receive subcutaneous (s.c.) injections of insulin analogues once daily for 52 weeks. intervention 3: Participants will receive subcutaneous (s.c.) injections of insulin analogues once daily for 52 weeks. intervention 4: Participants will receive subcutaneous (s.c.) injections of insulin analogues once daily for 52 weeks.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04760626 
Sponsor trial ID: 
NN1436-4481 
Official title of study: 
Effectiveness and safety of once weekly insulin icodec used 
with DoseGuide versus once daily basal insulin analogues in 
an insulin naïve type 2 diabetes population in a clinical 
practice setting (ONWARDS 5) 
Document date*: 
23 November 2020 
 
*Document date refers to the date on which the document was most recently updated. 


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Protocol 
 
Effectiveness and safety of once weekly insulin icodec used with DoseGuide 
versus once daily basal insulin analogues in an insulin naïve type 2 diabetes 
population in a clinical practice setting 
ONWARDS 5 
Substance: Insulin icodec 
Universal Trial Number: U1111-1247-5279  
EudraCT Number: 2020-000476-38  
IND Number:137406 
Trial phase: 3a 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) 
and/or site(s)  
Protocol version 2.0 
23 November 2020 
All countries 
Original protocol version 1.0 
12 November 2020 
All countries 
 
Overall rationale for preparing protocol, version 2.0: 
Section # and name 
Description of change 
Brief rationale 
Section 10.3.5 Reporting of 
SAEs 
Safety Information Form 
reporting timelines updated to 
5 days 
Safety reporting timeline was 
incorrectly stated as 7 days, 
has been corrected to ensure 
correct reporting.  
 
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Table of Contents    
 ........................................................................................................................................................ Page 
Table of Contents.............................................................................................................................................. 2 
1 
Protocol summary ..................................................................................................................................... 7 
1.1 
Synopsis ........................................................................................................................................... 7 
1.2 
Flowchart ....................................................................................................................................... 10 
2 
Introduction ............................................................................................................................................. 12 
2.1 
Trial rationale ................................................................................................................................. 12 
2.2 
Background .................................................................................................................................... 12 
2.3 
Benefit-risk assessment .................................................................................................................. 14 
2.3.1 
Risk assessment ............................................................................................................... 14 
2.3.2 
Benefit assessment ........................................................................................................... 17 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 18 
3 
Objectives and endpoints ........................................................................................................................ 18 
3.1 
Primary, secondary and exploratory objective and estimand......................................................... 18 
3.1.1 
Primary objective ............................................................................................................. 18 
3.1.2 
Secondary objective ......................................................................................................... 18 
3.2 
Primary, secondary and exploratory endpoints .............................................................................. 19 
3.2.1 
Primary endpoint ............................................................................................................. 19 
3.2.2 
Secondary endpoints ........................................................................................................ 19 
3.2.2.1 
Supportive secondary endpoints ..................................................................... 19 
3.2.3 
Exploratory endpoints ..................................................................................................... 20 
4 
Trial design .............................................................................................................................................. 20 
4.1 
Overall design ................................................................................................................................ 20 
4.2 
Scientific rationale for trial design ................................................................................................. 22 
4.3 
Justification for dose ...................................................................................................................... 23 
4.4 
End of trial definition ..................................................................................................................... 23 
5 
Trial population ....................................................................................................................................... 23 
5.1 
Inclusion criteria ............................................................................................................................ 24 
5.2 
Exclusion criteria ........................................................................................................................... 24 
5.3 
Lifestyle considerations ................................................................................................................. 25 
5.3.1 
Meals and dietary restrictions .......................................................................................... 25 
5.3.2 
Caffeine, alcohol and tobacco ......................................................................................... 25 
5.4 
Screen failures ................................................................................................................................ 25 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria...................................................... 25 
6 
Treatments ............................................................................................................................................... 25 
6.1 
Treatments administered ................................................................................................................ 25 
6.1.1 
Medical devices ............................................................................................................... 27 
6.1.1.1 
Investigational medical device ........................................................................ 27 
6.1.1.2 
Non-investigational medical device ................................................................ 28 
6.2 
Preparation/handling/storage/accountability .................................................................................. 28 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 29 
6.4 
Treatment compliance .................................................................................................................... 29 
6.5 
Concomitant medication ................................................................................................................ 30 
6.5.1 
Rescue medication or Rescue therapy ............................................................................. 30 
6.6 
Dose modification .......................................................................................................................... 31 
6.7 
Treatment after end of trial ............................................................................................................ 31 
7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 31 
7.1 
Discontinuation of trial treatment .................................................................................................. 32 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 33 
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7.1.2 
Rescue criteria ................................................................................................................. 33 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 33 
7.2.1 
Replacement of subjects .................................................................................................. 33 
7.3 
Lost to follow-up ........................................................................................................................... 33 
8 
Trial assessments and procedures ......................................................................................................... 34 
8.1 
Efficacy assessments ...................................................................................................................... 35 
8.1.1 
Self-measured plasma glucose (SMPG) .......................................................................... 35 
8.1.2 
Clinical outcome assessments ......................................................................................... 35 
8.1.3 
Clinical efficacy laboratory assessments ......................................................................... 36 
8.2 
Safety assessments ......................................................................................................................... 36 
8.2.1 
Insulin dose ...................................................................................................................... 36 
8.2.2 
Physical examinations ..................................................................................................... 37 
8.2.3 
Vital signs ........................................................................................................................ 37 
8.2.4 
Electrocardiograms .......................................................................................................... 37 
8.2.5 
Eye examination .............................................................................................................. 38 
8.2.6 
Clinical safety laboratory assessments ............................................................................ 38 
8.3 
Adverse events and serious adverse events .................................................................................... 39 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 41 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 41 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 41 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 41 
8.3.5 
Pregnancy ........................................................................................................................ 42 
8.3.6 
Cardiovascular and death events ..................................................................................... 42 
8.3.7 
Technical complaints ....................................................................................................... 42 
8.4 
Treatment of overdose ................................................................................................................... 42 
8.5 
Pharmacokinetics ........................................................................................................................... 43 
8.6 
Pharmacodynamics ........................................................................................................................ 43 
8.7 
Genetics ......................................................................................................................................... 43 
8.8 
Biomarkers ..................................................................................................................................... 43 
8.9 
Immunogenicity assessments ......................................................................................................... 43 
8.9.1 
Hypersensitivity ............................................................................................................... 43 
8.10 
Health economics ........................................................................................................................... 44 
9 
Statistical considerations ........................................................................................................................ 44 
9.1 
Statistical hypotheses ..................................................................................................................... 44 
9.2 
Sample size determination ............................................................................................................. 45 
9.3 
Populations for analyses ................................................................................................................ 46 
9.4 
Statistical analyses ......................................................................................................................... 47 
9.4.1 
General considerations .................................................................................................... 47 
9.4.2 
Primary endpoint ............................................................................................................. 47 
9.4.3 
Secondary endpoints ........................................................................................................ 48 
9.4.3.1 
Supportive secondary endpoints ..................................................................... 48 
9.4.4 
Exploratory endpoints ..................................................................................................... 50 
9.4.5 
Other safety analyses ....................................................................................................... 50 
9.4.6 
Other analyses ................................................................................................................. 50 
9.5 
Interim analyses ............................................................................................................................. 50 
9.6 
Data monitoring committee ........................................................................................................... 50 
9.7 
Reporting of the main part of the trial............................................................................................ 51 
10 Supporting documentation and operational considerations ............................................................... 51 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 51 
10.1.1 
Regulatory and ethical considerations ............................................................................. 51 
10.1.2 
Financial disclosure ......................................................................................................... 51 
10.1.3 
Informed consent process ................................................................................................ 52 
10.1.4 
Information to subjects during trial ................................................................................. 52 
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10.1.5 
Data protection ................................................................................................................ 52 
10.1.6 
Committees structure ....................................................................................................... 53 
10.1.6.1 Novo Nordisk safety committee...................................................................... 53 
10.1.6.2 Data monitoring committee............................................................................. 53 
10.1.6.3 Event adjudication committee ......................................................................... 53 
10.1.7 
Dissemination of clinical trial data .................................................................................. 53 
10.1.8 
Data quality assurance ..................................................................................................... 53 
10.1.8.1 Case report forms ............................................................................................ 53 
10.1.8.2 Monitoring ...................................................................................................... 54 
10.1.8.3 Protocol compliance ........................................................................................ 55 
10.1.9 
Source documents ............................................................................................................ 55 
10.1.10 Retention of clinical trial documentation ........................................................................ 55 
10.1.11 Trial and site closure ....................................................................................................... 56 
10.1.12 Responsibilities................................................................................................................ 56 
10.1.13 Indemnity statement ........................................................................................................ 57 
10.1.14 Publication policy ............................................................................................................ 57 
10.1.14.1 Communication of results ............................................................................... 57 
10.1.14.2 Authorship ....................................................................................................... 58 
10.1.14.3 Site-specific publication(s) by investigator(s)................................................. 58 
10.1.14.4 Investigator access to data and review of results ............................................ 58 
10.2 
Appendix 2: Clinical laboratory tests ............................................................................................ 59 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting ............................................................................................................................ 61 
10.3.1 
Definition of AE .............................................................................................................. 61 
10.3.2 
Definition of an SAE ....................................................................................................... 61 
10.3.3 
Description of event(s) for adjudication and AEs requiring additional data 
collection ......................................................................................................................... 62 
10.3.4 
Recording and follow-up of AE and/or SAE ................................................................... 64 
10.3.5 
Reporting of SAEs ........................................................................................................... 66 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ............................ 69 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ................................................................................................................. 72 
10.5.1 
Definition of technical complaint .................................................................................... 72 
10.5.2 
Recording and follow-up of technical complaints ........................................................... 72 
10.5.3 
Reporting of technical complaints ................................................................................... 73 
10.6 
Appendix 6: Medical device adverse events, adverse device effects, serious adverse events 
and device deficiencies: Definition and procedures for recording, evaluating, follow-up, and 
reporting ......................................................................................................................................... 74 
10.6.1 
Definition of AE and adverse device effects (ADE) ....................................................... 74 
10.6.2 
Definition of SAE, serious adverse device effect (SADE) and unanticipated serious 
adverse device effect (USADE) ...................................................................................... 74 
10.6.3 
Definition of device deficiency ....................................................................................... 75 
10.6.4 
Recording and follow-up of AE and/or SAE and device deficiencies ............................ 75 
10.6.5 
Reporting of SAEs ........................................................................................................... 78 
10.6.6 
Reporting of device deficiencies ..................................................................................... 78 
10.7 
Appendix 7: Retention of human biosamples ................................................................................ 78 
10.8 
Appendix 8: Hypoglycaemic episodes ........................................................................................... 80 
10.9 
Appendix 9: Titration guideline ..................................................................................................... 82 
10.10 Appendix 10: Country-specific requirements ................................................................................ 84 
10.11 Appendix 11: Abbreviations .......................................................................................................... 85 
11 References ................................................................................................................................................ 87 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
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Protocol attachment II Country list of key staff and relevant departments. 
 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
The present trial is a 52-week trial designed to investigate the effectiveness and safety of once 
weekly insulin icodec used with DoseGuide in comparison to once daily basal insulin analogues 
both in combination with any non-insulin antidiabetic medication in insulin-naïve subjects with type 
2 diabetes mellitus (T2D) in a clinical practice setting. This trial will provide data on adherence, 
persistence (stay-time on treatment, rate of discontinuation) and patient reported outcomes. In 
addition, the trial will provide long-term exposure data (52 weeks). The long-acting basal insulin 
products currently approved for treatment of T2D are administered once or twice daily. The once 
weekly treatment regimen for insulin icodec would become a more convenient basal insulin which 
could improve treatment adherence and overcome insulin initiation barriers as compared to once 
daily or twice daily basal insulin for subjects with T2D.  
Objectives and endpoints: 
The primary objective of this trial is to demonstrate the effectiveness on glycaemic control of once 
weekly insulin icodec used with DoseGuide in combination with non-insulin anti-diabetic drugs in 
insulin naïve subjects with T2D in a clinical practice setting. This includes comparing the treatment 
difference in change from baseline in HbA1c between insulin icodec and once daily basal insulin 
analogues after 52 weeks of treatment to a non-inferiority limit of 0.3%. 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline week 0 (V2) to week 52 (V6) 
%-point 
 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec used with DoseGuide and basal insulin analogues of the change in HbA1c from baseline to 
week 52 for all randomised subjects, irrespective of adherence to randomised treatment and changes 
to antidiabetic background medication. The following intercurrent events will be handled by the 
treatment policy strategy: discontinuation of randomised insulin treatment, and withdrawal from the 
trial (measurements collected after these intercurrent events are used in the primary analysis). This 
estimand aims to reflect effectiveness of the treatment on a population level in clinical practice.  
Overall design: 
This is a 52-week, randomised, open label, parallel-group, active-controlled, multi-centre, multi-
national trial with real world elements comparing insulin icodec versus once daily basal insulin 
analogues among insulin naïve T2D subjects in which insulin initiation is needed. Subjects 
randomised to insulin icodec will use insulin icodec with the DoseGuide App to guide their 
titration.  
The decision that insulin initiation is indicated is at the investigator’s discretion. Potential eligible 
subjects will be identified by the investigator and all eligible subjects should be provided with the 
subject information document and asked if they would like to participate in the trial. The 
investigator will have determined the subjects eligible for treatment with basal insulin including 
insulin icodec prior to informed consent. Which basal insulin the subjects are to initiate, either 
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insulin icodec or the once daily basal insulin analogue selected prior to randomisation by the 
investigator as per standard of care, will be allocated by 1:1 randomisation.  
Key inclusion criteria: 
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 above 7.0% (53 mmol/mol) as measured by central lab. 
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 antidiabetic 
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 non-insulin antidiabetic drug classes including combinations (≥ 
half of the maximum approved dose according to local label or maximum tolerated 
or effective dose): 
i. Sulfonylureas 
ii. Meglitinides (glinides) 
iii. DPP-4 inhibitors 
iv. SGLT2 inhibitors 
v. Thiazolidinediones 
vi. Alpha-glucosidase inhibitors 
vii. Oral combination products (for the allowed individual Oral Antidiabetic 
Drugs (OADs)) 
viii. Oral or injectable GLP-1-receptor agonists 
8. Intensification with insulin is indicated to achieve glycaemic target (4.4-7.2 mmol/L, 80-130 
mg/dL) at the discretion of the treating investigator. 
Key exclusion criteria: 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice). 
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 30 days before screening. * 
5. Any disorder which in the investigator’s opinion might jeopardise subject’s safety. 
 
*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 
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postinfectious conditions is allowed if the last dose of the investigational medicinal product has 
been received more than 30 days before screening 
Number of subjects: 
Approximately 1200 subjects will be screened to achieve 1096 subjects randomly assigned to trial 
product. 
Treatment groups and duration: 
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
a 52-week randomised treatment period and a 5-week follow-up period. Subjects will be 
randomised 1:1 to receive either insulin icodec or a once daily basal insulin analogue. Subjects 
randomised to insulin icodec will initiate with and use the DoseGuide App to support titration. 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, s.c., solution for injection, 3 mL PDS290 pre-filled 
pen-injector  
• DoseGuide System 
• Insulin Glargine 100 units/mL, s.c., solution for injection, 3 mL SoloSTAR pre-filled 
pen-injector   
• Insulin Glargine 300 units/mL, s.c., solution for injection, 1.5 mL SoloSTAR pre-filled 
pen-injector 
• Insulin Degludec 100 units/mL, s.c., solution for injection, 3 mL PDS290 pre-filled 
pen-injector 
Data monitoring committee: No 
 
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2 
Introduction 
Diabetes mellitus is a metabolic disorder characterised by the presence of hyperglycaemia due to 
defective insulin secretion, insulin action or both. The chronic hyperglycaemia of diabetes mellitus 
is associated with significant long-term complications, particularly damage, dysfunction and failure 
of various tissues – especially the kidney, eye, nerves, heart and blood vessels.1 Diabetes is 
generally classified according to aetiological factors, where type 1 diabetes (T1D) and type 2 
diabetes (T2D) constitute the vast majority of cases. In the latest edition of the International 
Diabetes Federation’s Diabetes Atlas (2019), the estimated worldwide diabetes prevalence was 463 
million, with a prediction that by 2045, the number of people with diabetes will have increased to 
700 million.2  
Insulin icodec (proposed INN) is a novel long-acting insulin analogue which is developed to safely 
cover the basal insulin requirements for a full week with a single subcutaneous (s.c.) injection. 
Insulin icodec has a terminal elimination half-life of approximately 196 hours. For patients with 
diabetes there is still an unmet medical need for products with the potential to improve clinical 
outcomes through reduced treatment burden, increased treatment adherence and persistence3 
compared to once or twice daily basal insulin administration. The aim of the development 
programme for insulin icodec is to improve clinical outcomes for patients with diabetes by limiting 
the burden associated with insulin treatment.  
2.1 
Trial rationale 
The present trial is a 52-week trial designed to investigate the effectiveness and safety of once 
weekly insulin icodec used with DoseGuide in comparison to once daily basal insulin analogues 
both in combination with any non-insulin antidiabetic medication in insulin-naïve T2D subjects in a 
clinical practice setting. This trial will provide data on adherence, persistence (stay-time on 
treatment, rate of discontinuation) and patient reported outcomes. In addition, the trial will provide 
long-term exposure data (52 weeks) for insulin icodec. The long-acting basal insulin products 
currently approved for treatment of T2D are administered once or twice daily. The once weekly 
treatment regimen for insulin icodec would become a more convenient basal insulin which could 
improve treatment adherence and overcome insulin initiation barriers as compared to once daily or 
twice daily basal insulin for subjects with T2D.  
Overall, the result of the present trial will be important for evaluating the safety and effectiveness of 
insulin icodec in a clinical practice setting and will be part of the clinical development programme 
for the marketing authorisation approval of insulin icodec.  
2.2 
Background 
Diabetes mellitus  
T2D is characterised by insulin resistance, impaired insulin secretion, increased hepatic glucose 
output due to glucagon dysregulation resulting in chronic hyperglycaemia.4 The pathogenesis is not 
fully understood but seems to be heterogeneous, involving environmental, lifestyle, and genetic 
factors leading to chronic hyperglycaemia caused by peripheral tissue insulin resistance, impaired 
insulin secretion due to abnormal beta-cell function and abnormal glucose metabolism in the liver.5 
The current treatment cascade follows a stepwise approach comprising lifestyle changes in 
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combination with pharmacological intervention. Metformin is recommended as initial 
pharmacological therapy, followed by combination therapy with other oral antidiabetic drugs 
(OADs), glucagon-like peptide 1 receptor agonists (GLP-1) and/or insulin as the disease 
progresses.6 On average, after failure of diet and exercise alone, patients require a new intervention 
with glucose-lowering agents every 3-4 years in order to obtain/retain good glycaemic control.7 
Clinical inertia, often resulting from a resistance to insulin initiation and intensification, is a major 
contributing factor to patients with T2D who are not achieving recommended glycaemic targets.8, 9 
Increased convenience is believed to support timely insulin initiation in the treatment for T2D and 
thereby overcoming the clinical inertia associated with insulin initiation. 
Insulin icodec  
Insulin icodec is a novel long-acting insulin analogue which is developed to safely cover the basal 
insulin requirements for a full week with a single subcutaneous (s.c.) injection. Insulin icodec has a 
terminal elimination half-life of approximately 196 hours. The molecule consists of a peptide 
backbone and a fatty acid-containing side-chain. The peptide backbone is more resistant towards 
proteolytical degradation compared to human insulin and the side chain gives a strong binding to 
albumin. Both features contribute to the long action of insulin icodec.  
The development programme for insulin icodec is currently ongoing. Three clinical pharmacology 
trials, NN1436-4314 [T2D], NN1436-4226 [renal impaired] and NN1436-4422 [T1D] have been 
completed. No unexpected safety concerns were identified. Two clinical pharmacology trials 
(NN1436-4462 [T2D]) and NN1436-4225 [T1D] are currently 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 (IGlar) U100 in subjects with T2D. 
Results from these trials were used in the development of the insulin icodec titration guideline 
(Appendix 9 (Section 10.9)).   
A comprehensive review of results from the non-clinical and clinical studies of insulin icodec can 
be found in the current edition of the investigator’s brochure (IB)10 and any updates hereof.  
DoseGuide System 
The DoseGuide System provides dose recommendations via the DoseGuide App for once weekly 
insulin icodec. The DoseGuide System is a cloud-based system containing a titration algorithm to 
provide dose guidance in accordance with standard clinical practice and the insulin icodec titration 
guidance (Appendix 9, Section 10.9). The DoseGuide System is considered an investigational 
software as a medical device (SaMD) in this trial and is documented as compliant with standards 
and regulations for medical devices in the trial countries.  
A comprehensive overview of the DoseGuide System is available in the current edition of the 
investigator’s brochure for the DoseGuide System and any updates hereof.  
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Once daily basal insulin analogues 
The comparator in this trial is commercially available once daily basal insulin analogues: insulin 
glargine U100, U300 and insulin degludec U100, fixed combinations with basal insulin are not 
allowed.  
The investigator will determine the subject eligible for treatment with basal insulin and select a 
once daily basal insulin analogue for the patient as per standard of care prior to randomisation (V1). 
Subjects will then be randomised to either receive insulin icodec or the once daily basal insulin 
analogue selected.  
For further details on the once daily basal insulin analogues, please refer to the respective 
Investigator’s Brochure, EMA Summary of Products Characteristics (SmPC), US Prescribing 
Information or locally approved Product Information.  
Trial population 
The trial population will consist of insulin naïve subjects with T2D on any non-insulin antidiabetic 
medication. The trial population has been chosen to mimic a relatively broad insulin naïve T2D 
patient group expected to receive the drug once marketed. Subjects should be indicated for 
intensification with insulin to achieve glycaemic target at the investigator’s discretion. Eligible 
subjects will be identified by the investigator within the normal clinical practice setting.  
For more information on the trial population, see Sections 4.2, for more information regarding 
inclusion and exclusion criteria see Sections 5.1 and 5.2, respectively 
2.3 
Benefit-risk assessment 
2.3.1 
Risk assessment 
Main benefits and risks are described in the below sections.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of insulin icodec10 and the DoseGuide System11 may be found in the 
respective Investigator’s Brochures and any updates hereof. 
For more information about known and expected benefits and risks for once daily basal insulin 
analogue comparators, refer to the respective Investigator’s Brochure, EMA SmPC or locally 
approved Product Information for the relevant product. 
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. 
A Trial Risk Assessment has been carried out in accordance with ISO 14155:2020 to identify 
potential additional risks associated with the participation in this trial compared to not participate.12 
The scope of the Trial Risk Assessment includes all procedures, products and their associated 
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residual risks, examined alone and in combination. Procedures similar to the standard clinical 
practice for treatment of subjects with T2D initiating basal insulin for the first time are outside 
scope of the Trial Risk Assessment. Key risks identified in the detailed Trial Risk Assessment are 
included below. 
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people with diabetes, put value in reducing the number of insulin injections18. Therefore, the 
treatment adherence and quality of life are expected to increase by introducing a once weekly basal 
insulin treatment. Further insulin icodec will be used together with DoseGuide which will provide a 
patient-facing titration guidance to aid subjects with titration.  
The trial population will consist of insulin naive subjects with T2D. For all subjects participating in 
this 52-week trial, the anticipated benefits include improved glycaemic control. The titration 
algorithm (Appendix 9, Section 10.9), which specifies recommended adjustments of basal insulin 
dose at different plasma glucose levels, will be used to ensure that subjects receive optimal 
treatment.  
2.3.3 
Overall benefit-risk conclusion 
Insulin icodec is efficacious at clinically relevant doses.  
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. The titration algorithm implemented in the DoseGuide 
System is based on the completed clinical trials and is similar in all phase 3a trials. The DoseGuide 
System has been developed to be, and is documented as, compliant with applicable standards and 
regulations for medical devices.11 
As an overall assessment, Novo Nordisk evaluates that the benefit-risk balance of insulin icodec 
used with DoseGuide remains favourable.  
Considering the measures taken to minimise risk to subjects participating in this trial, the risks 
identified in association with insulin icodec are justified by the anticipated benefits that may be 
afforded to subjects with diabetes mellitus.  
3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objective and estimand 
3.1.1 
Primary objective 
To demonstrate the effectiveness on glycaemic control of once weekly insulin icodec used with 
DoseGuide in combination with non-insulin anti-diabetic drugs in insulin naïve subjects with T2D 
in a clinical practice setting. This includes comparing the difference in change from baseline in 
HbA1c between insulin icodec used with DoseGuide and once daily basal insulin analogues after 52 
weeks of treatment to a non-inferiority limit of 0.3%. 
3.1.2 
Secondary objective 
To compare effect on safety and patient reported outcomes related to treatment satisfaction and 
compliance of once weekly insulin icodec used with DoseGuide versus once daily basal insulin 
analogues both in combination with any non-insulin antidiabetic drugs in insulin-naïve subjects 
with T2D in a clinical practice setting. 
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Estimand: 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec used with DoseGuide and basal insulin analogues of the change in HbA1c from baseline to 
week 52 for all randomised subjects, irrespective of adherence to randomised treatment and changes 
to antidiabetic background medication. The following intercurrent events will be handled by the 
treatment policy strategy: discontinuation of investigational medical products, and withdrawal from 
the trial (measurements collected after these intercurrent events are used in the primary analysis). 
This estimand aims to reflect effectiveness of the treatment on a population level in clinical 
practice.  
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 
(V6) 
%-point 
 
3.2.2 
Secondary endpoints 
3.2.2.1 
Supportive secondary endpoints 
Supportive secondary effectiveness endpoints  
Endpoint title 
Time frame 
Unit 
Time from baseline to treatment 
discontinuation or intensification 
From baseline week 0 (V2) to week 52 
(V6) 
Days 
Change in DTSQs (Diabetes Treatment 
Satisfaction Questionnaire) in total 
treatment satisfaction 
From baseline week 0 (V2) to week 52 
(V6) 
Score of 0-36.  
6 items scored on a scale of 0 
to 6. The higher the score the 
greater the satisfaction with 
treatment.  
Trim-D (Treatment Related Impact 
Measure for Diabetes) compliance 
domain 
At end of treatment week 52 (V6) 
Score of 4-20. 
4 items scored on a scale of 1 
to 5 Transformed to a 0-100 
scale with higher scores 
corresponding to better 
compliance. 
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Supportive secondary safety endpoints  
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3)  
From baseline week 0 (V2) to week 57 
(V8) 
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 57 
(V8) 
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 57 
(V8)  
Number of episodes 
  
3.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3)  
From baseline week 0 (V2) to week 52 
(V6)  
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 
(V6)  
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 
(V6)  
Number of episodes 
 
4 
Trial design 
4.1 
Overall design 
This is a 52-week, randomised, open label, parallel-group, active-controlled, multi-centre, multi-
national trial with real world elements comparing insulin icodec used with DoseGuide versus once 
daily basal insulin analogues among insulin naïve T2D subjects in which insulin initiation is 
needed.  
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
a 52-week randomised treatment period and a 5-week follow-up period. The overall trial design and 
visit schedule are outlined in Figure 4-1 and trial flowchart (see Section 1.2), respectively.  
 
 
 
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Figure 4-1 
Trial design 
 
 
Sites will be primarily selected based on generalisability and previous research experience, thus 
both primary care and endocrinologist settings will be selected. The investigator will preferably be 
the subject's practicing physician who in clinical practice would be initiating the subject on insulin.  
The decision that insulin initiation is indicated is at the investigator’s discretion. Potential eligible 
subjects will be identified by the investigator and all eligible subjects should be provided the subject 
information document and asked if they would like to participate in the trial. The investigator will 
have determined the subjects eligible for treatment with basal insulin including insulin icodec prior 
to informed consent; however, the allocation to initiate insulin icodec or once daily basal insulin 
analogue will be made by randomisation. Subjects will be randomised 1:1 to receive either insulin 
icodec or the once daily basal insulin analogue selected by the investigator prior to randomisation as 
per standard of care. No stratification will be conducted. 
Diagnostic and monitoring procedures outside of normal clinical practice are employed to ensure 
sufficient AE collection to comply with phase 3a requirements and further described below. The 
trial will include: Informed consent, randomisation and treatment initiation visit (dedicated 
randomisation visit), a dedicated trial visit at 13, 26 and 39 weeks and a dedicated end of treatment 
visit at 52 weeks scheduled one week after the last dose of once weekly insulin icodec 
administration.  
After end of treatment subjects will be transferred to a marketed product at the discretion of the 
investigator. AE collection will continue with 2 follow-up contacts (V7 and V8). The follow-up 
period is 5 weeks. Due to different dosing intervals (weekly vs daily) and the longer half-life of 
insulin icodec, the last follow-up visit (V8) is scheduled to take place 6 weeks after the last dose of 
once weekly insulin icodec and 5 weeks after the last dose of once daily basal insulin analogue.  
Additional visits are allowed throughout the trial. It is anticipated that investigators, as the subjects' 
physicians, ensure subjects undergo medical evaluation at regular intervals over the course of the 
trial as per standard of care. Subjects will be encouraged to reach out proactively if experiencing 
any alterations to their wellbeing which may represent an AE. AEs will be assessed at all contacts 
and subjects will have an eDiary to report hypoglycaemic episodes (Appendix 8, Section 10.8).  
To allow treatment according to local practice all non-insulin antidiabetic medications as standard 
of care are allowed at the investigator’s discretion during the trial. Add-on, discontinuation or dose 
modification of non-insulin antidiabetic medications is allowed at any time during the trial.  
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If the randomised basal insulin treatment is discontinued, intensification to basal bolus regimen is 
needed or use of DoseGuide is permanently discontinued, the subject should attend an early 
discontinuation follow-up visit (V6A) and continue marketed antidiabetic medications including 
insulins at the discretion of the investigator for the remainder of the trial. 
Event adjudication will be performed for acute coronary syndrome events (acute myocardial 
infarction and unstable angina pectoris requiring hospitalisation), cerebrovascular events (stroke 
and 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 effectiveness on glycaemic control and safety of insulin 
icodec used with DoseGuide in comparison to standard of care once daily basal insulin analogues 
both in combination with any non-insulin antidiabetic medication in insulin naïve T2D subjects in a 
clinical practice setting. The basal insulin analogues chosen as comparators in this trial have been 
selected based on their suitability for a once daily injection as well as being widely used for 
initiating insulin therapy in insulin naïve T2D patients.  
Assessing effectiveness requires a less stringent sponsor-controlled schedule to allow physicians to 
tailor their diabetes management to the individual subject. The trial design and subsequent visit 
frequency has been chosen to meet data collection requirements whilst allowing for local clinical 
practice to be maintained. Investigators, as the subjects’ physicians, are expected to schedule 
additional visits as they deem relevant. It is therefore expected that the investigator together with 
the patient agrees to a tailored visit schedule during the conduct of the trial in addition to the 
planned visits according to the flow chart. 
The treatment duration of 52 weeks is evaluated to be adequate time for assessing effectiveness on 
glycaemic control and safety. This duration will also allow for up-titrating of the basal insulin.  
A centralized treat-to-target approach will not be applied as titration of basal insulin analogues 
should be done according to local labelling and clinical practice. Use of a marketed titration support 
mobile app or tool to aid titration of the once daily basal insulin analogue comparators is allowed at 
the discretion of the investigator.  
Titration of insulin icodec should be conducted in accordance with the titration guideline, see 
Appendix 9 (Section10.9). Titration of insulin icodec will be aided by use of the DoseGuide 
System, which calculates the dose recommendations with the same titration algorithm as outlined in 
the titration guideline and will provide insulin icodec dose recommendations via the DoseGuide app 
to subjects. (see the current DoseGuide System IB for more information). 
During the treatment period, the subjects will have dedicated site visits every three months, in 
accordance with recommended clinical practice, with the option of additional site visits or phone 
contacts according to local clinical practice or need. The last follow-up visit is planned to be 6 
weeks after the last dose of insulin icodec, allowing appropriate time for wash-out of trial drug, 
following at least 5 half-lives of insulin icodec. 
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Subjects included in the trial can be on any non-insulin antidiabetic medication, however to 
minimise the risk of hypoglycaemia subjects treated with glinides or sulfonylureas (either alone or 
in combination with other OADs) will be asked to reduce the dose by approximately 50% at the 
discretion of the investigator. Underlying diseases such as recent cardiac problems, impaired liver 
or renal function will be documented prior to treatment initiation but are not exclusion criteria. 
However, any condition considered to jeopardise subject’s safety as assessed by the investigator 
will exclude the subject from trial participation. As no human data are available on pregnancies 
following exposure to insulin icodec, female subjects of childbearing potential can only be recruited 
if adequate contraceptive methods are used (see Appendix 4, Section 10.4).  
Overall, the eligibility criteria will allow for enrolment of a relatively broad insulin naïve T2D 
population resembling one of the key target populations for insulin icodec use.  
4.3 
Justification for dose 
Insulin icodec should be initiated at 70 units once weekly with aid from the DoseGuide App. One 
unit of insulin icodec has similar glucose lowering effect to one unit of insulin glargine 100 
units/mL and one unit of insulin degludec 100 units/mL, and therefore once weekly dosing 
corresponds to seven times the daily dose of a once daily basal insulin comparator. Basal insulin 
analogue comparators should be initiated as per the discretion of the investigator based on local 
clinical practice.   
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 will initiate insulin injections and this treatment should continue until 
52 weeks after randomisation where the subjects come in for the end of treatment visit (V6).  
Initiation and titration of daily basal insulin analogues will be done according to approved label and 
local clinical practice. Initiation and titration of insulin icodec should be conducted in accordance 
with the titration guideline aided by the use of the DoseGuide App, see Appendix 9 (Section 10.9).  
4.4 
End of trial definition 
A subject is considered to have completed the trial if he/she has completed all phases of the trial 
including the last visit. 
The end of the trial is defined as the date of the last visit of the last subject in the trial globally. 
5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
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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 above 7.0% (53 mmol/mol) as measured by central lab. 
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 antidiabetic 
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. Antidiabetic Drugs including combination products (≥ 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 Antidiabetic 
Drugs (OADs)) 
• Oral or injectable GLP-1-receptor agonists 
8. Intensification with insulin is indicated to achieve glycaemic target (4.4-7.2 mmol/L; 
80-130 mg/dL) at the discretion of the treating investigator. 
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. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice). 
4. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 30 days before screening. * 
5. Any disorder which in the investigator’s opinion might jeopardise subject’s safety. 
 
*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 
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postinfectious conditions is allowed if the last dose of the investigational medicinal product has 
been received more than 30 days before screening. 
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
Fasting is defined as at least 8 hours without food and drink intake, except for water and other 
prescribed medication.   
5.3.2 
Caffeine, alcohol and tobacco 
Tobacco use is defined as smoking at least once cigarette or equivalent daily. 
5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes informed consent date, 
demography, screen failure details and eligibility criteria. 
A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria 
This section is not applicable for this trial. 
6 
Treatments 
6.1 
Treatments administered 
Treatments include the investigational medicinal products (Section 6.1) and investigational medical 
device (Section 6.1.1.1) provided by Novo Nordisk. 
Investigational medicinal products (IMP) 
All investigational medical products (IMPs) provided by Novo Nordisk 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  
700U/mL 
(IMP, test product) 
Insulin Degludec 
100U/mL  
(IMP, reference 
therapy) 
Insulin Glargine 
100U/mL 
(IMP, reference 
therapy) 
Insulin Glargine 
300U/mL 
(IMP, reference 
therapy) 
Dosage form 
Solution for injection Solution for injection 
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)  
Subcutaneous (into the 
thigh, upper arm or 
abdomen) 
Subcutaneous (into the 
thigh, upper arm or 
abdomen) 
Recommended 
initial dose 
Please refer to 
Appendix 9  
Please refer to 
Appendix 9 
Please refer to 
Appendix 9 
Please refer to 
Appendix 9 
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. 
Administer insulin 
degludec once daily at 
any time of the day, but 
at the same time every 
day throughout the trial. 
Rotation of injection 
site 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.  
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 PDS290 pre-filled 
pen-injector 
3 mL SoloSTAR pre-
filled pen-injector 
1.5 mL SoloSTAR 
pre-filled pen-injector  
• Subjects should administer insulin icodec at site at the randomisation visit (V2). 
• Subjects should initiate basal insulin analogues as per clinic’s standard of care.   
• Subjects should be instructed to discard the needle after each injection and store the pen-
injector without a needle attached.  
• Subjects should be instructed to use one pen injector for the full in-use time period (see 
TMM). The subjects should change the pen-injector only if the inuse time is passed or a full 
dose can no longer be given. 
Non-investigational medicinal products (NIMP) 
After randomisation subjects can continue add-on or remove non-insulin anti-diabetic medication in 
agreement with the investigator and according to local clinical practice throughout the entire trial; 
however, subjects with glinides or sulfonylureas (either alone or in combination with other OADs) 
will be asked to reduce the dose by approximately 50% at the discretion of the investigator, at 
randomisation. There is no requirement that background medication should be stable or maintained 
at the pre-trial dose and dose adjustments are allowed during the entire treatment period. Please see 
section 6.5 for reporting of concomitant anti-diabetic medications. 
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 unless otherwise required by local regulations. 
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The investigator must document that training in the DFU for the DoseGuide App has been given to 
the subjects orally and in writing at randomisation (V2) and should be repeated during the trial to 
ensure correct use of the medical device. 
6.1.1.2 
Non-investigational medical device 
Needles for pre-filled pen-injectors are listed in Table 6-2. 
Blood Glucose Meter (BG Meter) 
For self-measuring of blood glucose during the trial, subjects will be provided with a BG meter at 
randomisation (V2) including auxiliaries and instructions for use.  
At randomisation (V2) the subjects must be instructed in how to use the BG meter. For subjects 
randomised to basal insulin analogues, the BG meter should be paired to the eDiary as described in 
the site guide. For subjects randomised to insulin icodec, the BG meter should be paired with the 
DoseGuide App as described in the DoseGuide Portal . 
For further information on the BG Meter, please refer to the manufacturer’s manual.  
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply trial product. Trial product includes both the investigational medical product and the 
investigational medical device. 
Investigational medicinal products 
• Acceptable temperature ranges and conditions for storage and handling of trial products 
when not in use and when in use are described in the Trial Material Manual (TMM) and trial 
product label. 
• Each site will be supplied with sufficient trial products for the trial on an ongoing basis. 
Trial product will be distributed to the sites according to screening and randomisation.  
• The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all trial products received, and that any discrepancies are 
reported and resolved before use of the trial products. 
• All trial products must be stored in a secure, controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to the 
investigator and delegated site staff. 
• The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. The trial product must not be dispensed to any subject before it 
has been evaluated and approved for further use by Novo Nordisk. Additional details 
regarding handling of temperature deviations can be found in the TMM. 
• The investigator or designee is responsible for drug accountability and record maintenance 
(i.e. receipt, accountability and final disposition records). 
• The investigator or designee must instruct the subject in what to return at next visit. 
• Drug accountability should be performed at pen level  
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• 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. 
Investigational medical device 
• 
The investigational medical device described in Section 6.1.1.1 will be supplied by 
Novo Nordisk and is only applicable for subjects randomised to insulin icodec. 
• 
The investigator or designee is responsible for DoseGuide App device accountability via 
subject access control through DoseGuide portal. 
• 
Device accountability should be performed at subject account level.  
• 
The provisioned study phone is not considered a medical device, but a carrier of the apps to 
be used in the trial. 
• 
The provisioned study phones must be returned by the subject at the end of trial visit. 
• 
All returned, unused or damaged study phones must be stored separately and returned at the 
latest at closure of the site. 
• 
Investigator accountability is not applicable for the DoseGuide Portal and the DoseGuide 
Cloud. Instead, Novo Nordisk will control and restrict access to these systems. 
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 blinded adjudication of selected 
events. 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. 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will encourage subject’s compliance as per standard clinical 
practice. 
When subjects self-administer IMP at home, compliance with trial product administration should be 
assessed by cross checking the following sources and comparing these to the expected use:  
• Drug accountability information; counting returned trial product, visual inspection of pens  
• Review of DoseGuide App, SMPG profiles, insulin dose and hypoglycaemia reporting via 
HCP web portals.  
• Evaluating glycaemic control and adherence to the visit schedule 
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• If any suspicion of non-compliance arises the site should enter into a dialogue with the 
patient as per standard clinical practice. This dialogue must be documented in the medical 
record.  
DoseGuide App Compliance 
The DoseGuide App is only applicable for subjects randomised to insulin icodec. Subjects should 
initiate insulin icodec with DoseGuide to aid titration.  
Permanent suspension of the DoseGuide App will result in discontinuation of insulin icodec 
treatment.   
6.5 
Concomitant medication 
Any medication other than the IMP and pre-trial non-insulin anti-diabetic medication that the 
subject is receiving from the screening visit (V1) until end of trial (V8) visit must be recorded along 
with: 
• Generic name or trade name   
• Indication  
• Dates of administration including start and stop dates 
Concomitant medication (diabetes) 
Any anti-diabetic medication that the subject receives from screening (V1) to end of trial (V8) must 
be recorded in a separate concomitant medication (diabetes) form in the eCRF. This does not 
include the IMP (insulin icodec or basal insulin analogue) that the subject was randomised to at V2.  
The following information must be recorded for oral antidiabetic drugs (OADs), GLP-1 RAs and 
insulin products including post-treatment insulin in the follow-up period: 
• Trade name and generic name 
• Doses and frequency (e.g. once daily, twice daily) 
• Dates of administration including start and stop dates  
If the investigator chooses to initiate anti-diabetic medication or change dose of pre-trial anti-
diabetic background medication prior to end of treatment, this should be registered in the eCRF as 
change in concomitant medication (diabetes). If subject requires intensification of basal insulin or 
continuous use of bolus insulin, please see Section 7. 
Changes in concomitant medication including antidiabetic and other indications must be recorded at 
each visit. If a change is due to an AE, then this must be reported according to Section 8.3. 
For information regarding concomitant medication collection including antidiabetic and other 
indications for subjects who discontinue trial product see Section 7.  
6.5.1 
Rescue medication or Rescue therapy 
This section is not applicable for this trial   
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6.6 
Dose modification 
Insulin icodec doses are adjusted according to the titration guidelines based on SMPG values as 
described in Appendix 9 (Section 10.9). 
The recommended insulin icodec doses are provided directly to subjects randomised to insulin 
icodec via the DoseGuide App. The subject receives dose recommendations through the DoseGuide 
App within the scope of a pre-planned treatment program from the investigator. 
The titration algorithm may not be applicable in certain clinical situations and the recommended 
doses can therefore be overruled. The investigator can view and change the dose recommendation 
based on the data collected via the DoseGuide Portal at his/her discretion. The investigator can also 
suspend or re-initiate use of the DoseGuide App at his/her discretion. Permanent discontinuation of 
the DoseGuide App will lead to discontinuation of insulin icodec treatment (see Section 6.4 and 7).   
For more information on the DoseGuide System, please refer to the IB and any updates thereof.  
Titration of once daily basal insulin analogue comparators is at the discretion of the investigator as 
per the clinic’s standard of care. The recommended doses for all once daily basal insulin analogues 
will be based on local label. Use of titration assistant applications or other tools is at the discretion 
of the investigator.  
Please see the Insulin Titration Guideline (Appendix 9, Section 10.9) for more information. 
6.7 
Treatment after end of trial 
When discontinuing trial product, the subject should be transferred to a suitable marketed product at 
the discretion of the investigator and according to local clinical practice. If the switch to post-trial 
treatment includes a new insulin treatment, please refer to the titration guideline 
Appendix 9 (Section 10.9).  
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. 
Efforts must be made to have the subjects who discontinue IMP attend the end of treatment visit 
(V6) as soon as possible to collect the required data for the analysis of the primary endpoint. Two 
follow-up visits, V7 and V8, must be performed after discontinuation of the IMP. V7 and V8 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 analogue. It is stressed that the 
visit window is plus 7 days for both V7 and V8. Further, it is important that discontinued subjects 
come in for the discontinuation follow-up visit V6A, 52 weeks after the randomisation visit. 
Continue to collect, record and report AEs as described in Section 8.3.  
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Only antidiabetic medication should be collected and recorded in the eCRF until V6A for 
discontinued subjects, no other concomitant medication will be collected. Please, refer to 
Section  6.7 for treatment after end of trial. 
Subjects who prematurely discontinue IMP should keep the study phone (containing the eDiary and 
DoseGuide App) and return it at V8. 
Subjects who prematurely discontinue insulin icodec should terminate use of the DoseGuide App 
but continue to use the eDiary. Permanent discontinuation of DoseGuide App will result in 
discontinuation of insulin icodec. 
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 IMP. 
Further, the site should stay in contact with discontinued subjects by phone and/or site visits to 
motivate subjects to attend the discontinuation visits until the discontinuation follow-up visit 
(V6A). 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. Patients should be advised not to participate in other clinical trials while participating in this 
trial. If done, treatment with trial product should be disctoninued.* 
5. Switch to another basal insulin analogue  
6. Intensification to a basal bolus regime or continuous use of bolus insulin  
*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’s discretion without discontinuing trial 
product 
The primary reason for discontinuation of IMP 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.  
If temporary or permanent discontinuation of DoseGuide App is related to a technical complaint or 
for safety reasons please see Appendix 5, Section 10.5.  
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 
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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 the Novo Nordisk medical specialist. 
7.1.1 
Temporary discontinuation of trial treatment 
The subject should adhere to the treatment to the extent possible, with the exception of any adverse 
events such as hospitalisation or safety concerns, at the discretion of the investigator. Subjects who 
have temporarily discontinued trial product (IMP & DoseGuide System) are allowed to restart trial 
product, unless any of the discontinuation criteria specified in section 7.1 applies. 
7.1.2 
Rescue criteria 
This section is 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 end of treatment visit (V6). See flowchart (1.2) for data to be collected. 
Final accountability must be performed even if the subject is not able to come to the site. A 
treatment discontinuation session must be made in the IWRS. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the eCRF. 
7.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
Before a subject is deemed lost to follow-up, the investigator or designee must make every effort to 
regain contact with the subject. These contact attempts should be documented in the subject's source 
document. Should the subject continue to be unreachable at end of trial (V8), he/she will be 
considered to have withdrawn from the trial with a primary reason of `lost to follow-up'. 
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8 
Trial assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart. 
• Informed consent must be obtained before any trial related activity, see Section 10.1.3. 
• All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all inclusion criteria and none of the exclusion criteria. 
• The investigator will maintain a screening log (e.g. electronic or paper) to record details of 
all subjects screened and to confirm eligibility or record reason for screen failure, as 
applicable. 
• At screening, subjects will be provided with a card stating that they are participating in a 
trial and giving contact details of relevant site staff that can be contacted in case of 
emergency.  
• At screening, after confirming eligibility, the investigator will select the once daily basal 
insulin analogue suitable for the subject. At V2, the subject will be randomised to either 
insulin icodec or the once daily basal insulin analogue selected at screening.  
• Adherence to the trial design requirements, including those specified in the flowchart, is 
essential for trial conduct however 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 assessments related to the eDiary, BG meter and DoseGuide System 
at randomisation visit (V2) is as follows: 
o The investigator should create a subject profile and record administrative 
information (e.g. subject ID, year of birth and gender and treatment arm) in the 
eDiary HCP web portal, and if the subject is randomised to insulin icodec also in the 
DoseGuide Portal 
o Subjects should be provided with a study phone and instructed in how to use the 
eDiary and the DoseGuide App if randomised to insulin icodec  
o The BG meter should be paired with the DoseGuide App (for subjects randomised 
to insulin icodec) or to the eDiary (for subjects randomised to basal insulin 
analogues). 
o SMPG should be measured using the BG meter (and transferred to the eDiary or 
DoseGuide App) 
o Dosing of trial product (and entry of dose in eDiary or DoseGuide App) 
• For information regarding the eDiary and eDiary web portal use please refer to the site 
guide.  
• For information regarding the DoseGuide System please refer to the IB or the DFUs. 
• Please refer to Section 6.4 for treatment compliance. 
• For data entered in the eDiary and DoseGuide System via the study phone, eDiary and 
DoseGuide databases are considered source data. The investigator should review all the data 
for the subjects through the eDiary web portal and the DoseGuide Portal, before or during 
each visit/phone contact and report any AEs in the eCRF. 
• 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 
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source data include, but is not limited to laboratory reports, BGM, pictures and ECG 
recordings.  
• Review of data on HCP web portal, 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, or DoseGuide App is 
needed, the subject must be questioned, and a conclusion made in the subject's source 
documents, the eDiary can be updated retrospectively if applicable. Care must be taken not 
to bias the subject. The investigator should ensure that the ePRO questionnaires are 
completed by the subject in the eDiary.  
• 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. 
8.1.1 
Self-measured plasma glucose (SMPG) 
Subjects will be provided with a BG meter including auxiliaries. The BG meters use test strips 
calibrated to plasma values. Therefore, all measurements performed with capillary blood are 
automatically calibrated to plasma equivalent glucose values, which will be shown on the display.  
The BG meter provided by Novo Nordisk should be used for the SMPG measurements required in 
the protocol, as described in the flow chart 1.2. 
A baseline SMPG value, should be collected using the BG meter at V2.  
Pre-breakfast daily SMPG  
Subjects should be instructed to measure their pre-breakfast SMPG daily from the day after 
randomisation (V2) to end of treatment (V6) and to transfer the SMPG values into the DoseGuide 
App (for subjects randomised to insulin icodec) or the eDiary (for subjects randomised to basal 
insulin analogues). Subjects should specify pre-breakfast SMPG in the corresponding App. Pre-
breakfast SMPG should be measured daily from end of treatment (V6) to end of trial (V8) and 
captured in the eDiary for all subjects.  
Selected titration data (e.g. certain SMPGs and dose data) will be used during the trial for central 
titration surveillance, to ensure compliance with DoseGuide supported titration 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 
Clinical outcome assessments  
The PRO questionnaires are to be completed by the subject without assistance of the site personnel. 
The questionnaires should be completed on site before any other visit related procedures are 
conducted. The three questionnaires take approximately five minutes to complete.  
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The following PRO questionnaires will be supplied in the eDiary in a linguistically validated 
version in all languages relevant for this trial:  
• 
Diabetes Treatment Satisfaction Questionnaire (DTSQ)  
o The questionnaire has been designed to measure satisfaction with diabetes treatment 
regimens in people with diabetes. The DTSQ questionnaire will be measured at 
baseline (V2), during conduct (V4) and end of treatment (V6).  
• Treatment Related Impact Measure for Diabetes (TRIM-D) Compliance domain  
o The TRIM-D questionnaire was developed to capture the impact of diabetes 
treatment on patients’ functioning and well-being. The compliance domain from the 
questionnaire will be used to measure the compliance between the treatment groups. 
The compliance domain of TRIM-D will be measured end of treatment (V6). 
• Diabetes Pen Experience Version 3.0 (DPEM)  
o The questionnaire is designed to measure patients experience of insulin injection 
pen in terms of easiness, convenience and satisfaction. The DPEM questionnaire 
will be measured at end of treatment (V6).  
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 and the laboratory manual. 
8.2 
Safety assessments  
Safety assessments should be carried out as per clinic’s standard of care if not otherwise specified 
and in accordance with the flowchart (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  
During the trial, starting at randomisation (V2), subjects must be instructed to report date and dose 
of once weekly insulin icodec in the DoseGuide App and date, dose and time of once daily insulin 
injections in the eDiary. In the follow-up period if the subject switches to a new basal insulin, the 
subject should report date, dose and time of the new basal insulin in the eDiary. 
While using the HCP web portal for titration of once daily basal insulin analogues, the daily insulin 
prescribed at this contact should be entered by investigator. 
The investigator must record the following in the eCRF for all subjects 
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• 
First and last date on trial product 
• 
First and last dose of trial product 
For information about recommended insulin doses please see Appendix 9, Section 10.9 
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 and skin. 
Investigators should pay special attention to clinical signs related to previous serious illnesses.  
The physical examination will be recorded in the eCRF as either ‘normal’ or ‘abnormal’. If 
‘abnormal’, a comment must be given together with an assessment of clinical significance (yes/no).  
Abnormal, clinically significant findings at screening should be recorded as concomitant illness in 
the eCRF. At the following visits, any new abnormal, clinically significant findings or clinically 
significant deteriorations from baseline should be reported as an AE (See Appendix 3, 
Section 10.3). 
Body measurements (e.g. height and weight) will be measured and recorded as specified in the 
flowchart 1.2  
• Body weight should be measured in kilogram (kg) or pounds (lb). Body weight will be 
recorded to one decimal.  
• Height should be measured in centimetres (cm) or inches (in) at screening visit (V1) without 
shoes. Height will be recorded to the nearest whole number. 
8.2.3 
Vital signs  
• Pulse rate, as well as systolic and diastolic blood pressure will be assessed as specified in the 
flowchart 1.2. 
• Manual techniques must be used only if an automated device is not available. 
• Blood pressure and pulse rate at V1 and V6 will consist of 3 systolic and diastolic blood 
pressure measurements with intervals of at least 1-2 minutes. An additional fourth blood 
pressure measurement must be performed if the first two readings on systolic or diastolic 
blood pressure differ by >10 mmHg. Systolic blood pressure will be calculated as the mean 
of the last 2 systolic blood pressure readings, and diastolic blood pressure as the mean of the 
last 2 diastolic blood pressure readings. Only the last 2 systolic and last 2 diastolic blood 
pressure readings must be recorded in the eCRF.   
• Pulse rate will be measured in connection to the blood pressure measurements. Record the 
pulse rate for the last 2 blood pressure measurements in the eCRF. The pulse rate will be 
calculated as the mean of the last 2 measurements.  
8.2.4 
Electrocardiograms 
• A 12-lead ECG must be performed by the investigator or delegated staff as outlined in the 
flowchart (1.2). 
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• The ECG should be preceded by at least 5 minutes of rest for the subject in a supine/sitting 
position in a quiet setting without distractions (e.g. no use of television, cell phones). 
• The ECG must be interpreted, signed and dated by the investigator to verify that the data has 
been reviewed.  
• The ECG required at screening can be obtained within 2 weeks prior to V2 but at the latest 
at V2, and the results must be interpreted by the investigator before randomisation in order 
to determine the eligibility of the subject. 
• The ECG required at V4 and the end of treatment (V6) visit can be obtained within 2 weeks 
prior to the visit, and the results must be available for evaluation at the visit. 
• Abnormal, clinically significant findings at screening should be recorded as concomitant 
illness in the eCRF. At the following visits, any new abnormal, clinically significant 
findings or clinically significant deteriorations from baseline should be reported as an AE 
(see Appendix 3, Section 10.3).  
8.2.5 
Eye examination  
Uncontrolled and potentially unstable diabetic retinopathy or maculopathy 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. 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. 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 (V6) 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 should indicate the outcome of each eye examination. Relevant findings prior to 
randomisation must be recorded as concomitant illness/medical history. While relevant findings 
occurring after randomisation should be reported as an AE, please refer to Appendix 3 
(Section 10.3). 
8.2.6 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart and laboratory manual. 
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8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an investigational medical product and/or investigational medical device 
AE or SAE.  
Investigators should train subjects to contact the site ongoingly throughout the duration of the trial 
in case of adverse events.  
The definition of AEs and SAEs can be found in Appendix 3 and Appendix 6 (Section 10.3 and 
Section 10.6), along with a description of AEs for adjudication and AEs requiring additional data 
collection. 
All AEs and investigational medical device deficiencies (DoseGuide System) that could have led to 
an SAE are reportable, see Appendix 5, (Section 10.5). 
All AEs occurring in subjects randomised to icodec require completion of specific adverse event 
investigational medical device form (Appendix 6, Section10.6). 
In addition, some AEs require additional data collection on a specific event form. This includes 
medication error, misuse and abuse of IMP. The relevant events are listed below in Table 8-1.  
AEs for adjudication require data collection on an adjudication form. Event adjudication will be 
performed in randomised subjects and will be evaluated by an independent external event 
adjudication committee (EAC) in a blinded manner, please refer to Section 10.1.6.3.   
Refer to Appendix 3 (Section 10.3) and Appendix 6 (Section10.6)for further details on reportable 
adverse events and reporting timelines (Figure 10-1).  
Hypoglycaemic episodes 
Hypoglycaemic episodes require data collection on a hypoglycaemic episode form in the eDiary for 
all randomised subjects. Non-serious hypoglycaemic episodes do not require an AE form to be 
completed. 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 completed in the 
eCRF, please refer to Appendix 3 (Section 10.3). If a non-serious hypoglycaemic episode is related 
to a DoseGuide System technical complaint, this should be reported along with the technical 
complaint, please refer to Appendix 5 (Section 10.5) For more information on hypoglycaemic 
episodes, please refer to Appendix 8 (Section 10.8). 
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Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs), and 
events for adjudication  
Event type  
AE requiring additional 
data collection 
Event for adjudication 
 
Medication error 
X 
 
Misuse and abuse 
X 
 
Acute coronary syndrome (acute myocardial 
infarction (MI) or unstable angina pectoris 
requiring hospitalisation) 
 
X 
Cerebrovascular events* (stroke or transient 
ischemic attack) 
 
X 
Heart failure (requiring hospitalisation or urgent 
heart failure visit) 
 
X 
Death 
 
X 
Hypersensitivity 
X 
 
Injection site reaction 
X 
 
*All cerebrovascular events are to be reported and sent for adjudication, however the EAC will only confirm strokes. 
A detailed description of the events mentioned in the above table can be found in Appendix 3 
(Section 10.3.3). 
Events for Adjudication 
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 (see 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.  
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An Event Adjudication Site Manual will be provided to each site detailing which source documents 
are relevant and how these should be provided to the adjudication supplier. The anonymization and 
labelling requirements are also described in the event adjudication site manual.  
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs must be collected from the randomisation visit and until V8 at the time points 
specified in the flowchart and as needed per the discretion of the investigator. For patients 
discontinuing IMP prematurely AEs must also be collected from V8 until the Early Discontinuation 
Follow-up visit (V6A). 
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) for the IMP and Appendix 6 (Section10.6) for the 
investigational medical device. All SAEs must be recorded and reported to Novo Nordisk within 24 
hours, and the investigator must submit any updated SAE data to Novo Nordisk within 24 hours of 
it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3) for the IMP 
and Appendix 6 (Section 10.6) for the investigational medical device. 
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) for IMP and Appendix 6 (Section 10.6) for 
the investigational medical device.  
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
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regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected serious 
adverse reaction (SUSAR) (for IMP) and unanticipated serious adverse device effect (USADE) (for 
the investigational medical device). 
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. 
8.3.7 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5 (Section 10.5). 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
8.4 
Treatment of overdose 
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.3 and Appendix 3 (Section 10.3) for further details. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities until the blood glucose is normalised and (or) 
signs/symptoms have been relieved.  
A specific overdose for insulin icodec cannot be defined; however, hypoglycaemia may develop 
over sequential stages if the doses administered are too high relative to the subject’s requirements.  
• 
Mild hypoglycaemia can be treated by oral administration of glucose or sugary products.  
• 
Severe hypoglycaemia, where the subject is not able to treat him/herself, can be treated by 
glucagon (0.5 to 1 mg) given i.m. or s.c. by a trained person, or by glucose given i.v. by a 
medical professional. Glucose must also be given i.v., if the patient does not respond to 
glucagon within 10-15 minutes. If the patient has been unconscious, administration of oral 
carbohydrates is recommended for the subject upon regaining consciousness, in order to 
prevent a relapse. 
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Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject. 
For more information on overdose, also consult the current version of the insulin icodec 
investigator's brochure and any updates hereof.  
Treatment for overdose of once daily basal insulin analogues should be at the discretion of the 
investigator and per standard care, for more information, consult the current version and any 
updates hereof of the Investigator’s Brochure, EMA Summary of Products Characteristics (SmPC), 
US Prescribing Information or locally approved Product Information for the relevant product.  
8.5 
Pharmacokinetics  
This section is not relevant for this trial  
8.6 
Pharmacodynamics 
This section is not relevant for this trial 
8.7 
Genetics 
This section is not relevant for this trial  
8.8 
Biomarkers 
This section is not relevant for this trial.  
8.9 
Immunogenicity assessments  
8.9.1 
Hypersensitivity  
Subjects and investigators will be instructed to detect signs and symptoms of systemic 
hypersensitivity. In the event of a systemic hypersensitivity (not locally at the injection site), the 
patient should be called in as soon as possible to have additional blood samples taken in order to 
analyse the following parameters:  
• 
Tryptase (optimal 0.5-2 hours post the hypersensitivity reaction) 
• 
Total immunoglobulin E (IgE) antibodies 
• 
Anti-insulin icodec IgE antibodies   
• 
Anti-insulin icodec binding antibodies  
• 
Anti-human insulin IgE antibodies  
The blood sampling should be repeated 2-4 weeks following onset of the systemic hypersensitivity 
reaction. If possible, the tests should also be performed on samples drawn prior to first 
administration of trial drug. 
For details related to blood sampling, plasma preparation and storage, please refer to the laboratory 
manual.  
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Analysis will be performed by Novo Nordisk or a Novo Nordisk appointed special laboratory 
(please refer to Attachment I). The results will be reported in a separate report and attached to the 
CTR. 
For retention of residual hypersensitivity samples, please refer to Appendix 7, Section 10.6. 
Digital pictures 
The investigator or the subject must take digital pictures of the affected area at time of 
identification, using any device available (mobile phone, camera etc.) and thereafter as often as 
judged necessary by the investigator. The pictures should include subject identification number, 
date and time, time after dosing and a ruler for scaling. All pictures must be stored as part of source 
documentation at site. 
8.10 
Health economics  
Not relevant for this trial.  
9 
Statistical considerations  
9.1 
Statistical hypotheses 
The primary hypothesis to be tested is that insulin icodec used with DoseGuide is non-inferior to 
once daily basal insulin analogues in terms of change from baseline to week 52 in HbA1c. 
Formally, let D be the treatment difference ‘insulin icodec used with DoseGuide’ minus ‘basal 
insulin analogues’ 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.19 Also, this margin is 
considered to provide sufficient assay sensitivity based on the below considerations: 
• 
The margin does not represent an unacceptable loss of efficacy with insulin icodec relative to 
treatment with a basal insulin analogue 
• 
It represents less than 50% of a suitably conservative estimate of insulin glargine’s treatment 
effect on HbA1c in a placebo-controlled trial in insulin naïve subjects (-0.85%-point [-1.04; -
0.66]95%CI versus placebo), which demonstrated insulin glargine’s superiority20. 
• 
Other basal insulin analogues have previously been shown to yield similar reductions in HbA1c 
compared to insulin glargine. 
The following describes the secondary confirmatory hypothesis. In order to control the overall Type 
I error at a 5% level, two sided, a hierarchical testing procedure will be used. If non-inferiority in 
glycaemic control is concluded in the primary analysis, confirmatory testing proceeds to the 
following hypothesis: 
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• Insulin icodec used with DoseGuide is superior to once daily basal insulin analogues in 
terms of change in HbA1c from baseline to week 52  
Formally, let D be the mean treatment difference ‘insulin icodec used with DoseGuide’ minus 
‘basal insulin analogues’ of the change in HbA1c from baseline to week 52. The null-hypothesis of 
insulin icodec used with DoseGuide not superior will be tested against the alternative hypothesis of 
superiority as given by: 
H0: D≥0.0% against HA: D <0.0% 
9.2 
Sample size determination  
The sample size is determined in order to have 90% power for declaring non-inferiority with a non-
inferiority margin of 0.3%-point with respect to change in HbA1c for the specified estimand and the 
full analysis set (primary analysis set). Based on CONFIRM, a trial that compared the real-world 
effectiveness of insulin degludec and glargine U300 in insulin-naïve subjects with T2D in routine 
US clinical practice, and market analytics on retention and switching from a basal insulin, it is 
expected that approximately 30% of insulin naïve subjects initiating insulin treatment will 
discontinue from their assigned insulin treatment within 52 weeks. Of these, one third is likely to 
switch back to OAD or to a GLP-1, one third to another basal insulin and one third to a basal-bolus 
treatment regimen. 
In the phase 3 randomised clinical trial (RCT) setting with a treat-to-target approach, the SD of 
HbA1c after 12 months of treatment with a basal insulin has previously been observed to be 1.0% or 
less (NN1250, NN9068). In-the Explorys, a database of electronic medical records representing 39 
integrated healthcare-delivery networks in the US, the SD for HbA1c 12 months (+/- 90 days) after 
insulin initiation was 1.9 % in T2D subjects not being treated with an insulin for at least 180 days. 
With the pragmatic nature of the present trial, while still being a randomised trial with pre-defined 
follow-up of subjects, it is expected that the SD for HbA1c after 12 months will be elevated 
compared to what is normally observed in a strict treat-to-target RCT by approximately one third of 
the increase that was seen in the Explorys database. I.e., the SD for the present trial is assumed to be 
1.3%. 
A treatment difference of 0.0%-point in subjects completing 52 weeks of treatment is expected. It is 
further conservatively assumed that the treatment difference will be 0.15%-point in favour of basal 
insulin analogues for subjects discontinuing randomised treatment prior to week 52. Accounting for 
treatment discontinuation, an adjusted treatment difference of 0.045%-point in favour of basal 
insulin analogues is therefore expected for the estimand. 
The trial should be powered to be able to demonstrate non-inferiority of insulin icodec used with 
DoseGuide versus once daily basal insulin analogues as well as having reasonable power to detect a 
treatment difference of 0.3%-point in favour of insulin icodec used with DoseGuide in all 
randomised as being statistically significant different from 0.0%-point for the primary endpoint of 
change in HbA1c from baseline to week 52. 
From the above assumptions and requirements, 1096 subjects will be randomised to trial product.  
This will ensure sufficient power (90%) of confirming non-inferiority while also having sufficient 
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marginal power (97%) to detect a treatment difference of 0.3%-point in favour of insulin icodec 
used with DoseGuide in all randomised as being statistically significant different from 0.0%-point. 
With an expected screening failure rate of 9%, approximately 1200 subjects will be screened to 
achieve 1096 subjects randomly assigned to trial product. 
This sample size appears to be reasonable also under deviations from the assumed treatment 
difference as illustrated in the table below displaying power for various alternative treatment 
differences and standard deviations. 
Table 9-1 
Power for various treatment differences and standard deviations 
SD 
(%-point) 
 
 
 
0.03 
Treatment difference 
(%-point) 
0.045 
 
 
0.06 
1.2 
96% 
94% 
91% 
1.3 
93% 
90% 
86% 
1.4 
89% 
85% 
81% 
SD: standard deviation. Power is computed for 1:1 randomisation and 1096 subjects randomised. 
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised 
Full analysis set  
Full analysis set (FAS): All subjects randomised. Subjects will be analysed 
according to the randomised treatment.  
Safety analysis set 
All subjects randomly assigned to trial treatment and who take at least 1 dose 
of trial product. Subjects are analysed according to the treatment they actually 
received.  
In exceptional cases, subjects or observations may be eliminated from the full analysis set. In such 
case the reasons for their exclusion will be documented before unblinding. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report (CTR). 
The following periods will be considered for the data collected: 
In-trial period 
The in-trial period starts at randomisation and ends at the date of: 
• 
The last direct subject-site contact 
• 
Withdrawal for subjects who withdraw their informed consent 
• 
The last subject-investigator contact as defined by the investigator for subjects who are lost 
to follow-up (i.e. possibly an unscheduled phone visit) 
• 
Death for subjects who die before any of the above 
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For subjects not randomised but exposed to trial product the in-trial period starts at the date of first 
dose of trial product. The end date is as defined as above.  
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 (V8) 
• 
The last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once 
weekly insulin (corresponding to 5 weeks after the end of the dosing interval for both 
treatment arms) 
• 
The end-date for the in-trial observation period 
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product.  
All efficacy endpoints will be summarised and analysed using the full analysis set (FAS) and the 
‘in-trial’ period. Safety endpoints will be evaluated using the on-treatment period with descriptive 
statistics being based on the safety analysis set (SAS) and statistical analyses being based on the 
FAS unless otherwise specified. 
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 used with DoseGuide, basal insulin analogues 
• Region: Europe, North America 
The regions will be defined as follows: 
• Europe: Germany, Greece, Hungary, Poland, Serbia, Turkey 
• North America: Canada, United States 
The last available assessment made prior to the first dose will be used as the baseline value. 
9.4.2 
Primary endpoint 
The primary endpoint is change in HbA1c from baseline to week 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 
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discontinuing their randomised treatment. Missing HbA1c at the week 52 visit (regardless of 
treatment completion status) will be imputed from trial participants, who have discontinued their 
randomised treatment prior to the week 52 visit and have a measurement at the week 52 visit in the 
following way:  
• First, one thousand (1000) copies of the dataset will be generated for HbA1c.  
• Second, for subjects who discontinued their randomised treatment 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 (LAOT) 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 value and the time point (study day) of this assessment 
as covariates. The estimated parameters, and their variances, from the model will be used to 
impute missing HbA1c values for the change from LAOT to the week 52 visit and 
subsequently the missing HbA1c value at the week 52 visit. 
• 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 standard deviations for the 1000 data sets will be pooled to 
one estimate and associated standard deviation using Rubin’s rule21. 
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinue randomised treatment. 
If non-inferiority is confirmed, i.e. if the 95% CI is strictly below 0.3%, then the primary endpoint 
will further be tested for superiority. Superiority for change in HbA1c will be considered confirmed 
if the 95% CI is strictly below zero. 
The following sensitivity analysis evaluating the robustness of the assumptions about the missing 
data will be carried out: 
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
subjects having imputed HbA1c measurement at the week 52 visit are assumed to have a worse 
outcome in the insulin icodec used with DoseGuide arm and a better outcome in the basal insulin 
analogues arm compared to what was imputed in the primary analysis. This is done by adding or 
subtracting values Δi to the imputed HbA1c values before analysing the data. The value of Δi will be 
varied independently in the two treatment arms. The non-inferiority margin of 0.3% will be among 
the Δi values investigated. The plausibility of the values of Δi where the conclusion of the primary 
analysis change will be evaluated to assess the robustness of the primary analysis result. 
9.4.3 
Secondary endpoints 
9.4.3.1 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
Efficacy endpoints 
Time from baseline to treatment discontinuation or intensification (from baseline week 0 (V2) to 
week 52 (V6)) 
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Time from baseline to treatment discontinuation or intensification will be analysed using a stratified 
log-rank test where randomised treatment will be included as strata in the model. Subjects lost to 
follow-up or withdrawing from trial before the completion of the treatment period will contribute to 
the analysis as discontinuing treatment at the time of the end of the in-trial period if the time of 
discontinuation is unknown. Cumulative incidence function by randomised treatment will be 
presented together with estimated and relative risks (risk ratio) at week 26 and week 52. The 25%, 
50% (median) and 75% percentiles based on the cumulative incidence function will also be 
presented. For details on additional analyses, please refer to SAP. 
Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment 
satisfaction from baseline week 0 (V2) to week 52 (V6) 
Missing DTSQs scores in total treatment satisfaction at the week 52 visit (regardless of treatment 
completion status), will be imputed from trial participants who are from the basal insulin analogues 
group, and who have completed and adhered to their randomised insulin treatment – i.e., data will 
be imputed based on the assumption that subjects with missing endpoint data will behave like 
subjects completing the treatment with basal insulin analogues. Specifically, the imputations will be 
carried as follows: 
• First, one thousand (1000) copies of the dataset will be generated for the DTSQs scores in 
total treatment satisfaction. 
• Second, for each dataset copy, an analysis of covariance (ANCOVA) model with a baseline 
value as a covariate will be fitted to DTSQs scores in total treatment satisfaction for subjects 
who completed their randomised treatment in the basal insulin analogues 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 standard deviations for the 1000 data sets will be pooled to one estimate 
and associated standard deviation using Rubin’s rule. 
Trim-D (Treatment Related Impact Measure for Diabetes) compliance domain at week 52 (V6) 
Trim-D compliance domain at week 52 will be analysed using the same model as specified for 
change in DTSQs in total treatment satisfaction, but without using the baseline value as a covariate. 
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 57 
(V8) 
• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 
mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 57 (V8) 
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• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 
mg/dL), confirmed by BG meter) or severe hypoglycaemic episodes (level 3) from baseline 
week 0 (V2) to week 57 (V8) 
For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 (V8) to planned end of the on-treatment period) will be imputed using a 
multiple imputation technique, assuming that the event rate pre follow-up 2 (V8) follows the 
respective treatment groups rate whilst post follow-up 2 (V8) event rate is the rate of the basal 
insulin analogues group. The imputation will be done as follows: 
• First, a Bayes negative binomial model with log-link function will be fitted to the event rate 
data to obtain the posterior distribution of model parameters. The model will include region 
and randomised treatment as fixed factors and the logarithm of the on-treatment period as 
offset. 
• Second, based on the estimated parameters for the basal insulin analogues group in this 
model, the number of episodes in the missing period will be imputed for subjects who 
discontinued their randomised treatment. Multiple copies (1000 copies) of a complete data 
set will be generated by sampling from the estimated distribution.  
• For each of the complete data sets, the number of episodes will be analysed using a negative 
binomial model with log-link, fixed factors and offset as described in step 1. The estimates 
and SDs for the 1000 data sets will be pooled to one estimate and associated SD using 
Rubin’s rule. 
For the definition and classification of hypoglycaemic episodes refer to Appendix 8 (Section 10.8). 
For details on analyses of additional supportive secondary endpoints, 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 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.  
9.5 
Interim analyses  
Not applicable for this trial. 
9.6 
Data monitoring committee  
Not applicable for this trial. 
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9.7 
Reporting of the main part of the trial 
Not applicable for this trial. 
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 Helsinki22 and applicable ICH Good Clinical Practice (GCP) Guideline23 and ISO 
1415512 
• Applicable laws and regulations 
• The protocol, informed consent form, investigator’s brochure (as applicable) and other 
relevant documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed 
and approved by the IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the CTR according to national requirements. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
safety hazard to trial subjects. 
• Before a site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received. 
• The investigator will be responsible for: 
o providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the 
IRB/IEC and/or regulatory authorities 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of the conduct of the trial at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
o ensuring submission of the CTR synopsis to the IRB/IEC 
o reporting any potential serious breaches to the sponsor immediately after discovery 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
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10.1.3 
Informed consent process 
• The investigator or his/her representative will explain the nature of the trial to the subject 
and answer all questions regarding the trial.  
• The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
• Subjects must be informed that their participation is voluntary. 
• Subjects must be informed about their privacy rights.  
• Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines23, Declaration of Helsinki22, ISO 1415524 
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.  
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• 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.  
10.1.6.2 
Data monitoring committee 
Not applicable for this trial.  
10.1.6.3 
Event adjudication committee 
An independent external EAC is established to perform ongoing blinded adjudication of selected 
AEs and deaths (see Table 8-1). 
The EAC will evaluate events sent for adjudication using pre-defined definitions and guidelines in 
accordance with the EAC charter. The evaluation is based on review of pre-defined clinical data 
collected by the sites. The EAC is composed of permanent members covering all required medical 
specialities. EAC members must disclose any potential conflicts of interest and must be independent 
of Novo Nordisk. The EAC will have no authority to impact trial conduct, trial protocol or 
amendments. The assessments made by both the event adjudication committee and the investigator 
will be evaluated and included in the CTR.  
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements, such as those of the International 
Committee of Medical Journal Editors (ICMJE)25, the Food and Drug Administration Amendment 
Act (FDAAA)26, European Commission Requirements27-29 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 websites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint, and is for this 
trial last subject first treatment (LSFT) + 52 weeks corresponding to visit V6. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed visit 
V6. 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. 
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• All subject data relating to the trial will be recorded on electronic CRFs (eCRFs) unless 
transmitted electronically to Novo Nordisk (e.g. laboratory, DoseGuide System data and 
eDiary data) or when applicable on paper CRF. The investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing the CRF.  
• The following will be provided as paper CRFs:  
o Pregnancy forms 
• The following will be provided as paper CRFs to be used when access to the eCRF is 
revoked or the eCRF is temporarily unavailable: 
o AE forms  
o Safety information forms 
o Technical complaint forms (also to be used to report complaints on trial product not 
yet allocated to a subject)  
o Device deficiency that could have led to an SAE form 
• 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.  
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• Monitors will review the subject’s medical records and other source data, to ensure 
consistency and/or identify omissions compared to the eCRF.  
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database.  
10.1.9 
Source documents 
All data entered in the eCRF must be verifiable in source documentation, except for the 
following data that has been transferred directly into the database and will be considered source 
data: 
• Data in the service providers’ database e.g. ePROs, eDiary data and DoseGuide System 
data, 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. 
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• Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
10.1.11 
Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the investigator must 
inform the subjects promptly and ensure appropriate therapy and follow-up. The investigator and/or 
Novo Nordisk must also promptly inform the regulatory authorities and IRBs/IECs and provide a 
detailed written explanation. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
• failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, Novo Nordisk procedures or GCP guidelines 
• inadequate recruitment of subjects by the investigator 
• discontinuation of further trial product development. 
10.1.12 
Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
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During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
10.1.13 
Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.  
10.1.14 
Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One or two investigators will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators.  
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
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right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.30 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects’ data and will be provided with the 
randomisation code after results are available. 
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10.2 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory. 
• Additional tests may be performed at any time during the trial as determined necessary by 
the investigator or required by local regulations. Only laboratory samples specified in the 
protocol should be sent to the central laboratory for analysis; if additional laboratory 
sampling is needed, e.g. to follow-up on AEs, this must be done at a local laboratory. 
• The central lab will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab SOPs. These data will not be transferred to the trial database. The 
investigator should review such values for AEs and report these according to this protocol. 
• The investigator must review all laboratory results for concomitant illnesses and AEs. 
• Laboratory samples will be destroyed no later than at finalisation of the CTR.  
• For haematology samples (differential count) where the test result is not normal, then a part 
of the sample may be kept for up to two years or according to local regulations.  
• Human biosamples for retention will be stored as described in Appendix 6 (Section 10.6). 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Glucose metabolism  
(V1, V2, V3, V4, V5, 
V6, V6A) 
• 
HbA1c 
Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory 
 assessments 
Parameters 
Haematology  
(V1, V6, V6A) 
• 
Erythrocytes 
• 
Haematocrit 
• 
Haemoglobin 
• 
Leucocytes 
• 
Thrombocytes 
• 
Basophils 
• 
Eosinophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Neutrophils 
Biochemistry1  
(V1, V6, V6A) 
• 
Alanine Aminotransferase (ALT) 
• 
Albumin 
• 
Alkaline phosphatase 
• 
Aspartate Aminotransferase (AST) 
• 
Creatinine 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
Lipids  
(V2, V6, V6A) 
• 
Cholesterol 
• 
High density lipoprotein (HDL) cholesterol 
• 
Low density lipoprotein (LDL) cholesterol 
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• 
Triglycerides 
• 
Free fatty acids 
Pregnancy Testing  
(V2, V8) 
• 
Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2 
Other tests  
 
• 
In case of systemic hypersensitivity (see section 8.9.1): 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. 
• 
eGRF calculated by the central laboratory based on the creatinine value using the 
CKD-EPI equation, eGRF is for screening purposes only. 
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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• 
All types of acute myocardial infarction and unstable angina pectoris requiring 
hospitalisation 
• Cerebrovascular event (stroke or transient ischemic attack) 
• 
Episode of focal or global neurological dysfunction that could be caused by brain, spinal 
cord, or retinal vascular injury as a result of haemorrhage or ischemia, with or without 
infarction 
• Heart failure (requiring hospitalisation or urgent outpatient clinic visit due to heart failure) 
• 
New episode or worsening of existing heart failure leading to an urgent, unscheduled 
hospital admission or clinic/office/emergency department visit 
Adverse events requiring additional data collection 
AEs requiring additional data collection on a specific event form.  
Injection site reaction 
If an event of injection site reaction is observed additional information must be obtained if 
available on a separate form 
Hypersensitivity 
Systemic hypersensitivity can be manifested as isolated symptoms such as urticaria, angioedema, 
conjunctivitis, rhinitis, bronchospasm, gastrointestinal symptoms (nausea, vomiting, diarrhoea, 
abdominal pain), or as anaphylaxis or anaphylactic shock. 
Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden 
release of mast cell- and basophil-derived mediators into the circulation31. 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 basophils32. 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 allergy33. 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 of systemic hypersensitivity must be reported, and in case of 
systemic hypersensitivity, additional information must be provided on a separate form.  
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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 
7. Premenarcheal 
8. 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. 
9. 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: 
• 
Amenorrhoea and 
• 
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.  
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, insulin glargine or insulin degludec in seminal fluid is unlikely34. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use at least an 
acceptable effective method of contraception consistently and correctly as described in Table 10-3 
below. As a minimum, contraception should be maintained until treatment discontinuation.  
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Nordisk within 14 calendar days. Generally, follow-up will not be required for longer than 1 
month beyond the delivery date. 
• Any termination of pregnancy will be reported regardless of the foetal status (presence or 
absence of anomalies) or indication for procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any adverse event in 
connection with pregnancy or elective termination of a pregnancy for medical reasons will 
be reported as an AE or SAE. If relevant, consider adding “gestational”, “pregnancy related” 
or similar term when reporting the AE/SAE. 
• Pregnancy outcome should be documented in the subject’s medical record. Abnormal 
pregnancy outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies 
and ectopic pregnancy) is considered an SAE. 
• AE/SAE in foetus or newborn child can only be reported on paper AE form and SIF and 
should follow the timelines in Figure 10-1. 
• Any SAE occurring as a result of a post-trial pregnancy which is considered 
possible/probably related to the IMP by the investigator will be reported to Novo Nordisk as 
described in Appendix 3 (Section 10.3) . While the investigator is not obligated to actively 
seek this information in former subjects, he or she may learn of an SAE through 
spontaneous reporting. 
Figure 10-2 Decision tree for determining the forms to complete with associated timelines 
for pregnancy.  
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
 
 
Any female subject who becomes pregnant while participating in the trial will discontinue IMP.  
 
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• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial product administration, will 
be considered and investigated. 
• 
The investigator will also consult the investigator’s brochure, for marketed products, in 
his/her 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 for AE or SAE. 
• 
There may be situations in which an AE/SAE has occurred, and the investigator has minimal 
information to include in the initial report to Novo Nordisk. However, it is very 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 send an AE/SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
AE/SAEs should be classified according to four different levels of causality: 
1. Not related 
2. Possible 
3. Probable 
4. Causal relationship 
 
1. Not related: Relationship to the device, comparator or procedures can be excluded when: 
- 
the event has no temporal relationship with the use of the investigational device, or the 
procedures related to application of the investigational device;  
- 
the serious adverse event does not follow a known response pattern to the medical 
device (if the response pattern is previously known) and is biologically implausible; 
- 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious adverse event; 
- 
the event involves a body-site or an organ that cannot be affected by the device or 
procedure; 
- 
the serious adverse event can be attributed to another cause (e.g. an underlying or 
concurrent illness/ clinical condition, an effect of another device, drug, treatment or 
other risk factors); 
- 
the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
In order to establish the non-relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious adverse event. 
 
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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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Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the PG value is ≥ 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance with current guidelines.40 
Repeated PG measurements and/or symptoms will by default be considered as one hypoglycaemic 
episode until a succeeding PG value is ≥ 3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved and should be reported as only one hypoglycaemic episode. 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 and/or symptom. The remaining values will be kept as source data. 
If the severity of a hypoglycaemic episode changes, only one hypoglycaemic episode will be 
reported, reflecting the most severe degree of hypoglycaemia. 
Regarding the question: “To feel better, did you need help to get a sugary drink, food, or 
medicine?” the investigator must instruct the subjects to answer “Yes”, if the episode was an event 
that required assistance of another person to actively administer carbohydrate, glucagon, or take 
other corrective actions. PG concentrations may not be available during an event, but neurological 
recovery following the return of PG to normal is considered sufficient evidence that the event was 
induced by a low PG concentration.40  
eDiary review 
At each contact the investigator should review the eDiary data via the HCP web portal 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 and report accordingly. 
For non-serious hypoglycaemic episodes in the insulin icodec arm related to the DoseGuide System, 
see Appendix 5, Section10.5. 
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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10.9 
Appendix 9: 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 once weekly insulin icodec or once 
daily basal insulin analogue, pre-specified by the investigator at screening. 
• Insulin icodec should be taken once weekly on the same day of the week. The starting dose 
should be 70U. 
• Insulin glargine U100 or U300 or Insulin degludec (once daily basal insulin analogues) 
should be taken once daily in accordance with the locally approved label.  
• There are no maximum or minimum insulin doses. 
Titration of once daily basal insulin analogues 
Titration of once daily basal insulin analogue comparators is at the discretion of the investigator 
according to local clinical practice. The recommended doses for all once daily basal insulin 
analogues will be based on the locally approved label.  
Use of titration assistant applications or other tools is at the discretion of the investigator.  
Titration of insulin icodec 
Titration of insulin icodec should be guided by the DoseGuide System. In case of temporary 
suspension of the DoseGuide System, titration of insulin icodec can be done in accordance with the 
guidance outlined below. 
Adjustment of insulin icodec will be done in accordance with Table 10-5. 
After randomisation insulin icodec should be considered adjusted once weekly: 
• The dose adjustment will be based on three pre-breakfast SMPG values measured on two 
day prior to titration and on the day of contact. 
• If one or more SMPG values are missing, the dose adjustment should be performed on the 
remaining SMPG value(s) 
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Table 10-5 
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 algorithms 
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  
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  
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 (V6).  
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 surveillance 
It is important that data regarding dose titration is reported in the eDiary or DoseGuide App (see 
Section 8.2.1). 
 
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10.10 Appendix 10: Country-specific requirements  
For Canada 
• 
Retention of clinical trial documentation: Part C, Division 5 of the Food and Drug 
Regulations [C.05.012] requires a 25 year retention period  
For Germany 
• 
Demography: Subject’s full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF.  
• 
Contraception requirements: Contraception requirements as per CTFG guideline. 
 
For Hungary 
• Demography: Subject’s full Date of Birth is not allowed to be collected and must be 
shortened to Year of Birth in CRF. 
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 Turkey  
• 
Blood samples from Turkey will be analysed by a central lab.  
• 
This is a phase 3 trial 
For USA 
• 
Retention of clinical trial documentation: 15 years 
• 
Financial disclosure: Verification under disclosures per Code of Federal Regulations 
(CFR) of Financial Conflict of Interest.  
 
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10.11 Appendix 11: Abbreviations  
AE 
adverse event 
ALT 
alanine aminotransferase 
ASADE 
anticipated serious adverse device effect  
AST 
aspartate aminotransferase 
BG 
blood glucose 
CRF 
case report form 
CTR 
clinical trial report 
DFU 
directions for use 
DMC 
data monitoring committee 
DRE 
disease related event 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
HbA1c 
glycated haemoglobin 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
LDL 
low-density lipoprotein 
LSLV 
last subject last visit 
MIDF 
monitor-initiated discrepancy form 
NIMP 
non-investigational medical product 
PCD 
primary completion date 
PG 
plasma glucose 
PRO 
patient reported outcome 
RNA 
ribonucleic acid 
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SADE 
serious adverse device effect  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMPG 
self-measured plasma glucose 
SUSAR 
suspected unexpected serious adverse reaction 
TMM 
trial materials manual 
USADE 
Unanticipated serious adverse device effect  
WOCBP 
woman of child bearing potential 
 
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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. 
35. 
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. 
36. 
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64. 
37. 
Abraham MB, Jones TW, Naranjo D, Karges B, Oduwole A, Tauschmann M, et al. ISPAD 
Clinical Practice Consensus Guidelines 2018: Assessment and management of 
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Date: 
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Protocol 
Version: 
2.0 
     
Status: 
Final 
     
Page: 
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hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2018;19 Suppl 
27:178-92. 
38. 
Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. 
Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 
Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, 
the American Association of Diabetes Educators, the American Diabetes Association, the 
Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable 
Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 
2017;40(12):1622-30. 
39. 
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. 
40. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95. 
 
 
 
 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04760626 
 
Sponsor trial ID: 
NN1436-4481 
Official title of study: 
Effectiveness and safety of once weekly insulin icodec used 
with DoseGuide versus once daily basal insulin analogues in 
an insulin naïve type 2 diabetes population in a clinical 
practice setting (ONWARDS 5) 
Document date*: 
14 April 2021 
 
*Document date refers to the date on which the document was most recently updated. 


Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
1 of 24 
Statistical Analysis Plan 
NN1436-4481 
Effectiveness and safety of once weekly insulin icodec used with 
DoseGuide versus once daily basal insulin analogues in an insulin 
naïve type 2 diabetes population in a clinical practice setting 
ONWARDS 5 
Author 
Insulin & Devices 
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Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
2 of 24 
 
Table of contents 
 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 3 
Table of tables ................................................................................................................................................... 3 
Version history .................................................................................................................................................. 4 
1 Introduction ................................................................................................................................................. 5 
1.1 
Objectives and endpoints .................................................................................................................... 5 
1.1.1 
Primary, secondary and exploratory objective and estimand .............................................. 5 
1.1.1.1 
Primary objective ............................................................................................. 5 
1.1.1.2 
Secondary objective ......................................................................................... 5 
1.1.1.3 
Estimand........................................................................................................... 5 
1.1.2 
Primary, secondary and exploratory endpoints ................................................................... 5 
1.1.2.1 
Primary endpoint .............................................................................................. 5 
1.1.2.2 
Secondary endpoints ........................................................................................ 6 
1.1.2.2.1 
Confirmatory secondary endpoints .......................................................... 6 
1.1.2.2.2 
Supportive secondary endpoints .............................................................. 6 
1.1.2.3 
Exploratory endpoints ...................................................................................... 6 
1.2 
Trial design ......................................................................................................................................... 7 
2 Statistical hypotheses .................................................................................................................................. 7 
3 Sample size determination .......................................................................................................................... 8 
4 Analysis sets ................................................................................................................................................. 8 
5 Statistical analyses ....................................................................................................................................... 9 
5.1 
General considerations ........................................................................................................................ 9 
5.2 
Subject disposition .............................................................................................................................. 9 
5.3 
Primary endpoint analysis ................................................................................................................. 10 
5.3.1 
Definition of endpoints ...................................................................................................... 10 
5.3.2 
Main analytical approach................................................................................................... 10 
5.3.3 
Sensitivity analysis ............................................................................................................ 11 
5.4 
Secondary endpoints analysis ........................................................................................................... 11 
5.4.1 
Supportive secondary endpoints ........................................................................................ 11 
5.4.1.1 
Effectiveness endpoints .................................................................................. 11 
5.4.1.2 
Safety endpoints ............................................................................................. 12 
5.5 
Exploratory endpoints analysis ......................................................................................................... 13 
5.6 
Other safety analyses ........................................................................................................................ 13 
5.6.1 
Nocturnal hypoglycaemic episodes ................................................................................... 14 
5.6.2 
Hypoglycaemic episodes based on SMPG measurements ................................................ 14 
5.6.3 
Record selection ................................................................................................................ 15 
5.7 
Other analyses ................................................................................................................................... 15 
5.7.1 
Other derivations and assessments .................................................................................... 15 
5.7.1.1 
Body weight ................................................................................................... 15 
5.7.1.2 
Achievement of HbA1c target ......................................................................... 15 
5.7.1.3 
Self-measured plasma glucose (SMPG) ......................................................... 16 
5.7.1.4 
Antidiabetic background medication ............................................................. 16 
5.7.1.5 
Insulin dose .................................................................................................... 16 
5.8 
Interim analyses ................................................................................................................................ 16 
5.8.1 
Data monitoring committee ............................................................................................... 16 
5.9 
Reporting of the main part of the trial ............................................................................................... 16 
6 Supporting documentation ....................................................................................................................... 17 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
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6.1 
Appendix 1: List of abbreviations ..................................................................................................... 17 
6.2 
Appendix 2: Changes to protocol-planned analyses ......................................................................... 18 
6.2.1 
Changes prior to first patient first visit .............................................................................. 18 
6.2.2 
Changes after first patient first visit but before the database lock ..................................... 18 
6.3 
Appendix 3: Definition and calculation of endpoints, assessments and derivations ........................ 19 
7 References .................................................................................................................................................. 24 
 
Table of figures 
 
Page 
Figure 1 
Trial design .................................................................................................................................. 7 
 
Table of tables 
 
Page 
Table 1 
SAP Version History Summary ................................................................................................... 4 
 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
4 of 24 
 
Version history 
This Statistical Analysis Plan (SAP) for trial NN1436-4481 is based on the protocol version 2.0 
dated 23-NOV-2020.  
Table 1 
SAP Version History Summary 
SAP 
Version 
Approval Date 
Change 
Rationale 
1.0 
See approval date in 
the electronic 
document 
management system 
Not Applicable 
Original version 
2.0 
See approval date in 
the electronic 
document 
management system 
Addition of summaries and 
analyses of hypoglycaemic 
episodes identified using 
an alternative definition 
based on SMPG 
measurements 
To supplement the protocol-
defined analyses due to the 
difference in the collection of 
hypoglycaemic episodes 
between the two arms 
 
 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
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1 
Introduction 
This statistical analysis plan (SAP) is based on the protocol: Effectiveness and safety of once weekly 
insulin icodec used with DoseGuide versus once daily basal insulin analogues in an insulin naïve 
type 2 diabetes population in a clinical practice setting, version 2.0 (dated 23-NOV-2020). Most of 
the statistical analyses and derivations of endpoints presented in this SAP are identical to those 
described in the protocol, but some have been updated or added for technical or clinical reasons. 
The SAP also contains specifications of additional derivations and analyses. The changes to the 
protocol-planned statistical analyses and the reasons for these changes are described in Appendix 2, 
section 6.2. 
1.1 
Objectives and endpoints 
1.1.1 
Primary, secondary and exploratory objective and estimand 
1.1.1.1 
Primary objective 
To demonstrate the effectiveness on glycaemic control of once weekly insulin icodec used with 
DoseGuide in combination with non-insulin anti-diabetic drugs in insulin naïve subjects with T2D 
in a clinical practice setting. This includes comparing the difference in change from baseline in 
HbA1c between insulin icodec used with DoseGuide and once daily basal insulin analogues after 52 
weeks of treatment to a non-inferiority limit of 0.3%. 
1.1.1.2 
Secondary objective 
To compare effect on safety and patient reported outcomes related to treatment satisfaction and 
compliance of once weekly insulin icodec used with DoseGuide versus once daily basal insulin 
analogues both in combination with any non-insulin antidiabetic drugs in insulin-naïve subjects 
with T2D in a clinical practice setting. 
1.1.1.3 
Estimand 
The estimand is the ‘treatment policy estimand’ defined as the treatment difference between insulin 
icodec used with DoseGuide and basal insulin analogues of the change in HbA1c from baseline to 
week 52 for all randomised subjects, irrespective of adherence to randomised treatment and changes 
to antidiabetic background medication. The following intercurrent events will be handled by the 
treatment policy strategy: discontinuation of investigational medical products, and withdrawal from 
the trial (measurements collected after these intercurrent events are used in the primary analysis). 
This estimand aims to reflect effectiveness of the treatment on a population level in clinical 
practice.  
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 (V6) 
%-point 
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Statistical Analysis Plan 
 
Date: 
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Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
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1.1.2.2 
Secondary endpoints 
1.1.2.2.1 
Confirmatory secondary endpoints 
Not applicable for this trial. 
1.1.2.2.2 
Supportive secondary endpoints 
Secondary effectiveness endpoints 
Endpoint title 
Time frame 
Unit 
Time from baseline to treatment 
discontinuation or intensification 
From baseline week 0 (V2) to week 52 (V6) 
Days 
Change in DTSQs (Diabetes 
Treatment Satisfaction 
Questionnaire) in total treatment 
satisfaction 
From baseline week 0 (V2) to week 52 (V6) 
Score of 0-36.  
6 items scored on a 
scale of 0 to 6. The 
higher the score the 
greater the satisfaction 
with treatment.  
Trim-D (Treatment Related Impact 
Measure for Diabetes) compliance 
domain 
At end of treatment week 52 (V6) 
Score of 4-20. 
4 items scored on a 
scale of 1 to 5 
Transformed to a 0-
100 scale with higher 
scores corresponding 
to better compliance. 
Secondary safety endpoints  
Endpoint title 
Time frame 
Unit 
Number of severe hypoglycaemic 
episodes (level 3)  
From baseline week 0 (V2) to week 57 (V8) 
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 57 (V8) 
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 57 (V8)  
Number of episodes 
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 52 (V6)  
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 (V6)  
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 (V6)  
Number of episodes 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
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1.2 
Trial design 
This is a 52-week, randomised, open label, parallel-group, active-controlled, multi-centre, multi-
national trial with real world elements comparing insulin icodec used with DoseGuide versus once 
daily basal insulin analogues among insulin naïve T2D subjects in which insulin initiation is 
needed.  
The trial duration is approximately 59 weeks, consisting of a 2-week screening period, followed by 
a 52-week randomised treatment period and a 5-week follow-up period. The overall trial design and 
visit schedule are outlined in Figure 1 and trial flowchart (protocol section 1.2), respectively. 
Figure 1 
Trial design 
 
For further details see protocol section 4.1. 
2 
Statistical hypotheses 
The primary hypothesis to be tested is that insulin icodec used with DoseGuide is non-inferior to 
once daily basal insulin analogues in terms of change from baseline to week 52 in HbA1c. 
Formally, let D be the treatment difference ‘insulin icodec used with DoseGuide’ minus ‘basal 
insulin analogues’ 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 effectiveness with insulin icodec relative 
to treatment with a basal insulin analogue 
• It represents less than 50% of a suitably conservative estimate of insulin glargine’s treatment 
effect on HbA1c in a placebo-controlled trial in insulin naïve subjects (-0.85%-point [-1.04; -
0.66]95%CI versus placebo), which demonstrated insulin glargine’s superiority.2 
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Statistical Analysis Plan 
 
Date: 
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Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
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EudraCT No: 2020-000476-38 
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• Other basal insulin analogues have previously been shown to yield similar reductions in HbA1c 
compared to insulin glargine. 
The following describes the secondary confirmatory hypothesis. In order to control the overall Type 
I error at a 5% level, two sided, a hierarchical testing procedure will be used. If non-inferiority in 
glycaemic control is concluded in the primary analysis, confirmatory testing proceeds to the 
following hypothesis: 
• Insulin icodec used with DoseGuide is superior to once daily basal insulin analogues in terms of 
change in HbA1c from baseline to week 52  
Formally, let D be the mean treatment difference ‘insulin icodec used with DoseGuide’ minus 
‘basal insulin analogues’ of the change in HbA1c from baseline to week 52. The null-hypothesis of 
insulin icodec used with DoseGuide not superior will be tested against the alternative hypothesis of 
superiority as given by: 
H0: D≥0.0% against HA: D <0.0% 
3 
Sample size determination 
See protocol section 9.2.  
4 
Analysis sets 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised 
Full analysis set  
Full analysis set: 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 1 dose of 
trial product. Subjects are analysed according to the treatment they actually 
received.  
In exceptional cases, subjects or observations may be eliminated from the full analysis set. In such 
case the reasons for their exclusion will be documented before unblinding. The subjects and 
observations excluded from analysis sets, and the reason for this, will be described in the clinical 
trial report. 
The following periods will be considered for the data collected: 
In-trial period 
The in-trial period starts at randomisation and ends at the date of: 
• The last direct subject-site contact 
• Withdrawal for subjects who withdraw their informed consent 
• The last subject-investigator contact as defined by the investigator for subjects who are lost to 
follow-up (i.e. possibly an unscheduled phone visit) 
• Death for subjects who die before any of the above 
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Statistical Analysis Plan 
 
Date: 
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Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
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For subjects not randomised but exposed to trial product the in-trial period starts at the date of first 
dose of trial product. The end date is as defined as above. 
Baseline assessments are always included in the in-trial observation period. 
On-treatment period 
The on-treatment period starts at the date of first dose of trial product as recorded on the eCRF, and 
ends at the first date of any of the following: 
• The end of trial visit (V8) 
• The last date on trial product + 5 weeks for once daily insulin and + 6 weeks for once weekly 
insulin (corresponding to 5 weeks after the end of the dosing interval for both treatment arms) 
• The end-date for the in-trial observation period 
The on-treatment period represents the time period in which a subject is considered exposed to trial 
product.  
Baseline assessments are always included in the on-treatment observation period. 
All effectiveness endpoints will be summarised and analysed using the full analysis set and the ‘in-
trial’ period. Safety endpoints will be evaluated using the on-treatment period with descriptive 
statistics being based on the safety analysis set and statistical analyses being based on the full 
analysis set unless otherwise specified. 
5 
Statistical analyses 
5.1 
General considerations 
Presentation of results from a statistical analysis will include the estimated mean treatment 
difference (or ratio) presented together with the two-sided 95% confidence interval and the 
corresponding two-sided p-value. 
In the statistical models, explanatory factors will be coded as follows: 
• Treatment: Once weekly insulin icodec used with DoseGuide, basal insulin analogues 
• Region: Europe, North America 
The regions will be defined as follows: 
• Europe: Germany, Greece, Hungary, Poland, Serbia, Turkey 
• North America: Canada, United States 
Baseline is defined as information collected at week 0 (V2). In case a measurement is not available 
at week 0 (V2) the most recent measurement prior to week 0 (V2) will be used as baseline. 
The number 541024 will be used as the seed for all imputations. 
5.2 
Subject disposition 
Subject disposition will be summarised descriptively.  
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
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5.3 
Primary endpoint analysis 
5.3.1 
Definition of endpoints 
The primary endpoint is change in HbA1c from baseline 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. Missing HbA1c at the week 52 visit (regardless of 
treatment completion status) will be imputed from trial participants, who have discontinued their 
randomised treatment prior to the week 52 visit and have a measurement at the week 52 visit in the 
following way:  
• First, one thousand (1000) copies of the dataset will be generated for HbA1c.  
• Second, for subjects who discontinued their randomised treatment 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 (LAOT) 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 value and the time point (study day) of this assessment as covariates. 
The estimated parameters, and their variances, from the model will be used to impute missing 
HbA1c values for the change from LAOT to the week 52 visit and subsequently the missing 
HbA1c value at the week 52 visit. 
• 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 standard deviations for the 1000 data sets will be pooled to one estimate and 
associated standard deviation using Rubin’s rule3. 
This analysis has the underlying assumption that subjects with missing data behave similarly as 
subjects that discontinue randomised treatment. 
In case the amount of data for the described imputation model (see second step above) is 
insufficient for meaningful imputation, the first alternative will be the following: 
• to simplify the imputation model by removing the following two covariates from the model: 
LAOT value and the time point (study day) of this assessment.  
If the amount of data for this reduced model is still insufficient for meaningful imputation, the 
following imputation strategy will be applied instead: 
• missing values at week 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 DTSQs in total treatment 
satisfaction (see section 5.4.1.1). 
 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
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If non-inferiority is confirmed, i.e. if the 95% CI is strictly below 0.3%, then the primary endpoint 
will further be tested for superiority. Superiority for change in HbA1c will be considered confirmed 
if the 95% CI is strictly below zero. 
Missing HbA1c at week 52 will be summarised by subject’s treatment completion status. 
5.3.3 
Sensitivity analysis 
The following sensitivity analysis evaluating the robustness of the assumptions about the missing 
data will be carried out: 
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
subjects having imputed HbA1c measurement at the week 52 visit are assumed to have a worse 
outcome in the insulin icodec used with DoseGuide arm and a better outcome in the basal insulin 
analogues 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 conclusions of the non-
inferiority or superiority change will be evaluated to assess the robustness of the results. 
5.4 
Secondary endpoints analysis 
5.4.1 
Supportive secondary endpoints 
Supportive secondary endpoints will be evaluated in the framework of the primary estimand. 
5.4.1.1 
Effectiveness endpoints 
Time from baseline to treatment discontinuation or intensification (from baseline week 0 (V2) to 
week 52 (V6)) 
Time from baseline to treatment discontinuation or intensification will be analysed using a stratified 
log-rank test where randomised treatment will be included as strata in the model. Subjects lost to 
follow-up or withdrawing from trial before the completion of the treatment period will contribute to 
the analysis as discontinuing treatment at the time of the end of the in-trial period if the time of 
discontinuation is unknown. Cumulative incidence function by randomised treatment will be 
presented together with estimated and relative risks (risk ratio) at week 26 and week 52. The 25%, 
50% (median) and 75% percentiles based on the cumulative incidence function will also be 
presented. 
Additionally, time from baseline to treatment discontinuation or intensification will be analysed 
using a stratified log-rank test with randomised treatment and region included as strata in the model. 
Cumulative incidence function by strata from the model, together with the 25%, 50% (median) and 
75% percentiles based on the cumulative incidence function will be presented. Estimated risks at 
week 26 and week 52 will also be shown. 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
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Change in DTSQs (Diabetes Treatment Satisfaction Questionnaire) in total treatment 
satisfaction from baseline week 0 (V2) to week 52 (V6) 
Missing DTSQs scores in total treatment satisfaction 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 values. Specifically, 
the imputations will be carried 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 values. 
• Second, the estimated residual standard deviation, s, from this model will be used to impute 
missing values by the baseline value, adding a random normally distributed term with mean 0 
and standard deviation s. This will be done a 1000 times. 
• For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region and randomised treatment as fixed factors and a baseline value as a covariate. The 
estimates and standard deviations for the 1000 data sets will be pooled to one estimate and 
associated standard deviation using Rubin’s rule. 
Trim-D (Treatment Related Impact Measure for Diabetes) compliance domain at week 52 (V6) 
Missing Trim-D compliance domain scores at week 52 visit (regardless of treatment completion 
status) will be imputed from trial participants who are from the basal insulin analogues group, and 
who have completed and adhered to their randomised insulin treatment – i.e., data will be imputed 
based on the assumption that subjects with missing endpoint data will behave like subjects 
completing the treatment with basal insulin analogues. Specifically, the imputations will be carried 
as follows: 
• First, one thousand (1000) copies of the dataset will be generated for the Trim-D compliance 
domain scores. 
• Second, for each dataset copy, an analysis of variance (ANOVA) model will be fitted to Trim-D 
compliance domain scores for subjects who completed their randomised treatment in the basal 
insulin analogues group. The estimated mean, and variances, from the model will be used to 
impute missing values in both treatment groups. 
• For each of the complete data sets, the endpoint will be analysed using an ANOVA model with 
region and randomised treatment as fixed factors. The estimates and standard deviations for the 
1000 data sets will be pooled to one estimate and associated standard deviation using Rubin’s 
rule. 
5.4.1.2 
Safety endpoints 
Hypoglycaemic episodes 
The following hypoglycaemic endpoints will be analysed separately using the method described 
below: 
• Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 57 (V8) 
• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) from baseline week 0 (V2) to week 57 (V8) 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
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• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) 
to week 57 (V8) 
For subjects who discontinued their randomised treatment, the number of episodes in the missing 
period (time of follow-up 2 (V8) to planned end of the on-treatment period) will be imputed using a 
multiple imputation technique, assuming that the event rate pre follow-up 2 (V8) follows the 
respective treatment groups rate whilst post follow-up 2 (V8) event rate is the rate of the basal 
insulin analogues group. The imputation will be done as follows: 
• First, a Bayes negative binomial model with log-link function will be fitted to the event rate data 
to obtain the posterior distribution of model parameters. The model will include region and 
randomised treatment as fixed factors and the logarithm of the on-treatment period as offset. 
• Second, based on the estimated parameters for the basal insulin analogues group in this model, 
the number of episodes in the missing period will be imputed for subjects who discontinued 
their randomised treatment. Multiple copies (1000 copies) of a complete data set will be 
generated by sampling from the estimated distribution.  
• For each of the complete data sets, the number of episodes will be analysed using a negative 
binomial model with log-link, fixed factors and offset as described in step 1. The estimates and 
SDs for the 1000 data sets will be pooled to one estimate and associated SD using Rubin’s rule. 
For the definition and classification of hypoglycaemic episodes refer to Protocol Appendix 
8 (Protocol Section 10.8). 
5.5 
Exploratory endpoints analysis 
Hypoglycaemic episodes 
The following hypoglycaemic endpoints will be analysed separately using the same method as 
described for supportive secondary hypoglycaemic endpoints (see section 5.4.1.2), substituting the 
on-treatment period with the period from week 0 to week 52 and the follow-up 2 visit (V8) with 
time of discontinuation: 
• Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 52 (V6) 
• 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 (V6) 
• 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 (V6). 
5.6 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (SAEs, 
AEs, safety laboratory parameters, vital signs, etc.) will be reported descriptively based on the 
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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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
14 of 24 
 
5.6.1 
Nocturnal hypoglycaemic episodes 
Nocturnal hypoglycaemic episodes 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive. 
The following nocturnal hypoglycaemic assessments will be analysed separately using the same 
method described for the supportive secondary hypoglycaemic endpoints (see section 5.4.1.2): 
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 57 (V8) 
• Number of nocturnal clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 
mg/dL), confirmed by BG meter) from baseline week 0 (V2) to week 57 (V8) 
• 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 57 (V8) 
The following nocturnal hypoglycaemic assessments will be analysed separately using the same 
method described for the supportive secondary hypoglycaemic endpoints, substituting the on-
treatment period with the period from week 0 to week 52, and substituting the time of follow-up 2 
visit (V8) with time of discontinuation: 
• Number of nocturnal severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to 
week 52 (V6) 
• 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 (V6) 
• 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 (V6). 
5.6.2 
Hypoglycaemic episodes based on SMPG measurements 
Alternative definition will be used to identify hypoglycaemic episodes based on SMPG 
measurements instead of reporting by subject. Hypoglycaemic episodes will be derived by applying 
the blood glucose thresholds for hypoglycaemia alert value (level 1) (<3.9 mmol/L (70 mg/dL)) and 
clinically significant hypoglycaemia (level 2) (<3.0 mmol/L (54 mg/dL)) directly to SMPG data. 
The SMPG measurements related to severe hypoglycaemic episodes (level 3) will not be used in the 
derivation of hypoglycaemia alert value episodes (level 1) or clinically significant hypoglycaemic 
episodes (level 2). The definition of severe hypoglycaemia (level 3) will not change. 
The following derivations will be summarised descriptively based on the on-treatment period: 
• Number of hypoglycaemia alert value (level 1) (<3.9 mmol/L (70 mg/dL), confirmed by BG 
meter) based on SMPG measurements 
• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) based on SMPG measurements 
• Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) based on SMPG measurements or severe hypoglycaemic episodes 
(level 3) 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
15 of 24 
 
All statistical analyses of the number of clinically significant hypoglycaemic episodes (level 2) and 
the number of clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic 
episodes (level 3) described in sections 5.4.1.2, 5.5 and 5.6.1 will be repeated for the 
hypoglycaemic episodes based on SMPG measurements. This will include analyses for the period 
from baseline week 0 (V2) to week 52 (V6) and the period from baseline week 0 (V2) to week 57 
(V8), together with the analyses of corresponding nocturnal hypoglycaemic episodes for both 
periods. 
5.6.3 
Record selection 
A re-test at any visit is defined as repeating the same laboratory assessment using new sample 
material. A re-test may be taken e.g. 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 
Body weight 
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. 
5.7.1.2 
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)  
• 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 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
16 of 24 
 
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. 
5.7.1.3 
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. 
5.7.1.4 
Antidiabetic background medication 
Subjects experiencing changes to non-insulin antidiabetic background medication during the trial 
lasting more than 2 weeks will be summarised descriptively by treatment including number and 
proportion of subjects. 
Changes to non-insulin antidiabetic background medication are considered to be both initiation / 
discontinuation of antidiabetic background medication and increase / decrease in dose level of 
antidiabetic background medication. 
5.7.1.5 
Insulin dose 
Weekly actual insulin doses will be summarised by treatment and week. 
Mean weekly insulin dose from two weeks before week 52 (two weeks before V6) to week 52 (V6) 
will be summarised by treatment, and log-transformed and analysed using the same statistical model 
as specified for Trim-D compliance domain. 
Flexibility of up to +/-3 days is allowed for the dosing of the weekly trial drug. Number of subjects 
utilizing this flexibility together with the number of times they have utilized it and the number of 
days they have deviated from the weekly dosing will be summarised.  
5.8 
Interim analyses 
Not applicable for this trial. 
5.8.1 
Data monitoring committee 
Not applicable for this trial. 
5.9 
Reporting of the main part of the trial 
Not applicable for this trial. 
 
 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
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6 
Supporting documentation 
6.1 
Appendix 1: List of abbreviations 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
BG 
Blood glucose 
CI 
Confidence interval 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
FDA 
Food and Drug Administration 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SMPG 
Self-measured plasma glucose 
T2D 
Type 2 Diabetes 
Trim-D 
Treatment Related Impact Measure for Diabetes 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
18 of 24 
 
6.2 
Appendix 2: Changes to protocol-planned analyses 
6.2.1 
Changes prior to first patient first visit 
In section 2 ‘unacceptable loss of efficacy’ was replaced with ‘unacceptable loss of effectiveness’ to 
align with the trial objective. 
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. ‘Efficacy endpoints’ was replaced with ‘effectiveness endpoints’ to align with the 
endpoints section. 
In section 5.1 the baseline definition has been updated to clarify that week 0 (V2) is considered as 
baseline and if not available the most recent measurement prior to week 0 (V2) will be used as 
baseline. In this section, the seed number for the imputations have also been included. 
In section 5.3.2 description of alternative imputation strategies in case of insufficient amount of data 
for meaningful imputation has been added. 
In section 5.3.3 it has been added that the sensitivity analysis will also be done for the superiority 
evaluation. 
In section 5.4.1.1 additional analyses of time from baseline to treatment discontinuation or 
intensification have been added. Moreover, based on recommendations from FDA, the method for 
imputing missing data for change in DTSQs in total treatment satisfaction has been changed from 
imputing missing data using completing comparator subjects to imputing from baseline values 
within own arm. 
In section 5.5 description of analyses of exploratory endpoints has been added. 
Besides that, additional derivations and assessments have been added to section 5.6 and 5.7 along 
with further details on data reporting and presentation. 
6.2.2 
Changes after first patient first visit but before the database lock 
Section 5.6.2 has been added with additional summaries and analyses of hypoglycaemic episodes 
identified using an alternative definition based on SMPG measurements. 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
19 of 24 
 
6.3 
Appendix 3: Definition and calculation of endpoints, assessments and derivations 
Type 
Title 
Time frame Unit 
Details 
Primary 
endpoint 
Change in HbA1c 
From baseline 
week 0 (V2) to 
week 52 (V6) 
%-point 
The HbA1c value at baseline week 0 
subtracted from the HbA1c value at 
week 52. 
Supportive 
secondary 
endpoint 
Time from baseline to 
treatment 
discontinuation or 
intensification 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Days 
Time from baseline to treatment 
discontinuation or intensification. 
Supportive 
secondary 
endpoint 
Change in DTSQs 
(Diabetes Treatment 
Satisfaction 
Questionnaire) in total 
treatment satisfaction 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Score 0-36 
6 items 
scored on a 
scale of 0 to 
6. The higher 
the score the 
greater the 
satisfaction 
with 
treatment  
The DTSQs score in total treatment 
satisfaction at baseline week 0 
subtracted from the DTSQs score in 
total treatment satisfaction at week 
52. 
Supportive 
secondary 
endpoint 
Trim-D (Treatment 
Related Impact 
Measure for Diabetes) 
compliance domain 
At end of 
treatment week 
52 (V6) 
Score of 4-20. 
4 items 
scored on a 
scale of 1 to 5 
Transformed 
to a 0-100 
scale with 
higher scores 
corresponding 
to better 
compliance. 
The Trim-D compliance domain 
score at week 52. 
Supportive 
secondary 
endpoint 
Number of severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Supportive 
secondary 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within the 
time frame. 
Supportive 
secondary 
endpoint 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) or severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
Exploratory 
endpoint 
Number of severe 
hypoglycaemic 
episodes (level 3)  
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 3) 
within the time frame. 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
20 of 24 
 
Type 
Title 
Time frame Unit 
Details 
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 52 (V6) 
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 52 (V6)  
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 57 (V8)  
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter)  
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) or nocturnal 
severe hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
severe hypoglycaemic 
episodes (level 3)  
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter)  
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) or nocturnal 
severe hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Assessment 
Change in body weight 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Kg 
The body weight value at baseline 
week 0 subtracted from the body 
weight value at week 52. 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
21 of 24 
 
Type 
Title 
Time frame Unit 
Details 
Derivation 
Achievement of 
HbA1c<7.0% after 52 
weeks (yes/no)  
Week 52 (V6)  
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c < 7.0% 
after 52 weeks 
 
No: subject did not achieve HbA1c < 
7.0% after 52 weeks 
Derivation 
Achievement of 
HbA1c<7.0% after 52 
weeks without severe 
(level 3) or clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) during the prior 
12 weeks (yes/no) 
Week 52 (V6)  
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c < 7.0% 
after 52 weeks without severe or 
clinically significant 
hypoglycaemic episodes during the 
prior 12 weeks 
 
No: subject did not achieve HbA1c < 
7.0% after 52 weeks or subject had 
a severe or clinically significant 
hypoglycaemic episode during the 
prior 12 weeks or subject 
discontinued randomised treatment 
prematurely 
Derivation 
Achievement of 
HbA1c<7.0% after 52 
weeks without severe 
hypoglycaemic 
episodes (level 3) 
during the prior 12 
weeks (yes/no) 
Week 52 (V6)  
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c < 7.0% 
after 52 weeks without severe 
hypoglycaemic episodes during the 
prior 12 weeks 
 
No: subject did not achieve HbA1c < 
7.0% after 52 weeks or subject had 
a severe hypoglycaemic episode 
during the prior 12 weeks or 
subject discontinued randomised 
treatment prematurely 
Derivation 
Achievement of 
HbA1c≤6.5% after 52 
weeks (yes/no)  
Week 52 (V6)  
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 52 weeks 
 
No: subject did not achieve HbA1c 
≤6.5% after 52 weeks 
Derivation 
Achievement of 
HbA1c≤6.5% after 52 
weeks without severe 
(level 3) or clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 
mmol/L (54 mg/dL), 
confirmed by BG 
meter) during the prior 
12 weeks (yes/no) 
Week 52 (V6)  
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 52 weeks without severe or 
clinically significant 
hypoglycaemic episodes during the 
prior 12 weeks 
 
No: subject did not achieve 
HbA1c ≤6.5% after 52 weeks or 
subject had a severe or clinically 
significant hypoglycaemic episode 
during the prior 12 weeks or 
subject discontinued randomised 
treatment prematurely 
Derivation 
Achievement of 
HbA1c≤6.5% after 52 
weeks without severe 
hypoglycaemic 
episodes (level 3) 
during the prior 12 
weeks (yes/no) 
Week 52 (V6)  
Count of 
subject 
Dichotomous outcome variable: 
Yes: subject achieved HbA1c ≤6.5% 
after 52 weeks without severe 
hypoglycaemic episodes during the 
prior 12 weeks 
 
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Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
22 of 24 
 
Type 
Title 
Time frame Unit 
Details 
No: subject did not achieve 
HbA1c ≤6.5% after 52 weeks or 
subject had a severe hypoglycaemic 
episode during the prior 12 weeks 
or subject discontinued randomised 
treatment prematurely 
Assessment 
Mean weekly insulin 
dose 
From two 
weeks before 
week 52 (two 
weeks before 
V6) to week 
52 (V6) 
U 
The mean of weekly insulin doses 
during the two weeks. 
Derivation 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) based on 
SMPG measurements 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) identified 
based on SMPG measurements 
within the time frame. 
Derivation 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) based on 
SMPG measurements 
or nocturnal severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) identified 
based on SMPG measurements  or 
severe hypoglycaemic episodes 
(level 3) within the time frame. 
Derivation 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) based on 
SMPG measurements 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) identified 
based on SMPG measurements 
within the time frame. 
Derivation 
Number of clinically 
significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) based on 
SMPG measurements 
or nocturnal severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L (54 mg/dL), 
confirmed by BG meter) identified 
based on SMPG measurements  or 
severe hypoglycaemic episodes 
(level 3) within the time frame. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) based on 
SMPG measurements 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
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CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
23 of 24 
 
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) based on 
SMPG measurements 
or nocturnal severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 57 (V8) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) based on 
SMPG measurements 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
Derivation 
Number of nocturnal 
clinically significant 
hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 
mg/dL), confirmed by 
BG meter) based on 
SMPG measurements 
or nocturnal severe 
hypoglycaemic 
episodes (level 3) 
From baseline 
week 0 (V2) to 
week 52 (V6) 
Number of 
episodes 
Nocturnal hypoglycaemic episodes: 
episodes occurring between 00:01 
and 05:59 both inclusive. 
NN1436-4481
NN1436
0
 |
VV-TMF-4264229
 .
-
 |
2
 |
 of
  SAP  4481
23
24
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
14 April 2021 Novo Nordisk 
Trial ID: NN1436-4481 
Version: 
2.0 
UTN: U1111-1247-5279 
Status: 
Final 
EudraCT No: 2020-000476-38 
Page: 
24 of 24 
 
7 
References 
 
1. 
Food and Drug Administration, CDER. Guidance for Industry. Diabetes Mellitus: 
Developing Drugs and Therapeutic Biologics for Treatment and Prevention, Draft Guidance. 
February 2008. 
2. 
Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs 
insulin glargine and placebo in combination with metformin and sulfonylurea therapy in 
type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 
2009;52(10):2046-55. 
3. 
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987. 
 
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CONFIDENTIAL