Clinical trial NCT05352815
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2022-06-01; Completion date: 2024-04-23
Enrollment: 1291 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will compare the new medicine IcoSema, which is a combination of insulin icodec and semaglutide, taken once a week, to insulin icodec taken once a week in people with type 2 diabetes.

The study will look at how well IcoSema controls blood sugar level in people with type 2 diabetes compared to insulin icodec.

Participants will either get IcoSema or insulin icodec. Which treatment participants get is decided by chance. IcoSema and insulin icodec are both new medicines that doctors cannot prescribe.

Participants will get IcoSema or insulin icodec, which participants must inject once a week with a pen, which has a small needle, in a skin fold in the thigh, upper arm, or stomach.

The study will last for about 1 year and 1 month. Participants will have 21 clinic visits, 31 phone/video calls with the study doctor, and 4 contacts with the site that can either be clinic visits or phone/video calls At 11 clinic visits participants will have blood samples taken. At 7 clinic visits participants cannot eat or drink (except for water) for 8 hours before the visit.

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

Not applicable for China: Participants will be asked to wear a sensor that measures their blood sugar level all the time during a 5 week period at the end of the study.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: IcoSema intervention 2: Insulin icodec
Intervention descriptions: intervention 1: Participants will receive once weekly IcoSema subcutanously (s.c. under the skin) with or without oral anti diabetic drugs for 52 weeks. intervention 2: Participants will receive once weekly Insulin icodec subcutanously (s.c. under the skin) with or without oral anti diabetic drugs for 52 weeks.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05352815 
Sponsor trial ID: 
NN1535-4591 
Official title of study: 
A 52-week study comparing the efficacy and safety of once 
weekly IcoSema and once weekly insulin icodec, both 
treatment arms with or without oral anti-diabetic drugs, in 
participants with type 2 diabetes inadequately controlled with 
daily basal insulin. COMBINE 1 
Document date*: 
23 March 2023 
*Document date refers to the date on which the document was most recently updated.


Protocol 
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0BProtocol 
Protocol Title:  
A 52-week study comparing the efficacy and safety of once weekly IcoSema and once weekly 
insulin icodec, both treatment arms with or without oral anti-diabetic drugs, in participants with 
type 2 diabetes inadequately controlled with daily basal insulin. COMBINE 1 
Substance: IcoSema (insulin icodec and semaglutide) 
Universal Trial Number: U1111-1260-8259 
EudraCT Number: 2020-005281-34   
IND Number: 145811 
Study phase: 3a 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or site(s) 
Protocol version 6.0 
23-Mar-2023
All countries 
Protocol version 5.0 
08-Feb-2022
Turkey only 
Protocol version 4.0 
18-Jan-2022
Japan only 
Protocol version 3.0 
10-Aug-2021
All countries 
Protocol version 2.0 
24-Jun-2021
All countries 
Original protocol version 1.0 
21-Jun-2021
Not submitted 
Protocol version 6.0 (23-Mar-2023) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union,1 because 
it neither significantly impacts the safety nor physical/mental integrity of participants nor the 
scientific value of the study. 
Overall rationale for preparing protocol, version 6.0: 
The protocol has been updated to correct the below errors detected, in addition to further changes 
shown below: 
Section # and name 
Description of change 
Brief rationale 
Section 1.3 – Flowchart – Phone 
contacts 
Addition of a Flowchart for phone 
contacts 
To clarify the procedures to be 
performed during phone contacts 
Section 2 Introduction 
Sentence added to describe that insulin 
icodec is a recombinant protein produced 
using yeast. 
Detailed information about the insulin 
icodec molecule has been deleted. 
PMDA requirement 
For alignment with phase 3b protocol. 
The information is not relevant for trial 
conduct 
Section 2.3 Benefit-rsik 
assessment 
Text crossed out was deleted as follows:  
The risks of IcoSema presented in this 
section are a combination of important 
and non-important risks for IcoSema and 
for the mono-components insulin icodec 
and semaglutide. All risks for 
mono-components that have not been 
identified for IcoSema directly, are 
classified as potential risks for IcoSema, 
although these may be classified as 
identified risks for the mono-components. 
New risks from the mono-components 
are now evaluated using clinical data 
for IcoSema 
Section 2.3.1 Risk assessment 
The IcoSema IB is added as reference for 
benefits and risks of insulin icodec and 
semaglutide instead of the IBs of the 
mono-components.    
Alignment with updated IBs 
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Section # and name 
Description of change 
Brief rationale 
Section 4.1. Continuous Glucose 
Monitoring 
Text crossed out was deleted as follows: 
To evaluate the initial glycaemic control 
of participants switching from pre-trial 
insulin dose of 20-80 units to randomized 
treatment, and to evaluate the overall 
glycaemic control as specified by 
The deleted text had been included by 
mistake. This study only has CGM 
period (at the end of study) 
Section 4.3 Justification for dose Text in italics was added, and text crossed 
out was deleted as follows: 
The maximum dose and the ratio of 
IcoSema is based on the clinical findings 
[reference to IcoSema IB] from the mono-
components insulin icodec4 and 
semaglutide s.c.6 
Alignment with updated IBs 
Section 5.3.1 – Meals and 
dietary restrictions 
Text in italics was added as follows: 
Randomised treatment and other glucose 
lowering agents should be withheld on the 
day of the fasting visit until blood 
sampling has been performed.  
To clarify that participants should not 
take glucose lowering agents on the day 
of fasting visits until blood sampling 
has been performed 
Sections 5.4, 6.2, 6.3, 7.1.1, 7.2, 
8, Appendix 12 Abbreviations 
Replacement of IWRS by RTSM 
To reflect the change in systems used 
in the study 
Section 8.2.2 – Physical 
Examinations 
Text in italics was added, and text crossed 
out was deleted as follows:    
From the body weight and height 
measured at V1, the body mass index 
(BMI) should be calculated at V2 to 
evaluate inclusion criteria no. 7  
To clarify that the BMI should be 
calculated using the weight measured at 
visit 1 
Section 8.3 Adverse events and 
other safety reporting 
Addition of the clarifying note: “All 
cerebrovascular events are to be reported 
and sent for adjudication, however the 
EAC will only confirm strokes”.  
To clarify that the EAC will only 
confirm strokes  
Section 8.2.1. Dose, Appendix 8: 
Titration guideline 
In the description of collection of injection 
site “and insulin icodec” is added and 
“should” has been changed to “must”.  
eCRF correctly collects injection site 
area collected in both arms, while 
protocol erroneously only described it 
for IcoSema. Injection site area in both 
arms is required for originally planned 
population PK analysis to assess a 
potential differential effect of injection 
region between IcoSema and the mono-
component 
Section 8.2.4. Eye examination 
Text in italics was added, and text crossed 
out was deleted as follows: For 
participants who discontinue randomised 
treatment, eye examination can be 
performed up to 2 weeks after the visit at 
week 52 visit 54A.  
Clarification of visit number to 54A 
Appendix 2: Clinical laboratory 
tests 
Text and footnotes in italics were added to 
table 10.2: 
Hypersensitivity data will not be shared 
with investigators until after CSR 
finalisation. 
To clarify which hypersensitivity tests 
will be performed by which 
laboratories  
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Section # and name 
Description of change 
Brief rationale 
c Samples collected from Chinese 
participants will be analysed by a central 
lab in China. Samples collected from 
participants in the rest of the world will be 
analysed by Novo Nordisk Måløv, 
Denmark  
d Samples will be analysed by Novo 
Nordisk Måløv, Denmark for all countries 
except China, where these tests will not be 
done (see Appendix 11, Section 10.11). 
e Samples collected from Chinese 
participants will be analysed in a special 
lab in China. Samples collected from 
participants in the rest of the world will be 
analysed by a special lab designated by 
Novo Nordisk. 
Appendix 8. Titration guidance 
Added text in italics:  
All participants should receive a loading 
dose at randomisation (V2), which 
consists of total daily basal insulin dose 
before randomisation x 7 + 50% of their 
total daily basal insulin dose x 7 
Error in text, but calculations correct in 
table 10.5 
Appendix 11: Country/Region 
specific requirements - China 
Added text in italics:  
The following hypersensitivity analytes 
are not possible to be tested in China, see 
Appendix 2 (Section 10.2), and will not be 
included in the hypersensitivity case 
assessment: 
 
Anti-human insulin IgE 
 
Anti-insulin icodec IgE 
 
Anti-semaglutide IgE 
The following hypersensitivity analytes 
will be tested by the Central lab in China: 
 
Tryptase 
 
Total IgE antibodies 
The following hypersensitivity analytes 
will be tested by special lab in China: 
 
Anti-insulin icodec binding antibodies 
 
Anti-semaglutide binding antibodies 
To clearly reflect which 
hypersensitivity tests will be conducted 
in China due to local unavailability of 
some test and the impossibility of 
exporting samples outside China 
Appendix 11: Country/Region 
specific requirements - Japan 
Text added to describe which 
contraceptive methods included in the 
protocol (Table 10-3) have not been 
approved in Japan.  
PMDA requirement 
Appendix 11: Country/Region 
specific requirements - Turkey 
Change of Exclusion Criteria 10 as 
follows: “Presence or history of 
pancreatitis (acute or chronic) within 180 
days before screening". 
 
The use of GLP-1 RA is avoided in 
patients who have suffered pancreatitis 
due to treatment practice in Turkey 
Section 11 References 
Renumbering of references, version 
numbers of the IBs are updated.  
 
 
Renumbering as previous ref #29 is 
now #1, newer versions of IBs have 
become available.  
 
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Section # and name 
Description of change 
Brief rationale 
The Ozempic® IB is deleted as reference. 
The relevant information from the 
Ozempic® is included in the updated 
IcoSema IB,  
 
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Table of Contents 
 
Page 
0BProtocol ......................................................................................................................................................... 1 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 6 
1 Protocol summary ..................................................................................................................................... 10 
1.1 
Synopsis ............................................................................................................................................ 10 
1.2 
Flowchart .......................................................................................................................................... 14 
1.3 
Flowchart – phone contacts .............................................................................................................. 17 
2 Introduction ............................................................................................................................................... 18 
2.1 
Study rationale .................................................................................................................................. 18 
2.2 
Background ....................................................................................................................................... 19 
2.3 
Benefit-risk assessment ..................................................................................................................... 20 
2.3.1 
Risk assessment ................................................................................................................. 21 
2.3.2 
Benefit assessment ............................................................................................................. 26 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 27 
3 Objectives, endpoints and estimands ....................................................................................................... 28 
3.1 
Objectives ......................................................................................................................................... 28 
3.1.1 
Primary objective ............................................................................................................... 28 
3.1.2 
Secondary objectives ......................................................................................................... 28 
3.2 
Endpoints .......................................................................................................................................... 28 
3.2.1 
Primary endpoint ............................................................................................................... 28 
3.2.2 
Secondary endpoints .......................................................................................................... 28 
3.2.2.1 
Confirmatory secondary endpoints ................................................................ 28 
3.2.2.2 
Supportive secondary endpoints .................................................................... 29 
3.2.3 
Exploratory endpoints........................................................................................................ 29 
3.3 
Primary estimand .............................................................................................................................. 29 
3.3.1 
Secondary estimands ......................................................................................................... 30 
4 Study design ............................................................................................................................................... 32 
4.1 
Overall design ................................................................................................................................... 32 
4.2 
Scientific rationale for study design .................................................................................................. 33 
4.3 
Justification for dose ......................................................................................................................... 34 
4.4 
End of study definition ...................................................................................................................... 35 
5 Study population ....................................................................................................................................... 36 
5.1 
Inclusion criteria ............................................................................................................................... 36 
5.2 
Exclusion criteria .............................................................................................................................. 36 
5.3 
Lifestyle considerations .................................................................................................................... 38 
5.3.1 
Meals and dietary restrictions ............................................................................................ 38 
5.3.2 
Caffeine, alcohol and tobacco ........................................................................................... 38 
5.4 
Screen failures ................................................................................................................................... 38 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria ......................................................... 38 
6 Study interventions and concomitant therapy ........................................................................................ 39 
6.1 
Study interventions administered ...................................................................................................... 39 
6.2 
Preparation, handling, storage and accountability ............................................................................ 41 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 42 
6.4 
Drug treatment compliance ............................................................................................................... 42 
6.5 
Dose modification ............................................................................................................................. 43 
6.6 
Continued access to randomised treatment after end of study .......................................................... 43 
6.7 
Treatment of overdose ...................................................................................................................... 43 
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6.8 
Concomitant therapy ......................................................................................................................... 44 
6.8.1 
Rescue medicine ................................................................................................................ 44 
7 Discontinuation of study intervention and participant withdrawal ..................................................... 45 
7.1 
Discontinuation of study intervention ............................................................................................... 45 
7.1.1 
Discontinuation of randomised treatment .......................................................................... 45 
7.1.2 
Temporary discontinuation of randomised treatment ........................................................ 46 
7.1.3 
Rescue criteria ................................................................................................................... 46 
7.2 
Participant withdrawal from the study .............................................................................................. 47 
7.2.1 
Replacement of participants .............................................................................................. 47 
7.3 
Lost to follow-up............................................................................................................................... 47 
8 Study assessments and procedures .......................................................................................................... 49 
8.1 
Efficacy assessments ......................................................................................................................... 50 
8.1.1 
Self-measured glucose ....................................................................................................... 50 
8.1.2 
Continuous glucose monitoring ......................................................................................... 50 
8.1.3 
Clinical outcome assessments ........................................................................................... 51 
8.1.4 
Clinical efficacy ................................................................................................................. 51 
8.2 
Safety assessments ............................................................................................................................ 51 
8.2.1 
Dose ................................................................................................................................... 52 
8.2.2 
Physical examinations ....................................................................................................... 52 
8.2.3 
Vital signs .......................................................................................................................... 53 
8.2.4 
Eye examination ................................................................................................................ 54 
8.2.5 
Electrocardiograms ............................................................................................................ 54 
8.2.6 
Clinical safety laboratory assessments .............................................................................. 55 
8.2.7 
Pregnancy testing ............................................................................................................... 55 
8.3 
Adverse events and other safety reporting ........................................................................................ 55 
8.3.1 
Time period and frequency for collecting adverse event information ............................... 56 
8.3.2 
Method of detecting adverse events .................................................................................. 57 
8.3.3 
Follow-up of adverse events .............................................................................................. 57 
8.3.4 
Regulatory reporting requirements for serious adverse events .......................................... 57 
8.3.5 
Pregnancy .......................................................................................................................... 57 
8.3.6 
Technical complaints ......................................................................................................... 57 
8.4 
Pharmacokinetics .............................................................................................................................. 57 
8.5 
Genetics ............................................................................................................................................ 58 
8.6 
Biomarkers ........................................................................................................................................ 58 
8.7 
Immunogenicity assessments ............................................................................................................ 58 
8.7.1 
Anti-drug antibodies .......................................................................................................... 58 
8.7.2 
Hypersensitivity ................................................................................................................. 59 
9 Statistical considerations .......................................................................................................................... 61 
9.1 
Statistical hypotheses ........................................................................................................................ 61 
9.1.1 
Multiplicity adjustment...................................................................................................... 62 
9.2 
Analysis sets...................................................................................................................................... 62 
9.3 
Statistical analyses ............................................................................................................................ 63 
9.3.1 
General considerations ...................................................................................................... 63 
9.3.2 
Primary estimand analysis ................................................................................................. 63 
9.3.2.1 
Sensitivity analysis ......................................................................................... 64 
9.3.3 
Secondary estimand analyses ............................................................................................ 64 
9.3.3.1 
Confirmatory secondary estimands ................................................................ 64 
9.3.3.1.1 
Estimand related to change in body weight from baseline week 0 
(V2) to week 52 (V54) ........................................................................... 64 
9.3.3.1.2 
Estimand related to number of clinically significant hypoglycaemic 
episodes (level 2) (<3.0 mmol/L [54 mg/dL], confirmed by BG 
meter) or severe hypoglycaemic episodes (level 3) from baseline 
week 0 (V2) to week 57 (V56) .............................................................. 65 
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9.3.3.2 
Supportive secondary estimands .................................................................... 65 
9.3.4 
Exploratory estimand analysis ........................................................................................... 65 
9.3.5 
Other safety analyses ......................................................................................................... 66 
9.3.6 
Other analyses ................................................................................................................... 66 
9.3.6.1 
Pharmacokinetic modelling ............................................................................ 66 
9.4 
Interim analysis ................................................................................................................................. 66 
9.5 
Sample size determination ................................................................................................................ 66 
9.6 
Partial database lock ......................................................................................................................... 70 
10 Supporting documentation and operational considerations.................................................................. 71 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations .............................................. 71 
10.1.1 
Regulatory and ethical considerations ............................................................................... 71 
10.1.2 
Financial disclosure ........................................................................................................... 71 
10.1.3 
Informed consent process .................................................................................................. 72 
10.1.4 
Information to participants during the study ..................................................................... 72 
10.1.5 
Data protection .................................................................................................................. 72 
10.1.6 
Committees structure ......................................................................................................... 73 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 73 
10.1.6.2 
Event adjudication committee ........................................................................ 73 
10.1.7 
Dissemination of clinical study data .................................................................................. 73 
10.1.8 
Data quality assurance ....................................................................................................... 74 
10.1.8.1 
Case report forms ........................................................................................... 74 
10.1.8.2 
Monitoring ..................................................................................................... 74 
10.1.8.3 
Protocol compliance ....................................................................................... 75 
10.1.9 
Source documents .............................................................................................................. 75 
10.1.10 Retention of clinical study documentation ........................................................................ 76 
10.1.11 Study and site closure ........................................................................................................ 76 
10.1.12 Responsibilities .................................................................................................................. 77 
10.1.13 Indemnity statement .......................................................................................................... 77 
10.1.14 Publication policy .............................................................................................................. 78 
10.1.14.1 
Communication of results .............................................................................. 78 
10.1.14.2 
Authorship ...................................................................................................... 78 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 79 
10.1.14.4 
Investigator access to data and review of results ........................................... 79 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 80 
10.3 Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................................................... 83 
10.3.1 
Definition of adverse event ................................................................................................ 83 
10.3.2 
Definition of a serious adverse event................................................................................. 83 
10.3.3 
Description of adverse events requiring additional data collection and other events 
requiring collection of additional information ................................................................... 85 
10.3.4 
Recording and follow-up of adverse event and/or serious adverse event .......................... 86 
10.3.4.1 
Adverse event and serious adverse event recording....................................... 86 
10.3.4.2 
Assessment of severity ................................................................................... 87 
10.3.4.3 
Assessment of causality ................................................................................. 87 
10.3.4.4 
Final outcome ................................................................................................. 88 
10.3.4.5 
Follow-up of adverse event and serious adverse event .................................. 88 
10.3.5 
Reporting of serious adverse events .................................................................................. 88 
10.3.6 
Reporting of adverse events for non-Novo Nordisk medical devices ............................... 90 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 91 
10.4.1 
Definitions ......................................................................................................................... 91 
10.4.2 
Contraceptive guidance ..................................................................................................... 91 
10.4.3 
Collection of pregnancy information ................................................................................. 92 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 94 
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10.5.1 
Definition of technical complaint ...................................................................................... 94 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 94 
10.5.3 
Reporting of technical complaints for products not included in the technical 
complaint form .................................................................................................................. 95 
10.6 Appendix 6: Retention of human biosamples ................................................................................... 96 
10.7 Appendix 7: Hypoglycaemic episodes .............................................................................................. 97 
10.8 Appendix 8: Titration guideline ........................................................................................................ 99 
10.9 Appendix 9:  Events requiring adjudication ................................................................................... 103 
10.10 Appendix 10: Mitigations to ensure participant safety and data integrity during an emergency 
situation ........................................................................................................................................... 105 
10.10.1 Definition and scope of appendix .................................................................................... 105 
10.10.2 Visits ................................................................................................................................ 105 
10.10.3 Assessments ..................................................................................................................... 106 
10.10.4 Study intervention ........................................................................................................... 107 
10.11 Appendix 11: Country/Region-specific requirements .................................................................... 116 
10.12 Appendix 12: Abbreviations ........................................................................................................... 122 
10.13 Appendix 13: Protocol amendment history .................................................................................... 124 
11 References ................................................................................................................................................ 126 
 
Protocol Attachment I Global list of key staff and relevant departments and suppliers 
Protocol Attachment II Country list of key staff and relevant departments 
 
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1 
Protocol summary 
1.1 
Synopsis 
This is an interventional, multi-national, multi-centre, randomised, 52-week, open label, parallel 
group, treat-to-target, confirmatory study with two treatment arms. 
Rationale 
This study is designed to investigate the efficacy and safety of once weekly IcoSema, which is a 
combination product of insulin icodec and semaglutide. IcoSema will be compared to once weekly 
insulin icodec, both treatment arms with or without oral anti-diabetic drugs, in participants with 
type 2 diabetes inadequately controlled with daily basal insulin. The purpose is to show that there is 
an added benefit of the combination product compared to the once weekly insulin icodec mono-
component according to regulatory guidelines on clinical development of fixed combination 
products. 
Overall, the results of the present study will be important for evaluating the efficacy and safety of 
IcoSema in daily basal insulin experienced participants with type 2 diabetes when intensification is 
needed. Furthermore, once weekly IcoSema is developed to provide a simple treatment regimen. 
Objectives, endpoints and estimand 
Primary objective 
To confirm superiority of once weekly IcoSema compared with once weekly insulin icodec both 
treatment arms with or without oral anti-diabetic drugs in terms of glycaemic control measured by 
change in HbA1c from baseline after 52 weeks in participants with type 2 diabetes inadequately 
controlled with daily basal insulin. 
Secondary objectives 
To confirm superiority of once weekly IcoSema compared to once weekly insulin icodec, both 
treatment arms with or without OADs, in participants with T2D inadequately controlled with daily 
basal insulin in terms of: 
 Change in body weight from baseline after 52 weeks 
 Number of clinically significant hypoglycaemic (level 2) or severe hypoglycaemic (level 3) 
episodes during 52 weeks and the 5 week follow-up period 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline week 0 (V2) to week 52 (V54) 
%-point  
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Secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From baseline week 0 (V2) to week 52 (V54) 
Kg  
Number of clinically significant 
hypoglycaemic episodes (level 2) (<3.0 
mmol/L (54 mg/dL), confirmed by BG 
meter) or severe hypoglycaemic episodes 
(level 3) 
From baseline week 0 (V2) to week 57 (V56) 
Number of episodes 
Estimand 
The primary estimand is described by the following 5 attributes: 
 Treatment condition: The effect of randomised treatment (titration of once weekly IcoSema 
versus titration of once weekly insulin icodec) with or without oral anti-diabetic drugs, 
regardless of initiation of non-randomised insulin treatment or additional anti-diabetic 
treatments for more than 2 weeks and adherence to randomised treatment 
 Population: type 2 diabetes inadequately controlled with daily basal insulin 
 Endpoint: Change in HbA1c from baseline to week 52 
 Remaining ICEs: None. The two intercurrent events are captured under treatment condition and 
handled as follows: 
 Initiation of non-randomised insulin treatment or additional anti-diabetic treatments for 
more than 2 weeks by the treatment policy strategy 
 Discontinuation of randomised treatment for any reason by the treatment policy strategy 
 Population-level summary: Difference in mean changes from baseline 
Overall design 
The study duration is approximately 59 weeks and consists of: 
 an up to 2 weeks screening period 
 a 52-week treatment period 
 a 5-week follow-up period 
Treatment arms and duration 
1290 participants will be randomised (1:1) to receive once weekly IcoSema or once weekly insulin 
icodec, both treatment arms with or without oral anti-diabetic drugs. 
When discontinuing randomised treatment, the participant will be transferred to a suitable marketed 
product at the discretion of the investigator. 
Investigational medicinal products 
 IcoSema 700 units/mL + 2 mg/mL, subcutaneous, solution for injection, 1.5 mL pre-filled 
PDS290 pen injector. 
 Insulin icodec 700 units/mL, subcutaneous, solution for injection, 3 mL pre-filled PDS290 
pen-injector 
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Participant characteristics 
The participants will be male or female diagnosed with type 2 diabetes, inadequately controlled 
with daily basal insulin, and aged above 18 years at inclusion. They will meet the following key 
inclusion criteria and none of the following key exclusion criteria: 
Key inclusion criteria 
1. Male or female and age above or equal to 18 years at the time of signing informed consent. 
2. Diagnosed with type 2 diabetes mellitus ≥ 180 days before screening. 
3. HbA1c of 7.0-10.0% (53.0-85.8 mmol/mol) (both inclusive) as assessed by central laboratory on 
the day of screening. 
4. Treated with once daily or twice-daily basal insulin (neutral protamine hagedorn insulin, insulin 
degludec, insulin detemir, insulin glargine 100 units/mL, or insulin glargine 300 units/mL) 
20-80 units/day ≥ 90 days before screening. Short term bolus insulin treatment for a maximum 
of 14 days before screening is allowed, as is prior insulin treatment for gestational diabetes. The 
treatment can be with or without any of the following anti-diabetic drugs with stable doses ≥ 90 
days before screening:  
 Metformin 
 Sulfonylureasa 
 Meglitinides (glinides)a 
 DPP-4 inhibitorsa 
 Sodium-glucose co-transporter 2 inhibitors 
 Alpha-glucosidase-inhibitors 
 Thiazolidinediones 
 Marketed oral combination products only including the products listed above. 
5. Body mass index (BMI) ≤ 40.0 kg/m2. 
a Sulfonylureas, meglitinides (glinides) and DPP-4 inhibitors must be discontinued at randomisation. 
Key exclusion criteria   
1. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using a highly effective contraceptive method. 
2. Anticipated initiation or change in concomitant medication (for more than 14 consecutive days) 
known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or 
systemic corticosteroids).  
3. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within 90 days before screening. 
4. Any episodesa of diabetic ketoacidosis within 90 days before screening. 
5. Presence or history of pancreatitis (acute or chronic) within 180 days before screening. 
6. Any of the following: Myocardial infarction, stroke, hospitalization for unstable angina pectoris 
or transient ischaemic attack within 180 days before screening. 
7. Chronic heart failure classified as being in New York Heart Association Class IV at screening. 
8. Recurrent severe hypoglycaemic episodes within the last year (12 months) as judged by the 
investigator. 
9. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days before screening or in the period between 
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screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination. 
 
a as declared by the participant or in the medical records.  
Data monitoring committee: No 
 
 
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1.2 
Flowchart 
Protocol 
Sections 
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
V1 
V2 
V3 V4 V5 V6 
V8 
V12 V16 V20 V24a V28 V30a V34a V38 V42a V46 V49 
V50b V51 V52 V53 V54b V55 V56 V54A 
 Weekly Phone Contact 
number (P) 
P7 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48 
 Timing of Visit (Weeks) 
<-2 
0 
1 
2 
3 
4 
6  
10 
14 
18 
22  
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 Visit Window (Days) 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2
±3 
±3 
±3 
-2/+3
+3
+3
    Informed Consent and 
Demography 
10.1.3 
(App 1)
X 
    Eligibility Criteria 
5.1, 5.2
X 
X 
    Concomitant Medication 
6.8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Medical 
History/Concomitant 
Illness 
8.2 
X 
X 
    Tobacco Use 
5.3.2 
X 
    Childbearing Potential 
10.4 
(App 4)
X 
    Pregnancy Test 
8.3.5, 
10.4 
(App 4)
X 
X 
X 
X 
X 
    Body Measurements 
8.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
8.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Vital Signs 
8.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Physical Examination 
8.2.2 
X 
X 
X 
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Protocol  
Sections 
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
 
V1 
V2 
V3 V4 V5 V6 
V8 
V12 V16 V20 V24a V28 V30a V34a V38 V42a V46 V49 
V50b V51 V52 V53 V54b V55 V56 V54A 
 Weekly Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of Visit (Weeks) 
 
<-2 
0 
1 
2 
3 
4 
6   
10 
14 
18 
22   
26 
28  
32  
36 
40  
44 
47 
48    
49 
50 
51 
52    
54 
57 
 
 Visit Window (Days) 
 
 
 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-2/+3 
+3 
+3 
 
    ECG 
8.2.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
    Eye Examination 
8.2.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
    CGM 
8.1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
    Self Measured Plasma 
Glucose 
8.1.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
    Adverse Eventc 
8.3, 
10.3 
(App 3) 
10.7 
(App 7) 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Laboratory Assessments 
10.2 
(App 2) 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
    HbA1c 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
    Antibodies 
8.7 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
    Pop-PK 
8.4 
 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
    Hypoglycaemia 
Unawareness 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Diabetes Treatment 
Preference Questionnaire 
(IcoSema arm only) d 
8.1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
X 
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Protocol  
Sections 
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
 
V1 
V2 
V3 V4 V5 V6 
V8 
V12 V16 V20 V24a V28 V30a V34a V38 V42a V46 V49 
V50b V51 V52 V53 V54b V55 V56 V54A 
 Weekly Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P10 
P11 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of Visit (Weeks) 
 
<-2 
0 
1 
2 
3 
4 
6   
10 
14 
18 
22   
26 
28  
32  
36 
40  
44 
47 
48    
49 
50 
51 
52    
54 
57 
 
 Visit Window (Days) 
 
 
 
±3 ±3 ±3 ±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-2/+3 
+3 
+3 
 
    Drug Dispensing 
6 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
  
 
 
 
    Training in Trial 
Product, Pen-handling 
6.1 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
    Hand Out and Instruct in 
Devices 
6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
    Attend Visit Fasting 
5.3.1 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
Notes: 
a Visits V24, V30, V34 and V42 can be performed as either site visits, or phone/video contacts, at the discretion of the Investigator 
b Special visit windows to optimize CGM data collection in relation to endpoints 
c All AEs and SAEs must be collected from first administration of randomised treatment  
d Questionnaire should be prompted to participants at V53 
 
 
 
 
 
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1.3 
Flowchart – phone contacts 
 
 
 
Protocol Sections 
P7-P48 
 Visit Window (Days) 
 
±3 
    Concomitant Medication 
6.8 
X 
    Self Measured Plasma Glucose 
8.1.1 
X 
    Adverse Eventa 
8.3, 
10.3 (App 3) 10.7 (App 7  
X 
a All AEs and SAEs must be collected from first administration of randomised treatment
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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. Chronic hyperglycaemia of diabetes mellitus is 
associated with significant long-term complications, particularly tissues damage and dysfunction or 
organ failure - especially the kidney, eye, and nerves.2 Diabetes is generally classified according to 
aetiological factors, where type 1 diabetes and type 2 diabetes (T2D) constitutes the vast majority of 
cases. In the International Diabetes Federation’s Diabetes Atlas (2019), the estimated worldwide 
diabetes prevalence was 463 million, with a prediction that by 2045, the number of people with 
diabetes will have increased to 700 million.3 
T2D is a progressive disease, and the need for treatment intensification over time can be covered in 
a simple setting by a titratable fixed ratio combination product as IcoSema. IcoSema is a 
combination product of insulin icodec and the glucagon-like peptide 1 (GLP-1) receptor agonist 
semaglutide, which is developed to provide an effective and convenient, once weekly treatment 
regimen for people with T2D.  
Insulin icodec is a novel long-acting insulin analogue which is under development (global phase 3a 
programme initiated during the fourth quarter of 2020) to safely cover the basal insulin 
requirements for a full week with a single subcutaneous (s.c.) injection. Insulin icodec has a 
terminal half-life of approximately 196 hours. Insulin icodec is a recombinant protein produced 
using yeast.  
Semaglutide is a GLP-1 receptor agonist with a half-life of 149 to 164 hours, suitable for once 
weekly s.c. administration.4 The long half-life was obtained by applying the fatty acid acylation 
technology that provides specific high-affinity albumin binding. Furthermore, semaglutide has full 
stability against DPP-4 degradation. Semaglutide exhibits GLP-1 receptor mediated effects, leading 
to lowering of glucose and decreased appetite through physiologically relevant mechanisms. As a 
result, semaglutide provides strong glycaemic control and weight loss. In addition, the 
cardiovascular safety of semaglutide has been confirmed. The mechanism of action of semaglutide 
was characterized in extensive non-clinical and clinical studies.5, 6 Semaglutide (Ozempic®) is 
currently approved in more than 60 countries for the treatment of T2D. In addition, semaglutide is 
approved for use in combination with insulin.5 
IcoSema is expected to provide an effect on HbA1c reduction through actions on both fasting and 
prandial glycaemic control. IcoSema is also expected to reduce the risk of hypoglycaemic episodes 
and to provide weight loss compared to basal insulin and basal-bolus insulin treatment, and to show 
a comparable or better gastrointestinal adverse event (AE) profile as compared to semaglutide. 
2.1 
Study rationale 
The present study is a 52-week, parallel study, with two treatment arms designed to investigate the 
efficacy and safety of once weekly IcoSema in comparison to once weekly insulin icodec, both 
treatment arms with or without oral anti-diabetic drugs (OADs), in participants with T2D 
inadequately controlled with daily basal insulin. The purpose is to show that there is an added 
benefit of the combination product compared to the once weekly insulin icodec mono-component 
according to regulatory guidelines on clinical development of fixed combination products.7 
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Overall, the results of the present study will be important for evaluating the efficacy and safety of 
IcoSema in daily basal insulin experienced participants with T2D when intensification is needed. 
Furthermore, once weekly IcoSema is developed to provide a simple treatment regimen.  
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.8 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.9 
Treatment of type 2 diabetes mellitus  
The current treatment cascade recommended by the American Diabetes Association and the 
European Association for the Study of Diabetes follows a stepwise approach comprising lifestyle 
changes in combination with pharmacological intervention.10 Metformin is recommended as initial 
therapy, followed by combination therapy with other OADs, GLP-1 receptor agonists and insulin as 
the disease progresses.10 
Despite the development of new treatments, a substantial proportion of people with T2D fail to 
achieve the recommended glycaemic targets. This clinical inertia prolongs the duration of peoples’ 
hyperglycaemia, which consequently puts them at an increased risk of diabetes-associated 
complications and reduced life expectancy. Specifically, there is an unmet medical need for 
products with the potential to improve clinical outcomes through reduced treatment burden, i.e. 
fewer injections, and increased treatment adherence and persistence11 compared to other treatment 
regimens requiring daily or several weekly injections. 
For people with advanced T2D in need of improved fasting and prandial glycaemic control, 
combined treatment with a GLP-1 receptor agonist and a basal insulin can provide improved 
glycaemic outcomes.12 Experiences with fixed ratio combination products e.g. insulin 
degludec/liraglutide (Xultophy®) has shown improved treatment effect whilst reducing the side 
effects compared to the mono-components.13 However, market research has shown that people with 
diabetes would prefer fewer injections14 and increased flexibility15 than currently provided by once 
daily treatment. 
IcoSema  
IcoSema is a once weekly injectable fixed ratio combination product comprising the novel insulin 
icodec and the GLP-1 receptor agonist semaglutide and is developed for late stage treatment 
intensification for people with advanced T2D. The development of IcoSema is based on learnings 
from other fixed ratio combination products e.g. insulin degludec/liraglutide (Xultophy®), showing 
that combination products benefit from the complementary actions of both mono-components on 
glycaemic control. Hence, IcoSema benefits from both insulin icodec and the potent GLP-1 receptor 
agonist semaglutide. IcoSema has been investigated in a clinical pharmacology study 
(NN1535-4359) in participants with T2D. Data from NN1535-4359 has contributed to development 
of the IcoSema titration guidelines included in the phase 3a development programme. A 
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comprehensive review of the results from the clinical pharmacology study can be found in the 
current investigator’s brochure16 or any updates hereof. 
Insulin icodec 
Insulin icodec is a novel long-acting insulin analogue under development which is designed for s.c. 
administration with the aim of developing a safe once weekly injectable basal insulin treatment, 
with a terminal elimination half-life of approximately 196 hours. Data from three completed 
phase 2 clinical studies (NN1436-4383, -4465 and -4466) showed that once weekly insulin icodec 
provided similar glucose lowering effects compared to once daily insulin glargine 100 units/mL. In 
addition, time in range was comparable or improved with once weekly insulin icodec compared to 
once daily insulin glargine 100 units/mL. Overall, once weekly insulin icodec was well tolerated 
and no new safety issues related to insulin treatment were identified in the phase 2 studies. A 
comprehensive review of results from the non-clinical and clinical studies of insulin icodec can be 
found in the current investigator’s brochure17 or any updates hereof. 
Study population 
The study population will consist of participants with T2D inadequately controlled with daily basal 
insulin. The study population is further described in Section 4.2. 
2.3 
Benefit-risk assessment 
The main benefits and risks related to participation in the study are described in the below sections.  
The risks of IcoSema presented in this section are a combination of important and non-important 
risks for IcoSema and for the mono-components insulin icodec and semaglutide.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of IcoSema may be found in the current investigator’s brochure16 or 
any updates hereof.  
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2.3.1 
Risk assessment 
Table 2-1 
Risk assessment 
Risk of clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
IcoSema 
Identified risk  
Gastrointestinal AEs (Nausea, 
vomiting and diarrhoea) 
Gastrointestinal AEs is a class risk 
for all GLP-1 receptor agonist 
products. The precise mechanism 
remains unclear but involves a 
GLP-1 receptor-mediated activation 
and it is therefore considered a class 
risk for all GLP-1 receptor agonist 
products. In general, these reactions 
are mild or moderate in severity, of 
short duration, and dose dependent.   
In the phase 1 single dose study 
NN1535‑4359, more participants 
experienced gastrointestinal AEs, 
predominantly nausea and vomiting, 
following administration of IcoSema 
compared to the mono-components. 
This was likely due to the relatively 
higher maximum concentration of 
semaglutide following IcoSema 
administration of 175 units / 0.5 mg 
compared to separate dose 
administration of 0.5 mg 
semaglutide. 
Gastrointestinal AEs have also been 
observed in non-clinical studies as 
well as the clinical studies with 
semaglutide. The most frequently 
reported AEs across the semaglutide 
clinical programmes were 
gastrointestinal AEs (e.g., nausea, 
vomiting and diarrhoea).   
 
To mitigate the risk of 
gastrointestinal AEs, once weekly 
IcoSema will be initiated at a low 
starting dose of 40 dose steps 
(equivalent to 40 units of insulin 
icodec and 0.114 mg of semaglutide, 
i.e. half the semaglutide starting dose 
of 0.25 mg) and titrated with 
±10 dose steps (equivalent to 
10 units of insulin icodec and 
0.029 mg of semaglutide) to a 
maximum dose of 350 dose steps 
(equivalent to 350 units of insulin 
icodec and 1 mg of semaglutide). 
Participants who experience 
vomiting and/or diarrhoea will be 
instructed to maintain adequate fluid 
intake to compensate for the volume 
depletion. 
Identified risk  
Hypoglycaemia 
 
Hypoglycaemia is an anticipated 
undesirable effect related to the 
pharmacological mechanism of 
insulin. 
In the phase 1 single dose study 
NN1535‑4359 hypoglycaemic 
episodes were reported in ~33% 
participants in the IcoSema arm and 
32% of the participants in the insulin 
icodec arm. No severe 
hypoglycaemic episodes were 
reported. Most hypoglycaemic 
episodes were asymptomatic.  
Hypoglycaemia has been observed 
in clinical studies with insulin 
icodec. There is a low risk of 
hypoglycaemic episodes when 
semaglutide is used as 
mono-therapy. 
Participants with known 
hypoglycaemic unawareness will be 
excluded from the study. 
Frequent blood glucose 
measurements are encouraged 
throughout drug exposure by means 
of a blood glucose (BG) meter. The 
participant will receive written 
information describing 
hypoglycaemic symptoms and how 
to manage low blood glucose levels. 
Prevention or worsening of 
hypoglycaemia will be sought by 
early detection and administration of 
carbohydrates and medical treatment, 
if needed.  
When adjusting IcoSema dose, 
recommended titration schemes 
should be followed.  
Potential risk:  
Hypersensitivity 
As with all protein-based drugs, 
treatment with IcoSema may evoke 
allergic reactions, including severe 
As a precaution, participants with 
suspected hypersensitivity to 
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Risk of clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
systemic hypersensitivity reactions 
and angioedema.  
One non-serious type-1 
drug-induced hypersensitivity 
reaction was reported in the IcoSema 
phase 1 single dose study NN1535-
4359. 
No systemic hypersensitivity 
reactions have been observed in 
clinical studies with insulin icodec.  
Hypersensitivity is an adverse 
reaction identified in phase 3a 
studies for semaglutide in 
participants with T2D. 
randomised treatment will not be 
enrolled in this study.  
Participants and investigators will be 
instructed about the signs and 
symptoms of allergic reactions and 
instructed to contact the site 
immediately in case of signs of 
hypersensitivity. 
 
 
Potential risk:  
Serious allergic reactions 
As with all protein-based drugs, 
treatment with IcoSema may evoke 
allergic reactions, including severe 
systemic hypersensitivity reactions 
and angioedema.  
No serious allergic reactions have 
been observed with IcoSema in the 
phase 1 single dose study 
NN1535-4359. 
No systemic hypersensitivity 
reactions have been observed in 
studies with insulin icodec.  
Events of allergic reactions 
(generally mild and non-serious) 
have been reported in participants 
with T2D treated with semaglutide. 
Few events of anaphylactic reaction 
were reported; however, none of 
these events were related to the 
treatment with semaglutide. Events 
of angioedema were also reported 
from post marketing sources. 
As a precaution, participants with 
suspected hypersensitivity to 
randomised treatment will not be 
enrolled in this study.  
Participants and investigators will be 
instructed about the signs and 
symptoms of allergic reactions and 
instructed to contact the site 
immediately in case of signs of 
hypersensitivity. 
 
 
Potential risk:  
Medication error due to potential 
mix-up  
Despite the open-label study design, 
medication error is still an applicable 
risk for participants treated with 
multiple insulins. Medication errors 
can have clinical consequences such 
as hypoglycaemia or 
hyperglycaemia.  
No information is available from 
completed clinical studies with 
IcoSema. Very few medication 
errors have been observed in the 
completed clinical studies with 
insulin icodec, none associated with 
AEs. 
Participants will be instructed to 
visually verify the dialled units on 
the dose counter of the pen. In 
studies involving different pens, 
participants must be instructed to 
always check the pen label before 
each injection to avoid potential 
mix-ups. 
 
Potential risk:  
Injection site reactions 
Injection site reactions may occur 
with all injectable peptide-based 
treatments.  
In the phase 1 single dose study 
NN1535-4359 with IcoSema, one 
event of injection site haematoma 
was reported after administration of 
the mono-component semaglutide. 
Participants will be instructed to 
monitor for signs and symptoms of 
injection site reactions. Participants 
should be instructed to contact the 
site immediately in case of signs of 
worsening of injection site reactions 
for further action.  
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Risk of clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Injection site reactions were 
observed in participants with T2D 
treated with insulin icodec.  
In the studies with semaglutide s.c. 
for T2D, injection site reactions 
were reported by a low 
(approximately 1%) proportion of 
participants with semaglutide and 
were not recurrent in those 
individuals.  
Participants will be instructed on the 
most appropriate injection 
techniques. Recommendations on 
rotation of the site of injection are 
included in Table 6-1. 
Potential risk 
Diabetic retinopathy complications  
 
The risk of diabetic retinopathy 
complications has been observed in 
T2D treated with semaglutide in 
clinical studies.  
In a 2-year clinical study with. 
semaglutide s.c (NN9535-3744) 
involving 3,297 participants with 
T2D, high cardio vascular risk, long 
duration of diabetes and poorly 
controlled blood glucose, 
EAC-confirmed events of diabetic 
retinopathy complications occurred 
in more participants treated with 
semaglutide s.c (3.0%) compared to 
placebo (1.8%). The absolute risk 
increase for diabetic retinopathy 
complications was larger among 
participants with a history of diabetic 
retinopathy at baseline. In the 
participants who did not have a 
documented history of diabetic 
retinopathy the number of events 
was similar for semaglutide s.c and 
placebo. In the other clinical studies 
up to 1 year involving 4,807 
participants with T2D, AEs related 
to diabetic retinopathy were reported 
in similar proportions of participants 
treated with semaglutide s.c (1.7%) 
and comparators (2.0%). 
Rapid improvement in glucose 
control has been associated with a 
temporary worsening of diabetic 
retinopathy, but other mechanisms 
cannot be excluded. Long-term 
glycaemic control decreases the risk 
of diabetic retinopathy. These 
participants should be monitored 
closely and treated according to 
clinical guidelines.  
Participants will have an eye 
examination performed at baseline 
and at week 52. Diagnostic artificial 
intelligence algorithms may possibly 
be used as screening tool. If 
diagnostic artificial intelligence 
algorithms are used and in case of 
changes indicated by the algorithm, 
an additional eye examination must 
be performed, see section 8.2.4. 
Uncontrolled and potentially 
unstable diabetic retinopathy or 
maculopathy is an exclusion criterion 
in this study.  
Potential risk:  
Acute pancreatitis  
Acute pancreatitis has been observed 
with the use of GLP-1 receptor 
agonists. In the completed phase 3 
studies with semaglutide s.c. and 
oral semaglutide, both the event rate 
and the proportion of participants 
experiencing confirmed pancreatitis 
were similar with semaglutide and 
comparator. Few events were 
confirmed; the events occurred 
throughout the study periods and the 
overall rates were similar to the rates 
reported in background populations. 
Participants should be informed of 
the characteristic symptoms of acute 
pancreatitis and if pancreatitis is 
suspected, IcoSema should be 
discontinued. If confirmed, IcoSema 
should not be restarted. 
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Risk of clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Potential risk:  
Neoplasms (malignant and non-
malignant) 
Participants with T2D, as well as 
participants with overweight or 
obesity, have an increased risk of 
certain types of cancer. There is no 
evidence from clinical studies that 
GLP-1-based therapies increase the 
risk of neoplasms. However, in the 
semaglutide s.c. as well as oral 
semaglutide phase 3a studies, the 
proportion of participants with 
neoplasms (malignant and non-
malignant) were slightly higher with 
semaglutide than with comparator. 
The number of participants exposed 
to semaglutide s.c. or oral 
semaglutide for a longer period is 
considered insufficient for a 
thorough assessment of the risk of 
neoplasms. 
 
Participants with presence or history 
of malignant neoplasm within 
5 years prior to the day of screening 
will not be enrolled in this study. 
Basal and squamous cell skin cancer 
and any carcinoma in-situ is allowed. 
 
 
Potential risk:  
Pancreatic cancer 
Participants with T2D have an 
increased risk of certain types of 
cancer such as pancreatic cancer. 
There is currently no support from 
non-clinical studies, clinical studies 
or post-marketing data that GLP-1 
based therapies increase the risk of 
pancreatic cancer. However, 
pancreatic cancer has been classified 
as a potential class risk for all 
marketed GLP-1 receptor agonists 
by regulatory agencies. There is no 
indication of an increased relative 
risk in the semaglutide treatment 
groups vs. comparator, including 
placebo. The rates of EAC-
confirmed events of pancreatic 
cancer were consistently low across 
studies. 
Participants with history of 
malignant neoplasm within 5 years 
prior to the day of screening will not 
be enrolled in this study. 
 
Potential risk:  
Medullary thyroid cancer 
Thyroid C-cell tumours were seen in 
mouse and rat carcinogenicity 
studies after daily exposure to 
semaglutide for 2 years. The rodent 
C-cell tumours are caused by a non-
genotoxic, specific GLP-1 receptor 
mediated mechanism to which 
rodents are particularly sensitive. No 
C-cell tumours were observed in 
monkeys after 52 weeks exposure up 
to 52-fold above the clinical plasma 
exposure at 14 mg/day. The GLP-1 
receptor is not expressed in the 
normal human thyroid, and therefore 
the clinical relevance of the findings 
is considered to be low. 
Exclusion criteria related to personal 
or first-degree relative(s) history of 
multiple endocrine neoplasia type 2 
or medullary thyroid carcinoma. 
 
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Risk of clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Study procedures 
Risk of COVID-19 infection in  
relation to participation in study  
Participants may be exposed to the 
risk of COVID-19 transmission and 
infection in relation to site visits if 
an outbreak is ongoing in the given 
country.  
 
 
The risk of COVID-19 transmission 
in relation to site visits is overall 
considered to be low, however this 
may vary between geographical 
areas. 
To minimize the risk as much as 
possible, the following measures 
have been taken: 
 Cautious participant 
recruitment planning ensures 
controlled participant 
enrolment in countries where 
the COVID-19 pandemic is 
evaluated to be sufficiently 
under control, and at sites 
where health care resources are 
evaluated to be adequate. 
 Study procedures including the 
number and frequency of study 
procedures and assessments 
have been critically evaluated 
to limit the number of on-site 
visits to the extent possible. 
Remote visits can be performed 
either by phone or by video call 
depending on the preference of 
the participant and the 
investigator.  
 Guidance is provided to site 
staff to request that on-site 
visits are planned to be as short 
as possible. Physical contact 
between participants and site 
staff will be limited to the 
extent possible, and protective 
measures will be implemented 
(describe e.g. use of masks, 
sanitizers, no 
aerosol-generating procedures 
etc.). 
 Please refer to Appendix 10 
(Section 10.10) which lists the 
additional actions to be taken 
in case a site or country are 
locked down and it is not 
possible for participants to visit 
the site. 
Other 
Device medication error  
If the pen-injector is damaged or 
used differently than described in the 
directions for use a risk of overdose 
or underdose of randomised 
treatment exists. This may cause 
hypoglycaemia due to overdose or 
hyperglycaemia due to underdose. 
Training in injections and use of 
devices and guidance materials for 
investigator, site staff and 
participants will be provided. 
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Risk of clinical significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
For more information about the 
known and expected benefits and 
risks of insulin icodec, please refer to 
the IcoSema investigator’s 
brochure.16 
For more information about the 
known and expected benefits and 
risks of semaglutide, please refer to 
the IcoSema investigator’s 
brochure,16 the current EMA 
summary of product characteristics 
for semaglutide,5 the US prescribing 
information for semaglutide,6 or any 
locally approved label. 
 
 
Pregnancy and fertility. 
Studies with insulin icodec in rats 
have shown no effects on fertility, 
embryo-foetal survival or on major 
and minor foetal abnormalities. In an 
embryo-foetal development study in 
rabbits, no effect on major and minor 
foetal visceral and skeletal 
abnormalities at any dose levels was 
observed. Consequently, insulin 
icodec is categorised as ‘unlikely 
risk of human 
teratogenicity/fetotoxicity. 
Studies in animals have shown 
reproductive toxicity in studies with 
semaglutide. There are limited data 
from the use of semaglutide in 
pregnant women. 
The randomised treatment should not 
be used during pregnancy. Women 
of childbearing potential are required 
to use highly effective contraceptive 
methods when participating in the 
study, see Appendix 4 (Section 10.4, 
Table 10-3). If a participant wishes 
to become pregnant, or pregnancy 
occurs, the randomised treatment 
should be discontinued, please refer 
to Section 8.3.5 for further 
guidance). The effect of IcoSema on 
fertility in humans is unknown.  
 
Risk assessment has been conducted for the PDS290 pen-injector for IcoSema in accordance with 
ISO 14971:2019 when using the PDS290 pen-injector in people with T2D. All identified risks (i.e. 
injection site reactions, see Table 2-1) associated with using the PDS290 pen-injector for IcoSema 
according to the clinical procedures specified in this protocol have been reduced as far as possible 
and are acceptable, taking into account the current state of the art. The use of the PDS290 
pen-injector for IcoSema, in this study is therefore considered to be of non-significant risk. 
2.3.2 
Benefit assessment 
Based on experience from the mono-components and on the learnings from insulin 
degludec/liraglutide as described in the introduction, we expect at positive benefit of the 
combination product IcoSema. This benefit assessment section is based on clinical data available 
for the mono-components insulin icodec and semaglutide in the T2D population. 
Insulin icodec is currently in development and has been shown to have a long and stable 
pharmacokinetic and pharmacodynamic profile supporting a once weekly treatment. Market 
research has shown that people with diabetes mellitus would prefer fewer injections and greater 
flexibility than those provided by the current once daily treatment regiment.14 Therefore, the 
compliance and quality of life are expected to increase by introducing a once weekly basal insulin 
treatment.  
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Clinical data on once weekly semaglutide have demonstrated superior glycaemic control, superior 
reductions in body weight versus placebo and active comparators, and reduced cardiovascular risk 
compared to placebo in participants with T2D. Further, once weekly dosing offers flexibility and 
fewer injections as opposed to current therapy.  
Based on these data, the combination of semaglutide and insulin icodec in a once weekly fixed ratio 
combination product is expected to provide superior efficacy on HbA1c lowering compared to the 
mono-components.  
IcoSema is also expected to provide weight loss and to reduce the risk of hypoglycaemic episodes 
compared to basal insulin.  
For all participants, the anticipated benefits include improved glycaemic control. To ensure all 
participants receive adequate treatment, investigators are encouraged to optimise glycaemic control 
every week throughout the study in accordance with the titration guidelines, see Appendix 8 
(Section 10.8). Participants will receive intense medical care by means of weekly contact with the 
sites.  
2.3.3 
Overall benefit-risk conclusion 
No new significant safety information that changes the current benefit-risk profile of IcoSema 
emerged from the completed phase 1 single dose IcoSema study NN1535-4359 or safety profile 
generated from clinical and non-clinical development programme for the mono-components. 
Necessary precautions have been implemented in the design and planned conduct of the study in 
order to minimise the risks and inconveniences of participation in the study. 
IcoSema is expected to provide an effect on HbA1c reduction through actions on both fasting and 
prandial glycaemic control. IcoSema is also expected to reduce the risk of hypoglycaemic episodes 
and to provide weight loss compared to basal insulin and basal-bolus insulin treatment, and to show 
a comparable or better gastrointestinal AE profile as compared to semaglutide. 
Considering the measures taken to minimise risk to participants, the potential risks identified in 
association with IcoSema are justified by the anticipated benefits that may be afforded to people 
with T2D. 
More detailed information about the known and expected benefits and risks of IcoSema can be 
found in the current investigator’s brochure16 or any updates hereof. 
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3 
Objectives, endpoints and estimands 
3.1 
Objectives 
3.1.1 
Primary objective 
To confirm superiority of once weekly IcoSema compared with once weekly insulin icodec, both 
treatment arms with or without OADs, in terms of glycaemic control measured by change in HbA1c 
from baseline after 52 weeks in participants with T2D inadequately controlled with daily basal 
insulin. 
3.1.2 
Secondary objectives 
To confirm superiority of once weekly IcoSema compared to once weekly insulin icodec, both 
treatment arms with or without OADs, in participants with T2D inadequately controlled with daily 
basal insulin in terms of: 
 Change in body weight from baseline after 52 weeks 
 Number of clinically significant hypoglycaemic (level 2) or severe hypoglycaemic (level 3) 
episodes during 52 weeks and the 5 week follow-up period 
To compare parameters of glycaemic control and safety of once weekly IcoSema with once weekly 
insulin icodec, both treatment arms with or without OADs, in participants with T2D inadequately 
controlled with daily basal insulin. 
3.2 
Endpoints 
3.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline week 0 (V2) to week 52 (V54) 
%-point  
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From baseline week 0 (V2) to week 52 (V54) 
Kg  
Number of clinically significant 
hypoglycaemic episodes (level 2) (<3.0 
mmol/L (54 mg/dL), confirmed by BG 
meter) or severe hypoglycaemic episodes 
(level 3) 
From baseline week 0 (V2) to week 57 (V56) 
Number of episodes 
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3.2.2.2 
Supportive secondary endpoints 
Secondary efficacy endpoints 
Endpoint title 
Time frame 
Unit 
Time in range 3.9-10.0 mmol/L (70-180 
mg/dL)* 
From week 48 (V50) to week 52 (V54) 
% of readings  
Time spent < 3.0 mmol/L (54 mg/dL)* 
From week 48 (V50) to week 52 (V54) 
% of readings  
Time spent > 10.0 mmol/L (180 mg/dL)* 
From week 48 (V50) to week 52 (V54) 
% of readings  
Change in fasting plasma glucose (FPG) 
From baseline week 0 (V2) to week 52 (V54) 
mmol/L  
Weekly basal insulin dose 
From week 50 (V52) to week 52 (V54) 
Units 
* using continuous glucose monitoring (CGM) system, Dexcom G6 
Secondary safety endpoints 
Endpoint title 
Time frame 
Unit 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by 
BG meter)   
From baseline week 0 (V2) to week 57 (V56) 
Number of episodes 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline week 0 (V2) to week 57 (V56) 
Number of episodes 
3.2.3 
Exploratory endpoints 
Not applicable for this study. 
3.3 
Primary estimand 
The primary clinical question of interest 
What is the treatment effect between once weekly IcoSema and once weekly insulin icodec in 
change in HbA1c from baseline to week 52 in participants with T2D inadequately controlled with 
daily basal insulin regardless of discontinuation of randomised treatment for any reason and 
regardless of initiation of non-randomised insulin treatment or additional anti-diabetic treatments 
for more than 2 weeks?  
The primary estimand is described by the following 5 attributes: 
 Treatment condition: The effect of randomised treatment (titration of once weekly IcoSema 
versus titration of once weekly insulin icodec) with or without OAD(s), regardless of initiation 
of non-randomised insulin treatment or additional anti-diabetic treatments for more than 2 
weeks and adherence to randomised treatment 
 Population: T2D inadequately controlled with daily basal insulin 
 Endpoint: Change in HbA1c from baseline to week 52 
 Remaining ICEs: None. The two intercurrent events are captured under treatment condition and 
handled as follows: 
 Initiation of non-randomised insulin treatment or additional anti-diabetic treatments for 
more than 2 weeks by the treatment policy strategy 
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 Discontinuation of randomised treatment for any reason by the treatment policy strategy 
 Population-level summary: Difference in mean changes from baseline 
The rationale for the primary estimand is that this estimand captures both the efficacy and safety of 
the randomised treatment with and without additional anti-diabetic/glucose-lowering medication 
and thus aims at reflecting clinical practice. 
3.3.1 
Secondary estimands 
The secondary clinical question of interest related to secondary objective regarding body 
weight 
What is the treatment effect between once weekly IcoSema and once weekly insulin icodec in 
change in body weight from baseline to week 52 in participants with T2D inadequately controlled 
with daily basal insulin regardless of discontinuation of randomised treatment for any reason and 
regardless of initiation of non-randomised insulin treatment or additional anti-diabetic treatments 
for more than 2 weeks?  
The estimand addressing this secondary clinical question of interest and the rationale is the same as 
for the primary estimand with the endpoint attribute specified as: change in body weight from 
baseline to week 52.  
The secondary clinical question of interest related to secondary objective regarding number of 
clinically significant hypoglycaemic episodes (level 2) or severe hypoglycaemic episodes 
(level 3) 
What is the treatment effect between once weekly IcoSema and once weekly insulin icodec on 
number of clinically significant hypoglycaemic (level 2) or severe hypoglycaemic (level 3) episodes 
during the time that participants are considered exposed to randomised treatment in participants 
with T2D inadequately controlled with daily basal insulin regardless of initiation of non-randomised 
insulin treatment or additional anti-diabetic treatments, had all participants adhered to randomised 
treatment until week 52? 
The secondary estimand addressing this clinical question of interest is described by the following 5 
attributes: 
 Treatment condition: The effect of randomised treatment (titration of once weekly IcoSema 
versus titration of once weekly insulin icodec) with or without OAD(s), regardless of initiation 
of non-randomised insulin treatment or additional anti-diabetic treatments for more than 2 
weeks and had all participants adhered to randomised treatment 
 Population: T2D inadequately controlled with daily basal insulin  
 Endpoint: Number of clinically significant hypoglycaemic (level 2) or severe hypoglycaemic 
(level 3) episodes during 52 weeks and the 5 week follow-up period 
 Remaining ICEs: None. The two intercurrent events are captured under treatment condition and 
handled as follows: 
 Initiation of non-randomised insulin treatment or additional anti-diabetic treatments for 
more than 2 weeks by the treatment policy strategy 
 Discontinuation of randomised treatment for any reason by the hypothetical strategy 
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 Population-level summary: Rate ratio 
Rationale for the secondary estimand: The estimand reflects the interpretation of the effect of 
randomised treatment with and without additional anti-diabetic/glucose-lowering medication 
without the confounding effect of discontinuation of randomised treatment. This interpretation is 
considered to be the most relevant interpretation for clinical practice and in alignment with the 
evaluation of other safety parameters included in the study. In addition, collection of 
hypoglycaemic episode data after discontinuation of randomised treatment (beyond the standard 
5 week follow-up period) will require operational measures that will increase the study burden on 
participants. This could lead to increased withdrawal rates and missing assessments on the primary 
endpoint jeopardising the primary objective of this study. 
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4 
Study design 
4.1 
Overall design 
This is an interventional, multi-national, multi-centre, randomised, 52-week, open label, parallel 
group, treat-to-target confirmatory study with two treatment arms. The study investigates the 
efficacy and safety of treatment with once weekly IcoSema compared to once weekly insulin 
icodec, both treatment arms with or without OADs, in participants with T2D inadequately 
controlled with daily basal insulin.  
The study duration is approximately 59 weeks and consists of: 
 an up to 2 weeks screening period 
 a 52-week treatment period 
 a 5-week follow-up period 
The study includes a screening visit (V1) to assess participant’s eligibility. After screening, all 
eligible participants will be randomised (1:1) at visit 2 (V2). The overall study design and visit 
schedule are outlined in Figure 4-1 and the study flowchart (Section 1.2), respectively.  
Figure 4-1 
Study design 
 
1290 participants will be randomised (1:1) to receive once weekly IcoSema or once weekly insulin 
icodec. With the exception of sulfonylureas, glinides and DPP-4 inhibitors that must be 
discontinued at randomisation (V2), the dose and dosing frequency of any pre-study OADs should 
not be changed during the study, unless due to safety concerns.  
During the study, participants will measure daily self-measured plasma glucose (SMPG). The 
SMPG measurements will be evaluated by the investigator at the weekly contact either as site visits, 
by phone or video call. At the weekly contacts, the dosing will be adjusted in accordance with the 
participant’s needs and safety, see also titration guidelines Appendix 8 (Section 10.8). However, it 
is always up to the discretion of the investigator to assess participant’s individual needs and safety 
in accordance with local standard of care. 
After the 52 weeks of treatment, participants will come in for visit V54, where data for the primary 
endpoint will be collected. The visit at week 52 (V54) will be one week after the last dose of once 
weekly IcoSema or once weekly insulin icodec. After the 52 weeks of treatment participants will be 
transferred to a suitable marketed product at the discretion of the investigator. See also titration 
guideline, Appendix 8 (Section 10.8).  
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The treatment period is followed by a 5-week follow-up period to ensure safety data collection. 
During the follow-up period, two follow-up visits (V55 and V56) will be performed, 2 and 5 weeks 
after the visit at week 52 (V54), respectively. Hence, the last follow-up visit (V56) will take place 
6 weeks after the last dose of once weekly IcoSema or once weekly insulin icodec. The last follow-
up visit (V56) is scheduled to allow for appropriate wash-out of randomised treatment, following at 
least 5 half-lives of once weekly IcoSema or once weekly insulin icodec. 
To  evaluate the overall glycaemic control as specified by the endpoints (see Section 3.2.2.2), 
participants will have continuous glucose monitoring (CGM) profiles collected, as specified by the 
flowchart (Section 1.2). The CGM will be blinded for both participants and investigators. 
In case of persistent and unacceptable hyperglycaemia as judged by the investigator based on the 
daily SMPGs, and in accordance with local standard of care, treatment with non-randomised insulin 
(basal or bolus) limited to up to 14 consecutive days can be considered to be added to the 
randomised treatment at the discretion of the investigator to safeguard the participants. Initiation of 
new anti-diabetic medication and any changes hereto must be recorded on the concomitant 
medication form in the eCRF. 
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 and urgent heart failure visit) 
and all-cause death. All AEs will be collected from visit 2 and recorded from visit 3. 
Overall, the measures taken to ensure participant’s safety, includes weekly contacts with site staff, a 
5-week follow-up period, training of investigators and other site staff, safety surveillance including 
event adjudication and titration surveillance. In addition, in accordance with GCP, it is the 
investigators responsibility to assess participant's safety and at their discretion act accordingly. 
4.2 
Scientific rationale for study design 
The study is designed in alignment with the estimands (Section 3) to investigate the efficacy and 
safety of once weekly IcoSema compared to once weekly insulin icodec during 52 weeks. 
In order to confirm the superiority of the fixed ratio combination of IcoSema to its insulin 
mono-component, once weekly insulin icodec is the comparator. The treatment arms will be open 
label in order to avoid the risk of pen-mix-up in a double-blind, double dummy study, as the 
initiation and titration doses of IcoSema and insulin icodec differ – specifically in terms of no 
loading dose/loading dose, respectively, see Appendix 8 (Section 10.8). Blinding of the study would 
increase the treatment complexity and hence increase the burden on the participants. Further, the 
maximum allowed weekly dose of IcoSema will be 350 dose steps (equivalent to 350 units insulin 
icodec and 1 mg semaglutide) while there is no maximum allowed weekly dose of insulin icodec. 
The treatment duration of 52 weeks is evaluated to be adequate for assessing efficacy on glycaemic 
control as well as safety. This duration will also ensure sufficient time to reach the maintenance 
dose of IcoSema for the broad study population and allow adequate time in maintenance phase. The 
treat-to-target approach has been chosen to ensure optimal titration of both treatment arms based on 
SMPG values with the aim of improving HbA1c in the treatment period.  
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The evaluation of time in range will be based on continuous glucose monitoring (CGM) profiles. To 
avoid influence on titration and the glycaemic control the CGM data will be blinded for both 
participants and investigator.  
Participants entering the study will be inadequately controlled with daily basal insulin with or 
without OADs ensuring a study population representative of a broad and advanced T2D population.  
Risk of hypoglycaemia increases when insulin secretagogues like sulfonylureas and glinides are 
used in association with insulin and combination injectable anti-diabetic therapy.10, 18 Hence, to 
minimise the risk, sulfonylureas and glinides are discontinued at randomisation (V2). DPP-4 
inhibitors must likewise be discontinued since the combined use of a GLP-1 receptor agonist 
(semaglutide component of IcoSema) and a DPP-4 inhibitor is not currently recommended.19 
To safeguard participants, the inclusion and exclusion criteria defined in this study will limit the 
study population to participants not suffering from advanced underlying diseases other than T2D 
and related diseases. This is to avoid compromising the safety of the participants, and to strengthen 
the conclusions regarding the efficacy and safety of IcoSema. 
For more information on the study population, see the inclusion and exclusion criteria, Sections 5.1 
and 5.2, respectively. 
4.3 
Justification for dose 
The IcoSema pen is developed with one ratio and one titration algorithm for the phase 3a 
programme in order to simplify the treatment regiments for patients and physicians.  
Once weekly IcoSema will be switched from the pre-study daily basal insulin. IcoSema will be 
initiated at 40 dose steps (equivalent to 40 units of insulin icodec and 0.114 mg of semaglutide), and 
titrated to target according to the principles outlined in the titration guideline in Appendix 8 
(Section 10.8).  
The starting dose of 40 dose steps (equivalent to 40 units of insulin icodec and 0.114 mg of 
semaglutide) is selected based on pharmacokinetics (PK) findings from the development 
programme of IcoSema. The combination of the starting dose and the titration algorithm of ±10 
dose step increments (equivalent to 10 units of insulin icodec and 0.029 mg of semaglutide) is 
considered to be safe, due to the combined action of the two mono-components on both fasting and 
prandial glycaemic control. Furthermore, the selected starting dose and titration algorithm are 
expected to ensure a comparable or better gastrointestinal adverse event (AE) profile as compared 
to semaglutide s.c.  
The maximum dose of 350 dose steps is equivalent to 350 units insulin icodec and 1 mg 
semaglutide, which is the currently approved maximum dose for semaglutide s.c. in treatment of 
T2D (as of 21 June 2021).5,6 The maximum dose and the ratio of IcoSema is based on the clinical 
findings16 and learnings from the once daily fixed ratio combination product, insulin 
degludec/liraglutide (Xultophy®).13 The ratio is selected with the focus on balancing the benefits 
from semaglutide and the expected durability of treatment with the insulin component. Providing 
350 units of insulin icodec to 1 mg of semaglutide, is expected to meet the clinical needs for the 
majority of the target population, while their safety is also ensured.  
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Once weekly insulin icodec will be switched from the pre-study daily basal insulin, and initiated 
according to the principles outlined in the titration guideline in Appendix 8 (Section 10.8). A 50% 
loading dose will be applied to avoid glycaemic deterioration during the first few weeks of 
treatment. No safety concerns have been identified in subjects with T2D, including vulnerable 
subjects, using a loading dose when initiating insulin icodec (trial NN1436-4466). 
After randomisation, participants should start once weekly injections of IcoSema or insulin icodec 
on the same day as randomisation. Due to the long half-life of the IcoSema and insulin icodec, the 
last once weekly injections must be taken 51 weeks after randomisation. 
Further details on dose adjustment can be found in the titration guideline in Appendix 8 (Section 
10.8).  
Guidance on missed doses can be found in the titration guideline in Appendix 8 (Section 10.8).  
4.4 
End of study definition 
The end of the study is defined as the date of the last visit of the last participant in the study 
globally. 
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the visit at week 52 (V54) and the last follow-up visit (V56). 
The primary endpoint is evaluated at the visit at week 52 (V54). The primary completion date is 
defined as the date of visit at week 52 (V54) on which the last participant in the clinical study has 
an assessment for the primary endpoint. If the last participant is withdrawn early from the study, the 
primary completion date is considered the date when the second-to-last participant completes the 
visit at week 52 (visit 54).  
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5 
Study population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Pre-screening is defined as review of the patient medical records, including handing out participant 
information, as well as database review. Any pre-screening activities must be documented on site 
by the investigator. 
For country-specific requirements to the inclusion and exclusion criteria, please refer to Appendix 
11 (Section 10.11) for further information.  
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Informed consent obtained before any study-related activities. Study-related activities are any 
procedures that are carried out as part of the study, including activities to determine suitability 
for the study. 
2. Male or female. 
3. Age above or equal to 18 years at the time of signing informed consent. 
4. Diagnosed with type 2 diabetes mellitus ≥ 180 days before screening. 
5. HbA1c of 7.0-10.0% (53.0-85.8 mmol/mol) (both inclusive) as assessed by central laboratory on 
the day of screening. 
6. Treated with once daily or twice-daily basal insulin (neutral protamine hagedorn insulin, insulin 
degludec, insulin detemir, insulin glargine 100 units/mL, or insulin glargine 300 units/mL) 
20-80 units/day ≥ 90 days before screening. Short term bolus insulin treatment for a maximum 
of 14 days before screening is allowed, as is prior insulin treatment for gestational diabetes. The 
treatment can be with or without any of the following anti-diabetic drugs with stable doses ≥ 90 
days before screening:  
 Metformin 
 Sulfonylureasa 
 Meglitinides (glinides)a 
 DPP-4 inhibitorsa 
 Sodium-glucose co-transporter 2 inhibitors 
 Alpha-glucosidase-inhibitors 
 Thiazolidinediones 
 Marketed oral combination products only including the products listed above. 
7. Body mass index (BMI) ≤ 40.0 kg/m2. 
8. Not currently using real time continuous or flash glucose monitoring. 
a Sulfonylureas, meglitinides (glinides) and DPP-4 inhibitors must be discontinued at randomisation. 
5.2 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Known or suspected hypersensitivity to randomised treatment or related products. 
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2. Previous participation in this study. Participation is defined as signed informed consent. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using a highly effective contraceptive method, as defined in Appendix 4. 
4. Participation (i.e., signed informed consent) in any interventional, clinical study within 90 days 
before screening. 
Note:  Simultaneous participation in a study with the primary objective of evaluating an 
approved or non-approved investigational medicinal product for prevention or treatment of 
COVID-19 disease or postinfectious conditions is allowed if the last dose of the investigational 
medicinal product has been received more than 30 days before screening in the current study 
and if simultaneous participation is allowed by local authorities.  
5. Any disorder, except for conditions associated with T2D, which in the investigator’s opinion 
might jeopardise participant’s safety or compliance with the protocol. 
6. Anticipated initiation or change in concomitant medication (for more than 14 consecutive days) 
known to affect weight or glucose metabolism (e.g. treatment with orlistat, thyroid hormones, or 
systemic corticosteroids).  
7. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within 90 days before screening. 
8. Any episodesa of diabetic ketoacidosis within 90 days before screening. 
9. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma. 
10. Presence or history of pancreatitis (acute or chronic) within 180 days before screening. 
11. Any of the following: Myocardial infarction, stroke, hospitalization for unstable angina pectoris 
or transient ischaemic attack within 180 days before screening. 
12. Chronic heart failure classified as being in New York Heart Association Class IV at screening. 
13. Planned coronary, carotid or peripheral artery revascularisation. 
14. Renal impairment measured as estimated glomerular filtration rate value of 
< 30 ml/min/1.73 m2 at screening as defined by KDIGO 2012.20 
15. Impaired liver function, defined as alanine aminotransferase ≥ 2.5 times or bilirubin > 1.5 times 
upper normal limit at screening. 
16. Known hypoglycaemic unawareness as indicated by the investigator according to Clarke’s 
questionnaire question 8.21. 
17. Recurrent severe hypoglycaemic episodes within the last year (12 months) as judged by the 
investigator. 
18. Inadequately treated blood pressure defined as systolic ≥ 180 mmHg or diastolic ≥ 110 mmHg 
at screening. 
19. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days before screening or in the period between 
screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination, see 8.2.4. 
20. Presence or history of malignant neoplasm (other than basal or squamous cell skin cancer, 
in-situ carcinomas of the cervix, or in situ prostate cancer) within 5 years before screening. 
a as declared by the participant or in the medical records. 
A participant, 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 
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an important protocol deviation, and the independent ethics committee/institutional review board 
(IEC/IRB) and regulatory authorities must be notified according to local requirements. 
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary restrictions 
The participants should be fasting when attending some of the visits, see flowchart (Section 1.2). 
Fasting is defined as at least eight hours without food and drink intake, except for water and other 
prescribed medication. Randomised treatment and other glucose lowering agents should be withheld 
on the day of the fasting visit until blood sampling has been performed. Any other prescribed 
medication should be taken as usual. If the participant attends a fasting visit in a non-fasting state, 
the blood sampling procedures and weight measurements should be re-scheduled.  
5.3.2 
Caffeine, alcohol and tobacco 
Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
5.4 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently eligible for participation according to the inclusion/exclusion criteria. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure participants 
to meet requirements from regulatory authorities. Minimal information includes informed consent 
date, demography, screen failure details, eligibility criteria. 
A screen failure session must be made in the Randomisation and Trial Supply Management system 
(RTSM). 
Individuals who do not meet the criteria for participation in this study may not be rescreened.  If the 
participant 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 sample), re-sampling is allowed for the affected parameter(s). 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria 
Not applicable for this study. 
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6 
Study interventions and concomitant therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study protocol. 
Study interventions comprise IcoSema, insulin icodec, and OADs. BG meter and CGM are not 
considered study interventions. 
Trial products comprise investigational medicinal products (IMPs), including placebo and 
comparators, non-investigational medicinal products (NIMPs) and/or investigational medical 
devices. 
Trial products consist of IcoSema and insulin icodec. OADs are NIMPs but not considered trial 
products in this protocol. 
Randomised treatment consists of IcoSema and insulin icodec. Hence randomised treatment and 
IMPs are covering the same. 
Trial products and randomised treatment consist of IcoSema and insulin icodec. Randomised 
treatment will be used throughout the protocol while trial products is used when addressing product 
accountability. 
6.1 
Study interventions administered 
Training in the pen-injectors is the responsibility of the investigator or a delegate and must be 
repeated during the study at regular intervals, as specified in the flowchart (see Section 1.2.) in 
order to ensure correct use of the pen-injector. The following documents must be provided to the 
participants: 
IcoSema: directions for use 
Insulin icodec: directions for use 
Investigational medicinal products (IMP) 
All IMPs are listed in Table 6-1. 
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Table 6-1 
Investigational medicinal products 
Intervention 
IcoSema treatment arm 
Comparator treatment arm 
Intervention name 
IcoSema  
Insulin icodec  
Intervention type 
IMP, test product 
IMP, reference therapy 
Pharmaceutical form 
Solution for injection 
Solution for injection 
Route of administration  
s.c. (into the thigh, upper arm or 
abdomen)  
s.c. (into the thigh, upper arm or 
abdomen)  
IMP strength 
700 units/mL + 2 mg/mL 
700 units/mL 
Dose and dose frequency 
Administer IcoSema once weekly, 
on the same day each week, at any 
time of the day. For more 
information, please refer to 
Appendix 8 (Section 10.8) 
Administer insulin icodec once 
weekly, on the same day each week, 
at any time of the day.  
For more information, please refer to 
Appendix 8 (Section 10.8) 
Dosing instructions and 
administration  
The day of weekly administration 
can be changed if necessary, by up to 
3 days. A minimum of 4 days 
between injections should always be 
ensured. 
Rotation of injection site within the 
same area is recommended. For 
more information, please refer to 
Appendix 8 (Section 10.8) 
The day of weekly administration 
can be changed if necessary, by up to 
3 days. A minimum of 4 days 
between injections should always be 
ensured. 
Rotation of injection site within the 
same area is recommended.  
For more information, please refer to 
Appendix 8 (Section 10.8) 
Transfer from other therapy 
Please refer to Appendix 8 
(Section 10.8) 
Please refer to Appendix 8 
(Section 10.8) 
Sourcing 
Manufactured and supplied by Novo 
Nordisk A/S  
Manufactured and supplied by Novo 
Nordisk A/S  
Packaging and labelling 
1.5 mL pre-filled PDS290 
pen-injector. 
3 mL pre-filled PDS290 
pen-injector. 
 
 At randomisation visit (V2) participants should administer IcoSema or insulin icodec at site. 
 Instructions on missed doses can be found in the titration guideline in Appendix 8 
(Section 10.8). 
 It is not allowed to split a dose between two pens. 
 Information about the PDS290 pre-filled pen-injector and can be found in the directions for use 
provided in the eDiary. 
Non-investigational medicinal products (NIMP) 
After randomisation participants should continue their pre-study OADs (see list of allowed OADs 
in Section 5.1) throughout the entire study except for treatment with sulfonylureas, glinides and 
DPP-4 inhibitors that must be discontinued at randomisation. The OADs should be maintained at 
the stable, pre-study dose and at the same frequency during the entire treatment period unless due to 
safety concerns, which will be assessed at the discretion of the investigator. Combination products 
containing either sulfonylureas, glinides or DPP-4 inhibitors must also be discontinued, while the 
residual anti-diabetic mono-component of the combination product should in general be maintained 
at the pre-study dose throughout the study similar to other OADs. If the pre-study dose of the 
residual anti-diabetic medication is not available, the participant should increase the dose to the next 
available dose. 
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In addition, the OADs: 
 are considered to be NIMP 
 will not be supplied or reimbursed by Novo Nordisk unless required by local law and should be 
purchased or otherwise delivered to participants in accordance with local health plans  
 should be used in accordance with standard of care or local label in the individual country. 
Auxiliary supplies including medical device(s) not under investigation 
Auxiliary supplies comprise supplies other than trial products. Auxiliary supplies will be provided 
in accordance with the Trial Materials manual, please also see Table 6-2. 
Table 6-2 
Auxiliary supplies  
Auxiliary 
Model 
Details 
Manufacturer 
Needles  
NovoFine® needles 
or similar according 
to local requirements 
 
Only needles with a max length of 6 mm 
provided and approved by Novo Nordisk 
must be used for administration 
of randomised treatment. 
Needle must be discarded after each 
injection and the pen-injector should be 
stored without a needle attached.  
Novo Nordisk 
Continuous Glucose 
Monitoring (CGM) 
system  
Dexcom G6® 
At week 47 (V49) participants must be 
instructed in handling of the CGM. 
Please refer to the provided Participant 
CGM Guide. For countries where the 
CGM system is not approved, please refer 
to Appendix 11 (Section 10.11) 
Dexcom Inc. 
Blood glucose (BG) 
meter (including 
auxiliaries) 
Roche Accu-Chek® 
Guide / Instant 
At randomisation (V2) participants must 
be instructed in how to use the BG meter 
and the BG meter should be linked to the 
eDiary as described in the eDiary site 
guide. 
Please refer to the Roche manufacturer’s 
guide. 
Roche Diabetes Care 
Inc. 
eDiary 
Electronic Patient 
Interaction Device 
(ePID)  
Participant Mobile App in Study Phone, 
HCP web portal in Trial tablet, & Cloud 
Service. 
Please refer to the eDiary site guide.  
Novo Nordisk 
6.2 
Preparation, handling, storage and accountability 
Only participants enrolled in the study may use randomised treatment and only delegated site staff 
may supply randomised treatment. Each site will be supplied with sufficient randomised treatment 
for the study on an ongoing basis according to recruitment and randomisation. 
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that any discrepancies are reported and 
resolved before use of the trial products. 
All trial products must be stored in a secure, controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator and 
delegated site staff. 
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The investigator must inform Novo Nordisk immediately if any trial product has been stored outside 
specified conditions. The trial product must not be dispensed to any participant before it has been 
evaluated and approved for further use by Novo Nordisk. Additional details regarding handling of 
temperature deviations can be found in the Trial Materials Manual. 
The investigator or designee is responsible for trial product accountability and record maintenance 
(i.e., receipt, accountability and final disposition records). Drug accountability should be performed 
in the RTSM. 
The investigator or designee must instruct the participant to return all IMPs (both used and not 
used) at the next dispensing visit. 
The investigator or designee must instruct the participant on how to manage and record the in-use 
time of the dispensed products. The in-use time can be found in the Trial Materials Manual. 
 
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 (used or un-used), expired or damaged trial products (for technical complaint samples, 
see Appendix 5 [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. 
Acceptable temperature ranges and conditions for storage and handling of each trial product when 
not in use and when in use are described in the Trial Materials Manual and trial product label. 
Each single pen should be accounted for. 
6.3 
Measures to minimise bias: Randomisation and blinding 
All participants will be screened and centrally randomised using an RTSM and assigned to the next 
available treatment according to the randomisation schedule. Trial product will be allocated by the 
RTSM and dispensed by the investigator at the study visits summarised in the flowchart 
(Section 1.2). 
This is an open-label study; however, the specific trial products for a participant will be assigned 
using an RTSM. The site will access the RTSM before the start of trial product administration for 
each participant. Potential bias will be reduced by central randomisation and adjudication. 
6.4 
Drug treatment compliance 
Throughout the study, the investigator will remind the participants to follow the study procedures 
and requirements to encourage participant compliance. 
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When participants self-administer trial product at home, compliance with trial product 
administration will be assessed, and the assessment documented in source documents at each visit 
where information is available. If any suspicion of non-compliance arises, the site must enter into a 
dialogue with the participant, re-emphasizing the importance of compliance and uncover barriers to 
compliance. This dialogue must be documented. Compliance will be assessed by cross checking the 
following sources and comparing these to the expected use:  
 Drug accountability information  
 Review of eDiaries including SMPG profiles, dosing and hypoglycaemia reporting 
 Evaluating glycaemic control and adherence to the visit schedule 
6.5 
Dose modification 
Doses are adjusted according to blood/plasma glucose values as described in Appendix 8 
(Section 10.8)  
6.6 
Continued access to randomised treatment after end of study 
Randomised treatment will not be accessible after end of study. When discontinuing randomised 
treatment, the participant should be transferred to a suitable marketed product at the discretion of 
the investigator, please see the titration guideline in Appendix 8 (Section 10.8). The medication 
should be recorded in the concomitant medication form, as described in Section 6.8.  
6.7 
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 participant for overdose-
related AEs/serious adverse events (SAEs). 
A specific overdose for IcoSema and insulin icodec cannot be defined; however, hypoglycaemia 
may develop over sequential stages if the doses administered are too high relative to the 
participant’s requirements.  
Mild hypoglycaemia can be treated by oral administration of glucose or sugary products.  
Severe hypoglycaemia where the participant is not able to treat him/herself, can be treated by 
glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, by other drugs 
for the indication of treatment hypoglycaemia in accordance with local guidelines or by glucose 
given intravenously by a medical professional. Glucose must also be given intravenously, if the 
participant does not respond to glucagon within 10-15 minutes. If the participant has been 
unconscious, administration of oral carbohydrates is recommended for the participant upon 
regaining consciousness, in order to prevent a relapse. 
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the participant and in accordance with local standard of care. 
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For more information on overdose, also consult the current version of the IcoSema16 and insulin 
icodec17 investigator’s brochures. 
6.8 
Concomitant therapy 
Any medication that the participant is receiving at screening visit (V1) or receives until the visit at 
week 52 (V54) must be recorded. From week 52 (V54) and until the last follow-up visit (V56) only 
anti-diabetic medication and medication related to SAEs must be recorded. The medication must be 
recorded along with: 
 Select predefined medication. If not listed, enter trade name or generic name 
 Primary indication  
 Dates of administration including start and stop dates 
 Relevant for participants in COVID-19 studies: Type of study and type of drug   
Changes in concomitant therapy must be recorded. If a change is due to an AE, then this must be 
reported according to Section 8.3.  
For information regarding restrictions to anti-diabetic medication other than the randomised 
treatment, please see Section 6.1. 
For information regarding concomitant medication collection for participants who discontinue 
randomised treatment, see Section 7.1.1. 
6.8.1 
Rescue medicine 
Not applicable for this study. In case of lack of efficacy, please refer to section 7.1.1.  
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7 
Discontinuation of study intervention and participant withdrawal 
Discontinuation of specific sites or of the study as a whole is detailed in Appendix 1 
(Section 10.1.11). 
7.1 
Discontinuation of study intervention 
Study intervention may be discontinued at any time during the study at the discretion of the 
participant or at the discretion of the investigator for safety, behavioural, compliance or 
administrative reasons. 
7.1.1 
Discontinuation of randomised treatment 
Discontinuation of randomised treatment corresponds to discontinuation of IcoSema or insulin 
icodec. 
If a participant discontinues randomised treatment, the participant should as soon as possible attend 
the discontinuation visit (V54A).  
The investigator should change participant status in the healthcare professional (HCP) web portal to 
'follow-up' at the discontinuation visit (V54A) to ensure that the participant should no longer report 
randomised treatment dose. 
The participant should also complete the two follow-up visits (V55 and V56).  
 
Hypoglycaemic episodes will not be collected after the last follow-up visit (V56). 
Efforts must be made to have the participants who discontinue randomised treatment attend the visit 
at week 52 (V54) to collect: 
 Data for primary endpoint (HbA1c). 
 Data for confirmatory secondary endpoint for body weight. 
AEs, medication related to SAEs, and anti-diabetic medication should be collected and recorded in 
the eCRF until the visit at week 52 (V54). No other concomitant medication than medication related 
to SAEs and anti-diabetic medication will be collected and reported in the eCRF for participants 
who discontinue randomised treatment. 
Please, refer to Section 6.6 for treatment after discontinuation of randomised treatment. 
The site should stay in contact with the participants who discontinue randomised treatment by 
phone, video call and/or site visits to motivate the participants to attend the follow-up visits (V55 
and V56) and the visit at week 52 (V54). Site contacts should be documented in the medical record. 
In case of any uncertainty regarding the scheduling of the visits after discontinuation of randomised 
treatment or questions to said visits, the investigator should consult Novo Nordisk for further 
guidance. 
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Only participants who withdraw consent will be considered as withdrawn from the study. 
Participants must be informed about the continued scientific importance of their data, even if they 
discontinue randomised treatment. 
The randomised treatment must be discontinued, if any of the following applies for the participant: 
1. Safety concern related to randomised treatment or unacceptable intolerability 
2. Pregnancy 
3. Intention of becoming pregnant 
4. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical study 
Note:  Simultaneous participation in a study with the primary objective of evaluating an 
approved or non-approved investigational medicinal product for prevention or treatment of 
COVID-19 disease or post-infectious conditions is allowed at the investigator’s discretion 
without discontinuation of randomised treatment if simultaneous participation is allowed by 
local authorities.  
5. Lack of efficacy, defined as fulfilment of ALL criteria (a, b and c) below after week 8 and 
onwards: 
a. 
Mean of pre-breakfast SMPG values (on the two days before and on the day of visit) of 3 
consecutive weeks after week 8 are above 15 mmol/L (270 mg/dL), AND 
b. 
no treatable intercurrent cause for the hyperglycaemia (e.g. non-compliance) has been 
identified. 
c. 
In such case, the participant must be called for a confirmatory fasting plasma glucose 
(FPG) measurement as soon as possible. A confirmatory FPG must be obtained and 
analysed by the central laboratory. If this FPG exceeds 15 mmol/L (270 mg/dL), 
participant fulfils the lack of efficacy criteria. 
To allow time for up-titration of the randomised treatment and to observe the expected effect of 
randomised treatment on glycaemic parameters, lack of efficacy criteria will be applied on week 8 
and onwards. 
The primary reason for discontinuation of randomised treatment must be specified in the CRF, and 
final trial product accountability must be performed. A discontinuation session must be made in the 
RTSM.  
7.1.2 
Temporary discontinuation of randomised treatment 
The participant should adhere to the randomised treatment to the extent possible, with the exception 
of any AEs such as hospitalisation or safety concerns, at the discretion of the investigator. If a 
participant due to an AE or safety concern temporarily has discontinued randomised treatment, 
she/he is allowed to restart randomised treatment, unless any of the discontinuation criteria 
specified in Section 7.1 applies. 
7.1.3 
Rescue criteria 
Not applicable for this study. 
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7.2 
Participant withdrawal from the study 
A participant may withdraw consent at any time at his/her own request. 
If a participant withdraws consent prior to randomisation, he/she will not be asked to have any 
follow-up assessments performed. The following data must be collected: Demography, completed 
eligibility criteria, date of informed consent, date of screening and the date when participant’s 
participation ended. The end of study form must be completed. 
If a participant withdraws consent after randomisation, the investigator must ask the participant if 
he/she is willing, as soon as possible, to have assessments performed according to discontinuation 
visit V54A. The investigator should also ask the participant if he/she is willing to attend the two 
follow-up visits V55 and V56 (see Section 7.1 regarding the scheduling of the follow-up visits). See 
the flowchart for data to be collected. 
Final trial product accountability must be performed even if the participant is not able to come to 
the site. A discontinuation session must be made in the RTSM. 
If the participant withdraws consent, Novo Nordisk may retain and continue to use any data 
collected before such a withdrawal of consent for the purpose of the study or scientific research. 
If a participant withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the medical record. 
Although a participant 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 participant’s 
rights. Where the reasons are obtained, the primary reason for withdrawal must be specified in the 
CRF. 
7.2.1 
Replacement of participants 
If a participant discontinues randomised treatment, withdraws consent or is withdrawn from the 
study by the investigator, he/she will not be replaced. 
7.3 
Lost to follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a participant fails to return to the site for a required visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the study. 
 Before a participant is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the participant  (where possible, at least three telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s source document. 
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 Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of ‘lost to follow-up’.  
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8 
Study assessments and procedures 
The following sections describe the assessments and procedures, while their timing is summarised 
in the flowchart (Section 1.2). 
Informed consent must be obtained before any study-related activity, see Appendix 1 
(Section 10.1.3). 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all inclusion criteria and none of the exclusion criteria. 
The investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
At screening, participants will be provided with a card stating that they are participating in a study 
and giving contact details of relevant site staff that can be contacted in case of emergency.  
Adherence to the study design requirements, including those specified in the flowchart 
(Section 1.2), is essential and required for study conduct. 
Assessments should be carried out according to the clinic’s standard of practice unless specified in 
the current section. Efforts should be made to limit the bias between the assessments. The suggested 
order of the assessments at randomisation visit (V2) is as follows: 
 Blood sample collection 
 Other assessments to confirm eligibility 
 Randomisation in RTSM 
 The investigator should create a participant profile and record administrative information (e.g. 
subject ID, year of birth and gender) and treatment arm in the HCP web portal  
 Participants should be provided with an eDiary and instructed in how to use it  
 The BG meter should be connected with the eDiary  
 A fasting SMPG should be measured using the BG meter 
 Dispensing and dosing of randomised treatment. 
For information regarding the eDiary and HCP web portal please refer to the site guide.  
Please refer to Section 6.4 for drug treatment compliance. 
All data entered in the eDiary is considered source data. The investigator should review all the data 
for the participants through the HCP web portal, before or during each visit/phone contact. 
Review of eDiaries, ECG, laboratory reports, eye- and physical examinations must be documented 
in the source documents or the participant’s medical record. If clarification of entries or 
discrepancies in the eDiary is needed, the participant must be questioned, and a conclusion made in 
the participant’s source documents. Care must be taken not to bias the participant. 
Source data of clinical assessments performed and recorded in the eCRF must be available and will 
usually be in the participant’s medical records. 
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Repeat samples may be taken for technical issues and unscheduled samples or assessments may be 
taken for safety reasons. Please refer to Appendix 2 (Section 10.2) for further details on laboratory 
samples. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2) and in 
appendix 2 10.2. 
8.1.1 
Self-measured glucose  
Participants will be provided with a blood glucose meter (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 measurements required in the 
protocol. 
Participants must be instructed in how to transfer the results of the SMPG values daily into the 
eDiary.  
A baseline SMPG value, in fasting condition, should be collected using the BG meter at V2. 
Pre-breakfast daily self-measured plasma glucose  
Participants should be instructed to measure their pre-breakfast SMPG daily from week 0 (V2) to 
last follow-up visit (V56) and to transfer the measured SMPG values into the eDiary.  
Selected titration data (e.g. certain SMPGs and dose data) from the eDiary will be used during the 
study for central titration surveillance, to ensure compliance with the titration guideline in 
Appendix 8 (Section 10.8). All data will be stored by Novo Nordisk, see Appendix 1 (Section 10.1). 
8.1.2 
Continuous glucose monitoring  
Participants will be equipped with a CGM device during the treatment period from week 47 (V49) 
to week 52 (V54). The CGM system used in this study will be the Dexcom G6®. The CGM 
readings will be blinded to both the participant and investigator and will not be used for any insulin 
dose titration or hypoglycaemic episode reporting. 
If a participant withdraws consent during the study at a timepoint where she/he wears CGM, a site 
visit should be scheduled in order to remove the CGM sensor and to ensure data upload 
CGM fitting and training  
The site staff will closely supervise and assist on fitting of the sensor and transmitter on the 
participant during the site visits. Training in the CGM is the responsibility of the investigator or site 
staff at the relevant visits. For information on fitting, and changing of the CGM parts, please refer to 
the Investigator’s CGM manual and participant CGM guide provided. 
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If a participant is to have an x-ray, Magnetic Resonance Imaging, Computed Tomography scan or 
high-frequency electrical heat (diathermy), the Dexcom G6 sensor, transmitter, and receiver should 
be removed. 
CGM sensor check  
The CGM sensor has an in-use period of 10 days. The sensor will automatically stop recording data 
exactly 10 days after sensor insertion and start. This should be taken into account when scheduling 
the clinic visits.  
The site staff should ensure that the participant has fitted the sensor correctly and that the CGM 
receiver is working. This will be done during the clinic visit, as specified in the flowchart (Section 
1.2).  
CGM data upload 
CGM data must be uploaded at the site by the site staff to the CGM software following the 
instruction provided to the sites. The upload will be documented by the system directly. Special 
visit windows are included to optimize CGM data collection, please see Section 1.2. 
The serial number of the CGM receiver must be recorded in the eCRF at the start of each CGM 
period. In case the CGM receiver is being replaced, the serial number should be updated.  
8.1.3 
Clinical outcome assessments 
This section is only relevant for participants randomised to IcoSema. No clinical outcome 
assessments will be measured for the participants randomised to insulin icodec. The patient reported 
outcome questionnaire is to be completed by the participant without assistance of the site personnel. 
It takes approximately 5 minutes to complete the questionnaire. 
The following patient reported outcome questionnaire will be supplied in the eDiary in a 
linguistically validated version in all languages relevant for this study:  
 Diabetes Treatment Preference Questionnaire (DTPQ). The DTPQ will be used to measure the 
preference of treatment and reasons for preference of participants randomised to IcoSema, 
considering pre-study basal insulin as comparator. Data will be collected between week 51 and 
week 52 (V54).  
8.1.4 
Clinical efficacy 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart (Section 1.2) and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart (Section 1.2) and in 
appendix 2 10.2.  
Medical history is a medical event that the participant experienced prior to the time point from 
which AEs are collected. All relevant medical history as judged by the investigator will be recorded 
in the eCRF. 
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As part of the medical history, information on the following will be collected: 
 History of diabetes 
 History of cardiovascular disorder and procedure  
 History of non-alcoholic fatty liver disease (NAFLD) 
 COVID-19 vaccines 
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 study procedures performed before 
exposure to study intervention under clinical investigation. 
In case of an abnormal and clinically significant finding fulfilling the definition of medical history 
or concomitant illness, the investigator must record the finding on the medical history/concomitant 
illness form. 
Information on hypoglycaemia unawareness will be recorded according to Clarke's questionnaire, 
question 8.21 The investigator must ask the participant in the following way: "To what extent can 
you tell by your symptoms that your blood glucose is low?" Participants answering ‘never, rarely or 
sometimes’ are considered to have impaired awareness of hypoglycaemia, whereas those answering 
‘often or always’ are not. 
8.2.1 
Dose  
The prescribed IcoSema and insulin icodec doses will be determined by the investigator in 
accordance with the titration guideline, see Appendix 8 (Section 10.8). 
The investigator must record the first and last date of trial product in the eCRF.  
During the study, starting at randomisation (V2), participants must be instructed to report date, 
actual dose applied and time of once weekly IcoSema or once weekly insulin icodec in the eDiary. 
The injection site area of IcoSema and insulin icodec must be reported in the eCRF.  
Please refer to Appendix 8 (Section 10.8) for more information. 
8.2.2 
Physical examinations 
A physical examination will include assessments of: 
 Head, ears, eyes, nose, throat, neck 
 Respiratory system 
 Cardiovascular system 
 Gastrointestinal system including mouth 
 Musculoskeletal system 
 Central and Peripheral Nervous System 
 Skin 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
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Abnormal, clinically significant findings at screening should be recorded as concomitant illness in 
the eCRF. At the following visits, any new abnormal, clinically significant findings or clinically 
significant deteriorations after randomisation should be reported as an AE, see Appendix 3 (Section 
10.3). 
Body measurements will be measured and recorded in the eCRF. Height will be measured and 
recorded at screening visit V1. Body weight will be measured and recorded accordingly to the 
flowchart (Section 1.2). Waist circumference will be measured and recorded at visits V2, V28, V54 
and V54A (if applicable). 
 Fasting body weight should be measured in kilogram (kg) or pounds (lb) without coat and shoes 
wearing only light clothing. Body weight will be recorded to one decimal.  
 Body weight should be assessed with the same equipment throughout the study, if possible. 
 Height should be measured in centimetres (cm) or inches (in) without shoes. Height will be 
recorded to the nearest whole number. 
 The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest and will be measured using a non-stretchable 
measuring tape. The measurement of waist circumference should be performed and recorded in 
the eCRF to the nearest ½ cm or ¼ in using the same measuring tape throughout the study. The 
waist circumference should be measured in a standing position with an empty bladder and 
wearing light clothing with accessible waist. The participant should be standing with arms down 
their side and feet together. The tape should touch the skin but not compress soft tissue. The 
participant should be asked to breathe normally, and the measurement should be taken when the 
subject is breathing out gently. 
From the body weight and height measured at V1, the body mass index (BMI) should be calculated 
to evaluate inclusion criteria no.7 and recorded in the participant’s medical records 
8.2.3 
Vital signs 
Pulse rate as well as systolic and diastolic blood pressure will be assessed. 
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., no use of television, cell phones). 
Blood pressure and pulse rate measurements will be assessed sitting with a completely automated 
device. Manual techniques must be used only if an automated device is not available. 
Blood pressure and pulse rate are collected at screening (V1), randomisation (V2), V12, V20, V28, 
V38, V46, V54, and V54A. 
Blood pressure 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. No more than four 
measurements should be performed. 
 
 The last 2 systolic and last 2 diastolic blood pressure measurements should be recorded in the 
CRF. 
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Pulse rate will be measured in connection to the blood pressure measurements. 
 
 The pulse rate for the last 2 measurements should be recorded in the CRF.  
8.2.4 
Eye examination 
Participants with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist or another suitably qualified health 
care provider (e.g., optometrist) possibly aided by diagnostic artificial intelligence algorithms 
approved by FDA and/or CE-marked must be available and evaluated by the investigator before 
randomisation to assess eligibility. The eye examination should be performed as a fundus 
photography (e.g., 2-field 60 degree or better, colour or red-free) or by slit-lamp biomicroscopy 
examination (e.g., using a pre-corneal or corneal contact lens examination). Pharmacological pupil-
dilation is a requirement unless using a digital fundus photography camera specified for non-dilated 
examination. If diagnostic artificial intelligence algorithms are used an additional eye examination 
may be necessary if indicated so by the algorithm. 
If the participant 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 participant has experienced worsening of visual function 
since the last examination. If the applicable eye examination was performed before the participant 
signed the informed consent form, it must be documented that the reason for performing the 
examination was not related to this study. 
It is recommended that high risk T2D patients (individuals with T2D duration of ≥10 years, a 
baseline HbA1c >8% and confirmed diabetic retinopathy at baseline) will have an additional eye 
examination in accordance with local standard of care, i.e. every 6-month performed by an 
ophthalmologist or another suitably qualified health care provider (e.g., optometrist) possibly aided 
by diagnostic artificial intelligence algorithms approved by FDA and/or CE-marked. 
Eye examinations required at the visit at week 52 (V54) can be performed within 2 weeks before 
the visit, if results are available for evaluation at the visit. For participants who discontinue 
randomised treatment, eye examination can be performed up to 2 weeks after visit 54A. The 
investigator should examine the outcome of each eye examination. Relevant findings before 
randomisation must be recorded as concomitant illness/medical history. While relevant findings 
occurring after randomisation should be reported as an AE, please refer to Section 8.3 and 
Appendix 3 (Section 10.3).  
8.2.5 
Electrocardiograms 
The ECG should be preceded by at least 5 minutes of rest for the participant in a supine/sitting 
position in a quiet setting without distractions (e.g. no use of television, cell phones). 
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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 two weeks before randomisation (V2) but at 
the latest at randomisation (V2). The results must be interpreted by the investigator before 
randomisation in order to determine the eligibility of the participant. 
The ECG required at the visit at week 52 (V54) can be obtained within two weeks before the visit. 
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 after randomisation should be reported as an AE, see 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 protocol flowchart (Section 1.2) and the laboratory manual. 
8.2.7 
Pregnancy testing  
Woman of childbearing potential (WOCBP) should only be included after a negative, highly 
sensitive urine pregnancy test (refer to Appendix 2 (Section 10.2)). 
Pregnancy testing should be performed whenever a menstruation is missed or when pregnancy is 
otherwise suspected. 
Additional pregnancy testing should be performed during the treatment period, if required locally, 
refer to Appendix 11 (Section 10.11). 
8.3 
Adverse events and other safety reporting 
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE. 
 
The definition of AEs and SAEs can be found in Appendix 3 (Section 10.3), along with a 
description of AEs requiring additional data collection. The definition and description of events for 
adjudication can be found in Appendix 9 (Section 10.9). 
 
Some AEs require additional data collection on a specific event form. The relevant event(s) are 
listed below in Table 8-1, together with event(s) for adjudication and other events requiring 
collection of additional information. 
Events for adjudication require completion of an adjudication form, please refer to Appendix 9 
(Section 10.9). 
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Table 8-1 
AEs requiring additional data collection, events for adjudication and other 
events requiring collection of additional information 
Event type  
AE requiring 
additional data 
collection 
Event for adjudication 
 
Other events requiring 
collection of additional 
information 
Medication error  
X 
 
 
Misuse and abuse 
X 
 
 
Hypersensitivity 
X 
 
 
Injection site reactions 
X 
 
 
Acute gallbladder diseases 
X 
 
 
Malignant neoplasms 
X 
 
 
Hypoglycaemic episodes  
 
 
X 
Death 
 
X 
 
Acute coronary syndrome 
(including acute myocardial 
infarction and unstable angina 
pectoris requiring 
hospitalisation) 
 
X 
 
Cerebrovascular event 
(including stroke and transient 
ischemic attack)a 
 
X 
 
Heart failure (including 
requiring hospitalisation and 
urgent heart failure visit) 
 
X 
 
a All cerebrovascular events are to be reported and sent for adjudication, however the EAC will only confirm strokes 
 
Definitions and reporting timelines for the events mentioned in the above table can be found in 
Appendix 3 (Section 10.3) and Appendix 7 (Section 10.7) for hypoglycaemic episodes and 
Appendix 9 (Section 10.9) for events requiring adjudication. 
8.3.1 
Time period and frequency for collecting adverse event information 
All AEs and SAEs must be collected from first administration of randomised treatment and until the 
last follow-up visit in accordance with the flowchart (Section 1.2) or whenever, within the above 
time period, the site becomes aware of an AE or SAE. 
Conditions present prior to the timepoint from which AEs are collected and anticipated day-to-day 
fluctuations of these conditions, including those identified during screening or during other study-
related procedures performed before exposure to randomised treatment, will be recorded as medical 
history/concomitant illness. 
AE and SAE reporting timelines can be found in Appendix 3 (Section  10.3). All SAEs must be 
recorded and reported to Novo Nordisk within 24 hours, and the investigator must submit any 
updated SAE data to Novo Nordisk within 24 hours of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant has 
been discontinued from/completed the study, and the investigator considers the event to be related 
to the randomised treatment or related to study participation, the investigator must promptly notify 
Novo Nordisk. 
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8.3.2 
Method of detecting adverse events  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about events. 
8.3.3 
Follow-up of adverse events  
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or until the 
participant is lost to follow-up as described in Section 7.3. Further information on follow-up and 
final outcome of events is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for serious adverse events 
Prompt notification by the investigator to Novo Nordisk of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention 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 study intervention under clinical investigation. Novo 
Nordisk will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. This also includes suspected unexpected 
serious adverse reactions (SUSARs). 
An investigator who receives an investigator safety report describing an 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 participants will be collected after first exposure to IMP and until 
the new-born infant is one month of age. For details regarding collection and reporting of pregnancy 
information, please refer to Appendix 4 (Section 10.4). 
8.3.6 
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 
Pharmacokinetics 
Samples will be used to evaluate the PK of insulin icodec and semaglutide. For participants 
randomised to IcoSema, PK samples of insulin icodec and semaglutide will be collected, and for 
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participants randomised to insulin icodec, PK samples of insulin icodec will be collected. PK 
samples will be collected at the visits outlined in the flowchart (Section 1.2). The investigator must 
record the exact date and time for blood sampling in the laboratory requisition form.  
Procedures for sampling, handling, storage, labelling and shipments of the specimens must be 
performed in accordance with the laboratory manual. A randomisation list will be provided to the 
special laboratory.  
Bioanalysis of insulin icodec samples will be performed at a special laboratory using a validated 
luminescent oxygen channelling immunoassay. The exact method will be outlined in a bioanalytical 
report. Bioanalysis of semaglutide samples will be performed at a special laboratory using a 
validated Liquid Chromatography Mass Spectometry assay. The exact methods will be outlined in a 
bioanalytical report. 
Genetic analyses will not be performed on these plasma/serum/whole blood samples. Participant 
confidentiality will be maintained. 
For retention of metabolism samples (PK samples), please refer to Appendix 6 (Section 10.6). 
 
Participants should be instructed to report dosing information in the eDiary as per Section 8.2.1. 
 
The investigator will not be able to review the PK analysis report during the study, as the results 
will only be available after the last participant’s last visit. Results from the PK analyses measured 
according to the flowchart (Section 1.2) will be available to Investigators after the completion of the 
study.  
8.5 
Genetics 
Not applicable for this study.  
8.6 
Biomarkers 
Not applicable for this study.  
8.7 
Immunogenicity assessments 
8.7.1 
Anti-drug antibodies  
Anti-drug antibody samples will be collected according to the flowchart (Section 1.2). For 
participants randomised to IcoSema, anti-insulin icodec antibody samples and anti-semaglutide 
antibody samples will be collected. For participants randomised to insulin icodec, 
anti-insulin icodec antibody samples will be collected.  
All samples must be drawn before administration of randomised treatment if randomised treatment 
administration is planned on the sampling day. Assessment of anti-drug antibodies in serum will be 
performed at a Novo Nordisk appointed laboratory. For details on blood sampling, serum 
preparation and storage, please refer to the laboratory manual.  
Analysis for anti-drug antibodies will be done as listed in flowchart (Section 1.2) with a binding 
anti-drug antibody assay. Positive samples to insulin icodec will be further characterised for titre, 
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and cross-reactivity to human insulin. Positive samples to anti-semaglutide antibodies will be 
further characterised for titre, and cross-reactivity to human GLP-1. 
Detailed description of the assay methods will be included in an analytical report. Antibody assays 
were validated according to international guidelines and recommendations. 
 
At the end of the study, the following data will be transferred to the Novo Nordisk database:  
 Anti-insulin icodec binding antibodies (positive/negative) 
 Anti-semaglutide binding antibodies (positive/negative) 
 Titre of anti-insulin icodec antibody positive samples 
 Titre of anti-semaglutide antibody positive samples 
 Anti-insulin icodec binding antibodies cross-reacting with human insulin status 
(positive/negative) 
 Anti-semaglutide binding antibodies cross-reacting with human GLP-1 status 
(positive/negative).  
The investigator will not be able to review the results of antibody measurements in relation to AEs 
as the results will only be available after the last participant’s last visit. Results from the binding 
anti-drug antibody analyses measured according to the flowchart (Section 1.2) will be available to 
Investigators after the completion of the study.  
For retention of antibody samples, please refer to Appendix 6 (Section 10.6).  
8.7.2 
Hypersensitivity 
Participants randomised to IcoSema or insulin icodec and investigators will be instructed to detect 
signs and symptoms of systemic hypersensitivity. 
In the event of a systemic hypersensitivity reaction (not locally at the injection site), the participant 
should be called in as soon as possible to have additional blood samples taken (Section 10.2). 
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 before first 
administration of IcoSema or insulin icodec. 
For details related to blood sampling, plasma preparation and storage, please refer to the laboratory 
manual. 
Analysis will be performed by Novo Nordisk or a Novo Nordisk appointed special laboratory 
(please refer to Attachment I). The results will be reported in a separate report and attached to the 
clinical study report. 
For retention of residual hypersensitivity samples, please refer to Appendix 6 (Section 10.6). 
Digital pictures 
For participants randomised to IcoSema and icodec the investigator or the participant must take 
digital pictures of the affected area at time of identification, using any device available (mobile 
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phone, camera etc.) and thereafter as often as judged necessary by the investigator. The pictures 
should include subject ID, date and time, time after dosing and a ruler for scaling. All pictures must 
be stored as part of source documentation at site. 
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9 
Statistical considerations 
The statistical analysis plan (SAP) will be finalised prior to first participant 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 the primary and confirmatory secondary endpoints. 
9.1 
Statistical hypotheses 
The primary objective is to show that IcoSema is superior to insulin icodec in terms of change in 
HbA1c from baseline week 0 (V2) to week 52 (V54). 
Formally, let D be the mean treatment difference ‘IcoSema’ minus ‘insulin icodec’ of the change in 
HbA1c (%) from baseline week 0 (V2) to week 52 (V54). The null-hypothesis of IcoSema not being 
superior will be tested against the alternative hypothesis of superiority as given by  
H0: D ≥ 0% against HA: D < 0% 
Superiority will be considered confirmed if the upper bound of the two-sided 95% confidence 
interval for D is strictly below 0 %. 
The following sections detail the confirmatory secondary hypotheses. The confirmatory secondary 
objectives are to show that:  
 IcoSema is superior to insulin icodec in terms of change in body weight from baseline week 0 
(V2) to week 52 (V54) 
 IcoSema is superior to insulin icodec in terms of number of hypoglycaemic episodes (level 2 
and 3 combined) from baseline week 0 (V2) to week 57 (V56) 
Formally, let DW be the mean treatment difference ‘IcoSema’ minus ‘insulin icodec’ in change in 
body weight (kg) from baseline week 0 (V2) to week 52 (V54). The null-hypothesis of IcoSema not 
being superior will be tested against the alternative hypothesis of superiority as given by: 
H0: DW ≥ 0 kg against HA: DW < 0 kg. 
Superiority will be considered confirmed if the test procedure was not stopped, see section 9.1.1 for 
details on the testing procedure, and if the upper bound of the two-sided 95% confidence interval 
for DW is strictly below 0 kg.  
Let RR be the rate ratio ‘IcoSema’ compared to ’insulin icodec’ of the rate of hypoglycaemic 
episodes (level 2 and level 3 combined). The null-hypothesis of IcoSema not being superior will be 
tested against the alternative hypothesis of superiority as given by: 
H0: RR ≥ 1 against HA: RR < 1. 
Superiority will be considered confirmed if the test procedure was not stopped, see section 9.1.1 for 
details on the testing procedure, and if the upper bound of the two-sided 95% confidence interval 
for RR is strictly below 1.   
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9.1.1 
Multiplicity adjustment 
The type I error will be controlled in the strong sense using a hierarchical (fixed sequence) testing 
procedure. This is based on priority ordering of the null hypotheses and testing them in this order 
using the 2-sided 95% confidence interval approach until an insignificant result appears. 
Consequently, the null hypothesis will only be tested if the previous null hypotheses have been 
rejected in favour of IcoSema. 
The steps in the hierarchical testing procedure are as follows: 
 Step 1: Change in HbA1c from baseline week 0 (V2) to week 52 (V54) superiority of IcoSema 
versus insulin icodec 
 Step 2: Change in body weight from baseline week 0 (V2) to week 52 (V54) superiority of 
IcoSema versus insulin icodec 
 Step 3: Number of hypoglycaemic episodes (level 2 and 3 combined) from baseline week 0 
(V2) to week 57 (V56) superiority of IcoSema versus insulin icodec. 
9.2 
Analysis sets 
The following populations are defined: 
Participant analysis set 
Description 
Full analysis set  
All randomised participants. Participants will be included in the analyses 
according to the planned randomised treatment. 
Safety analysis set 
All randomised participants who are exposed to randomised treatment. 
Participants will be included in the analyses according to the randomised 
treatment they actually received. 
 
The following data points sets are defined: 
Data points sets 
Description 
In-study 
All data from randomisation until the last date of any of the following: 
 
The last direct participant-site contact 
 
Withdrawal for participants who withdraw their informed consent 
 
The last participant-investigator contact as defined by the investigator 
for participants who are lost to follow-up (i.e. possibly an unscheduled 
phone visit) 
 
Death for participants who die before any of the above 
On-treatment 
All data from the date of first dose of randomised treatment as recorded on the 
eCRF until the first date of any of the following: 
 
The last follow-up visit (V56) 
 
The last date on randomised treatment +6 weeks (corresponding to 5 
weeks after the end of the dosing interval for both treatment arms) 
 
The end-date for the in-study data points sets  
 
The on-treatment data points set represent data collected in the period in which a participant is 
considered exposed to randomised treatment. 
Baseline assessments are always included in the in-study and on-treatment data points sets. 
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The full analysis set and the in-study data points set will be used to estimate the primary estimand 
and the confirmatory secondary estimand related to body weight. For the confirmatory secondary 
estimands related to hypoglycaemic episodes the full analysis set and the on-treatment data points 
set will be used. 
9.3 
Statistical analyses 
9.3.1 
General considerations 
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. 
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:  
 Randomised treatment: Once weekly IcoSema, Once weekly insulin icodec 
 Region: Asia, Europe, North America, Other 
The regions will be defined as follows: 
 Asia: Japan, China, Taiwan, South Korea 
 Europe: Italy, Poland, Serbia, Romania, Bulgaria, Croatia, Belgium, Finland, Norway, Portugal 
 North America: United States 
 Other: India, South Africa, Turkey, Russia, Mexico, Australia 
9.3.2 
Primary estimand analysis 
The primary endpoint is change in HbA1c from baseline week 0 (V2) to week 52 (V54). 
The estimand (see Section 3), will be estimated based on the full analysis set using the in-study data 
points set which includes all HbA1c measurements obtained at week 52 (V54) especially 
measurements from participants experiencing intercurrent events. The imputation approach for the 
primary estimand is a multiple imputation similar to the one described by McEvoy.22 
 Missing HbA1c measurements at week 52 (V54) for participants experiencing intercurrent 
events will be imputed from participants experiencing intercurrent events and have a 
measurement at week 52 (V54) in each treatment arm. 
 Missing HbA1c measurements at week 52 (V54) for participants not experiencing intercurrent 
events are imputed from available measurements at week 52 (V54) from participants not 
experiencing intercurrent events in each treatment arm.  
The multiple imputation approach will be done the following way:  
 Imputation: An ANCOVA model for change in HbA1c from baseline week 0 (V2) to week 52 
(V54) for participants experiencing intercurrent events and have a measurement at week 52 
(V54) with randomised treatment as fixed factor, last available planned on-treatment HbA1c 
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observation without initiation of non-randomised insulin treatment or additional anti-diabetic 
treatments for more than 2 weeks, the time point (study day) of last available planned on-
treatment HbA1c observation without initiation of non-randomised insulin treatment or 
additional anti-diabetic treatments for more than 2 weeks and baseline HbA1c as covariate. If 
participants not experiencing intercurrent events are missing measurements at week 52 (V54) an 
ANCOVA model will be defined in a similar way using available data from participants not 
experiencing intercurrent events. The estimated parameters, and their variances, from the 
imputation models will be used to impute missing HbA1c measurements at week 52 (V54). This 
will be done 1000 times and results in 1000 complete datasets.  
 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 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.23 
 From the pooled estimate and standard deviation the 95% confidence interval for the treatment 
difference will be calculated. The corresponding two-sided p-value will also be calculated. 
This analysis has the underlying assumption that participants with missing data behave similarly as 
comparable participants within the same treatment arm i.e. that participants experiencing 
intercurrent events with missing data at week 52 (V54) behave like participants experiencing 
intercurrent events with data at week 52 (V54) within the same treatment arm and similar for 
participants not experiencing intercurrent events. 
9.3.2.1 
Sensitivity analysis 
The following sensitivity analysis will evaluate the robustness of the results towards the missing 
data assumption. 
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
participants having imputed HbA1c measurement at week 52 (V54) are assumed to have a worse 
outcome in the IcoSema arm and a better outcome in the insulin icodec 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 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 results. 
9.3.3 
Secondary estimand analyses 
9.3.3.1 
Confirmatory secondary estimands 
9.3.3.1.1 
Estimand related to change in body weight from baseline week 0 (V2) to week 
52 (V54) 
The secondary estimand regarding change in body weight from baseline week 0 (V2) to week 52 
(V54) will be estimated using a model similar to the primary analysis above substituting body 
weight for HbA1c. 
The robustness of the results towards the missing data assumption will be evaluated using an 
method following similar principles as for the primary estimand. 
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9.3.3.1.2 
Estimand related to number of clinically significant hypoglycaemic episodes 
(level 2) (<3.0 mmol/L [54 mg/dL], confirmed by BG meter) or severe 
hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 57 (V56) 
The secondary estimand regarding number of clinically significant hypoglycaemic episodes (level 
2) (<3.0 mmol/L [54 mg/dL], confirmed by BG meter) or severe hypoglycaemic episodes (level 3) 
from baseline week 0 (V2) to week 57 (V56) will be analysed as described below. The endpoint is 
defined as described in Appendix 7 (Section 10.7). 
For participants who discontinued randomised treatment, the number of episodes in the period 
where hypoglycaemic episodes are not collected (the period from time of follow-up 2 visit (V56) to 
planned end of the on-treatment data point set) will be imputed using a multiple imputation 
technique, assuming that the episode rate pre-follow-up 2 (V56) follows the respective treatment 
arms rate whilst post-follow-up 2 (V56) episode rate is the rate of the comparator arm. The 
imputation will be done as follows:  
 First, a Bayes negative binomial model with log-link function is fitted to the number of episodes 
data for participants in the comparator arm to obtain the posterior distribution of model 
parameters. The model will include region as fixed factor and the logarithm of the time period 
in which a participant is considered exposed to randomised treatment as offset. 
 Second, based on the estimated parameters for the comparator arm in this model, the number of 
episodes in the missing period will be imputed for participants having discontinued randomised 
treatment. One thousand (1000) complete dataset are generated by sampling from the estimated 
distribution. 
 For each of the complete datasets, the number of episodes will be analysed using a negative 
binomial model with log-link function, treatment and region fixed factors and offset as 
described in step 1. The estimates and standard errors for the 1000 data sets will be pooled to 
one estimate and associated standard deviation using Rubin’s rule.23 
 From the pooled estimate and standard deviation the 95% confidence interval will be calculated 
and back-transformed to the original scale resulting in a treatment ratio and a 95% confidence 
interval for the treatment ratio. The corresponding two-sided p-value will also be calculated. 
The analysis has the underlying assumption that participants discontinuing randomised treatment 
behave similarly to participants in the comparator arm after the follow-up period. The robustness of 
the results towards the missing data assumption will be evaluated using a method following similar 
principles as for the primary estimand. 
9.3.3.2 
Supportive secondary estimands 
Details on analysis of secondary estimands related to supportive secondary endpoints will be 
included in a SAP. 
9.3.4 
Exploratory estimand analysis 
Not applicable for this study. 
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9.3.5 
Other safety analyses 
The standard safety assessments (AEs, safety laboratory parameters, vital signs, etc.) will be 
reported descriptively; including any notable changes of clinical interest in laboratory parameters. 
9.3.6 
Other analyses 
9.3.6.1 
Pharmacokinetic modelling 
Insulin icodec serum concentration data and semaglutide plasma concentration data will be used for 
population PK analysis. The objective of the population PK analysis is to evaluate the effects of 
relevant covariates on insulin icodec and semaglutide exposure. 
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo 
Nordisk. A more technical and detailed elaboration of the population PK analysis will be given in a 
modelling analysis plan, which will be prepared before database lock. In brief, previously 
developed PK models for insulin icodec and semaglutide will be applied. The absorption rate 
constants in the models will be fixed, and the apparent clearance and volume of distribution 
parameters will be re-estimated. The covariates of interest will be incorporated into the PK models 
using criteria which will be specified in the modelling analysis plan. 
The population PK analysis will be reported in a separate modelling report, which will not be part 
of the clinical study report. The individual insulin icodec serum concentration data and the 
individual semaglutide plasma concentration data will be tabulated in the bioanalytical report. 
9.4 
Interim analysis 
Not applicable for this study. 
9.5 
Sample size determination 
The sample size is determined in order to have at least 90% power for meeting the primary 
hypothesis and reasonable marginal power (at least 90%) for also meeting the confirmatory 
secondary hypotheses. 
It is assumed that the amount of participants experiencing an intercurrent event will be similar to 
what was observed in the subcutaneous semaglutide for T2D development program, and that the 
intercurrent events will have the same impact on effect size and are equally distributed between 
treatment arms. The amount of participants experiencing an intercurrent event ranged from 14.1% 
to 25.7% in open-label studies with various durations except for semaglutide 0.5 mg in the Japan 
studies, see Table  9-1. Based on this the percentage of participants experiencing an intercurrent 
event is expected to be 17%. 
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Table  9-1 
Participants experiencing an intercurrent event – open-label subcutaneous 
semaglutide for diabetes studies (NN9535) 
Study 
ID 
Description 
Study 
duration 
Participants experiencing 
intercurrent events (%) 
Semaglutide 
0.5 mg 
Semaglutide 
1.0 mg 
3624 
SUSTAIN 3: Semaglutide 1.0 mg vs. Exenatide ER 2.0 mg 
56 weeks 
 
25.7 
3625 
SUSTAIN 4: Semaglutide 1.0/0.5 mg vs. Insulin glargine 
30 weeks 
17.4 
17.8 
4216 
SUSTAIN 7: Semaglutide 1.0/0.5 mg vs. Dulaglutide 1.5/0.75 mg 
40 weeks 
16.6 
16.6 
4339 
SUSTAIN 10: Semaglutide 1.0 mg vs. Liraglutide 1.2 mg 
30 weeks 
 
15.5 
4092 
SUSTAIN Japan: Semaglutide 1.0/0.5 mg vs. Sitagliptin 
30 weeks 
3.9 
14.7 
4091 
SUSTAIN Japan: Semaglutide 1.0/0.5 mg vs. One additional OAD 
56 weeks 
6.3 
14.1 
Participants experiencing an intercurrent event is participants discontinuing randomised treatment or initiating rescue 
medication. The definition of rescue medication differ across the studies and is different from the current study. 
For the primary hypothesis and confirmatory secondary hypothesis that IcoSema is superior to 
insulin icodec in terms of change from baseline to week 52 (V54) in HbA1c and body weight 
respectively, the sample size considerations are based on the IDegLira (insulin degludec/liraglutide) 
studies where participants are previously treated with a basal insulins, see Table 9-2.  
Table 9-2 
HbA1c and body weight results – IDegLira studies (NN9068)  
Study 
ID 
Description 
Study 
duration 
Change from baseline in 
HbA1c (%-point) 
Change from baseline in 
body weight (kg) 
ETD [95% CI] 
SD 
ETD [95% CI] 
SD 
3912 
DUAL II: IDegLira vs. IDeg 
26 weeks -1.04 [-1.25;-0.84] 
1.0 
-2.51 [-3.21;-1.82] 
3.5 
3952 
DUAL V: IDegLira vs. IGlar 
26 weeks -0.66 [-0.80;-0.52] 
0.8 
-3.20 [-3.77;-2.64] 
3.4 
4184 
DUAL II Japan: IDegLira vs. IDeg 
26 weeks -1.23 [-1.45;-1.01] 
0.8 
-1.41 [-2.26;-0.56] 
3.1 
4166 
DUAL II China: IDegLira vs. IDeg 
26 weeks -0.92 [-1.09;-0.75] 
0.9 
-1.13 [-1.72;-0.55] 
3.0 
CI: Confidence interval, ETD: Estimated treatment difference, IDeg: Insulin degludec, IGlar: Insulin glargine, 
IDegLira: insulin degludec/liraglutide, SD: Standard deviation. In the DUAL II studies the insulin degludec dose was 
capped at 50 units. Data from after participants discontinuing randomised treatment were not collected in the studies. 
Change from baseline in HbA1c and change from baseline in body weight for DUAL II China were analysed using a 
mixed-effect model for repeated measurements. Change from baseline in body weight for DUAL II, DUAL II Japan and 
DUAL V were analysed using an analysis of variance model where missing data was imputed using last observation 
carried forward. 
However, the current study and the IDegLira studies in Table 9-2 are different in key study design 
aspects such as: in the IDegLira studies the insulin degludec dose was capped at 50 units (except 
NN9068-3952), the titration target was lower (4.0-5.0 mmol/L [72-90 mg/dL]), the study duration 
was shorter, the population was different e.g. pre-study basal insulin dose was 20-50 units per day 
and for participants discontinuing randomised treatment data were not collected after 
discontinuation and hence not included. In addition the statistical methods to be used in the current 
study also differ. The differences across development programmes are expected to impact the 
expected treatment differences. Based on these considerations it is considered reasonable to be able 
to detect a treatment difference of at least a -0.33%-point in change in HbA1c between the treatment 
arms for participants not experiencing intercurrent events and no treatment difference for 
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participants experiencing intercurrent events. Thus, with 17% of participants expected to experience 
any of the specified intercurrent events before week 52 (V54), this leads to a mean treatment 
difference of (1-0.17) ∙ -0.33%-point = -0.274%-point for the specified primary estimand in the 
overall population. The standard deviation (SD) is assumed to be 1.1%-point based on the IDegLira 
studies. 
To be able to detect a treatment difference of -0.274%-point with the above considerations it 
requires 680 participants to ensure 90% power. 
Based on the same considerations as above for change in HbA1c it is considered reasonable to be 
able to detect at least a -2.5 kg difference for change in body weight between treatment arms for 
participants not experiencing intercurrent events and no treatment difference for participants 
experiencing intercurrent events. Thus, with 17% of participants expected to experience any of the 
specified intercurrent events before week 52 (V54), this leads to a mean treatment difference of 
(1-0.17) ∙ -2.5kg = -2.075kg for the specified secondary estimand in the overall population. The 
standard deviation (SD) is assumed to be 4.5 kg based on the IDegLira studies. 
To be able to detect a treatment difference of -2.075kg with the above considerations it requires 200 
participants to ensure 90% power. 
For the confirmatory secondary hypothesis that IcoSema is superior to insulin icodec in terms of 
number of hypoglycaemic episodes (level 2 and 3 combined) the sample size considerations are 
based on results from IDegLira studies for severe or BG confirmed hypoglycaemic episodes, see 
Table  9-3. However considering that the hypoglycaemic episode definition is different and the 
titration target is higher in the current study, which result in fewer hypoglycaemic episodes,24 it is 
therefore expected that participants treated with IcoSema will experience 0.8 hypoglycaemic 
episodes (level 2 and 3 combined) per year compared to 0.8 / 0.65 = 1.23 episodes per year for 
participants treated with insulin icodec (Expected Rate ratio (RR) of 0.65). It is assumed that there 
is no treatment difference in rates after experiencing intercurrent events, corresponding to a 
treatment ratio of 1 in this period. Discontinuation of randomised treatment is assumed to be 
distributed equally over the study duration. Thus, with 17% of participants expected to experience 
any of the specified intercurrent events before week 52 (V54), this leads to an expected RR of 
1 ∙ 0.17 / 2 + 0.65 ∙ (1 - 0.17 / 2) = 0.68 for the specified secondary estimand in the overall 
population. The dispersion parameter is assumed to be 3.6 based on the IDegLira studies. 
Table  9-3 
Severe or BG confirmed hypoglycaemic episodes results – IDegLira studies 
(NN9068) 
Study 
ID 
Description 
Episode rate per year 
Estimated rate ratio 
[95% CI] 
Dispersion 
parameter 
IDegLira 
Comparator 
3912 
DUAL II: IDegLira vs. IDeg 
1.2 
1.8 
0.66 [0.39; 1.13] 
5.7 
3952 
DUAL V: IDegLira vs. IGlar 
1.3 
2.9 
0.43 [0.30; 0.61] 
3.3 
4184 
DUAL II Japan: IDegLira vs. IDeg 
2.2 
1.9 
1.16 [0.57; 2.34] 
5.2 
4166 
DUAL II China: IDegLira vs. IDeg 
0.3 
0.5 
0.53 [0.30; 0.94] 
3.2 
CI: Confidence interval, IDeg: Insulin degludec, IGlar: Insulin glargine, IDegLira: insulin degludec/liraglutide. In the 
DUAL II studies the insulin degludec dose was capped at 50 units. The number of hypoglycaemic episodes was 
analysed using a negative binomial regression model. 
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From the above assumptions 1290 participants will be required to ensure sufficient marginal power 
(90%) for the confirmatory secondary hypothesis that IcoSema is superior to insulin icodec in terms 
of number of hypoglycaemic episodes (level 2 and 3 combined) and this is the hypothesis 
determining the sample size.  
In table Table 9-4 the assumptions the sample size calculation is based on is summarised along with 
the marginal and joint power with 1290 participants.  
Table 9-4 
Sample size assumptions and power with 1290 randomised participants 
Hypothesis 
Assumptions 
Randomised 
participants 
Marginal 
power 
Joint 
power 
Change in HbA1c, 
superiority 
Treatment difference: -0.33%-point 
Standard deviation: 1.1% 
Intercurrent events: 17% 
Treatment difference adjusted: -0.274%-point  
1290 
99.4% 
99.4% 
Change in body weight, 
superiority 
Treatment difference: -2.5 kg 
Standard deviation: 4.5 kg 
Intercurrent events: 17% 
Treatment difference adjusted: -2.075kg 
1290 
>99.9% 
99.4% 
Number of hypoglycaemic 
episodes (level 2 and 3 
combined), superiority 
Rate ratio: 0.65 
IcoSema episode rate per year: 0.8 
icodec episode rate per year: 1.23 
Intercurrent events: 17% 
Rate ratio adjusted: 0.68 
Dispersion parameter: 3.6 
1290 
90% 
89.5% 
The joint power is calculated under the assumption of independence of the hypotheses by multiplying the respective 
marginal powers. 
The sample size calculation above is sensitive to the assumptions made for the confirmatory 
secondary hypothesis of superiority in terms of number of hypoglycaemic episodes (level 2 and 
level 3 combined), and in Table 9-5 the power is presented for different rate assumptions. 
Table 9-5 
Power with different rates for level 2 and 3 (combined) hypoglycaemic episodes 
Randomised 
participants 
IcoSema episode 
rate per year 
icodec episode 
rate per year 
Rate ratio 
Adjusted 
rate ratio 
Marginal 
power 
Joint power 
1290 
1.0 
1.54 
0.65 
0.68 
91.2% 
90.7% 
1290 
0.8 
1.23 
0.65 
0.68 
90.0% 
89.5% 
1290 
0.6 
0.92 
0.65 
0.68 
88.0% 
87.5% 
1290 
1.0 
1.42 
0.70 
0.73 
77.0% 
76.5% 
1290 
0.8 
1.14 
0.70 
0.73 
75.1% 
74.7% 
1290 
0.6 
0.86 
0.70 
0.73 
72.2% 
71.8% 
1290 
1.0 
1.33 
0.75 
0.77 
60.9% 
60.5% 
1290 
0.8 
1.07 
0.75 
0.77 
58.9% 
58.6% 
1290 
0.6 
0.80 
0.75 
0.77 
56.0% 
55.6% 
Adjusted rate ratio is adjusted for 17% of participants experiencing intercurrent events. Dispersion parameter is set to 
3.6. 
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From the above assumptions and requirements for the primary and confirmatory secondary 
analyses, 1290 participants will be randomly assigned to treatment. This will ensure sufficient 
marginal power of 90% for confirming superiority for the primary and the confirmatory hypotheses, 
and a joint power of 89.5%. 
9.6 
Partial database lock 
A partial database lock may be performed at the end of the treatment period for all participants, i.e. 
after the date of the last participant last treatment visit. The database will be updated after the partial 
database lock to include remaining safety information. The full database lock will be performed 
after the date of the last participant last visit. 
The analysis of the primary endpoint and all other efficacy endpoints will be performed based on 
the data from the partial database lock. Analysis of safety data will be performed after the full 
database lock. This approach is implemented to allow earlier availability of IcoSema to a T2D 
patient population in need of treatment intensification expected to benefit from an insulin and 
GLP-1 combination product. A detailed plan for data handling and operational aspects of the partial 
database lock and the database update will be finalised before the partial database lock. 
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki25 and applicable ICH Good Clinical Practice (GCP) Guideline26 
 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 study is initiated. 
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the CSR according to national requirements. 
Any amendments to the protocol will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate safety hazard to 
study participants. 
Before a site is allowed to start screening participants, written notification from Novo Nordisk must 
be received. 
The investigator will be responsible for: 
 providing written summaries of the status of the study annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC and/or 
regulatory authorities 
 notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
 providing oversight of the conduct of the study at the site and adherence to requirements of ICH 
guidelines, the IRB/IEC, and all other applicable local regulations 
 ensuring submission of the CSR synopsis to the IRB/IEC 
 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 study and one 
year after completion of the study. 
Verification under disclosures per Code of Federal Regulations (CFR) of Financial Conflict of 
Interest. 
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10.1.3 
Informed consent process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study. This includes the use of 
an impartial witness where required according to local requirements. 
The investigator must ensure the participant ample time to come to a decision whether or not to 
participate in the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign and date a statement of informed consent that meets the requirements of local regulations, ICH 
GCP26 guidelines, Declaration of Helsinki,25 privacy and data protection requirements, where 
applicable, and the IRB/IEC or site. 
The medical record must include a statement that written informed consent was obtained before any 
study-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 
study-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. 
Participants must be re-consented to the most current version of the informed consent form(s) 
during their participation in the study. 
A copy of the informed consent form(s) must be provided to the participant. 
10.1.4 
Information to participants during the study 
The site will be offered a communication package for the participant during the conduct of the 
study. The package content is issued by Novo Nordisk. The communication package will contain 
written information intended for distribution to the participants. The written information will be 
translated and adjusted to local requirements and distributed to the participant at the discretion of 
the investigator. The participant may receive a “thank you for your participation letter” after 
completion of the study. Further, the participant may receive other written information during the 
study. 
All written information to participants 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 
Participants will be assigned a 6-digit unique identifier, a subject ID. Any participant records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct identifiers 
from the participant are transferred to Novo Nordisk. 
The participant and any biological material obtained from the participant will be identified by 
subject ID, visit number and study ID. Appropriate measures such as encryption or leaving out 
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certain identifiers will be enforced to protect the identity of participants as required by local, 
regional and national requirements. 
The participant must be informed about his/her privacy rights, including that his/her personal study-
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 participant. 
The participant 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. 
Personal data may be collected from participants due to process requirements from Novo Nordisk’s 
suppliers. This data is needed to ensure that the relevant data analysis for the study can be 
performed, but will not be part of the data transferred to Novo Nordisk, the assessment of the study 
endpoints or the clinical study report. A list of any such data values must be kept as part of the 
study documentation along with an explanation of why it was required. 
10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal study-independent ad hoc 
group may be established in order to maintain the blinding of the study personnel. 
10.1.6.2 
Event adjudication committee 
An independent external EAC is established to perform ongoing blinded adjudication of selected 
AEs and deaths (see Table 8-1 and Appendix 9 (Section 10.9)). 
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 study conduct, study protocol or 
amendments. The assessments made by both the event adjudication committee and the investigator 
will be evaluated and included in the CSR. 
10.1.7 
Dissemination of clinical study data 
Study information will be disclosed at clinicaltrials.gov and novonordisk-trials.com and, if 
applicable, also on other national or regional study registries. It will be disclosed according to 
applicable requirements, relevant recommendations or regulations, such as the Declaration of 
Helsinki,25 the International Committee of Medical Journal Editors (ICMJE),27 the Food and Drug 
Administration Amendment Act (FDAAA),28 European Commission Requirements1, 29, 30 and in 
accordance with Novo Nordisk commitment to clinical transparency. If a participant requests to be 
included in the study via the Novo Nordisk e-mail contact at these web sites, Novo Nordisk may 
disclose the investigator’s contact details to the participant. As a result of increasing requirements 
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for transparency, some countries require public disclosure of investigator names and their 
affiliations. 
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 study including quality 
checking of the data. 
To demonstrate his/her oversight of the collected data, the investigator should sign the eCRF on a 
regular basis during the conduct of the study as well as at the end of the study, as described in the 
eCRF completion guideline, and review the HCP web portal. 
All participant data relating to the study will be recorded on CRFs and eDiary unless transmitted 
electronically to Novo Nordisk or designee (e.g., laboratory and eDiary data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The following will be provided as paper CRFs: 
 Pregnancy forms 
The following will be provided as paper CRFs to be used when access to the CRF is revoked or the 
CRF is temporarily unavailable: 
 AE forms 
 Safety information forms 
 Technical complaint forms (also to be used to report complaints on study intervention not yet 
allocated to a participant) 
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 study-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 study. If the electronic source data 
does not have a visible audit trail, the investigator must provide the monitor with signed and dated 
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printouts. In addition, the relevant site staff should be available for discussions at monitoring visits 
and between monitoring visits (e.g., by telephone). 
Study monitors will perform ongoing source data verification of critical data points to confirm that 
data entered into the CRF by authorised site personnel are accurate, complete and verifiable from 
source documents. Study monitors will perform ongoing source data review to ensure that the study 
is being conducted in accordance with the current approved protocol and any other study 
agreements, ICH GCP26, and all applicable regulatory requirements, evaluating the adequacy of 
critical processes at site for the execution of the protocol, collection of study data, to ensure that the 
safety and rights of participants are being protected. 
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. 
Quality tolerance limits (QTLs) will be predefined in the relevant monitoring plan to identify 
systematic issues that can impact participant safety and/or reliability of study results. These 
predefined parameters will be monitored during the study, and important deviations from the QTLs 
and remedial actions taken will be summarised in the clinical study report. 
Monitors will review the participant’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 CRF or via listings from the study database. 
10.1.9 
Source documents 
All data entered in the eCRF or paper CRF must be verifiable in source documentation. 
Data in the service providers’ database is considered source data e.g. laboratory data and CGM. For 
eDiary (including patient reported outcomes), data in eDiary database is considered source data, 
unless stated otherwise in source documentation agreements. 
 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the site. Any source data generated by 
investigator’s subcontractors must be archived and accessible by the site. 
Data that is transcribed into the eCRF or paper CRF 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. 
If source data is entered directly in a paper CRF, each data entry or clear series of data entries must 
be signed and dated separately by the study staff making the entry. 
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It must be possible to verify participant’s medical history in source documents, such as participant’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 must 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 study documentation 
Records and documents, including signed informed consent forms, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after end of study 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 study documents without involving Novo Nordisk in 
any way. If applicable, electronic CRF (eCRF) and other participant data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. Site-specific CRFs and other participant 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. 
Participant’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
10.1.11 Study and site closure 
Novo Nordisk reserves the right to close the site or terminate the study at any time for any reason at 
the sole discretion of Novo Nordisk. If the study is suspended or terminated, the investigator must 
inform the participants 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 study completion. A site is considered closed when all required documents 
and study 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 participants by the investigator 
 discontinuation of further study intervention development. 
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10.1.12 Responsibilities 
The investigator is accountable for the conduct of the study at his/her site and must ensure adequate 
supervision of the conduct of the study 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 study-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the study. It is the investigator’s responsibility to supervise the 
conduct of the study and to protect the rights, safety, and well-being of the participants. 
A qualified physician, who is an investigator or a sub investigator for the study, must be responsible 
for all study-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 study and the quality of the data 
produced) in the investigator trial master file. The documents, including the participant 
identification code list must be kept in a secure locked facility so that no unauthorised persons can 
get access to the data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. This also 
includes ensuring that no indirect sharing of user credentials for IT systems used in this study takes 
place (e.g., by not sharing IT equipment with others in a way where user credentials have the 
possibility of being shared). The investigator must be able to provide the necessary information or 
otherwise demonstrate to Novo Nordisk that such technical and organisational safety measures have 
been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
participants to a specific qualified physician who will be readily available to participants 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 studies 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 study or by persons for whom the said site or investigator are 
responsible. 
 
Novo Nordisk accepts liability in accordance with local laws/acts/guidelines, see Section 10.11 for 
more information.  
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10.1.14 Publication policy 
The information obtained during the conduct of this study 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 study intervention. All information supplied by Novo Nordisk in connection 
with this study 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 study. 
The information obtained during this study may be made available to other investigators who are 
conducting other clinical studies with the study intervention, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this study to researchers who require access for research projects studying the same 
or related diseases and/or study intervention studied in this study. 
Novo Nordisk may publish on its clinical studies website a redacted CSR for this study. 
One or two investigators will be appointed by Novo Nordisk to review and sign the CSR (signatory 
investigators) on behalf of all participating investigators. 
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of studies 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 study 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 CSR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire study. 
At the end of the study, 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 study 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 
2content 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 study concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
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Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.31 
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 study, analyses based on single-site data usually have significant 
statistical limitations and frequently do not provide meaningful information for healthcare 
professionals or participants, 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 study. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the study database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research participants’ 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 and by 
the special laboratories. 
Additional tests may be performed at any time during the study 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 laboratory 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 laboratory Standard Operating Procedures. These data will not be transferred to 
the study 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, with the 
exception of the pharmacokinetics and antibodies (sections 8.4 and 8.7.1), as these results will not 
be available to the investigator until after finalisation of the clinical study report. 
The investigator must keep an overview, e.g. a log, of laboratory samples not handled according to 
the laboratory manual. In addition, the investigator must keep an overview, e.g. a log, of laboratory 
samples stored at site. 
Laboratory samples will be destroyed no later than at the end of the study or no later than at 
finalisation of the CSR. 
Human bio samples will be stored as described in Appendix 6 (Section 10.6). 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Glucose metabolism  
V2, V12, V20, V28, 
V38, V46, V54/V54A 
 Fasting plasma glucose (FPG)a 
 HbA1c (also at V1) 
NOTES: 
aAn FPG result <3.9 mmol/L (70 mg/dL) in relation to planned fasting visits should not be reported as a 
hypoglycaemic episode but as an AE at the discretion of the investigator (Appendix 3, Section 10.3). 
Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory 
assessments 
Parameters 
Haematology  
V1, V12, V28, V38, 
V54/V54A 
 
 Erythrocytes 
 Haematocrit 
 Haemoglobin 
 Leucocytes 
 Thrombocytes 
 Basophils 
 Eosinophils 
 Lymphocytes 
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Laboratory 
assessments 
Parameters 
 Monocytes 
 Neutrophils 
Biochemistrya 
V1, V12, V28, V38, 
V54/V54A 
 
 Alanine Aminotransferase (ALT) 
 Albumin 
 Alkaline phosphatase (ALP) 
 Aspartate Aminotransferase (AST) 
 Creatinine 
 Potassium 
 Sodium 
 Total bilirubin 
 Gamma-glutamyltransferase (GGT) (only at V1, V28 and 54/V54A) 
Lipids  
V2, V12, V20, V28, 
V38, V46, V54/V54A 
 
 Cholesterol 
 High density lipoprotein (HDL) cholesterol 
 Low density lipoprotein (LDL) cholesterol 
 Very low density lipoprotein (VLDL) cholesterol 
 Triglycerides 
 Free fatty acids 
Pregnancy testingb 
V1, V2, V54/V54A, V56 
 Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test  
Anti-drug antibodies  
V2, V4, V8, V12, V20, 
V28, V38, V54/V54A, 
V56 
 Anti-insulin icodec binding antibodies (IcoSema and icodec arms) 
 Anti-semaglutide binding antibodies (IcoSema arm) 
Pharmacokinetics  
(V4, V8, V12, V20, V28, 
V38, V54/V54A, V56)  
 Insulin-icodec serum concentration (IcoSema and icodec arms) 
 Semaglutide plasma concentration (IcoSema arm) 
Other tests 
 
Hypersensitivity samples 
should be collected as 
soon as possible after the 
systemic hypersensitivity 
reaction, and again 2-4 
weeks following onset of 
the systemic 
hypersensitivity reaction 
 eGFR calculated by the central laboratory based on the creatinine value using the 
CKD-EPI equation (V1).  
 
 In case of systemic hypersensitivity reaction in participants in the IcoSema arm 
(Section 8.7.2):  
 
Tryptase (optimal 0.5-2 hours post the hypersensitivity reaction)c 
 
Total immunoglobulin E (IgE) antibodiesc 
 
Anti-human insulin IgE antibodiesd 
 
Anti-insulin icodec IgE antibodiesd 
 
Anti-insulin icodec binding antibodiese 
 
Anti-semaglutide IgE antibodiesd 
 
Anti-semaglutide binding antibodies.e 
 
 
In case of systemic hypersensitivity reaction in participants in the icodec arm 
(Section 8.7.2):  
 
Tryptase (optimal 0.5-2 hours post the hypersensitivity reaction)c 
 
Total immunoglobulin E (IgE) antibodiesc 
 
Anti-human insulin IgE antibodiesd 
 
Anti-insulin icodec IgE antibodiesd 
 
Anti-insulin icodec binding antibodiese 
Hypersensitivity data will not be shared with investigators until after CSR finalisation. 
Notes: 
aDetails of required actions for increased liver parameters are given in Appendix 3 (Section 10.3). 
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Laboratory 
assessments 
Parameters 
bFor women of childbearing potential, as needed, local urine testing will be standard unless serum testing is required 
by local regulation or IRB/IEC, see Appendix 4 (Section 10.4). 
c Samples collected from Chinese participants will be analysed by a central lab in China. Samples collected from 
participants in the rest of the world will be analysed by Novo Nordisk Måløv, Denmark  
d Samples will be analysed by Novo Nordisk Måløv, Denmark for all countries except China, where these tests will 
not be done (see Appendix 11, Section 10.11). 
e Samples collected from Chinese participants will be analysed in a special lab in China. Samples collected from 
participants in the rest of the world will be analysed by a special lab designated by Novo Nordisk. 
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10.3 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures 
for recording, evaluating, follow-up, and reporting 
10.3.1 
Definition of adverse event 
An AE is any untoward medical occurrence in a clinical study participant that is temporally 
associated with the use of IMP, whether or not considered related to the IMP. An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or 
disease (new or exacerbated) temporally associated with the use of an IMP. 
Events to be reported as AEs: 
 Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgment of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected 
 Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected 
 Exacerbation/worsening of a chronic or intermittent condition including either an increase in 
frequency and/or intensity of the condition 
 Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction 
 Signs, symptoms or the clinical sequelae of a suspected overdose of IMP regardless of intent 
A ‘lack of efficacy’ or ‘failure of expected pharmacological action’ per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfil the definition. 
Events NOT to be reported as adverse events: 
 Conditions present prior to the time point from which AEs are collected and anticipated day-to-
day fluctuations of these conditions. This includes those conditions identified during screening 
or identified during other study procedures performed before exposure to IMP.  
Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
 Medical or surgical procedures (e.g., endoscopy, appendectomy). The condition that leads to the 
procedure is the AE. 
 Medical or surgical procedures not preceded by an AE or worsening of a known condition. 
10.3.2 
Definition of a serious adverse event 
An SAE is any untoward medical occurrence that fulfils at least one of the following criteria: 
 Results in death 
 
 Is life-threatening 
 The term ‘life-threatening’ refers to an event in which the participant was at risk of death at 
the time of the event. It does not refer to an event which hypothetically might have caused 
death, if it were more severe. 
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 Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Hospitalisation signifies that the participant has been admitted at the hospital or emergency 
ward for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalisation are 
AEs. If a complication prolongs hospitalisation or fulfils any other seriousness criteria, the 
event is serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, 
the AE should be considered serious. 
 Hospitalisation for elective treatment (e.g., elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note: Hospitalisations for administrative, study-related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
medical or surgical procedures, planned before study inclusion, are not considered AEs or SAEs 
 Results in persistent or significant disability/incapacity 
 The term ‘disability’ means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experience of relatively minor 
medical significance, such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (e.g., sprained ankle), that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 
 Important medical event: 
 Medical or scientific judgment should be exercised by the investigator in deciding whether 
SAE reporting is appropriate in other situations. This includes important medical events that 
may not be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the participant or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These events should usually be considered 
serious and reported as SAEs using the important medical event criterion. 
 The following must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable: 
o 
Suspicion of transmission of infectious agents via IMP 
o 
Risk of liver injury defined as alanine aminotransferase or aspartate 
aminotransferase >3x UNL and total bilirubin >2x UNL where no alternative 
aetiology exists (Hy’s law) 
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10.3.3 
Description of adverse events requiring additional data collection and other events 
requiring collection of additional information 
Adverse events requiring additional data collection 
An AE requiring additional data collection is an AE where Novo Nordisk has evaluated that 
additional data is needed in the evaluation of safety. A specific event form needs to be completed 
for these events.  
Medication error: 
 A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the participant, such as: 
 administration of wrong drug 
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug. 
 wrong route of administration, such as intramuscular instead of subcutaneous 
 accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the study 
participant were likely to happen as judged by the investigator, although they did not 
necessarily occur. 
Misuse and abuse: 
 Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g., overdose to maximise effect) 
 Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g., overdose with the intention to cause harm) 
Note: Medication error, misuse and abuse must always be reported on an AE form and a specific 
event form must be completed. The AE diagnosis on the AE form must reflect what occurred (e.g., 
accidental overdose, intentional overdose or other). If the medication error and/or misuse and abuse 
resulted in a clinical consequence, this must be reported on an additional AE 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 circulation.32 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 basophils33. 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. 
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Local hypersensitivity reactions, including rash, redness, pruritus and oedema, may occur at the site 
of investigational drug injection. 
Drug hypersensitivity reactions are the adverse effects of pharmaceutical formulations (including 
active drugs and excipients) that clinically resemble allergy.34 They can be allergic and non-allergic. 
If a hypersensitivity event is suspected, the participants must contact the site staff as soon as 
possible for further guidance. All events must be reported, and in case of systemic hypersensitivity, 
additional information must be provided on a separate form.  
Injection site reactions: 
If an event of injection site reaction is observed, additional information must be obtained if 
available on a separate form. 
 
Acute gallbladder diseases: 
Events of symptomatic acute gallbladder disease (including gallstones and cholecystitis) 
Malignant neoplasms: 
Confirmed malignant neoplasm by histopathology or other substantial clinical evidence 
Other events requiring collection of additional information 
Hypoglycaemic episodes  
All hypoglycaemic episodes must be recorded by the participant in the eDiary. Instructions on how 
to transfer SMPG values to the eDiary will be given to the participants. If the hypoglycaemic 
episode fulfils the criteria for an SAE the investigator/site must report it as such. One AE form and 
safety information form can cover several hypoglycaemic episodes, if the participant has not 
recovered between the episodes. For more information on hypoglycaemic episodes, please refer to 
Appendix 7 (Section 10.7). 
10.3.4 
Recording and follow-up of adverse event and/or serious adverse event 
10.3.4.1 
Adverse event and serious adverse event recording 
The investigator will record all relevant AE/SAE information in the CRF. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory and diagnostics reports) related to the event. 
There may be instances when copies of source documents (e.g., medical records) for certain cases 
are requested by Novo Nordisk. In such cases, all participant identifiers, with the exception of the 
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subject ID, must be redacted on the copies of the source documents before submission to Novo 
Nordisk. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the study at the latest. For sign-off of SAE-related forms, refer to “AE and SAE reporting via 
paper CRF” later in this section. 
Novo Nordisk products used as concomitant medication or NIMP: if an AE is considered to have a 
causal relationship with a Novo Nordisk marketed product used as NIMP or concomitant 
medication in the study, it is important that the suspected relationship is reported to Novo Nordisk, 
e.g., in the alternative aetiology section on the safety information form. Novo Nordisk may need to 
report this AE to relevant regulatory authorities. 
10.3.4.2 
Assessment of severity 
The investigator will assess severity for each event reported during the study and assign it to one of 
the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with an SAE. Both AEs and 
SAEs can be assessed as severe. 
10.3.4.3 
Assessment of causality 
The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. The investigator will use clinical judgment to determine the relationship. 
Relationship between an AE/SAE and the relevant IMP should be assessed as: 
 Probable - Good reason and sufficient documentation to assume a causal relationship. 
 Possible - A causal relationship is conceivable and cannot be dismissed. 
 Unlikely - The event is most likely related to aetiology other than the IMP. 
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, 
as well as the temporal relationship of the event to IMP administration, should be considered and 
investigated. 
The investigator should use the investigator’s brochure and/or product information, for marketed 
products, for the assessment. For each AE/SAE, the investigator must document in the medical 
records that he/she has reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator always 
makes an assessment of causality for every event before the initial transmission of the SAE 
data. 
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The investigator may change his/her opinion of causality, in light of follow-up information, and 
update the causality assessment in the CRF. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements 
10.3.4.4 
Final outcome 
The investigator will select the most appropriate outcome: 
 Recovered/resolved: The participant has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed when first documented 
 Recovering/resolving: The condition is improving, and the participant is expected to recover 
from the event.  This term may also be applicable for AEs ongoing at the time of death (where 
death was due to another AE). 
Note: For SAEs, this term is only applicable if the participant has completed the follow-up 
period and is expected to recover. 
 Recovered/resolved with sequelae: The participant has recovered from the condition but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
 Not recovered/not resolved: The condition of the participant has not improved, and the 
symptoms are unchanged, or the outcome is not known. This term may be applicable in cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE). 
 Fatal: This term is only applicable if the participant died from a condition related to the 
reported AE. Outcomes of other reported AEs in a participant before he/she died should be 
assessed as ‘recovered/resolved’, ‘recovering/resolving’, ‘recovered/resolved with sequelae’ or 
‘not recovered/not resolved’. An AE with a fatal outcome must be reported as an SAE. 
 Unknown: This term is only applicable if the participant is lost to follow-up 
10.3.4.5 
Follow-up of adverse event and serious adverse event 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g., severe hypersensitivity reactions, Hy’s 
law). This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognised follow-up period, the 
investigator should, upon request, provide Novo Nordisk with a copy of the autopsy report 
including histopathology. 
New or updated information should be recorded in the CRF. 
10.3.5 
Reporting of serious adverse events 
Adverse event and serious adverse event reporting via CRF 
Relevant forms must be completed in the CRF. 
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For SAEs, initial notification via telephone is acceptable, although it does not replace the need for 
the investigator to complete the AE and safety information forms within the designated reporting 
timelines (see Figure 10-1): 
 AE form within 24 hours 
 Safety information form within 5 calendar days 
 AE form and safety information form must be signed within 7 calendar days after first 
knowledge by the investigator. 
 Specific event form within 14 calendar days. 
 For timelines related to events for adjudication, refer also to Appendix 9 (Section 10.9) and 
Figure 10-1. 
If the eCRF is unavailable for more than 24 hours, then the sites will use the paper AE form, and if 
the eCRF is unavailable for more than 5 calendar days, then the site will use the paper safety 
information form. The site should enter the SAE data in the eCRF as soon as it becomes available. 
The relevant CRF forms (AE and safety information forms) must be forwarded to Novo Nordisk  in 
accordance with Section 10.1.5. 
After the study is completed, the study database will be locked, and the CRF will be 
decommissioned to prevent the entry of new data or changes to existing data.  If a site receives a 
report of a new SAE from a participant or receives updated information on a previously reported 
SAE after CRF decommission, the site can report this information on a paper AE and safety 
information form (see below) or to Novo Nordisk by telephone. 
 
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Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
 
For further information on events for adjudication, refer to Appendix 9 (Section 10.9). 
If the event adjudication system (EAS) is not available for document upload, the investigator should ensure that the 
relevant source documents are collected and saved locally until the EAS is available again. 
 
Contact details for SAE reporting can be found in the investigator trial master file. 
10.3.6 
Reporting of adverse events for non-Novo Nordisk medical devices  
Reporting of adverse events for non-Novo Nordisk medical devices provided by Novo Nordisk 
for use in the study 
All complaints should be reported directly to the manufacturer. Any AEs related to the complaint 
should be reported to both the manufacturer and Novo Nordisk. 
AE identified
AE form    24 hours
SIF   5 calendar days
Sign off   7 calendar days
Is the AE serious, or 
non-serious or an 
AESI?
Does the AE require 
additional data 
collection?
Non-serious
Serious
No
Specific event form
(For SAEs: 
  14 calendar days)
Yes

Timelines are from the awareness of an AE.

All hypoglycaemic episodes must be recorded by the participant in the eDiary. If 
the hypoglycaemic episode fulfils the criteria for an SAE, the investigator/site 
must report it as such.

Queries and follow-up requests to be resolved   14 calendar days.

In general data must be recorded in the CRF as soon as possible, preferably within 
5 working days (see Appendix 1)
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
AE Form
No additional 
action
Is the event to be 
adjudicated?
Adjudication form
   14 calendar days
Source data    4 weeks
Yes
No additional 
action
No
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
10.4.1 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
 
Documented total hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
For 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 study enrolment. 
3. Postmenopausal female: 
 A postmenopausal state is defined as amenorrhoea for at least 12 months without an 
alternative medical cause in a female > 45 years of age.  Alternative medical causes for 
amenorrhoea include, but are not limited to, hormonal contraception or hormonal 
replacement therapy.  
 Females ≥ 60 years of age can be considered postmenopausal. 
Females on hormone replacement therapy and whose menopausal status is in doubt are considered 
of childbearing potential and will be required to use one of the highly effective contraception 
methods.  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of participant’s 
medical records, medical examination or medical history interview. 
10.4.2 
Contraceptive guidance 
Male participants 
No contraception measures are required as the risk of teratogenicity/fetotoxicity caused by transfer 
of insulin icodec or semaglutide in seminal fluid is unlikely.35   
Female participants  
Female participants of childbearing potential are eligible to participate if they agree to use methods 
of contraception consistently and correctly. Table 10-3 lists the highly effective methods of 
contraception allowed. Local regulations may apply, see Appendix 11 (Section 10.11). 
Highly effective contraception should be utilised until the end of treatment. 
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Highly effective contraception should be utilised for a least 35 days after last dose of IMP 
(corresponding to time during treatment and until the end of relevant systemic exposure). 
Table 10-3 
Highly effective contraceptive methods allowed36 
Highly effective methodsa (Failure rate of <1% per year when used consistently and correctly): 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb 
 oral 
 intravaginal 
 transdermal 
 Progestogen-only hormone contraception associated with inhibition of ovulation 
 oral 
 injectable 
 implantable 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner 
Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential, and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days. 
 Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 
NOTES 
a. Contraceptive use by men or women should comply with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b. If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action. 
 
The following methods are not acceptable methods of contraception: Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM). 
10.4.3 
Collection of pregnancy information 
Female participants who become pregnant 
Investigator will collect pregnancy information on any female participant who becomes pregnant 
while participating in this study. 
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a participant’s pregnancy (see Figure 10-2). 
The participant will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on participant and neonate which will be forwarded to Novo Nordisk 
within 14 calendar days. Generally, follow-up will not be required for longer than 1 month beyond 
the delivery date. 
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Any termination of pregnancy will be reported, regardless of foetal status (presence or absence of 
anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, any AE in connection with pregnancy 
or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. If 
relevant, consider adding ‘gestational’, ‘pregnancy-related’ or a similar term when reporting the 
AE/SAE. 
Pregnancy outcome should be documented in the participant’s medical record. Abnormal pregnancy 
outcome (e.g., spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. In case of abnormal pregnancy outcome, paternal information 
should be recorded in the appropriate form after obtaining the necessary signed paternal informed 
consent. 
If the investigator learns of an SAE occurring as a result of a post-study pregnancy which is 
considered related to the IMP by the investigator, the SAE should be reported to Novo Nordisk as 
described in Appendix 3 (Section 10.3.) 
Figure 10-2 Decision tree for determining the forms to complete for collection of pregnancy 
information and timelines for reporting – For female participants 
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 participants 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 participants
 
Any female participant who becomes pregnant while participating in the study will discontinue 
randomised treatment. 
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10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.5.1 
Definition of technical complaint 
A technical complaint is any written, electronic or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE but does not 
concern the AE itself.  
Examples of technical complaints: 
 Problems with the physical or chemical appearance of IMPs or auxiliary supplies (e.g., 
discoloration, particles or contamination) 
 Problems with packaging material including labelling 
 Problems related to devices (e.g., to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and the needle) 
Time period for detecting technical complaints 
All technical complaints which occur from the time of receipt of the product at site until the time of 
the last usage of the product must be collected for products predefined on the technical complaint 
form. 
10.5.2 
Recording and follow-up of technical complaints 
Reporting of technical complaints to Novo Nordisk 
For contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints on products allocated to a participant must be reported on a separate technical 
complaint form: 
1. For products with DUN: One technical complaint form must be completed for each affected 
DUN. 
2. For products without DUN: One technical complaint form must be completed for each batch, 
code or lot number. 
Timelines for reporting technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
 24 hours if related to an SAE 
 5 days calendar for all other technical complaints  
If the CRF is unavailable, or when reporting a technical complaint on a product that is not yet 
allocated to a participant, the information must be provided on a paper form to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the CRF becomes available 
again, the investigator must enter the information on the technical complaint form in the CRF. 
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Follow-up of technical complaints 
The investigator is responsible for ensuring that new or updated information will be recorded on the 
originally completed form. 
Collection, storage and shipment of technical complaint samples 
The investigator must collect the technical complaint sample and all associated parts and notify the 
monitor within 5 calendar days of obtaining the sample at site. The sample and all associated parts 
must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a 
copy of the completed technical complaint form. The technical complaint sample should contain the 
batch, code or lot number and, if available, the DUN. If the technical complaint sample is 
unobtainable, the reason must be stated on the technical complaint form. If several samples are 
shipped in one shipment, the sample and the corresponding technical complaint form should be kept 
together. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the study intervention. 
10.5.3 
Reporting of technical complaints for products not included in the technical 
complaint form 
Technical complaints on products not included in the technical complaint form should be reported 
to manufacturing holder. 
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10.6 
Appendix 6: Retention of human biosamples 
Hypersensitivity reaction samples 
In case of a systemic hypersensitivity reaction, the additional blood samples taken in relation to the 
reaction (Section 8.7 and 10.2)  may be retained to follow-up on the hypersensitivity reaction. If 
deemed relevant by Novo Nordisk, relevant exploratory tests may be performed, e.g. histamine 
release (basophil activation). If measured, such data will be reported in a separate report. 
The samples will be stored at a central laboratory, at a central storage facility, and/or at an analysing 
laboratory contracted by Novo Nordisk. The samples might be transferred to other countries, if not 
prohibited by local regulations. Only Novo Nordisk staff and bio-repository personnel will have 
access to the stored samples. The samples may be shipped to a contract research organisation for 
analysis. 
The samples will be anonymised (identified only by a unique sample ID, visit number, study 
identification number and sampling date). Confidentiality and personal data protection will be 
ensured during storage after the end of the study and no direct identification of the participant will 
be stored together with the samples.  
Potential further analyses of the samples will not have any consequences for the participant and 
their relatives. Participants can contact the investigator if they wish to be informed about results 
derived from stored antibody samples obtained from their own body. 
The samples will be stored at Novo Nordisk or a Novo Nordisk designated referral central 
bio-repository after the end of the study and until marketing authorisation approval or until the 
research project terminates, but no longer than 15 years from the end of the study, after which they 
will be destroyed. 
Antibody samples  
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug, if required by health authorities or for safety reasons. A fraction of the 
individual participant samples may be pooled and used for further development of antibody assays, 
or for generating reagents for in study validation and control of future assay performance. 
The antibody samples will be stored at Novo Nordisk or at a designated referral central 
bio-repository after the end of the study and until marketing authorisation approval or until the 
research project terminates, but no longer than 15 years from the end of the study after which they 
will be destroyed. 
Metabolism samples (PK samples) 
Samples for metabolism analysis may be retained for later analysis of metabolites if needed. The 
samples will be stored at Novo Nordisk or at a designated referral central bio-repository after end of 
study and until marketing authorisation approval or until the research project terminates, but no 
longer than 15 years from end of study after which they will be destroyed. 
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10.7 
Appendix 7: Hypoglycaemic episodes 
Table 10-4 
Classification of hypoglycaemia 
Classification of hypoglycaemia 
Level 
Glycaemic criteria 
Description 
Hypoglycaemia alert value 
(level 1) 
< 3.9 mmol/L (70 mg/dL) and  
≥ 3.0 mmol/L (54 mg/dL) 
Sufficiently low for treatment with fast-acting 
carbohydrate and dose adjustment of glucose-lowering 
therapy 
Clinically significant 
hypoglycaemia (level 2) 
< 3.0 mmol/L (54 mg/dL) 
Sufficiently low to indicate serious, clinically important 
hypoglycaemia 
Severe hypoglycaemia 
(level 3)1 
No specific glucose threshold 
1Hypoglycaemia associated with severe cognitive 
impairment requiring external assistance for recovery 
Notes: The Novo Nordisk terms are adapted from The International Hypoglycaemia Study Group,37 ADA,38 ISPAD,39 
type 1 diabetes outcomes program,40 Advanced Technologies & Treatments for Diabetes.41 Severe hypoglycaemia as 
defined by Seaquist42 and ISPAD.39 
 
Severe hypoglycaemia 
1Severe hypoglycaemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be 
available during an event, but neurological recovery following the return of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.42 
Nocturnal hypoglycaemia 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive. 
Reporting of hypoglycaemic episodes 
Reporting of hypoglycaemic episodes by BG meters: 
Plasma glucose (PG) should always be recorded in the (e)diary when a hypoglycaemic episode is 
suspected. 
When a participant experiences a hypoglycaemic episode, the participant should record the general 
information in relation to the hypoglycaemia (timing, PG measurements, symptoms, etc.) as 
described in the e-diary. The investigator should ensure correct reporting of the hypoglycaemic 
episode. In case a participant is not able to fill in the e-diary (e.g., in case of hospitalisation), the 
investigator should still report the hypoglycaemic episode on the hypoglycaemic episodes form. 
Upon onset of a hypoglycaemic episode the participant 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.42 
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 
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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 participants 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.42 
Please refer to Section 10.3.3 for information regarding reporting of hypoglycaemia in the eDiary. 
Diary review 
At each contact the investigator must review the diary data for correct reporting of PG values and 
hypoglycaemic episodes. In case of incomplete or incorrect data in the diary, the participant must be 
questioned whether there have been any severe hypoglycaemic episodes since the last visit and 
report accordingly. 
Re-training of participants 
The participant must be re-trained in how to report hypoglycaemic episodes if the investigator 
identifies low PG values not reported as hypoglycaemic episodes. The training should be 
documented by the investigator in source documents. 
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10.8 
Appendix 8: Titration guideline 
Titration guidelines have been developed, providing recommended dose adjustments at different PG 
levels to ensure that participants receive an optimal treatment. However, it is recognised that 
treatment with insulin and combination products containing insulin 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 participant’s level of 
glycaemic control, is taken into consideration when decisions on dosing are made. The investigator 
is responsible for the treatment of the participants and can therefore overrule the guidelines to avoid 
safety hazards. 
Initiation of trial products 
At randomisation, eligible participants will be randomised to receive IcoSema or insulin icodec. 
IcoSema should be taken once weekly at the same day of the week. The starting dose at 
randomisation (V2) will be 40 dose steps, which is equivalent to 40 units of insulin icodec and 
0.114 mg of semaglutide. 
Insulin icodec should be taken once weekly at the same day of the week. All participants should 
receive a loading dose at randomisation (V2), which consists of total daily basal insulin dose before 
randomisation x 7 + 50% of their total daily basal insulin dose x 7. The following weekly dose (V3) 
should be the total daily dose x 7. In Table 10-5, the weekly V2 and V3 doses for participants 
receiving from 20 units to 80 units per day have been calculated. Please, note that the displayed 
values are rounded to the nearest dose that is dividable by 10. 
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Table 10-5 
V2 and V3 doses for participants randomised to insulin icodec   
Total daily dose 
before 
randomisation 
V2 insulin icodec 
dose 
V3 insulin icodec 
dose 
 Total daily dose 
before 
randomisation 
V2 insulin icodec 
dose 
V3 insulin icodec 
dose 
20 
210 
140 
 51 
540 
360 
21 
220 
150 
 52 
550 
360 
22 
230 
150 
 53 
560 
370 
23 
240 
160 
 54 
570 
380 
24 
250 
170 
 55 
580 
390 
25 
260 
180 
 56 
590 
390 
26 
270 
180 
 57 
600 
400 
27 
280 
190 
 58 
610 
410 
28 
290 
200 
 59 
620 
410 
29 
300 
200 
 60 
630 
420 
30 
320 
210 
 61 
640 
430 
31 
330 
220 
 62 
650 
430 
32 
340 
220 
 63 
660 
440 
33 
350 
230 
 64 
670 
450 
34 
360 
240 
 65 
680 
460 
35 
370 
250 
 66 
690 
460 
36 
380 
250 
 67 
700 
470 
37 
390 
260 
 68 
710 
480 
38 
400 
270 
 69 
720 
480 
39 
410 
270 
 70 
740 
490 
40 
420 
280 
 71 
750 
500 
41 
430 
290 
 72 
760 
500 
42 
440 
290 
 73 
770 
510 
43 
450 
300 
 74 
780 
520 
44 
460 
310 
 75 
790 
530 
45 
470 
320 
 76 
800 
530 
46 
480 
320 
 77 
810 
540 
47 
490 
330 
 78 
820 
550 
48 
500 
340 
 79 
830 
550 
49 
510 
340 
 80 
840 
560 
50 
530 
350 
  
 
 
Dose adjustment of trial products during the study 
After randomisation IcoSema and insulin icodec should be adjusted once weekly by the investigator 
in connection with the visits/phone contacts. 
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The dose adjustment will be based on the three pre-breakfast SMPG values measured on two days 
prior to the dose adjustment and on the day of the contact. 
If one or more pre-breakfast SMPG values are missing, the dose adjustment should be performed on 
the remaining SMPG value(s). 
Adjustment of IcoSema and insulin icodec will be done in accordance with Table 10-6. 
Table 10-6 
Adjustment of trial products 
Pre-breakfast SMPG 
Icodec adjustment 
IcoSema adjustment 
Value to use 
mmol/L 
mg/dL 
Units 
dose steps 
Lowest of the 
SMPG values 
<4.4 
<80 
-20 
-10 
Mean of the SMPG 
values 
4.4-7.2 
80-130 
0 
0 
>7.2 
>130 
+20 
+10 
Deviations from the algorithm 
It is recommended that the algorithm is followed. However, it is also important that the decision to 
adjust insulin doses is based on all relevant information. A reason for deviating from the algorithm 
should be entered into the HCP portal by the investigator, as applicable. 
Missing IcoSema and insulin icodec dose guidance 
If an IcoSema or insulin icodec dose is missed for ≤ 3 days after the planned dosing day, the 
participants should inject the planned dose. If the dose is missed for > 3 days, the participants 
should await the next planned day of injection. Please note that the visit window is +/- 3 days. 
Dose recommendation from end of treatment and during follow-up 
If it is decided that the participant should continue basal insulin treatment after end of study it is 
recommended that the participant is switched from IcoSema or insulin icodec to any available daily 
basal insulin at the discretion of the investigator. The following should be considered: 
 Calculate the new daily basal insulin dose by dividing the latest IcoSema dose in dose step or 
insulin icodec dose in units by 7. 
 Initiate the new daily basal insulin two weeks after the last injection of IcoSema or 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), consider initiating the daily basal insulin dose earlier than 
two weeks after the last dose of IcoSema or 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. 
If it is decided that the participant is switched to a GLP-1 receptor agonist, the start should also 
await two weeks off IcoSema. Thereafter, the treatment can be initiated in accordance with local 
label for the individual product. 
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Data collection 
The participant should be instructed to report the following: 
 Date, dose and time of IcoSema or insulin icodec injections should be reported in the eDiary. 
 Injection site area of IcoSema and insulin icodec. The investigator must then register the 
injection site area in the eCRF 
 SMPG values with an indication of “pre-breakfast” or “other” should be reported in the eDiary. 
 Hypoglycaemic episodes as described in Appendix 3 (Section 10.3) and Appendix 7 (Section 
10.7) should be reported in the eDiary. 
While using the HCP web portal for titration, the following will be entered by investigator: 
 
IcoSema or insulin icodec doses prescribed at this contact. 
 
Reasons for deviation from the titration algorithm, if applicable. 
Data surveillance 
Surveillance of titration data will be performed centrally by Novo Nordisk in an unbiased manner. 
The data will be reviewed and significant deviations from the titration algorithm will be followed 
up. 
Titration data will consist of: 
 Relevant SMPG values 
 Recommended IcoSema or insulin icodec doses 
 Prescribed IcoSema or insulin icodec doses 
 Actual IcoSema or insulin icodec doses taken by the participant 
 Reasons for deviation from the titration guidelines. Deviations are divided into 
 “hypoglycaemia” 
 “gastrointestinal adverse event” 
 “other, please specify” 
 Hypoglycaemia information 
It is important that titration data are entered into the eDiary and into the eCRF in a timely manner, 
as the aim is to reduce the time in which the participant may receive inadequate treatment. 
The titration data should be reviewed by Novo Nordisk within 24 hours (on workdays). Novo 
Nordisk may contact the investigator by phone or via an online portal (CONNECT) after e-mail 
notification to clarify reasons for deviation or to request entry of missing data. When the 
investigator receives an inquiry, a response should be received at Novo Nordisk within 24 hours (on 
workdays). 
Novo Nordisk will also monitor changes in HbA1c. Novo Nordisk’s medical staff may (virtually) 
visit at regular intervals to discuss progress in glycaemic control and titration of individual 
participants.
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10.9 
Appendix 9:  Events requiring adjudication 
Event adjudication will be performed in randomised participants. An event for adjudication is a 
selected AE or death evaluated by an independent external Event adjudication committee (EAC) in 
a blinded manner, please refer to Table 10-7 for event types in scope.  
For details on the EAC, refer to Appendix 1 (Section 10.1.6.2). 
Table 10-7 
Adverse events requiring event adjudication 
Event type (AE category) 
(serious and non-serious AEs) 
Description  
Death 
 All cause death  
Acute coronary syndrome (acute myocardial 
infarction and unstable angina pectoris requiring 
hospitalisation) 
 All types of acute myocardial infarction and unstable angina 
pectoris requiring hospitalisation 
Cerebrovascular event (stroke and 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 and 
urgent heart failure visits) 
 New episode or worsening of existing heart failure leading to an 
urgent, unscheduled hospital admission or 
clinic/office/emergency department visit 
 
There are four ways to identify events relevant for adjudication as described below: 
1. Investigator-reported events for adjudication: investigator selects the appropriate AE category 
relevant for adjudication (see Table 10-7). 
2. AEs reported with fatal outcome 
3. 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 CRF. 
4. 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 CRF 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 CRF within 14 days (Figure 10-1). 
Copies of source documents should be uploaded to the EAS as soon as possible and preferably 
within 4 weeks (Figure 10-1). In cases where the EAS is not accessible for document upload, the 
investigator should ensure that the relevant source documents are collected and saved locally until 
the EAS is available. 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. 
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10.10 Appendix 10: Mitigations to ensure participant safety and data integrity during an 
emergency situation 
10.10.1 Definition and scope of appendix 
A major emergency is defined as a situation that causes substantial restrictions to study site access 
for participants and/or sponsor representatives. 
In case local restrictions due to a major emergency, e.g. due to a COVID-19 outbreak, lead to lock-
down of a site, the site must contact Novo Nordisk to allow for implementation of mitigations 
mentioned in this appendix based on mutual agreement. 
According to local regulation, health authorities and independent ethics committees should be 
notified in case elements of the emergency appendix are activated. 
Table 10-8 indicates the minimum requirements for assessments that should be performed during a 
lock-down, but sites should always try to follow the assessments outlined in the original flowchart 
(Section 1.2) to the extent possible. Implementation of specific mitigations should be based on 
assessment of feasibility at the individual site.  
Alternative visit formats are examples of the mitigations that can be implemented: 
 Home visits: visits to be performed at the participant´s home  
 Off-site visits: visits to be performed at a place other than the site or the participant´s home  
Alternative visit formats and all other mitigations mentioned in this appendix can be implemented 
only if allowed and deemed feasible according to local regulations, requirements and/or guidelines 
at the sites and countries and should be performed by the site-staff. As a pre-requisite, sites need to 
ensure that the study site staff is covered by workers' compensation insurance, also when 
performing home and off-site visits. 
Sites should comply with local regulations, requirements and/or guidelines if they are issued. 
10.10.2 Visits 
Screening (V1) and randomisation/baseline (V2) should always be performed as on-site visits. If a 
site is unable to perform these visits on-site, screening and randomisation of new participants at that 
site should be on hold until on-site visits are possible. 
Visits 4 and 8 should always be performed as on-site visits to ensure collection of, at least, 
antibodies and PK samples.  
The visit at week 52 (V54) should always be performed as on-site visit. The visit window can be 
extended for up to 28 days. Participants should continue randomised treatment until the visit at 
week 52 (V54) takes place.  
The last follow-up visit (V56) should always be performed as on-site visit to ensure, at least, 
collection of antibodies and PK samples. 
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On-site visits (visits V3, V5, V6, V12, V16, V20, V24, V28, V30, V34, V38, V42, V46, V49, V50, 
V51, V52, V53, V55) can be converted to remote visits (video, phone or similar) or home or off-site 
visits.  
At each visit, the investigator must indicate in the CRF how the visit was performed and specify the 
reason for the preferred assessment method. 
10.10.3 Assessments 
Assessments used for safety or the confirmatory endpoints (i.e., HbA1c, and body weight) should 
be prioritised, as well as antibodies, PK and CGM. The preferred order for the method of 
assessment is shown in Table 10-8): 
HbA1c should be prioritised and be performed on-site at least at V1, V2 and V54. 
Body weight should be prioritised and be performed on-site at least at V1, V2 and V54. 
Antibodies and PK should be prioritised and be performed on-site at least at V2 (antibodies only), 
V4, V8, V54 and V56. 
CGM fitting and training at V49 should be prioritised and preferably be on-site visit, but if not 
possible then home and off-site visit can be performed. If not on site remember to perform device 
initialisation at site before meeting the participant for CGM fitting. 
The site staff is responsible for providing appropriate training to the participant, enabling the 
participants to change the sensor by themselves. 
The site should instruct the participants in manually stopping the sensor in the receiver menu when 
each sensor session is complete, and to keep the battery charged. 
If not possible to perform V50, V52 and V53 as on-site visit, this can be performed as home, 
off-site visit or be conducted over the phone or as video call. 
CGM fitting at V51 should be prioritised and preferably be on-site visit, but if not possible then 
home and off-site visit can be performed. CGM data must be uploaded by the site staff to the CGM 
software. 
The site staff should ensure that the participant has fitted the sensor correctly and that the CGM 
receiver is working, especially when fitting of the sensor is performed over the phone or as video 
call. 
CGM data upload at V54 should be prioritised and be performed as on-site visit. CGM data must be 
uploaded at the site by the site staff to the CGM software. 
The site should instruct the participants in manually stopping the sensor in the Receiver menu when 
the CGM period is complete, and to keep the battery charged. The site staff can collect the receiver 
from the participant up to 4 weeks later and bring the receiver to the site for CGM data upload. 
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Specifications regarding how to perform these assessments using remote visits (phone visits or 
video contact) or as home visits or off-site visits will be provided by Novo Nordisk or the vendor. 
All laboratory samples should be analysed at the central and special laboratories.  In case of lock 
down of the site, samples of V1, V2, V4, V8, V54 and V56 should be prioritised, and the Lack of 
Efficacy Criteria 5, Section 7.1.1 would be evaluated based on the SMPG only (instead of 
evaluating based on SMPG and FPG). 
Home measurements of pregnancy tests and vital signs (other than the ones to be collected at V1, 
V2 and V54) can be performed if on-site visits are not possible and if deemed feasible for the 
participant. Only findings meeting the definition for an AE (refer to Appendix 3 [Section 10.3]) 
should be reported in the CRF. Pregnancy tests and equipment to perform vital signs can be 
delivered to the participants if on-site visits are not possible. The site is responsible for contracting a 
suitable courier and costs will be reimbursed by Novo Nordisk. Participants´ own home scales 
cannot be used for measuring body weight. 
If the assessments indicated in Table 10-8 cannot be performed as on-site visits, home-visits or 
remote visits (video, phone or similar), they should be performed at the first possible timepoint 
following the originally scheduled visit in agreement with Novo Nordisk. 
10.10.4 Study intervention 
Alternative dispensing methods of study intervention may be implemented, and details will be 
communicated and documented. The dispensing options will be provided by Novo Nordisk A/S and 
will be based on options and requirements at country level and if permitted by local regulations. 
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Table 10-8 
Minimum assessments following randomisation 
Please refer to Section 1.2 for the full flowchart. 
Procedures marked with a X should be prioritised and be performed on-site. 
Procedures marked with an X can be performed at the participant´s home, off-site, via the phone or video call if deemed necessary because of the lockdown. 
Procedures marked with a red X can subsequently be cancelled. 
 
Protocol 
Sections
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
(preferred visit 
format) 
 
V1 V2 
V3 
V
4 
V5 
V6 
V
8 
V12 
V16 
V20 
V24 
V28 
V30 
V34 
V38 
V42 
V46 
V49 
V50 
V51 
V52 
V53 
V5
4 
V55 
V5
6 
V54
A 
 Alternative 
visit format 
 
 
 
 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
 
 
 Weekly 
Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P1
0 
P1
1 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of 
Visit (Weeks) 
 
<-
2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 
 Visit Window 
(Days) 
 
 
 
±3 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-
2/+
28 
+3 
+3 
 
    Informed 
Consent and 
Demography 
10.1
.3 
(Ap
p 1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Version: 
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Page: 
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Protocol 
Sections
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
(preferred visit 
format) 
 
V1 V2 
V3 
V
4 
V5 
V6 
V
8 
V12 
V16 
V20 
V24 
V28 
V30 
V34 
V38 
V42 
V46 
V49 
V50 
V51 
V52 
V53 
V5
4 
V55 
V5
6 
V54
A 
 Alternative 
visit format 
 
 
 
 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
 
 
 Weekly 
Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P1
0 
P1
1 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of 
Visit (Weeks) 
 
<-
2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 
 Visit Window 
(Days) 
 
 
 
±3 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-
2/+
28 
+3 
+3 
 
    Eligibility 
Criteria 
5.1, 
5.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
Concomitant 
Medication 
6.8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Medical 
History/Conco
mitant Illness 
8.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Tobacco 
Use 
5.3.
2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
Childbearing 
Potential 
10.
4 
(Ap
p 4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Novo Nordisk 
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Version: 
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Page: 
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Protocol 
Sections
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
(preferred visit 
format) 
 
V1 V2 
V3 
V
4 
V5 
V6 
V
8 
V12 
V16 
V20 
V24 
V28 
V30 
V34 
V38 
V42 
V46 
V49 
V50 
V51 
V52 
V53 
V5
4 
V55 
V5
6 
V54
A 
 Alternative 
visit format 
 
 
 
 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
 
 
 Weekly 
Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P1
0 
P1
1 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of 
Visit (Weeks) 
 
<-
2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 
 Visit Window 
(Days) 
 
 
 
±3 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-
2/+
28 
+3 
+3 
 
    Pregnancy 
Test 
8.3.
5, 
10.
4  
(Ap
p 4) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
    Body 
Measurements 
8.2.
2 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
Body Weight 8.2.
2 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
    Vital Signs 
8.2.
3 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
    Physical 
Examination 
8.2.
2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
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Protocol 
      
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Status: 
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Novo Nordisk 
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Version: 
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Page: 
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Protocol 
Sections
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
(preferred visit 
format) 
 
V1 V2 
V3 
V
4 
V5 
V6 
V
8 
V12 
V16 
V20 
V24 
V28 
V30 
V34 
V38 
V42 
V46 
V49 
V50 
V51 
V52 
V53 
V5
4 
V55 
V5
6 
V54
A 
 Alternative 
visit format 
 
 
 
 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
 
 
 Weekly 
Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P1
0 
P1
1 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of 
Visit (Weeks) 
 
<-
2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 
 Visit Window 
(Days) 
 
 
 
±3 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-
2/+
28 
+3 
+3 
 
    ECG 
8.2.
5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
    Eye 
Examination 
8.2.
4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
    CGM 
8.1.
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
X 
Xc 
X 
X 
X 
 
 
 
    Self 
Measured 
Plasma 
Glucose 
8.1.
1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Protocol 
      
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Status: 
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Novo Nordisk 
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Version: 
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Page: 
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Protocol 
Sections
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
(preferred visit 
format) 
 
V1 V2 
V3 
V
4 
V5 
V6 
V
8 
V12 
V16 
V20 
V24 
V28 
V30 
V34 
V38 
V42 
V46 
V49 
V50 
V51 
V52 
V53 
V5
4 
V55 
V5
6 
V54
A 
 Alternative 
visit format 
 
 
 
 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
 
 
 Weekly 
Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P1
0 
P1
1 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of 
Visit (Weeks) 
 
<-
2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 
 Visit Window 
(Days) 
 
 
 
±3 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-
2/+
28 
+3 
+3 
 
    Adverse 
Eventa 
8.3,  
10.
3 
(Ap
p 3) 
 
 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Laboratory 
Assessmentsb 
10.
2 
(Ap
p 2) 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
    HbA1cb 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
    Antibodiesb 
8.7 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
    Pop-PKb 
8.4 
 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
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Protocol 
Sections
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
(preferred visit 
format) 
 
V1 V2 
V3 
V
4 
V5 
V6 
V
8 
V12 
V16 
V20 
V24 
V28 
V30 
V34 
V38 
V42 
V46 
V49 
V50 
V51 
V52 
V53 
V5
4 
V55 
V5
6 
V54
A 
 Alternative 
visit format 
 
 
 
 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
 
 
 Weekly 
Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P1
0 
P1
1 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of 
Visit (Weeks) 
 
<-
2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 
 Visit Window 
(Days) 
 
 
 
±3 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-
2/+
28 
+3 
+3 
 
    
Hypoglycaemi
a Unawareness 
8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Diabetes 
Treatment 
Preference 
Questionnaire 
(IcoSema arm 
only)d 
8.1.
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
    Drug 
Dispensing 
6 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
  
 
 
 
    Training in 
Trial Product, 
Pen-handling 
6.1 
 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
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Protocol 
Sections
Screening 
Randomisation 
Treatment period 
Follow up 
Discontinuation 
 Visit 
(preferred visit 
format) 
 
V1 V2 
V3 
V
4 
V5 
V6 
V
8 
V12 
V16 
V20 
V24 
V28 
V30 
V34 
V38 
V42 
V46 
V49 
V50 
V51 
V52 
V53 
V5
4 
V55 
V5
6 
V54
A 
 Alternative 
visit format 
 
 
 
 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
H/O/
R/P 
 
H/O/
R/P 
 
 
 Weekly 
Phone Contact 
number (P) 
 
 
 
 
 
 
P7 
P9 
P1
0 
P1
1 
P13 
P14 
P15 
P17 
P18 
P19 
P21 
P22 
P23 
P25 
P26 
P27 
P29 
P31 
P32 
P33 
P35 
P36 
P37 
P39 
P40 
P41 
P43 
P44 
P45 
P47 
P48  
 
 
 
 
 
 
 
 
 
 Timing of 
Visit (Weeks) 
 
<-
2 
0 
1 
2 
3 
4 
6 
10 
14 
18 
22 
26 
28 
32 
36 
40 
44 
47 
48 
49 
50 
51 
52 
54 
57 
 
 Visit Window 
(Days) 
 
 
 
±3 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3/+2 
±3 
±3 
±3 
-
2/+
28 
+3 
+3 
 
    Hand Out 
and Instruct in 
Devices 
6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
    Attend Visit 
Fasting 
5.3.
1 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Notes: 
a All AEs and SAEs must be collected from first administration of randomised treatment  
b Laboratory assessments, including HbA1c, PK and antibodies, should be collected at the site and sent to the central laboratory. All efforts should be made to collect the samples on-site at 
the original frequency, but if on-site visits are not possible due to lock-down, then the sample collection can be  
cancelled.  
c CGM fitting and/or training at V49 and V51 should be prioritised and preferably be on-site visit, but if not possible then home and off-site visit can be performed. 
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d Questionnaire should be prompted to participants at V53 
Abbreviations for visit formats: V, on-site visit; H, home visit; O, off-site visit; R, remote video call; P, phone visit
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10.11 Appendix 11: Country/Region-specific requirements 
Australia 
Indemnity Statement: Comply with Medicines Australia Guidelines for Compensation for Injury 
Resulting from Participation in a Company Sponsored Clinical Trial, version 160104 16 January 
2004. 
Belgium 
 Indemnity statement: "Law concerning experiments on the human person of 07 May 2004 - 
Article 29: §1. Even if without fault, the sponsor is liable for the damage which the subject 
and/or his rightful claimants sustain and which shows either a direct or an indirect connection 
with the trial. 
Bulgaria 
According to Regulation 31 (for defining the rules of Good Clinical Practice, 12 Aug 2007), art. 4, 
par. (2) - The protocol is prepared according to the requirements of GCP and contains as a 
minimum the following: 1) assessment of the expected benefits and risks; 2) definition of inclusion 
and exclusion criteria; 3) rationale for study population, especially when it is expected to include 
participants that cannot consent personally and other vulnerable groups; 4) description of the 
procedures for recruiting participants and getting informed consent when it is expected to include 
patients who are temporarily or constantly unable to consent personally and when it is expected to 
receive consent from an independent witness; 5) description of the plan and the procedures for 
assuring complementary medical care for the participants after the study is ended; 6) monitoring 
procedures; 7) publication policy. 
Contraceptive guidance: Hormonal contraception (oral, intravaginal, injectable, implantable), 
vasectomised partner or sexual abstinence. 
Home and off-site visits in case of lock-downs: Home and off-site visits are not applicable for 
Bulgaria. 
China 
 Continuous Glucose Monitor: CGM will not be used in China.  
 Study Population: pre-screening activities are not applicable in China. 
 Regulatory and ethical considerations: 
 Regulatory authorities will receive the clinical trial application, protocol amendments, 
reports on SAEs, and the CSR according to national requirements. 
 For China, an international cooperative relevant report of related China’s Human Genetic 
Resources will be submitted based on local regulation. 
 Clinical laboratory tests: All laboratory assessments will be analysed in a central laboratory or 
special laboratory located in China. There will be no exploratory tests/exploratory 
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endpoints/investigations for Chinese participants. In case of systemic hypersensitivity reaction, 
the samples required in Section 8.7.2 and 10.2 should be taken and stored at the central 
laboratory before further analysis in the special laboratory.  
The following hypersensitivity analytes are not possible to be tested in China, see Appendix 2 
(Section 10.2), and will not be included in the hypersensitivity case assessment: 
 Anti-human insulin IgE 
 Anti-insulin icodec IgE 
 Anti-semaglutide IgE 
The following hypersensitivity analytes will be tested by the Central lab in China: 
 Tryptase 
 Total IgE antibodies 
The following hypersensitivity analytes will be tested by special lab in China: 
 Anti-insulin icodec binding antibodies 
 Anti-semaglutide binding antibodies 
 Retention of human biosamples: 
 Laboratory samples for Chinese participants including samples for antibody analysis will be 
destroyed according to local regulatory requirement. No sample will be stored after the latest 
date of local regulatory approval. 
 For China, remaining samples after test at site local laboratory, will be immediately 
destroyed according to local bio-waste procedure. 
 Remaining samples after test at the central laboratory will be destroyed according to bio-
waste procedure after the protocol required test. 
 If required by health authorities, Antibody samples, Biomarker samples, Gene test samples 
and other special test samples will be retained for further analysis and/or characterisation of 
responses towards drug. These samples (include their backup) will be stored at a central bio-
repository after end of trial and until marketing authorisation approval or until the research 
project terminates, after which they will be destroyed. 
 All samples' collection, shipment, analysis, temporary storage and destruction will be clearly 
recorded. 
 The participant’s identity will remain confidential and the samples will be identified only by 
subject ID, visit number and trial identification number. No direct identification of the 
participant will be stored together with the samples.  
 Only Novo Nordisk staff and laboratory personnel involved in the analyses will have access 
to the stored antibody samples.  
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 Participants can contact the investigator if they wish to be informed about results derived 
from stored antibody samples obtained from their own body. 
 Dissemination of clinical study data: Information of the study will be disclosed at 
clinicaltrials.gov, chinadrugtrials.org.cn and novonordisk-trials.com. 
 Inclusion and Exclusion criteria: The inclusion/exclusion criteria will be assessed at the 
investigator's discretion unless otherwise stated. 
 Exclusion criteria 4:  the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the last 
dose of the investigational medicinal product has been received more than 30 days before 
screening in the current study and if simultaneous participation is allowed by local authorities” 
is not applicable for China.  
 Discontinuation criteria 4: the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or post-infectious conditions is allowed at the 
investigator’s discretion without discontinuation of randomised treatment if simultaneous 
participation is allowed by local authorities, is not applicable for China. 
 Retention of clinical trial documentation: About site specific data storage, sites have the 
equal right with sponsor. Long term preservation of Chinese Patients’ Trial Data is Prohibited in 
any other entities. 
Croatia 
 Exclusion criteria 4:  the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the last 
dose of the investigational medicinal product has been received more than 30 days before 
screening in the current study and if simultaneous participation is allowed by local authorities” 
is not applicable for Croatia.  
 Discontinuation criteria 4: the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or post-infectious conditions is allowed at the 
investigator’s discretion without discontinuation of randomised treatment if simultaneous 
participation is allowed by local authorities, is not applicable for Croatia. 
Italy 
 Additional exclusion criteria: known severe diabetic autonomic neuropathy as judged by the 
investigator. 
Japan 
 Inclusion criteria 3: age ≥ 20 years at the time of signing informed consent 
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 Preparation/Handling/Storage/Accountability: The head of the study site or the study 
product storage manager assigned by the head of the study site (a pharmacist in principle) is 
responsible for control and accountability of the trial products. 
 Trial governance consideration: A name and seal is accepted as signature. 
 Exclusion criteria 4:  the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the last 
dose of the investigational medicinal product has been received more than 30 days before 
screening in the current study and if simultaneous participation is allowed by local authorities” 
is not applicable for Japan.  
 Discontinuation criteria 4: the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or post-infectious conditions is allowed at the 
investigator’s discretion without discontinuation of randomised treatment if simultaneous 
participation is allowed by local authorities, is not applicable for Japan. 
 Table 10-3: Following contraceptive methods are not approved in Japan. 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: 
o intravaginal 
o transdermal 
 
 Progestogen-only hormone contraception associated with inhibition of ovulation 
o injectable 
o implantable 
Mexico 
Withdrawal from the study: Should the participant, his/her family members, parents or legal 
representative decide to withdraw the consent for participation in the study, the participant will be 
entitled to receive appropriate, free of charge medical care and/or trial product during the follow-up 
period of the protocol when it will be established with certainty that no untoward medical 
consequences of the participant´s participation in the research occurred. 
Study governance considerations: In the case of Mexico, the following responsibilities for the 
head of the Institution/Health Care Establishment, Ethics, Research and, when applicable, Biosafety 
Committees and sponsor within their scope of responsibility: a) Investigation follow-up; b) 
Damages to health arising from the investigation development; as well as those arising from 
interruption or advanced suspension of treatment due to non-attributable reasons to the Participant; 
c) Timely compliance of the terms in which the authorization of a research for health in human 
beings had been issued; d) To present in a timely manner the information required by the Health 
Authority. 
Indemnity Statement: a) Novo Nordisk carries product liability for its products assumed under the 
special laws, acts/and/or guidelines for conducting studies in any country, including those 
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applicable provisions on the Mexican United States.   If the participant feels that something goes 
wrong during the course of this study, the participant should contact the study staff in the first 
instance. 
b) If during their participation in the study the participant experiences a disease or injury that, 
according to the study doctor and the sponsor, is directly caused by the study medication and/or a 
study procedure that otherwise would not have been part of his/her regular medical care, the 
participant will receive from the institution or medical care establishment and free of charge, the 
appropriate medical treatment as required. In this case, the costs resulting from such treatment as 
well as the costs of any indemnification established by law will be covered by the study sponsor in 
accordance with the terms provided by all applicable regulations; even if the participant 
discontinues his/her participation in the study by his own will or by a decision from the investigator. 
c) By signing the informed consent, the participant will not renounce to any compensation or 
indemnification he/she may be entitled to by law, nor will he/she will incur any additional expense 
as a result of his/her participation in the study; any additional expense resulting from the 
participant’s participation in the study will be covered by the trial sponsor. 
South Korea 
 Exclusion criteria 4:  the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID 19 disease or postinfectious conditions is allowed if the last 
dose of the investigational medicinal product has been received more than 30 days before 
screening in the current study and if simultaneous participation is allowed by local authorities” 
is not applicable for South Korea.  
 Discontinuation criteria 4: the note “Simultaneous participation in a study with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or post-infectious conditions is allowed at the 
investigator’s discretion without discontinuation of randomised treatment if simultaneous 
participation is allowed by local authorities, is not applicable for South Korea. 
 Home and off-site visits in case of lock-downs: Home and off-site visits are not applicable 
for South Korea 
Taiwan 
Inclusion criteria: Legal age in Taiwan is 20 years per local law. Thus, age limitation for adult 
studies shall be above or equal to 20 years in the entry criteria. 
Turkey 
Study assessments and procedures: blood samples will be shipped outside of Turkey and will be 
analysed by a central lab according to Attachment I of the protocol. 
Exclusion criteria 10: stricter criteria applies in Turkey as follows: Presence or history of 
pancreatitis (acute or chronic). 
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For USA: 

Haematology samples: 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.

FDA Form 1572: All US investigators will sign FDA Form 1572
For USA sites: Intended for US sites. Conducted under the IND 
All US investigators, as described above, will sign FDA Form 1572 
For sites outside the USA: Intended for participating sites outside of the USA. Not conducted 
under the IND 
All investigators outside of the USA will not sign FDA form 1572 
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial. 
For Russia, Mexico, Serbia, Taiwan and India, where CGM Dexcom G6 is not approved at 
the time of the final protocol version 1.0: 
The CGM will be regarded as an investigational device and will be labelled to indicate for 
investigational use only.  
The CGM has been selected in order to provide the best data accuracy and to be consistent in the 
global clinical programme. Technical complaints on the CGM must be reported to 
 on a 
special technical complaint paper form. 
Timelines for reporting, from the trial site obtaining knowledge of the technical complaint: 

Technical complaint assessed as related to a SAE within 24 hours

All other technical complaints within 5 calendar days
AEs and SAEs related to the technical complaint must be reported both on the special technical 
complaint paper form and in the eCRF. In addition they must be reported in accordance with the 
standard protocol requirements for AE and SAE reporting as described in Section 8.3. 
At the end of the trial CGM must be collected by the investigator. 
If the CGM is approved in any of the countries during the trial conduct, the procedures above are 
not applicable any more in the said country and technical complaints reporting should follow the 
standard vigilance procedures. 
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10.12 Appendix 12: Abbreviations 
 
ADA 
American Diabetes Association 
AE 
adverse event 
BG 
blood glucose 
CGM 
continuous glucose monitoring  
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
CTFG 
Clinical Trial Facilitation Group 
DMSES 
diabetes management self-efficacy  
DPP-4 
dipeptidyl peptidase-4 
DRE 
disease related event 
DTPQ 
Diabetes Treatment Preference Questionnaire  
DTSQ 
Diabetes Treatment Satisfaction Questionnaire  
DUN 
dispensing unit number 
EAC 
Event Adjudication Committee 
EASD 
European Association for the Study of Diabetes 
EAS 
event adjudication system 
ECG 
electrocardiogram 
EMA  
European Medical Agency 
eCRF 
electronic case report form 
ETD 
estimated treatment difference 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPG 
fasting plasma glucose 
GLP-1 
glucagon-like peptide 1 
GCP 
Good Clinical Practice 
HbA1c 
glycated haemoglobin 
HCP 
healthcare professional  
ICE 
intercurrent event 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IHSG 
The International Hypoglycaemia Study Group 
IMP 
investigational medicinal product 
IND 
investigational new drug 
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IRB 
institutional review board 
ISO 
International Organization for Harmonization 
ISPAD 
International Society for Pediatric and Adolescent Diabetes 
NIMP 
non-investigational medicinal product 
OAD 
oral anti-diabetic drug 
PG 
plasma glucose 
PK 
pharmacokinetics 
RTSM 
Randomisation and Trial Supply Management system 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
s.c. 
subcutaneous  
SD 
standard deviation 
SmPC 
summary of product characteristics  
SMPG 
self-measured plasma glucose 
T2D 
type 2 diabetes mellitus 
SUSAR 
suspected unexpected serious adverse reaction 
V 
visit 
WOCBP 
woman of childbearing potential 
 
 
 
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10.13 Appendix 13: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Overall rationale for preparing protocol, version 5.0, 08-Feb-2022, Turkey only: 
The protocol has been amended to implement the below changes to reflect the treatment practice in 
Turkey:  
Section # and name 
Description of change 
Brief rationale 
Appendix 11: Country/Region-
specific requirements-Turkey 
Change of Exclusion Criteria 10 as 
follows:  
“Presence or history of 
pancreatitis (acute or chronic) 
within 180 days before 
screening". 
 
The use of GLP-1 RA is avoided in 
patients who have suffered 
pancreatitis due to treatment practice 
in Turkey 
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Protocol version 4.0, including versions 1, 2 and 3: 18 January 2022, Japan only 
Overall rationale for preparing protocol, version 4.0: 
The protocol has been amended to implement the below changes per request of the PMDA:  
Section # and name 
Description of change 
Brief rationale 
Introduction 
Sentence added to describe that 
Insulin icodec is a recombinant 
protein produced using yeast. 
PMDA request 
Appendix 11: Country/Region-
specific requirements - Japan 
Text added to describe which 
contraceptive methods in the protocol 
(Table 10-3) have not been approved 
in Japan.  
PMDA request 
 
Protocol version 3.0, including versions 1 and 2: 10-Aug-2021, global 
The protocol has been updated to correct the below errors detected:  
Section # and name 
Description of change 
Brief rationale 
Protocol amendment summary of 
changes table 
Date format changed from DD-MM-
YYYY to DD-MMM-YYYY 
DD-MMM-YYYY is the standard 
Novo Nordisk date format. 
1.1 Synopsis, Key Exclusion Criteria,  
5.2  Exclusion criteria 
 
Anticipated initiation or change in 
concomitant medication (for more 
than 14 consecutive days) known to 
affect weight or glucose metabolism 
(e.g. treatment with orlistat, thyroid, 
hormones, or systemic 
corticosteroids).  
Typo. It should say “thyroid 
hormones”, not “thyroid, hormones” 
Table 6-2, Auxiliary supplies 
NovoFine® Plus 32G, 4 mm needles 
and NovoFine® Plus 32G, 6 mm 
needles were renamed to NovoFine® 
needles or similar according to local 
requirements 
Typo in the name NovoFine® Plus 
32G, 6mm (it should not contain 
“Plus”). NovoFine® needles is more 
general and it covers all sizes needed. 
“or similar according to local 
requirements” allows the use of 
similar needles if NovoFine® is not 
approved in a specific country. 
 
10.2 Appendix 2 Clinical laboratory 
tests 
Addition of tryptase to systemic 
hypersensitivity samples (IcoSema 
arm) 
Tryptase should be collected in both 
arms in case of systemic 
hypersensitivty. 
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11 References 
1. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
2. 
American Diabetes Association. 2. Classification and Diagnosis of Diabetes:. Diabetes Care. 
2019;42(Suppl 1):S13-S28. 
3. 
International Diabetes Federation. IDF Diabetes Atlas, 9th Edition. 2019. 
4. 
Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a once-weekly 
human GLP-1 analog, does not reduce the bioavailability of the combined oral 
contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharmacol. 2015;55(5):497-504. 
5. 
Novo Nordisk A/S. Ozempic® (semaglutide), EU Summary of product characteristics 
(SmPC). 27 Mar 2020. 
6. 
Novo Nordisk A/S. Ozempic® (semaglutide), US prescribing Information (PI). Jan 2020. 
7. 
European Medicines Agency, CHMP. Guideline on clinical development of fixed 
combination medicinal products. 2017. 
8. 
Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res. 2005;36(3):197-209. 
9. 
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 
2004;88(4):787-835, ix. 
10. 
Davies M, D’Alessio D, Fradkin J, Kernan W, Mathieu C, Mingrone G, et al. Management 
of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes 
Association (ADA) and the European Association for the Study of Diabetes (EASD). 
Diabetes Care. 2018;41(12):2669-701. 
11. 
Alatorre C, Fernández Landó L, Yu M, Brown K, Montejano L, Juneau P, et al. Treatment 
patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 
receptor agonists: Higher adherence and persistence with dulaglutide compared with once-
weekly exenatide and liraglutide. Diabetes Obes Metab. 2017;19(7):953-61. 
12. 
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. 
Update to a position statement of the American Diabetes Association and the European 
Association for the Study of Diabetes. Diabetologia. 2015;58(3):429-42. 
13. 
Novo Nordisk A/S. Xultophy® (Insulin Degludec/Liraglutide), EU Summary of Product 
Characteristics (SmPC). 2015. 
14. 
Boye KS, Matza LS, Walter KN, Van Brunt K, Palsgrove AC, Tynan A. Utilities and 
disutilities for attributes of injectable treatments for type 2 diabetes. Eur J Health Econ. 
2011;12(3):219-30. 
15. 
Evans M, Jensen HH, Bøgelund M, Gundgaard J, Chubb B, Khunti K. Flexible insulin 
dosing improves health-related quality-of-life (HRQoL): a time trade-off survey. J Med 
Econ. 2013;16(11):1357-65. 
16. 
Novo Nordisk A/S. Investigator's Brochure, IcoSema, NN1535, (edition 4). 17 March 2023. 
17. 
Novo Nordisk A/S. Investigator's Brochure, insulin icodec, NN1436, (edition 9). 16 March 
2023. 
18. 
American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment:. 
Diabetes Care. 2021;44(Suppl 1):S111-S24. 
19. 
American Diabetes Association. American Diabetes Association standards of medical care 
in diabetes 2019. Diabetes Care2019. p. S1–S187. 
20. 
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease. http://www.kidney-international.org. 2013 2013. 
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21. 
Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
frequency and associated symptoms. Diabetes Care. 1995;18(4):517-22. 
22. 
McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6. 
23. 
Little R, Rubin D. Statistical analysis with missing data. Sons. JW, editor. New York.: John 
Wiley & Sons. 1987. 
24. 
Blonde L, Merilainen M, Karwe V, Raskin P. Patient-directed titration for achieving 
glycaemic goals using a once-daily basal insulin analogue: an assessmentof two different 
fasting plasma glucose targets - the TITRATETM study. Diabetes Obes Metab. 2009;11:623-
31. 
25. 
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013. 
26. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Current 
step 4 version. 09 Nov 2016. 
27. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
28. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
29. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
30. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
31. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org. 
32. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second Symposium on the Definition and Management of Anaphylaxis: Summary report - 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network Symposium. Annals of Emergency Medicine. 2006;47(4):373-80. 
33. 
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin 
Immunol. 2002;110(3):341-8. 
34. 
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised 
nomenclature for allergy for global use: Report of the Nomenclature Review Committee of 
the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-6. 
35. 
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. 
36. 
Clinical Trial Facilitation Group (CTFG), Heads of Medicines Agency. Recommendations 
related to contraception and pregnancy testing in clinical trials. 21 Sep 2020. 
37. 
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 
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the American Diabetes Association and the European Association for the Study of Diabetes. 
Diabetes Care. 2017;40(1):155-7. 
38.
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64.
39.
Abraham MB, Jones TW, Naranjo D, Karges B, Oduwole A, Tauschmann M, et al. ISPAD
Clinical Practice Consensus Guidelines 2018: Assessment and management of
hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2018;19 Suppl
27:178-92.
40.
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.
41.
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.
42.
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 
NCT05352815 
Sponsor trial ID: 
NN1535-4591 
Official title of study: 
A 52 week study comparing the efficacy and safety of once 
weekly IcoSema and once weekly insulin icodec, both 
treatment arms with or without oral anti diabetic drugs, in 
participants with type 2 diabetes inadequately controlled with 
daily basal insulin. COMBINE 1 
Document date*: 
16 March 2022 
 
*Document date refers to the date on which the document was most recently updated. 


Statistical Analysis Plan 
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Statistical Analysis Plan 
A 52 week study comparing the efficacy and safety of once weekly IcoSema and once weekly 
insulin icodec, both treatment arms with or without oral anti diabetic drugs, in participants with type 
2 diabetes inadequately controlled with daily basal insulin. COMBINE 1
Substance: IcoSema (insulin icodec and semaglutide)
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Table of contents 
 
 
Page 
Table of contents ............................................................................................................................................... 2 
Version History ................................................................................................................................................. 4 
1 Introduction ................................................................................................................................................. 5 
1.1 
Objectives, Endpoints, and Estimands ................................................................................................ 5 
1.1.1 
Objectives ............................................................................................................................ 5 
1.1.1.1 
Primary objective ............................................................................................. 5 
1.1.1.2 
Secondary objectives ........................................................................................ 5 
1.1.2 
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 
1.1.3 
Estimands ............................................................................................................................ 6 
1.1.3.1 
Primary Estimand ............................................................................................. 6 
1.1.3.2 
Confirmatory Secondary Estimands ................................................................ 7 
1.1.3.3 
Supportive Secondary Estimands ..................................................................... 7 
1.2 
Study Design ....................................................................................................................................... 7 
2 Statistical Hypotheses ................................................................................................................................. 8 
2.1 
Multiplicity Adjustment ...................................................................................................................... 9 
3 Analysis Sets ................................................................................................................................................ 9 
4 Statistical Analyses .................................................................................................................................... 10 
4.1 
General Considerations ..................................................................................................................... 10 
4.2 
Primary Estimand Analysis ............................................................................................................... 11 
4.2.1 
Definition of Endpoint ....................................................................................................... 11 
4.2.2 
Main Analytical Approach ................................................................................................ 11 
4.2.3 
Sensitivity Analysis ........................................................................................................... 12 
4.2.4 
Supplementary Analysis .................................................................................................... 13 
4.3 
Secondary Estimands Analyses ........................................................................................................ 13 
4.3.1 
Confirmatory Secondary Estimands .................................................................................. 13 
4.3.1.1 
Estimand related to change in body weight from baseline week 0 (V2) to 
week 52 (V54) ................................................................................................ 13 
4.3.1.2 
Estimand related to number of clinically significant hypoglycaemic 
episodes (level 2) (<3.0 mmol/L [54 mg/dL], confirmed by BG meter) 
or severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) 
to week 57 (V56) ............................................................................................ 13 
4.3.2 
Supportive Secondary Estimands ...................................................................................... 14 
4.3.2.1 
Supportive Secondary Efficacy Estimands .................................................... 14 
4.3.2.1.1 
Change in fasting plasma glucose (FPG) from baseline week 0 
(V2) to week 52 (V54) ........................................................................... 15 
4.3.2.1.2 
Time in range 3.9-10.0 mmol/L (70-180 mg/dL) from week 48 
(V50) to week 52 (V54) ......................................................................... 15 
4.3.2.1.3 
Time spent < 3.0 mmol/L (54 mg/dL) from week 48 (V50) to week 
52 (V54) ................................................................................................. 16 
4.3.2.1.4 
Time spent > 10.0 mmol/L (180 mg/dL) from week 48 (V50) to 
week 52 (V54) ....................................................................................... 16 
4.3.2.1.5 
Weekly basal insulin dose from week 50 (V52) to week 52 (V54) ....... 16 
4.3.2.2 
Supportive Secondary Safety Estimands ....................................................... 16 
4.3.2.2.1 
Hypoglycaemic episodes ....................................................................... 16 
4.4 
Exploratory Estimands Analysis ....................................................................................................... 16 
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4.5 
Other Safety Analyses ....................................................................................................................... 16 
4.5.1 
Hypoglycaemic episodes ................................................................................................... 17 
4.5.2 
Relative change in lipids from baseline week 0 (V2) to week 52 (V54) ........................... 17 
4.5.3 
Change in vital signs from baseline week 0 (V2) to week 52 (V54) ................................. 17 
4.5.4 
Anti-insulin icodec antibodies ........................................................................................... 17 
4.5.5 
Anti-semaglutide antibodies .............................................................................................. 18 
4.5.6 
Record selection ................................................................................................................ 18 
4.6 
Other Analyses .................................................................................................................................. 19 
4.6.1 
Other Variables and/or Parameters .................................................................................... 19 
4.6.1.1 
Change in waist circumference from baseline week 0 (V2) to week 52 
(V54) .............................................................................................................. 19 
4.6.1.2 
Achievement of targets .................................................................................. 19 
4.6.2 
Pharmacokinetic modelling ............................................................................................... 20 
4.7 
Interim Analysis ................................................................................................................................ 20 
4.8 
Changes to Protocol-planned Analysis ............................................................................................. 20 
4.9 
Partial database lock ......................................................................................................................... 20 
5 Sample size determination ........................................................................................................................ 21 
6 Supporting Documentation ...................................................................................................................... 22 
6.1 
Appendix 1: List of abbreviations ..................................................................................................... 22 
6.2 
Appendix 2: Definition and calculation of endpoints, assessments and derivations ........................ 22 
6.3 
Appendix 3: Attributable intercurrent events .................................................................................... 30 
7 References .................................................................................................................................................. 31 
 
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Version History 
This Statistical Analysis Plan (SAP) for study NN1535-4591 is based on the protocol version 3.0 
dated 10Aug2021 applicable in all countries except Japan and Turkey, protocol version 4.0 dated 
18Jan2022 applicable in Japan and protocol version 5.0 dated 08Feb2022 applicable in Turkey. 
SAP Version 
Date 
Change 
Rationale 
1.0 
24Jun2021 
Not Applicable 
Original version 
2.0 
10Aug2021 
Reference to protocol 
version updated 
The protocol was updated to version 3.0 
3.0 
16Mar2022 
Clarification of analysis 
The offset in a statistical analysis has been clarified. 
 
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1 
Introduction 
This SAP is based on the protocol: A 52-week study comparing the efficacy and safety of once 
weekly IcoSema and once weekly insulin icodec, both treatment arms with or without oral 
anti-diabetic drugs, in participants with type 2 diabetes inadequately controlled with daily basal 
insulin. COMBINE 1. This SAP include details on analysis of secondary estimands related to 
supportive secondary endpoints. There are no changes to the analyses described in the protocol, 
however additional information has been included in case of insufficient data for meaningful 
imputation of missing data for the primary analysis. The SAP also contains specification of 
additional derivations and analyses. 
1.1 
Objectives, Endpoints, and Estimands 
1.1.1 
Objectives 
1.1.1.1 
Primary objective 
To confirm superiority of once weekly IcoSema compared with once weekly insulin icodec, both 
treatment arms with or without OADs, in terms of glycaemic control measured by change in HbA1c 
from baseline after 52 weeks in participants with T2D inadequately controlled with daily basal 
insulin.  
1.1.1.2 
Secondary objectives 
To confirm superiority of once weekly IcoSema compared to once weekly insulin icodec, both 
treatment arms with or without OADs, in participants with T2D inadequately controlled with daily 
basal insulin in terms of: 
• Change in body weight from baseline after 52 weeks 
• Number of clinically significant hypoglycaemic (level 2) or severe hypoglycaemic (level 3) 
episodes during 52 weeks and the 5 week follow-up period 
 
To compare parameters of glycaemic control and safety of once weekly IcoSema with once weekly 
insulin icodec, both treatment arms with or without OADs, in participants with T2D inadequately 
controlled with daily basal insulin. 
1.1.2 
Endpoints 
1.1.2.1 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline week 0 (V2) to week 52 (V54) 
%-point  
 
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1.1.2.2 
Secondary endpoints 
1.1.2.2.1 
Confirmatory secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From baseline week 0 (V2) to week 52 (V54) 
Kg  
Number of clinically significant 
hypoglycaemic episodes (level 2) (<3.0 
mmol/L (54 mg/dL), confirmed by BG 
meter) or severe hypoglycaemic episodes 
(level 3) 
From baseline week 0 (V2) to week 57 (V56) 
Number of episodes 
 
1.1.2.2.2 
Supportive secondary endpoints 
Secondary efficacy endpoints 
Endpoint title 
Time frame 
Unit 
Time in range 3.9-10.0 mmol/L (70-180 
mg/dL)* 
From week 48 (V50) to week 52 (V54) 
% of readings  
Time spent < 3.0 mmol/L (54 mg/dL)* 
From week 48 (V50) to week 52 (V54) 
% of readings  
Time spent > 10.0 mmol/L (180 mg/dL)* 
From week 48 (V50) to week 52 (V54) 
% of readings  
Change in fasting plasma glucose (FPG) 
From baseline week 0 (V2) to week 52 (V54) 
mmol/L  
Weekly basal insulin dose 
From week 50 (V52) to week 52 (V54) 
Units 
* using continuous glucose monitoring (CGM) system, Dexcom G6  
Secondary safety endpoints 
Endpoint title 
Time frame 
Unit 
Number of clinically significant 
hypoglycaemic episodes (level 2) 
(<3.0 mmol/L (54 mg/dL), confirmed by 
BG meter)   
From baseline week 0 (V2) to week 57 (V56) 
Number of episodes 
Number of severe hypoglycaemic 
episodes (level 3) 
From baseline week 0 (V2) to week 57 (V56) 
Number of episodes 
 
1.1.3 
Estimands 
1.1.3.1 
Primary Estimand 
The primary estimand is described by the following 5 attributes: 
• Treatment condition: The effect of randomised treatment (titration of once weekly IcoSema 
versus titration of once weekly insulin icodec) with or without OAD(s), regardless of 
initiation of non-randomised insulin treatment or additional anti-diabetic treatments for more 
than 2 weeks and adherence to randomised treatment 
• Population: T2D inadequately controlled with daily basal insulin 
• Endpoint: Change in HbA1c from baseline to week 52 
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• Remaining ICEs: None. The two intercurrent events are captured under treatment condition 
and handled as follows: 
o Initiation of non-randomised insulin treatment or additional anti-diabetic treatments 
for more than 2 weeks by the treatment policy strategy 
o Discontinuation of randomised treatment for any reason by the treatment policy 
strategy 
• Population-level summary: Difference in mean changes from baseline 
1.1.3.2 
Confirmatory Secondary Estimands 
Estimand related to change in body weight from baseline to week 52 
The estimand is the same as for the primary estimand except with the endpoint attribute specified 
as: Change in body weight from baseline to week 52. 
Estimand related to number of clinically significant hypoglycaemic episodes (level 2) or severe 
hypoglycaemic episodes (level 3) 
The estimand is described by the following 5 attributes: 
• Treatment condition: The effect of randomised treatment (titration of once weekly IcoSema 
versus titration of once weekly insulin icodec) with or without OAD(s), regardless of 
initiation of non-randomised insulin treatment or additional antidiabetic treatments for more 
than 2 weeks and had all participants adhered to randomised treatment 
• Population: T2D inadequately controlled with daily basal insulin  
• Endpoint: Number of clinically significant hypoglycaemic (level 2) or severe 
hypoglycaemic (level 3) episodes during 52 weeks and the 5 week follow up period 
• Remaining ICEs: None. The two intercurrent events are captured under treatment condition 
and handled as follows: 
o Initiation of non-randomised insulin treatment or additional antidiabetic treatments 
for more than 2 weeks by the treatment policy strategy 
o Discontinuation of randomised treatment for any reason by the hypothetical strategy  
• Population-level summary: Rate ratio  
1.1.3.3 
Supportive Secondary Estimands 
Supportive secondary estimands related to supportive secondary endpoints are similar to the 
estimand specified for hypoglycaemic episodes except for the endpoints attributes being specified 
as the respective supportive secondary endpoint and for time in range 3.9-10.0 mmol/L (70-180 
mg/dL) and change in fasting plasma glucose (FPG) the population-level summary attribute being 
specified as “Difference in mean”. 
1.2 
Study Design 
This is an interventional, multi-national, multi-centre, randomised, 52-week, open label, parallel 
group, treat-to-target confirmatory study with two treatment arms. The study investigates the 
efficacy and safety of treatment with once weekly IcoSema compared to once weekly insulin 
icodec, both treatment arms with or without OADs, in participants with T2D inadequately 
controlled with daily basal insulin.  
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The study duration is approximately 59 weeks and consists of: 
• an up to 2 weeks screening period 
• a 52-week treatment period 
• a 5-week follow-up period 
The overall study design is outlined in Figure 1-1. For further details see the study protocol. 
Figure 1-1 Study design 
 
2 
Statistical Hypotheses 
The primary objective is to show that IcoSema is superior to insulin icodec in terms of change in 
HbA1c from baseline week 0 (V2) to week 52 (V54). 
Formally, let D be the mean treatment difference ‘IcoSema’ minus ‘insulin icodec’ of the change in 
HbA1c (%) from baseline week 0 (V2) to week 52 (V54). The null-hypothesis of IcoSema not being 
superior will be tested against the alternative hypothesis of superiority as given by  
H0: D ≥ 0% against HA: D < 0% 
Superiority will be considered confirmed if the upper bound of the two-sided 95% confidence 
interval for D is strictly below 0 %. 
The following sections detail the confirmatory secondary hypotheses. The confirmatory secondary 
objectives are to show that:  
• IcoSema is superior to insulin icodec in terms of change in body weight from baseline week 
0 (V2) to week 52 (V54) 
• IcoSema is superior to insulin icodec in terms of number of hypoglycaemic episodes (level 2 
and 3 combined) from baseline week 0 (V2) to week 57 (V56) 
Formally, let DW be the mean treatment difference ‘IcoSema’ minus ‘insulin icodec’ in change in 
body weight (kg) from baseline week 0 (V2) to week 52 (V54). The null-hypothesis of IcoSema not 
being superior will be tested against the alternative hypothesis of superiority as given by: 
H0: DW ≥ 0 kg against HA: DW < 0 kg. 
Superiority will be considered confirmed if the test procedure was not stopped, see section 2.1 for 
details on the testing procedure, and if the upper bound of the two-sided 95% confidence interval 
for DW is strictly below 0 kg.  
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Let RR be the rate ratio ‘IcoSema’ compared to ’insulin icodec’ of the rate of hypoglycaemic 
episodes (level 2 and level 3 combined). The null-hypothesis of IcoSema not being superior will be 
tested against the alternative hypothesis of superiority as given by: 
H0: RR ≥ 1 against HA: RR < 1. 
Superiority will be considered confirmed if the test procedure was not stopped, see section 2.1 for 
details on the testing procedure, and if the upper bound of the two-sided 95% confidence interval 
for RR is strictly below 1.   
2.1 
Multiplicity Adjustment 
The type I error will be controlled in the strong sense using a hierarchical (fixed sequence) testing 
procedure. This is based on priority ordering of the null hypotheses and testing them in this order 
using the 2-sided 95% confidence interval approach until an insignificant result appears. 
Consequently, the null hypothesis will only be tested if the previous null hypotheses have been 
rejected in favour of IcoSema. 
The steps in the hierarchical testing procedure are as follows: 
• Step 1: Change in HbA1c from baseline week 0 (V2) to week 52 (V54) superiority of 
IcoSema versus insulin icodec 
• Step 2: Change in body weight from baseline week 0 (V2) to week 52 (V54) superiority of 
IcoSema versus insulin icodec 
• Step 3: Number of hypoglycaemic episodes (level 2 and 3 combined) from baseline week 0 
(V2) to week 57 (V56) superiority of IcoSema versus insulin icodec.  
3 
Analysis Sets 
The following populations are defined: 
Participant analysis set 
Description 
Full analysis set  
All randomised participants. Participants will be included in the analyses 
according to the planned randomised treatment. 
CGM full analysis set 
All randomised participants except participants from mainland China. 
Participants will be included in the analyses according to the planned 
randomised treatment. 
Safety analysis set 
All randomised participants who are exposed to randomised treatment. 
Participants will be included in the analyses according to the randomised 
treatment they actually received. 
 
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The following data points sets are defined: 
Data points sets 
Description 
In-study 
All data from randomisation until the last date of any of the following: 
• 
The last direct participant-site contact 
• 
Withdrawal for participants who withdraw their informed consent 
• 
The last participant-investigator contact as defined by the investigator 
for participants who are lost to follow-up (i.e. possibly an unscheduled 
phone visit) 
• 
Death for participants who die before any of the above 
On-treatment 
All data from the date of first dose of randomised treatment as recorded on the 
eCRF until the first date of any of the following: 
• 
The last follow-up visit (V56) 
• 
The last date on randomised treatment +6 weeks (corresponding to 5 
weeks after the end of the dosing interval for both treatment arms) 
• 
The end-date for the in-study data points sets  
 
The on-treatment data points set represent data collected in the period in which a participant is 
considered exposed to randomised treatment. 
Baseline assessments are always included in the in-study and on-treatment data points sets. 
The full analysis set and the in-study data points set will be used to estimate the primary estimand 
and the confirmatory secondary estimand related to body weight. For the confirmatory secondary 
estimands related to hypoglycaemic episodes the full analysis set and the on-treatment data points 
set will be used. 
Efficacy will be evaluated using the full analysis set and in-study data points set. Whereas safety 
will be evaluated using the on-treatment data points set with descriptive statistics being based on the 
safety analysis set and statistical analyses being based on full analysis set unless otherwise 
specified.  
The CGM full analysis set and in-study data points set will be used for reporting of endpoints and 
derivations based on CGM measurements. 
4 
Statistical Analyses 
4.1 
General Considerations 
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. 
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:  
• Randomised treatment: Once weekly IcoSema, Once weekly insulin icodec 
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• Region: Asia, Europe, North America, Other 
The regions will be defined as follows: 
• Asia: Japan, China, Taiwan, South Korea 
• Europe: Italy, Poland, Serbia, Romania, Bulgaria, Croatia, Belgium, Finland, Norway, 
Portugal 
• North America: United States 
• Other: India, South Africa, Turkey, Russia, Mexico, Australia 
4.2 
Primary Estimand Analysis 
4.2.1 
Definition of Endpoint 
The primary endpoint is change in HbA1c from baseline week 0 (V2) to week 52 (V54). 
4.2.2 
Main Analytical Approach 
The estimand (see Section 1.1.3.1), will be estimated based on the full analysis set using the in-
study data points set which includes all HbA1c measurements obtained at week 52 (V54) especially 
measurements from participants experiencing intercurrent events. The imputation approach for the 
primary estimand is a multiple imputation similar to the one described by McEvoy.1 
• Missing HbA1c measurements at week 52 (V54) for participants experiencing intercurrent 
events will be imputed from participants experiencing intercurrent events and have a 
measurement at week 52 (V54) in each treatment arm. 
• Missing HbA1c measurements at week 52 (V54) for participants not experiencing 
intercurrent events are imputed from available measurements at week 52 (V54) from 
participants not experiencing intercurrent events in each treatment arm.  
The multiple imputation approach will be done the following way:  
• Imputation: An ANCOVA model for change in HbA1c from baseline week 0 (V2) to week 
52 (V54) for participants experiencing intercurrent events and have a measurement at week 
52 (V54) with randomised treatment as fixed factor, last available planned on-treatment 
HbA1c observation without initiation of non-randomised insulin treatment or additional 
anti-diabetic treatments for more than 2 weeks, the time point (study day) of last available 
planned on-treatment HbA1c observation without initiation of non-randomised insulin 
treatment or additional anti-diabetic treatments for more than 2 weeks and baseline HbA1c as 
covariate. If participants not experiencing intercurrent events are missing measurements at 
week 52 (V54) an ANCOVA model will be defined in a similar way using available data 
from participants not experiencing intercurrent events. The estimated parameters, and their 
variances, from the imputation models will be used to impute missing HbA1c measurements 
at week 52 (V54). This will be done 1000 times and results in 1000 complete datasets.  
• 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 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.2 
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• From the pooled estimate and standard deviation the 95% confidence interval for the 
treatment difference will be calculated. The corresponding two-sided p-value will also be 
calculated. 
This analysis has the underlying assumption that participants with missing data behave similarly as 
comparable participants within the same treatment arm i.e. that participants experiencing 
intercurrent events with missing data at week 52 (V54) behave like participants experiencing 
intercurrent events with data at week 52 (V54) within the same treatment arm and similar for 
participants not experiencing intercurrent events. 
In case the amount of data for the described imputation model is insufficient for meaningful 
imputation, the first alternative will be the following: 
1. Simplifying the imputation model by removing the following covariates from the imputation 
model: Last available planned on-treatment HbA1c observation without initiation of non-
randomised insulin treatment or additional anti-diabetic treatments for more than 2 weeks and 
the time point (study day) of last available planned on-treatment HbA1c observation without 
initiation of non-randomised insulin treatment or additional anti-diabetic treatments for more 
than 2 weeks. 
 
If the amount of data for this reduced model is still insufficient for meaningful imputation, the 
following imputation strategy will be applied instead: 
2. Missing values at week 52 (V54) 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 discontinuation of randomised treatment as described for change in FPG (see section 
4.3.2.1.1). 
Missing HbA1c at week 52 (V54) will be summarised by participant randomised treatment 
completion status. 
4.2.3 
Sensitivity Analysis 
The following sensitivity analysis will evaluate the robustness of the results towards the missing 
data assumption. 
For the primary endpoint, a two-dimensional tipping point analysis will be performed where 
participants having imputed HbA1c measurement at week 52 (V54) are assumed to have a worse 
outcome in the IcoSema arm and a better outcome in the insulin icodec 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 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 results. 
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4.2.4 
Supplementary Analysis 
The following supplementary analysis addressing a attributable estimand similar to the one 
described by Darken3 will be prepared. This estimand aims at estimating the effect of randomised 
treatment had all participants stayed on the randomised treatment for the entire 52 weeks treatment 
period. Intercurrent events that are considered adversely related to randomised treatment are 
considered attributable and are handled with a composite estimand strategy and a hypothetical 
estimand strategy is used for the remainder intercurrent events and data missing e.g. due to 
participants being lost to follow-up.  
The supplementary analysis will be done the following way: 
• Participants experiencing intercurrent events that are considered attributable are identified, 
see Appendix 3 (section 6.3) for split into attributable and none attributable intercurrent 
events. 
• Outcome after intercurrent events which are deemed attributable to randomised treatment 
are assigned the same unfavourable value in the following way: 
o A mixed-effect model for repeated measurements (MMRM) for change from 
baseline in HbA1c is fitted to data obtained before experiencing intercurrent events. 
The model include treatment, visit and interaction between treatment and visit as 
fixed effects, and subject as random effect. 
o The unfavourable value is assigned as the estimated change from baseline from the 
comparator arm at week 52 (V54) plus the standard deviation of the random 
intercept multiplied by the 90th percentile of the standard normal distribution. 
• The remaining missing data is imputed using a similar approach as for the primary analysis.  
4.3 
Secondary Estimands Analyses 
4.3.1 
Confirmatory Secondary Estimands 
4.3.1.1 
Estimand related to change in body weight from baseline week 0 (V2) to week 52 
(V54) 
The secondary estimand regarding change in body weight from baseline week 0 (V2) to week 52 
(V54) will be estimated using a model similar to the primary analysis above substituting body 
weight for HbA1c. 
The robustness of the results towards the missing data assumption will be evaluated using a method 
following similar principles as for the primary estimand. 
4.3.1.2 
Estimand related to number of clinically significant hypoglycaemic episodes (level 
2) (<3.0 mmol/L [54 mg/dL], confirmed by BG meter) or severe hypoglycaemic 
episodes (level 3) from baseline week 0 (V2) to week 57 (V56) 
The secondary estimand regarding 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) 
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from baseline week 0 (V2) to week 57 (V56) will be analysed as described below. The endpoint is 
defined as described in Protocol Appendix 7. 
For participants who discontinued randomised treatment, the number of episodes in the period 
where hypoglycaemic episodes are not collected (the period from time of follow-up 2 visit (V56) to 
planned end of the on-treatment data point set) will be imputed using a multiple imputation 
technique, assuming that the episode rate pre-follow-up 2 (V56) follows the respective treatment 
arms rate whilst post-follow-up 2 (V56) episode rate is the rate of the comparator arm. The 
imputation will be done as follows:  
• First, a Bayes negative binomial model with log-link function is fitted to the number of episodes 
data for participants in the comparator arm to obtain the posterior distribution of model 
parameters. The model will include region as fixed factor and the logarithm of the time period 
in which a participant is considered exposed to randomised treatment as offset. 
• Second, based on the estimated parameters for the comparator arm in this model, the number of 
episodes in the missing period will be imputed for participants having discontinued randomised 
treatment. One thousand (1000) complete dataset are generated by sampling from the estimated 
distribution. 
• For each of the complete datasets, the number of episodes will be analysed using a negative 
binomial model with log-link function, treatment and region fixed factors and offset as 
described in step 1 plus the missing period for which the number of episodes have been 
imputed. The estimates and standard errors for the 1000 data sets will be pooled to one estimate 
and associated standard deviation using Rubin’s rule.2 
• From the pooled estimate and standard deviation the 95% confidence interval will be calculated 
and back-transformed to the original scale resulting in a treatment ratio and a 95% confidence 
interval for the treatment ratio. The corresponding two-sided p-value will also be calculated. 
The analysis has the underlying assumption that participants discontinuing randomised treatment 
behave similarly to participants in the comparator arm after the follow-up period. The robustness of 
the results towards the missing data assumption will be evaluated using a method following similar 
principles as for the primary estimand. 
 
4.3.2 
Supportive Secondary Estimands 
4.3.2.1 
Supportive Secondary Efficacy Estimands 
The following subsections describe how the supportive secondary estimands related to supportive 
secondary efficacy endpoints (see section 1.1.3.3) will be estimated. The subsections refer to the 
corresponding supportive secondary endpoint. For calculation of endpoints please see appendix 2, 
section 6.2. 
Following international consensus criteria it will be required that at least 70% of the planned CGM 
measurements during the last four weeks are available for data to be included in the analysis.4 
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4.3.2.1.1 
Change in fasting plasma glucose (FPG) from baseline week 0 (V2) to week 52 
(V54) 
The supportive secondary estimand regarding change in FPG from baseline week 0 (V2) to week 52 
(V54) will be estimated using a multiple imputation model as described below. 
Missing FPG values at week 52 (V54) (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 last available observation before experiencing intercurrent events. 
Specifically, the imputations and analyses will be carried out as follows: 
• First, an ANCOVA model with region and randomised treatment as fixed factors, and a baseline 
value as a covariate will be fitted to the last available observation before experiencing 
intercurrent events. 
• 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 
zero and standard deviation s. This will be done 1000 times. 
• For each of the complete data sets, the endpoint will be analysed using an ANCOVA model 
with region and randomised treatment as fixed factors, and a baseline value as a covariate. The 
estimates and SDs for the 1000 data sets will be pooled to one estimate and associated SD using 
Rubin’s rule.2  
• From the pooled estimate and standard deviation the 95% confidence interval for the treatment 
difference will be calculated. The corresponding two-sided p-value will also be calculated.  
4.3.2.1.2 
Time in range 3.9-10.0 mmol/L (70-180 mg/dL) from week 48 (V50) to week 52 
(V54) 
The supportive secondary estimand regarding time in range 3.9-10.0 mmol/L (70-180 mg/dL) (TIR) 
from week 48 (V50) to week 52 (V54) will be estimated using a multiple imputation model as 
described below. 
Missing time in target range 3.9-10.0 mmol/L (70-180 mg/dL) from week 48 (V50) to week 52 
(V54) will be imputed based on the assumption that participants with missing endpoint data behave 
similarly as participants in the comparator arm who have not experienced intercurrent events. 
Specifically, the imputations and analyses will be carried out as follows: 
• First, one thousand (1000) copies of the dataset will be generated for TIR. 
• Second, for each dataset copy, an analysis of variance (ANOVA) model will be fitted to TIR 
values for participants in the comparator arm who did not experience intercurrent events prior to 
week 52 (V54). The estimated mean, and variances, from the model will be used to impute 
missing values in both treatment groups. 
• For each of the completed 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.2 
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• From the pooled estimate and standard deviation the 95% confidence interval for the treatment 
difference will be calculated. The corresponding two-sided p-value will also be calculated.   
4.3.2.1.3 
Time spent < 3.0 mmol/L (54 mg/dL) from week 48 (V50) to week 52 (V54) 
The supportive secondary estimand regarding time spent < 3.0 mmol/L (54 mg/dL) (below range) 
from week 48 (V50) to week 52 (V54) will be estimated using a negative binomial model on the 
number of recorded measurements below range, with a log-link function and the logarithm of the 
total number of recorded measurements as offset. The model will include randomised treatment and 
region as factors. The treatment difference and the 95% confidence interval will be back-
transformed to the original scale resulting in a treatment ratio and a 95% confidence interval for the 
treatment ratio. The corresponding two-sided p-value will also be calculated. 
4.3.2.1.4 
Time spent > 10.0 mmol/L (180 mg/dL) from week 48 (V50) to week 52 (V54) 
The supportive secondary estimand regarding time spent > 10.0 mmol/L (180 mg/dL) (above range) 
from week 48 (V50) to week 52 (V54) will be estimated using a model similar to the analysis for 
time spent < 3.0 mmol/L substituting below range with above range. 
4.3.2.1.5 
Weekly basal insulin dose from week 50 (V52) to week 52 (V54) 
The supportive secondary estimand regarding weekly basal insulin dose from week 50 (V52) to 
week 52 (V54) will be estimated using a model similar to the analysis for change in FPG 
substituting weekly basal insulin dose for FPG and including baseline HbA1c as a covariate in 
addition to pre-study weekly basal insulin dose in the analysis model (step 3). 
4.3.2.2 
Supportive Secondary Safety Estimands 
4.3.2.2.1 
Hypoglycaemic episodes 
The supportive secondary estimands regarding the following supportive secondary safety endpoints 
will be analysed separately using the same model as specified for the confirmatory secondary 
estimand related to number of hypoglycaemic 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 (V56) 
• Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 57 
(V56) 
 
The endpoints are defined as described in Protocol Appendix 7. 
4.4 
Exploratory Estimands Analysis 
Not applicable for this study. 
4.5 
Other Safety Analyses 
The standard safety assessments (AEs, safety laboratory parameters, vital signs, etc.) will be 
reported descriptively; including any notable changes of clinical interest in laboratory parameters. 
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4.5.1 
Hypoglycaemic episodes 
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 (V56) will be derived and analysed using the same model as 
specified for the confirmatory secondary estimand related to number of hypoglycaemic episodes. 
The following derivations will be analysed separately using the model as specified for the 
confirmatory secondary estimand related to number of hypoglycaemic episodes substituting the on-
treatment data point set with data points from baseline week 0 (V2) to week 52 (V54), and 
substituting ‘follow-up 2 visit (V56)’ with ‘discontinuation of randomised treatment’: 
• 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 (V54) 
• 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 (V54) 
• Number of severe hypoglycaemic episodes (level 3) from baseline week 0 (V2) to week 52 
(V54) 
The derivations is defined as described in Protocol Appendix 7. 
4.5.2 
Relative change in lipids from baseline week 0 (V2) to week 52 (V54) 
Relative change in lipids from baseline week 0 (V2) to week 52 (V54) will be analysed separately 
for each of the lipid parameters (see Protocol Appendix 2) using a model similar to the analysis for 
change in FPG substituting the respective lipid parameter for FPG. A multiplicative model will be 
used, i.e. the parameter together with the corresponding baseline value will be log-transformed 
before analysis. The treatment difference and the 95% confidence interval will be back-transformed 
to the original scale resulting in a treatment ratio and a 95% confidence interval for the treatment 
ratio. 
4.5.3 
Change in vital signs from baseline week 0 (V2) to week 52 (V54) 
Change in vital signs (pulse rate, systolic and diastolic blood pressure) from baseline week 0 (V2) 
to week 52 (V54) will be analysed separately for each of the parameters using a model similar to the 
analysis for change in FPG substituting the respective vital signs parameter for FPG. 
4.5.4 
Anti-insulin icodec antibodies 
Antibodies will be evaluated using the in-study data points set. The following will be summarised 
by visit: 
• Anti-insulin icodec binding antibodies (positive/negative) 
• Anti-insulin icodec antibodies cross-reactivity to human insulin status (positive/negative)  
• Anti-insulin icodec antibody titres and change from baseline in anti-insulin icodec antibody 
titres  
 
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The correlation between anti-insulin icodec antibodies titres and actual weekly basal insulin dose, 
HbA1c, and change from baseline in HbA1c, respectively, will be illustrated using mean plots by 
treatment week for quartiles of peak post baseline to week 52 (V54) titre values.  
The Spearman’s rank correlation coefficient between change in anti-insulin icodec antibodies titres 
at week 52 (V54) and each of the following assessments will be derived with the corresponding p-
value for test of no correlation: 
• actual weekly basal insulin dose from week 50 (V52) to week 52 (V54) 
• HbA1c at week 52 (V54) 
• change from baseline in HbA1c at week 52 (V54) 
• level 2 and level 3 combined hypoglycaemic episodes for episodes in the on-treatment data 
points set  
 
Number and percentage of participants with “treatment-induced” and “treatment-boosted” anti-
insulin icodec antibodies will also be summarised. “Treatment-induced” anti-insulin icodec 
antibodies are defined as cases in which participants switch from negative anti-insulin icodec 
antibodies at baseline to positive anti-insulin icodec antibodies during the study. “Treatment-
boosted” anti-insulin icodec antibodies are defined as cases in which participants, who have positive 
anti-insulin icodec antibodies at baseline, experience that anti-insulin icodec antibodies titres 
increase by at least two 2-fold dilution steps during the study. 
4.5.5 
Anti-semaglutide antibodies 
Antibodies will be evaluated using the in-study data points set. The following will be summarised 
by visit for participants randomised to IcoSema: 
• Anti-semaglutide binding antibodies (positive/negative) 
• Anti-semaglutide antibodies cross-reactivity to human GLP-1 status (positive/negative)  
• Anti-semaglutide antibody titres  
 
If relevant, the correlation between anti-semaglutide antibodies titres, HbA1c, and change from 
baseline in HbA1c, respectively, will be illustrated.  
Number and percentage of participants with “treatment-induced” and “treatment-boosted” anti-
semaglutide antibodies will also be summarised. “Treatment-induced” anti-semaglutide antibodies 
are defined as cases in which participants switch from negative anti-semaglutide antibodies at 
baseline to positive anti-semaglutide antibodies during the study. “Treatment-boosted” anti-
semaglutide antibodies are defined as cases in which participants, who have positive anti-
semaglutide antibodies at baseline, experience that anti-semaglutide antibodies titres increase by at 
least two 2-fold dilution steps during the study. 
4.5.6 
Record selection 
A re-test at any visit is defined as repeating the same laboratory assessment using new sample 
material. A re-test may be taken if a participant shows up in a non-fasting state for a laboratory 
assessment that is to be taken in a fasting condition or when sample material is lost or damaged. 
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In case of multiple eligible assessments at same planned time point (where only one was planned) 
only the first value will be selected. 
4.6 
Other Analyses 
4.6.1 
Other Variables and/or Parameters 
For calculation of derivations please see appendix 2, section 6.2. 
4.6.1.1 
Change in waist circumference from baseline week 0 (V2) to week 52 (V54) 
Change in waist circumference from baseline week 0 (V2) to week 52 (V54) will be analysed using 
a model similar to the analysis for change in FPG substituting waist circumference for FPG. 
4.6.1.2 
Achievement of targets 
The following derivations will be analysed separately using the method described below: 
• Achievement of HbA1c<7.0% at week 52 (V54) (yes/no)  
• Achievement of HbA1c<7.0% at week 52 (V54) 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% at week 52 (V54) without severe hypoglycaemic episodes (level 
3) during the prior 12 weeks (yes/no) 
• Achievement of HbA1c≤6.5% at week 52 (V54) (yes/no)  
• Achievement of HbA1c≤6.5% at week 52 (V54) 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% at week 52 (V54) without severe hypoglycaemic episodes (level 
3) during the prior 12 weeks (yes/no) 
• Achievement of HbA1c<7.0% at week 52 (V54) without body weight gain (yes/no)  
• Achievement of HbA1c<7.0% at week 52 (V54) without body weight gain and 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% at week 52 (V54) without body weight gain and severe 
hypoglycaemic episodes (level 3) during the prior 12 weeks (yes/no) 
• Achievement of HbA1c≤6.5% at week 52 (V54) without body weight gain (yes/no)  
• Achievement of HbA1c≤6.5% at week 52 (V54) without body weight gain and 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% at week 52 (V54) without body weight gain and severe 
hypoglycaemic episodes (level 3) during the prior 12 weeks (yes/no) 
 
See Appendix 2, section 6.2, for further details. 
Missing change in HbA1c at week 52 (V54) and missing change in body weight at week 52 (V54)  
will be imputed in the same way as for the primary analysis (step 1 in section 4.2.2), substituting 
body weight for HbA1c when imputing missing body weight assessments, before deriving the 
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dichotomous outcome. Participants who discontinue randomised treatment will have the 
dichotomous outcome also evaluating hypoglycaemia set to ‘no’. For each of the 1000 complete 
data sets, the derivation will be analysed using a logistic regression model with region and 
randomised treatment as fixed factors, and baseline HbA1c value as a covariate. The estimates and 
standard deviations for the 1000 data sets will be pooled to one estimate and associated standard 
deviation using Rubin’s rule.2 
4.6.1.3 
Self-measured plasma glucose (SMPG) 
Mean pre-breakfast SMPG used for dose adjustment will be summarised by visit and randomised 
treatment. Furthermore, number and percentage of participants achieving mean pre-breakfast SMPG 
used for dose adjustment within range (4.4–7.2 mmol/l) will be presented by visit and randomised 
treatment. 
4.6.1.4 
Antidiabetic background medication 
Participants experiencing changes to antidiabetic background medication during the study lasting 
more than 2 weeks will be summarised descriptively by randomised treatment including number 
and proportion of participants. 
4.6.2 
Pharmacokinetic modelling 
Insulin icodec serum concentration data and semaglutide plasma concentration data will be used for 
population PK analysis. The objective of the population PK analysis is to evaluate the effects of 
relevant covariates on insulin icodec and semaglutide exposure. 
The population PK analysis will be performed by Quantitative Clinical Pharmacology, Novo 
Nordisk. A more technical and detailed elaboration of the population PK analysis will be given in a 
modelling analysis plan, which will be prepared before database lock. In brief, previously 
developed PK models for insulin icodec and semaglutide will be applied. The absorption rate 
constants in the models will be fixed, and the apparent clearance and volume of distribution 
parameters will be re-estimated. The covariates of interest will be incorporated into the PK models 
using criteria which will be specified in the modelling analysis plan. 
The population PK analysis will be reported in a separate modelling report, which will not be part 
of the clinical study report. The individual insulin icodec serum concentration data and the 
individual semaglutide plasma concentration data will be tabulated in the bioanalytical report. 
4.7 
Interim Analysis 
Not applicable for this study. 
4.8 
Changes to Protocol-planned Analysis 
There are no changes to the protocol-planned analysis. 
4.9 
Partial database lock 
A partial database lock may be performed at the end of the treatment period for all participants, i.e. 
after the date of the last participant last treatment visit. The database will be updated after the partial 
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database lock to include remaining safety information. The full database lock will be performed 
after the date of the last participant last visit. 
The analysis of the primary endpoint and all other efficacy endpoints will be performed based on 
the data from the partial database lock. Analysis of safety data will be performed after the full 
database lock. This approach is implemented to allow earlier availability of IcoSema to a T2D 
patient population in need of treatment intensification expected to benefit from an insulin and 
GLP-1 combination product. A detailed plan for data handling and operational aspects of the partial 
database lock and the database update will be finalised before the partial database lock.  
5 
Sample size determination 
Please see the protocol section 9.5. 
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6 
Supporting Documentation 
6.1 
Appendix 1: List of abbreviations 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BG 
Blood glucose 
CGM 
Continuous glucose monitoring 
FPG 
Fasting plasma glucose 
ICE 
Intercurrent event 
MMRM 
Mixed-effect model for repeated measurements 
OAD 
Oral anti-diabetic drug 
PK 
Pharmacokinetic 
SAP 
Statistical analysis plan 
SMPG 
Self-measured plasma glucose 
T2D 
Type 2 diabetes mellitus 
TIR 
Time in range 
6.2 
Appendix 2: 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  
%-point 
The HbA1c value at baseline 
week 0 subtracted from the 
HbA1c value at week 52. 
Confirmatory 
secondary endpoint 
Change in body weight 
From baseline 
week 0 (V2) to 
week 52 (V54) 
Kg  
The body weight value at 
baseline week 0 subtracted from 
the body weight value at week 
52. 
Supportive 
secondary efficacy 
endpoint 
Weekly basal insulin 
dose  
From week 50 
(V52) to week 52 
(V54) 
Units 
The mean of weekly basal 
insulin doses during the two 
weeks. 
Supportive 
secondary efficacy 
endpoint 
Time in range 3.9-10.0 
mmol/L (70-180 
mg/dL)* 
From week 48 
(V50) to week 52 
(V54) 
% of readings  Calculated as 100 times the 
number of recorded 
measurements in the given 
glycaemic range, divided by the 
total number of recorded 
measurements. Following 
international consensus criteria, 
it will be required that at least 
70% of the planned CGM 
measurements during the last 
four weeks of randomised 
treatment are available for 
endpoint data to be included in 
the analysis. 
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Type 
Title 
Time frame 
Unit 
Details 
Supportive 
secondary efficacy 
endpoint 
Time spent < 3.0 
mmol/L (54 mg/dL)* 
From week 48 
(V50) to week 52 
(V54) 
% of readings  Calculated as 100 times the 
number of recorded 
measurements below 3.0 
mmol/L (54 mg/dL) divided by 
the total number of recorded 
measurements. Following 
international consensus criteria, 
it will be required that at least 
70% of the planned CGM 
measurements during the last 
four weeks of randomised 
treatment are available for 
endpoint data to be included in 
the analysis. 
Supportive 
secondary efficacy 
endpoint 
Time spent > 10.0 
mmol/L (180 mg/dL)* 
From week 48 
(V50) to week 52 
(V54) 
% of readings  Calculated as 100 times the 
number of recorded 
measurements above 10 
mmol/L (180 mg/dL) divided 
by the total number of recorded 
measurements. Following 
international consensus criteria, 
it will be required that at least 
70% of the planned CGM 
measurements during the last 
four weeks of randomised 
treatment are available for 
endpoint data to be included in 
the analysis. 
Supportive 
secondary efficacy 
endpoint 
Change in fasting 
plasma glucose (FPG) 
From baseline 
week 0 (V2) to 
week 52 (V54) 
mmol/L  
The FPG value at baseline week 
0 subtracted from the FPG 
value at week 52. 
Confirmatory 
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 (V56) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic 
episodes (level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed by BG 
meter) or severe hypoglycaemic 
episodes (level 3) within the 
time frame. 
Supportive 
secondary safety 
endpoint 
Number of clinically 
significant 
hypoglycaemic episodes 
(level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed 
by BG meter)   
From baseline 
week 0 (V2) to 
week 57 (V56) 
Number of 
episodes 
The count of all clinically 
significant hypoglycaemic 
episodes (level 2) 
(<3.0 mmol/L (54 mg/dL) 
confirmed by BG meter) within 
the time frame. 
Supportive 
secondary safety 
endpoint 
Number of severe 
hypoglycaemic episodes 
(level 3) 
From baseline 
week 0 (V2) to 
week 57 (V56) 
Number of 
episodes 
The count of all severe 
hypoglycaemic episodes (level 
3) within the time frame. 
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Type 
Title 
Time frame 
Unit 
Details 
Derivation 
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 (V54) 
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 clinically 
significant 
hypoglycaemic episodes 
(level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed 
by BG meter)   
From baseline 
week 0 (V2) to 
week 52 (V54) 
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. 
Derivation 
Number of severe 
hypoglycaemic episodes 
(level 3) 
From baseline 
week 0 (V2) to 
week 52 (V54) 
Number of 
episodes 
The count of all 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) or 
nocturnal severe 
hypoglycaemic episodes 
(level 3) 
From baseline 
week 0 (V2) to 
week 57 (V56) 
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 (V56) 
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 57 (V56) 
Number of 
episodes 
Nocturnal hypoglycaemic 
episodes: episodes occurring 
between 00:01 and 05:59 both 
inclusive. 
Derivation 
Achievement of 
HbA1c<7.0% (yes/no)  
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
<7.0% 
No: Participant did not achieve 
HbA1c <7.0% 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis 
before deriving the 
dichotomous outcome.  
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Type 
Title 
Time frame 
Unit 
Details 
Derivation 
Achievement of 
HbA1c<7.0% without 
severe (level 3) or 
clinically significant 
hypoglycaemic episodes 
(level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed 
by BG meter) during the 
prior 12 weeks (yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
<7.0% without severe or 
clinically significant 
hypoglycaemic episodes during 
the prior 12 weeks 
No: Participant did not achieve 
HbA1c <7.0% or participant 
had a severe or clinically 
significant hypoglycaemic 
episode during the prior 12 
weeks or participant had 
discontinued randomised 
treatment 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c<7.0% without 
severe hypoglycaemic 
episodes (level 3) during 
the prior 12 weeks 
(yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
<7.0% without severe 
hypoglycaemic episodes during 
the prior 12 weeks 
No: Participant did not achieve 
HbA1c <7.0% or participant had 
a severe hypoglycaemic episode 
during the prior 12 weeks or 
participant had discontinued 
randomised treatment 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c≤6.5% (yes/no)  
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
≤6.5% 
No: Participant did not achieve 
HbA1c ≤6.5% 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c≤6.5% without 
severe (level 3) or 
clinically significant 
hypoglycaemic episodes 
(level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed 
by BG meter) during the 
prior 12 weeks (yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
≤6.5% without severe or 
clinically significant 
hypoglycaemic episodes during 
the prior 12 weeks 
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Type 
Title 
Time frame 
Unit 
Details 
No: Participant did not achieve 
HbA1c ≤6.5% or participant 
had a severe or clinically 
significant hypoglycaemic 
episode during the prior 12 
weeks or participant had 
discontinued randomised 
treatment 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c≤6.5% without 
severe hypoglycaemic 
episodes (level 3) during 
the prior 12 weeks 
(yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
≤6.5% without severe 
hypoglycaemic episodes during 
the prior 12 weeks 
No: Participant did not achieve 
HbA1c ≤6.5% or participant had 
a severe hypoglycaemic episode 
during the prior 12 weeks or 
participant had discontinued 
randomised treatment 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c<7.0% without 
body weight gain 
(yes/no)  
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
<7.0% and change in body 
weight from baseline week 0 to 
week 52 ≤ 0 kg 
No: Participant did not achieve 
HbA1c <7.0% or participant had 
a change in body weight from 
baseline week 0 to week 52 > 0 
kg 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis and 
missing body weight data will 
be imputed in the same way as 
in analysis of body weight 
before deriving the 
dichotomous outcome.  
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Type 
Title 
Time frame 
Unit 
Details 
Derivation 
Achievement of 
HbA1c<7.0% without 
body weight gain and 
severe (level 3) or 
clinically significant 
hypoglycaemic episodes 
(level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed 
by BG meter) during the 
prior 12 weeks  (yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
<7.0% without severe or 
clinically significant 
hypoglycaemic episodes during 
the prior 12 weeks and change 
in body weight from baseline 
week 0 to week 52 ≤ 0 kg 
No: Participant did not achieve 
HbA1c <7.0% or participant 
had a severe or clinically 
significant hypoglycaemic 
episode during the prior 12 
weeks or participant had 
discontinued randomised 
treatment or participant had a 
change in body weight from 
baseline week 0 to week 52 > 0 
kg 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis and 
missing body weight data will 
be imputed in the same way as 
in analysis of body weight 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c<7.0% without 
body weight gain and 
severe hypoglycaemic 
episodes (level 3) during 
the prior 12 weeks 
(yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
<7.0% without severe 
hypoglycaemic episodes during 
the prior 12 weeks and change 
in body weight from baseline 
week 0 to week 52 ≤ 0 kg 
No: Participant did not achieve 
HbA1c <7.0% or participant had 
a severe hypoglycaemic episode 
during the prior 12 weeks or 
participant had discontinued 
randomised treatment or 
participant had a change in 
body weight from baseline 
week 0 to week 52 > 0 kg 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis and 
missing body weight data will 
be imputed in the same way as 
in analysis of body weight 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c≤6.5% without 
body weight gain 
(yes/no)  
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
≤6.5% and change in body 
weight from baseline week 0 to 
week 52 ≤ 0 kg 
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Type 
Title 
Time frame 
Unit 
Details 
No: Participant did not achieve 
HbA1c ≤6.5% or participant had 
a change in body weight from 
baseline week 0 to week 52 > 0 
kg 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis and 
missing body weight data will 
be imputed in the same way as 
in analysis of body weight 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c≤6.5% without 
body weight gain and 
severe (level 3) or 
clinically significant 
hypoglycaemic episodes 
(level 2) (<3.0 mmol/L 
(54 mg/dL), confirmed 
by BG meter) during the 
prior 12 weeks  (yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
≤6.5% without severe or 
clinically significant 
hypoglycaemic episodes during 
the prior 12 weeks and change 
in body weight from baseline 
week 0 to week 52 ≤ 0 kg 
No: Participant did not achieve 
HbA1c ≤6.5% or participant 
had a severe or clinically 
significant hypoglycaemic 
episode during the prior 12 
weeks or participant had 
discontinued randomised 
treatment or participant had a 
change in body weight from 
baseline week 0 to week 52 > 0 
kg 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis and 
missing body weight data will 
be imputed in the same way as 
in analysis of body weight 
before deriving the 
dichotomous outcome.  
Derivation 
Achievement of 
HbA1c≤6.5% without 
body weight gain and 
severe hypoglycaemic 
episodes (level 3) during 
the prior 12 weeks 
(yes/no) 
At week 52 (V54) 
Count of 
subject 
Dichotomous outcome variable: 
Yes: Participant achieved HbA1c 
≤6.5% without severe 
hypoglycaemic episodes during 
the prior 12 weeks and change 
in body weight from baseline 
week 0 to week 52 ≤ 0 kg 
No: Participant did not achieve 
HbA1c ≤6.5% or participant had 
a severe hypoglycaemic episode 
during the prior 12 weeks or 
participant had discontinued 
randomised treatment or 
participant had a change in 
body weight from baseline 
week 0 to week 52 > 0 kg 
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Type 
Title 
Time frame 
Unit 
Details 
Missing HbA1c data at 52 weeks 
will be imputed in the same way 
as in the primary analysis and 
missing body weight data will 
be imputed in the same way as 
in analysis of body weight 
before deriving the 
dichotomous outcome.  
Derivation 
Change in waist 
circumference 
From baseline 
week 0 (V2) to 
week 52 (V54) 
cm 
The waist circumference value 
at baseline week 0 subtracted 
from the waist circumference 
value at week 52. 
Derivation 
Change in systolic blood 
pressure 
From baseline 
week 0 (V2) to 
week 52 (V54) 
mmHg 
The systolic blood pressure 
value at baseline week 0 
subtracted from the systolic 
blood pressure value at week 
52. 
Derivation 
Change in diastolic 
blood pressure 
From baseline 
week 0 (V2) to 
week 52 (V54) 
mmHg 
The diastolic blood pressure 
value at baseline week 0 
subtracted from the diastolic 
blood pressure value at week 
52. 
Derivation 
Change in pulse 
From baseline 
week 0 (V2) to 
week 52 (V54) 
bpm 
The pulse value at baseline 
week 0 subtracted from the 
pulse value at week 52. 
Parameter 
Cholesterol 
At week 52 (V54) 
mmol/L 
 
Parameter 
High density lipoprotein 
(HDL) cholesterol 
At week 52 (V54) 
mmol/L 
 
Parameter 
Low density lipoprotein 
(LDL) cholesterol 
At week 52 (V54) 
mmol/L 
 
Parameter 
Very low density 
lipoprotein (VLDL) 
cholesterol 
At week 52 (V54) 
mmol/L 
 
Parameter 
Triglycerides 
At week 52 (V54) 
mmol/L 
 
Parameter 
Free fatty acids 
At week 52 (V54) 
mmol/L 
 
* using continuous glucose monitoring (CGM) system, Dexcom G6  
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Statistical Analysis Plan 
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Date: 
16 March 2022 Novo Nordisk 
Study ID: NN1535-4591 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
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6.3 
Appendix 3: Attributable intercurrent events 
Intercurrent event 
Attributable 
Initiation of non-randomised insulin treatment or additional antidiabetic treatments 
for more than 2 weeks  
Yes 
Discontinuation of randomised treatment 
for any reason  
Adverse events possible or probable 
related to randomised treatment 
Yes 
Adverse events not possible or probable 
related to randomised treatment 
No 
Hypoglycaemic episodes 
Yes 
Included in the study in violation of the 
inclusion and/or exclusion criteria 
Yes 
Simultaneous use of an approved or non-
approved investigational medicinal 
product in another clinical study 
Yes 
Lack of efficacy 
Yes 
Withdrawal of consent 
Yes 
Pregnancy or intention of becoming 
pregnant 
No 
Other 
No 
 
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Statistical Analysis Plan 
CONFIDENTIAL 
Date: 
16 March 2022 Novo Nordisk 
Study ID: NN1535-4591 
Version: 
3.0 
Status: 
Final 
Page: 
31 of 31 
7 
References 
1.
McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat.
2016;26(1):30-6.
2.
Little RJA, Rubin DB. Statistical analysis with missing data. New York: Wiley. 1987. xiv,
278 p. p.
3.
Darken P, Nyberg J, Ballal S, Wright D. The attributable estimand: A new approach to
account for intercurrent events. Pharm Stat. 2020;19(5):626-35.
4.
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.
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