Clinical trial NCT05478252
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2022-08-03; Completion date: 2023-09-18
Enrollment: 388 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study compares two semaglutide medicines and looks at how well they control blood sugar levels, in participants with type 2 diabetes (T2D). Participants will either get the currently available semaglutide or the semaglutide which is produced through a new manufacturing process. Participants need to take one injection of semaglutide once a week, on the same day of every week. Participants will have a total of 11 clinic visits and the study will last for about 35 weeks (approximately 8 months).

Detailed description:

Arms: arm 1: Participants will initially receive 0.25 milligrams (mg) subcutaneous injections of semaglutide J once weekly (OW) and the dose will be then escalated once in 4 weeks for 8 weeks until the target maintenance dose of 1.0 mg is reached which will be maintained for a period of 20 weeks. Metformin will be considered as background therapy during the trial. arm 2: Participants will initially receive 0.25 mg subcutaneous injections of semaglutide B OW and the dose will be then escalated once in 4 weeks for 8 weeks until the target maintenance dose of 1.0 mg is reached which will be maintained for a period of 20 weeks. Metformin will be considered as background therapy during the trial.
Interventions: intervention 1: Semaglutide J intervention 2: Semaglutide B
Intervention descriptions: intervention 1: Participants will initially receive 0.25 mg subcutaneous injections of semaglutide J OW and the dose will be then escalated once in 4 weeks for 8 weeks until the target maintenance dose of 1.0 mg is reached which will be maintained for a period of 20 weeks: 0.25 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 28). intervention 2: Participants will initially receive 0.25 mg subcutaneous injections of semaglutide B OW and the dose will be then escalated once in 4 weeks for 8 weeks until the target maintenance dose of 1.0 mg is reached which will be maintained for a period of 20 weeks: 0.25 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 28).

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05478252  
Sponsor trial ID: 
NN9535-4820 
Official title of study: 
Investigation of Clinical Comparability of Semaglutide Drug 
Products Based on the Proposed and the Approved Drug 
Substance Manufacturing Processes in Participants with Type 2 
Diabetes  
Document date* 
20 February 2023 
   *Document date refers to the date on which the document was most recently updated. 
     Note: The date in the header of Page 2, 93 is the date of compilation of the documents and not of an update to content. 
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 Protocol
Protocol Title: Investigation of Clinical Comparability of Semaglutide Drug Products Based 
on the Proposed and the Approved Drug Substance Manufacturing Processes in Participants 
with Type 2 Diabetes 
Substance: Semaglutide 
Universal Trial Number: U1111-1266-2391 
EudraCT Number: 2021-001501-69 
Study phase: 3b 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in countries and/or sites  
Protocol version 4.0 
20 February 2023 
Global 
Protocol version 3.0 
05 October 2022 
Global 
Protocol version 2.0 
08 April 2022 
Global 
Original protocol version 1.0 
31 January 2022 
Global 
 
Protocol version 4.0 (20 February 2023) 
This amendment is considered 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 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Section 3.1.1 Primary estimand 
Section 4.2 Scientific rationale for 
study design 
Section 9.1 Statistical hypothesis 
Section 9.5 Sample size determination 
Non-inferiority margin changed from -0.3 to 
0.3 and the statistical hypothesis has been 
corrected to reflect the actual test for 
non-inferiority of semaglutide J against 
semaglutide B 
This has been done to 
correct wrong specification 
Section 1.1 Synopsis 
Section 3.1 Objectives and endpoints 
Section 9.2 Analysis sets 
 
The additional estimand has been changed to 
be the primary estimand and vice versa. 
Moreover, the primary estimand has changed 
to follow a treatment policy strategy, while the 
additional estimand has changed to follow a 
mix of the hypothetical strategy and the 
treatment policy estimand 
This has been done in 
accordance with feedback 
received from health 
authority 
 
 
Section 9.3.2 Primary endpoint analysis 
Section 9.3.3 Secondary endpoint 
analysis - is implicitly affected due to 
direct referencing to Section 9.3.2 
The strategies for handling missing data have 
been updated 
This has been done in 
accordance with the change 
of the estimands 
Section 9.3.2.2 Additional estimand  
The imputation strategy for the new primary 
estimand that follows the treatment policy 
strategy has been updated such that it is 
performed under the non-inferiority 
null-hypothesis 
 
This has been done to 
preserve the conservatism of 
the primary analysis and is 
aligned with feedback 
received from health 
authority 
 
Section 1.3 Flowchart – PK sampling 
Section 10.2 Appendix 2: Clinical 
laboratory tests 
The sampling time range in footnote ‘c’ and 
Table 10-4 has been changed from ‘96 to 119 
hours’ to ‘96 to 144 hours’ 
This has been done to 
correct the time range for 
sampling 
Section 4.3 Justification for dose 
The wordings have been corrected in order to 
clarify that the target maintenance dose of 1.0 
mg will be performed during the first 8 weeks 
after randomisation 
This has been done to 
maintain consistency 
between Section 4.3 and 
Section 6.1  
Section 10.10 Appendix 10 
Abbreviations 
The abbreviations ‘AIC’ and ‘MMRM’ has 
been removed 
This has been removed as it 
is no longer defined in 
protocol 
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Table of Contents 
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 3 
1 Protocol summary ....................................................................................................................................... 7 
1.1 
Synopsis .............................................................................................................................................. 7 
1.2 
Flowchart .......................................................................................................................................... 11 
1.3 
Flowchart – PK sampling .................................................................................................................. 14 
2 Introduction ............................................................................................................................................... 15 
2.1 
Study rationale .................................................................................................................................. 15 
2.2 
Background ....................................................................................................................................... 15 
2.3 
Benefit-risk assessment ..................................................................................................................... 16 
2.3.1 
Risk assessment ................................................................................................................. 16 
2.3.2 
Benefit assessment ............................................................................................................. 19 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 19 
3 Objectives, endpoints and estimand ........................................................................................................ 20 
3.1 
Objectives and endpoints .................................................................................................................. 20 
3.1.1 
Primary estimand ............................................................................................................... 21 
3.1.2 
Additional estimand ........................................................................................................... 21 
4 Study design ............................................................................................................................................... 22 
4.1 
Overall design ................................................................................................................................... 22 
4.2 
Scientific rationale for study design .................................................................................................. 22 
4.3 
Justification for dose ......................................................................................................................... 23 
4.4 
End of study definition ...................................................................................................................... 23 
5 Study population ....................................................................................................................................... 24 
5.1 
Inclusion criteria ............................................................................................................................... 24 
5.2 
Exclusion criteria .............................................................................................................................. 24 
5.3 
Lifestyle considerations .................................................................................................................... 25 
5.3.1 
Meals and dietary restrictions ............................................................................................ 25 
5.3.2 
Tobacco use ....................................................................................................................... 25 
5.4 
Screen failures ................................................................................................................................... 25 
5.5 
Randomisation criteria ...................................................................................................................... 25 
6 Study intervention(s) and concomitant therapy ..................................................................................... 26 
6.1 
Study intervention(s) administered ................................................................................................... 26 
6.2 
Preparation, handling, storage and accountability ............................................................................ 29 
6.3 
Measures to minimise bias: Randomisation and blinding................................................................. 30 
6.4 
Study intervention compliance.......................................................................................................... 31 
6.5 
Dose modification ............................................................................................................................. 31 
6.6 
Continued access to study intervention after end of study ................................................................ 31 
6.7 
Treatment of overdose ...................................................................................................................... 31 
6.8 
Concomitant therapy ......................................................................................................................... 32 
6.8.1 
Rescue medicine ................................................................................................................ 32 
7 Discontinuation of study intervention and participant discontinuation/withdrawal .......................... 33 
7.1 
Discontinuation of study intervention ............................................................................................... 33 
7.1.1 
Temporary discontinuation of study intervention .............................................................. 33 
7.1.2 
Rescue criteria ................................................................................................................... 34 
7.2 
Participant discontinuation/withdrawal from the study .................................................................... 34 
7.2.1 
Replacement of participants .............................................................................................. 35 
7.3 
Lost to follow-up............................................................................................................................... 35 
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8 Study assessments and procedures .......................................................................................................... 36 
8.1 
Efficacy assessments ......................................................................................................................... 36 
8.1.1 
Clinical efficacy assessments ............................................................................................ 36 
8.2 
Safety assessments ............................................................................................................................ 37 
8.2.1 
Physical examinations ....................................................................................................... 37 
8.2.2 
Vital signs .......................................................................................................................... 38 
8.2.3 
Eye examination ................................................................................................................ 38 
8.2.4 
Self-measured plasma glucose ........................................................................................... 39 
8.2.5 
Clinical safety laboratory assessments .............................................................................. 40 
8.2.6 
Pregnancy testing ............................................................................................................... 40 
8.3 
Adverse events and other safety reporting ........................................................................................ 40 
8.3.1 
Time period and frequency for collecting AE information ............................................... 41 
8.3.2 
Method of detecting AEs ................................................................................................... 41 
8.3.3 
Follow-up of AEs .............................................................................................................. 41 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................... 41 
8.3.5 
Pregnancy .......................................................................................................................... 42 
8.3.6 
Technical complaints ......................................................................................................... 42 
8.4 
Pharmacokinetics and pharmacodynamics ....................................................................................... 42 
8.4.1 
Pharmacokinetics ............................................................................................................... 42 
8.4.2 
Pharmacodynamics ............................................................................................................ 42 
8.5 
Genetics ............................................................................................................................................ 42 
8.6 
Biomarkers ........................................................................................................................................ 43 
8.7 
Immunogenicity assessments ............................................................................................................ 43 
8.8 
Human biosamples for future research ............................................................................................. 43 
8.9 
Health economics .............................................................................................................................. 43 
9 Statistical considerations .......................................................................................................................... 44 
9.1 
Statistical hypotheses ........................................................................................................................ 44 
9.1.1 
Multiplicity adjustment...................................................................................................... 44 
9.2 
Analysis sets...................................................................................................................................... 44 
9.3 
Statistical analyses ............................................................................................................................ 45 
9.3.1 
General considerations ...................................................................................................... 45 
9.3.2 
Primary endpoint analyses ................................................................................................. 45 
9.3.2.1 
Primary estimand analysis.............................................................................. 45 
9.3.2.1.1 
Sensitivity analysis ................................................................................ 46 
9.3.2.2 
Additional estimand ....................................................................................... 46 
9.3.2.2.1 
Sensitivity analysis ................................................................................ 46 
9.3.3 
Secondary endpoint analyses ............................................................................................. 46 
9.3.3.1 
Secondary supportive endpoints .................................................................... 46 
9.3.3.1.1 
Change in body weight (kg) ................................................................... 46 
9.3.3.1.2 
Number of treatment-emergent AEs ...................................................... 47 
9.3.3.1.3 
Anti-semaglutide antibodies .................................................................. 47 
9.3.4 
Exploratory endpoints analysis .......................................................................................... 47 
9.3.5 
Safety analyses .................................................................................................................. 47 
9.3.6 
Other analyses ................................................................................................................... 47 
9.4 
Interim analysis ................................................................................................................................. 48 
9.5 
Sample size determination ................................................................................................................ 48 
10 Supporting documentation and operational considerations.................................................................. 50 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations .............................................. 50 
10.1.1 
Regulatory and ethical considerations ............................................................................... 50 
10.1.2 
Financial disclosure ........................................................................................................... 50 
10.1.3 
Informed consent process .................................................................................................. 51 
10.1.4 
Information to participants during the study ..................................................................... 51 
10.1.5 
Data protection .................................................................................................................. 52 
10.1.6 
Committees structure ......................................................................................................... 52 
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10.1.6.1 
Novo Nordisk safety committee..................................................................... 52 
10.1.7 
Dissemination of clinical study data .................................................................................. 52 
10.1.8 
Data quality assurance ....................................................................................................... 53 
10.1.8.1 
Case report forms ........................................................................................... 53 
10.1.8.2 
Monitoring ..................................................................................................... 53 
10.1.8.3 
Protocol compliance ....................................................................................... 54 
10.1.9 
Source documents .............................................................................................................. 54 
10.1.10 Retention of clinical study documentation ........................................................................ 55 
10.1.11 Study and site closure ........................................................................................................ 55 
10.1.12 Responsibilities .................................................................................................................. 55 
10.1.13 Indemnity statement .......................................................................................................... 56 
10.1.14 Publication policy .............................................................................................................. 56 
10.1.14.1 
Communication of results .............................................................................. 57 
10.1.14.2 
Authorship ...................................................................................................... 57 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 58 
10.1.14.4 
Investigator access to data and review of results ........................................... 58 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 59 
10.3 Appendix 3: Adverse Events and Serious Adverse Events: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................................................... 62 
10.3.1 
Definition of AE ................................................................................................................ 62 
10.3.2 
Definition of an SAE ......................................................................................................... 62 
10.3.3 
Description of AEs requiring additional data collection and other events requiring 
collection of additional information .................................................................................. 63 
10.3.4 
Recording and follow-up of AE and/or SAE ..................................................................... 64 
10.3.4.1 
AE and SAE recording ................................................................................... 64 
10.3.4.2 
Assessment of severity ................................................................................... 65 
10.3.4.3 
Assessment of causality ................................................................................. 65 
10.3.4.4 
Final outcome ................................................................................................. 66 
10.3.4.5 
Follow-up of AE and SAE ............................................................................. 66 
10.3.5 
Reporting of SAEs ............................................................................................................. 66 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 68 
10.4.1 
Definitions ......................................................................................................................... 68 
10.4.2 
Contraceptive guidance ..................................................................................................... 68 
10.4.3 
Collection of pregnancy information ................................................................................. 69 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 71 
10.5.1 
Definition of technical complaint ...................................................................................... 71 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 71 
10.5.3 
Reporting of technical complaints for products not included in the technical 
complaint form .................................................................................................................. 72 
10.6 Appendix 6: Retention of human biosamples ................................................................................... 73 
10.7 Appendix 7: Hypoglycaemic episodes .............................................................................................. 74 
10.8 Appendix 8: Mitigations to ensure participant safety and data integrity during an emergency 
situation ............................................................................................................................................. 76 
10.8.1 
Definition and scope of appendix ...................................................................................... 76 
10.8.2 
Visits .................................................................................................................................. 76 
10.8.3 
Assessments ....................................................................................................................... 76 
10.8.4 
Study intervention ............................................................................................................. 77 
10.9 Appendix 9: Country-specific requirements ..................................................................................... 81 
10.10 Appendix 10: Abbreviations ............................................................................................................. 83 
10.11 Appendix 16: Protocol amendment history ...................................................................................... 85 
11 References .................................................................................................................................................. 88 
 
Protocol Attachment I Global list of key staff and relevant departments and suppliers 
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Protocol Attachment II Country list of key staff and relevant departments 
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1 
Protocol summary  
1.1 
Synopsis  
This is an interventional, 28-week, multinational, multicentre, double-blinded, randomised, active 
controlled study with two treatment arms. 
Rationale: 
The aim of this clinical comparability study is to establish non-inferiority of semaglutide drug 
product based on the proposed drug substance manufacturing process (semaglutide J s.c.) against 
the currently approved semaglutide drug product based on the approved drug substance 
manufacturing process (semaglutide B s.c.) based on efficacy when measured by HbA1c (%) and 
also to evaluate any potential risk for unexpected differences in safety, in participants with type 2 
diabetes (T2D). 
Semaglutide, a potent human glucagon like peptide-1 receptor agonist is approved in many 
countries for the treatment of T2D, and in several countries including the United States, it is 
moreover approved in adults with T2D and established cardiovascular disease to reduce the risk of 
major adverse cardiovascular events. Other benefit of semaglutide s.c. in patients with T2D is 
reduction in body weight.  
To ensure adequate manufacturing capacity and safeguarding supply of semaglutide for the market, 
the manufacturing process of the drug substance used for the approved semaglutide drug product for 
s.c. use will be optimised by replacing the currently used Saccharomyces cerevisiae yeast strain 
with a more productive Saccharomyces cerevisiae yeast strain which has been enhanced to generate 
a higher yield and is currently used for manufacturing of semaglutide drug substance approved for 
oral administration. The drug product using the drug substance manufactured by the proposed 
process conform to the specifications approved for semaglutide s.c. The drug product 
manufacturing process from drug substance including excipients, which are already used in the 
approved semaglutide drug product, will remain unchanged. 
Objectives, endpoints and estimands: 
Primary objective 
 To establish non-inferiority of semaglutide J s.c. against semaglutide B s.c. on change from 
baseline in HbA1c at week 28 in participants with T2D as add-on to stable dose of 
metformin. 
Primary endpoint 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From baseline visit (visit 2; week 0) to end of treatment visit 
(visit 10; week 28) 
%-point 
Secondary objective 
 To compare the effect of semaglutide J s.c. and semaglutide B s.c. on change from baseline 
in body weight at week 28 in participants with T2D as add-on to stable dose of metformin 
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
To compare the number of treatment AEs between semaglutide J s.c. and semaglutide B s.c.
in participants with T2D as add-on to stable dose of metformin

To compare the development of anti-semaglutide antibodies between semaglutide J s.c. and
semaglutide B s.c. in participants with T2D as add on to stable dose of metformin
Key supportive secondary endpoint 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From baseline visit (visit 2; week 0) to end of treatment visit 
(visit 10; week 28) 
kg 
Primary estimand 
The primary clinical question of interest for the primary objective is to evaluate whether 
semaglutide J s.c. is non-inferior to semaglutide B s.c. in its effect on change from baseline to 
week 28 in HbA1c (%-points) with a threshold margin of 0.3%-points in patients with T2D 
irrespective of treatment discontinuation and use of rescue medication. 
The primary estimand is defined by the following five attributes as defined in ICH E9(R1):2 

Population: Patients with T2D.

Endpoint: Change in HbA1c (%-points) from baseline to week 28.

Intervention condition: Except for trial product, the treatment regimen evaluated is the same for
both intervention groups and is defined as the trial product taken for up to 28 weeks with or
without initiation of glycaemic rescue medications. The treatment regimen is add-on to
background metformin including possible changes in dose.

Remaining intercurrent events: No further events are identified. The three intercurrent events
are addressed in the intervention condition attributes. Treatment discontinuation for any reason,
initiation of rescue medication, and changes to metformin dose is handled by the treatment
policy strategy.

Population-level summary: Difference in mean changes between semaglutide J s.c. and
semaglutide B s.c.
Additional estimand 
An additional clinical question of interest is to evaluate whether semaglutide J s.c., if taken for the 
planned 28 weeks, is non-inferior to semaglutide B s.c. in its effect on change from baseline to 
week 28 in HbA1c (%-points) with a threshold margin of 0.3%-points in patients with T2D had they 
not required glycaemic rescue medication. 
The estimand attributes: population, endpoint and population-level summary are the same as for the 
primary estimand. The remaining estimand attributes are: 

Intervention condition: Except for trial product, the treatment regimen evaluated is the same
for both intervention groups and is defined as the trial product taken for 28 weeks without
initiation of glycaemic rescue medications. The treatment regimen is add-on to background
metformin including possible changes in dose.

Remaining intercurrent events: No further events are identified. The three intercurrent
events are addressed in the intervention condition attributes. Treatment discontinuation for
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any reason and initiation of rescue medication is handled with the hypothetical strategy. 
Changes to metformin dose is handled by the treatment policy strategy. 
Overall design: 
The study consists of: 
 a 2-week screening period 
 a 28-week intervention period 
 a 5-week follow-up period 
The intervention period comprises an 8-week dose escalation period with dose escalation every 
4 weeks followed by a 20-week maintenance period. 
Study intervention groups and duration: 
Participants will be randomised in a 3:1 manner to receive either semaglutide J s.c. or 
semaglutide B s.c. An unbalanced randomisation with a higher proportion of participants 
randomised to receive semaglutide J s.c. is applied in order to maximise the exposure, and thereby 
the number of observations available to evaluate any unexpected adverse clinical consequences 
related to semaglutide J s.c. 
The maximum duration of the intervention is 28 weeks, and the maximum duration of study is 
35 weeks. 
Investigational medicinal products 
 Semaglutide J 1.34 mg/mL, s.c., solution for injection, 1.5 mL PDS290 prefilled pen injector. 
 Semaglutide B 1.34 mg/mL, s.c., solution for injection, 1.5 mL PDS290 prefilled pen injector 
Number of participants: 
Approximately 475 participants will be screened to achieve 380 participants randomly assigned to 
receive either once-weekly semaglutide J s.c. or semaglutide B s.c. 
Participant characteristics: 
The participants will be male or female, aged between 18-64 years at the time of signing informed 
consent who meet the following key inclusion criteria and none of the following key exclusion 
criteria: 
Key inclusion criteria 
1. Diagnosed with T2D mellitus ≥ 180 days before screening. 
2. Stable daily dose(s) ≥ 90 days prior to the day of screening of metformin ≥ 1500 mg or 
maximum tolerated or effective dose. 
3. HbA1c of 7.0-10.5% (53-91.3 mmol/mol) (both inclusive). 
Key exclusion criteria 
1. Known or suspected hypersensitivity to study intervention(s) or related products. 
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2. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within 90 days before screening. However, short term insulin treatment for a 
maximum of 14 days and prior insulin treatment for gestational diabetes are allowed. 
3. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within 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 nondilated examination. 
Efficacy and safety data will be collected at regular intervals throughout the study.  
Data monitoring committee: No
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2 
Introduction 
2.1 
Study rationale 
Semaglutide is a potent human glucagon like peptide-1 (GLP-1) analogue that acts as a GLP-1 
receptor agonist (RA), with a long half-life (approximately 1 week) suitable for once-weekly 
dosing. Semaglutide subcutaneous (s.c.) is approved in many countries for the treatment of type 2 
diabetes (T2D). In several countries including the United States (US), semaglutide s.c. is moreover 
approved in adults with T2D and established cardiovascular disease to reduce the risk of major 
adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction (MI) or 
nonfatal stroke). Other benefits from treatment with semaglutide s.c. in T2D patients are reduction 
in bodyweight and due to its glucose dependent mode of action, a low risk of hypoglycaemic 
episodes.3, 4 
To ensure adequate manufacturing capacity and safeguarding supply of semaglutide for the market, 
the manufacturing process of the drug substance (DS) used for the approved semaglutide drug 
product (DP) for s.c. use will be optimised. The currently used Saccharomyces cerevisiae yeast 
strain will be replaced with a more productive Saccharomyces cerevisiae yeast strain which has 
been optimized to generate a higher yield and which is currently used for manufacturing of 
semaglutide DS approved for oral administration. Hence, the corresponding fermentation process 
and subsequent recovery process currently used for manufacturing of semaglutide DS approved for 
oral administration will be implemented in the manufacturing process of semaglutide DS for s.c. 
administration. The DP using the DS manufactured by the proposed process conform to the 
specifications approved for semaglutide s.c. The DP manufacturing process from DS including 
excipients, which are already used in the approved semaglutide s.c. DP, will remain unchanged. 
Throughout this document, semaglutide J s.c. will refer to the semaglutide DP based on the 
proposed DS manufacturing process and semaglutide B s.c. will refer to the currently approved 
semaglutide DP based on the approved DS manufacturing process. 
This clinical comparability study is designed to establish non-inferiority of semaglutide J s.c. 
against semaglutide B s.c. based on efficacy when measured by glycosylated haemoglobin 
(HbA1c (%)) and also to evaluate any potential risk for unexpected differences in safety. Hereby 
ensuring that the safety and efficacy of semaglutide s.c. is not affected by the manufacturing 
change. 
2.2 
Background  
Semaglutide J s.c. has been evaluated according to the Food and Drug Administration (FDA) 
Guidance for Industry ‘Changes to an approved New Drug Application (NDA) or Abbreviated New 
Drug Application (ANDA)’ and European Medicines agency’s (EMA) ‘Note for Guidance on 
Biotechnological/Biological Products Subject to Changes in their Manufacturing Process’.5, 6  
Based on appropriate comparison of relevant quality attributes, the DP manufactured by proposed 
and approved DS manufacturing process are highly similar and considered comparable, i.e., no 
adverse impact on safety or efficacy profiles is foreseen.6 The impurities specific to the proposed 
process has previously been clinically and non-clinically qualified without any issues related to 
immunogenicity being observed. 
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3.1.1 
Primary estimand 
The primary clinical question of interest for the primary objective is to evaluate whether 
semaglutide J s.c. is non-inferior to semaglutide B s.c. in its effect on change from baseline to week 
28 in HbA1c (%-points) with a threshold margin of 0.3%-points in patients with T2D irrespective of 
treatment discontinuation and use of rescue medication. 
The primary estimand is defined by the following five attributes as defined in ICH E9(R1):0 2 
 Population: Patients with T2D. 
 Endpoint: Change in HbA1c (%-points) from baseline to week 28.  
 Intervention condition: Except for trial product, the treatment regimen evaluated is the same for 
both intervention groups and is defined as the trial product taken for up to 28 weeks with or 
without initiation of glycaemic rescue medications. The treatment regimen is add-on to 
background metformin including possible changes in dose. 
 Remaining intercurrent events: No further events are identified. The three intercurrent events 
are addressed in the intervention condition attributes. Treatment discontinuation for any reason, 
initiation of rescue medication, and changes to metformin dose is handled by the treatment 
policy strategy. 
 Population-level summary: Difference in mean changes between semaglutide J s.c. and 
semaglutide B s.c. 
3.1.2 
Additional estimand 
An additional clinical question of interest is to evaluate whether semaglutide J s.c., if taken for the 
planned 28 weeks, is non-inferior to semaglutide B s.c. in its effect on change from baseline to 
week 28 in HbA1c (%-points) with a threshold margin of 0.3%-points in patients with T2D had they 
not required glycaemic rescue medication. 
The estimand attributes: population, endpoint and population-level summary are the same as for the 
primary estimand. The remaining estimand attributes are: 
 Intervention condition: Except for trial product, the treatment regimen evaluated is the same 
for both intervention groups and is defined as the trial product taken for 28 weeks without 
initiation of glycaemic rescue medications. The treatment regimen is add-on to background 
metformin including possible changes in dose. 
 Remaining intercurrent events: No further events are identified. The three intercurrent 
events are addressed in the intervention condition attributes. Treatment discontinuation for 
any reason and initiation of rescue medication is handled with the hypothetical strategy. 
Changes to metformin dose is handled by the treatment policy strategy. 
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4 
Study design 
4.1 
Overall design 
This is an interventional, 28-week, multinational, multicentre, double-blinded, randomised, active 
controlled study comparing semaglutide J s.c. with semaglutide B s.c. in participants with T2D 
inadequately controlled on a stable dose of metformin with a baseline HbA1c of 7.0–10.5%.  
A total of 380 participants will be randomised in a 3:1 manner to receive either semaglutide J s.c. or 
semaglutide B s.c. The study consists of a 2-week screening period, a 28-week intervention period 
followed by a 5-week follow-up period. The intervention period comprises an 8-week dose 
escalation period with dose escalation every 4 weeks followed by a 20-week maintenance period. 
The planned study duration for the individual participant will be approximately 35 weeks (including 
screening period). The study design is illustrated in Figure 4-1. 
Figure 4-1 
Study design 
 
4.2 
Scientific rationale for study design 
The primary objective is to establish non-inferiority on efficacy when measured by HbA1c (%) of 
semaglutide J s.c. against semaglutide B s.c. with a non-inferiority margin of 0.3%-points. This 
margin is considered acceptable as it is in line with the 'Guideline on clinical investigation of 
medicinal products in the treatment or prevention of diabetes mellitus' and within the range of 
previously approved applications.8 
Randomisation and double blinding are applied to minimise bias in the non-inferiority evaluation. 
An unbalanced randomisation (3:1) with a higher proportion of participants randomised to receive 
semaglutide J s.c. is applied in order to maximise the exposure, and thereby the number of 
observations available to evaluate any unexpected adverse clinical consequences related to 
semaglutide J s.c. 
The 28-week intervention period is sufficient for evaluation of the primary endpoint. A 5-week 
follow-up period (corresponding to roughly 5 times t1/2) is implemented to avoid drug interference 
in the anti-drug antibody assays. 
 
 
 
 
Semaglutide J
0.25 mg
Semaglutide J
0.5 mg
Semaglutide J
1 mg
Semaglutide B
0.25 mg
Semaglutide B
0.5 mg
Semaglutide B
1 mg
Week 0
Randomisation
Week 4
Dose escalation
Week 8
Dose escalation
Week 28
End of treatment
Week 33
End of study
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4.3 
Justification for dose 
Semaglutide s.c. 0.5 mg and 1.0 mg are currently approved for treatment of patients with T2D 
(Ozempic®). Participants will be initiated at a once-weekly dose of 0.25 mg and follow the 
approved fixed-dose escalation regimen, with dose increases every 4 weeks (to doses of 
0.5 mg/week and 1.0 mg/week), until the target maintenance dose of 1.0 mg is reached during the 
first 8 weeks after randomisation (i.e., at visit 5 or the first dosing date after visit 5).  
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 they have completed all periods of the 
study including the last visit. 
The primary endpoint is evaluated from visit 2 (week 0) to visit 10 (week 28). The primary 
completion date (PCD) is defined as the date of visit 10 (week 28) on which the last participant in 
the clinical study has an assessment for the primary endpoint. If the last participant is withdrawn 
early, the PCD is considered the date when the last participant would have completed visit 10 
(week 28). The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
the Food and Drug Administration Amendment Act (FDAAA) (Section 10.1.7). 
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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 participant’s medical records, including handing out 
participant information, as well as database review. Any pre-screening activities must be 
documented by the investigator. 
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. Aged 18-64 years (both inclusive) at the time of signing informed consent. 
4. Diagnosed with T2D mellitus ≥ 180 days before screening. 
5. Stable daily dose(s) ≥ 90 days prior to the day of screening of metformin ≥ 1500 mg or 
maximum tolerated or effective dose. 
6. HbA1c of 7.0-10.5% (53-91.3 mmol/mol) (both inclusive). 
For country specific requirements in Canada, please refer to Appendix 9 (Section 10.9). 
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Known or suspected hypersensitivity to study intervention(s) or related products. 
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 adequate contraceptive method, as defined in Appendix 4 (Section 10.4). 
4. Participation in any clinical study of an approved or non-approved IMP within 30 days before 
screening. 
5. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma.a 
6. Presence or historya of pancreatitis (acute or chronic). 
7. Renal impairment with estimated Glomerular Filtration Rate (eGFR) < 30 ml/min/1.73 m2 at 
screening. 
8. Impaired liver function, defined as alanine aminotransferase (ALT) ≥ 2.5 times or bilirubin >1.5 
times upper normal limit at screening. 
9. Inadequately treated blood pressure defined as systolic ≥180 mmHg or diastolic ≥110 mmHg at 
screening. 
10. MI, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 
days before screening. 
11. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at 
screening. 
12. Planned coronary, carotid or peripheral artery revascularisation. 
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13. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within 90 days before screening. However, short term insulin treatment for a 
maximum of 14 days and prior insulin treatment for gestational diabetes are allowed. 
14. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within 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 nondilated examination.  
15. 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. 
16. Use of any medication with unknown or unspecified content within 90 days before screening. 
17. Any disorder which in the investigator’s opinion might jeopardise participant’s safety or 
compliance with the protocol. 
aAs declared by the participant or reported in the medical records. 
5.3 
Lifestyle considerations  
5.3.1 
Meals and dietary restrictions  
 Participants must attend the visits fasting according to the flowchart (Section 1.2). 
 Fasting is defined as at least 6 hours prior to the visit (visit 2, 7 and 10) without food or liquids, 
except for water.  
 For end of trial visit (visit 11) fasting is defined as at least 2 hours prior to the visit without food 
or liquid, except for water. 
 If the participant is not fasting as required, the participant should be called in for a new visit 
within the visit window to have the fasting procedures done. 
5.3.2 
Tobacco use 
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, and any serious adverse event (SAE). 
A screen failure session must be performed in the randomisation and trial supplies management 
system (RTSM)/interactive web response system (IWRS). 
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 samples), re-sampling is allowed for the affected parameters. 
5.5 
Randomisation criteria 
Not applicable for this study. 
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6 
Study intervention(s) and concomitant therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), or medical 
device(s) intended to be administered to a study participant according to the study protocol. 
Trial product comprise IMP(s), including comparator(s), non-investigational medicinal product(s) 
(NIMP(s)) and medical devices. 
6.1 
Study intervention(s) administered 
Table 6-1 provides an overview of the study interventions.  
Table 6-1 
Study interventions 
Intervention/Arm name 
Semaglutide J  
Semaglutide B 
 
Intervention name 
Semaglutide J. 
Semaglutide B. 
Intervention type 
IMP, test product. 
 
IMP, reference product. 
 
Pharmaceutical form 
Solution for injection. 
Route of administration  
s.c. 
Medical device 
Not applicable. 
See ‘Packaging’ for device constituent. 
 
Trial product strength 
1.34 mg/mL (1.5 mL). 
Dose and dose frequency 
Visit 2-4: 
0.25 mg once-weekly (initiated at V2). 
Visit 4-5: 
0.5 mg once-weekly (initiated at V4). 
Visit 5-10: 
1.0 mg once-weekly (initiated at V5). 
Dosing instructions and 
administration  
s.c. (into the thigh, upper arm or abdomen). 
Sourcing 
Manufactured and supplied by Novo Nordisk A/S. 
 
Packaging 
 
1.5 mL PDS290 prefilled pen injector. 
The device constituent is not under investigation. 
 
Labelling 
Labelled and packaged by Novo Nordisk A/S. 
Labelled in accordance with Annex 13,9 local regulations and study requirements. 
 
Abbreviations: IMP = investigational medicinal product; s.c. = subcutaneous. 
The investigator must document that training in device was given to the participant verbally and in 
writing as directions for use (DFU) documents at the first dispensing visit (visit 2).  It must also be 
documented that verbal training in device was given at visit 4 and visit 6 (as specified in the 
flowchart; see Section 1.2). If the investigator finds it relevant, additional training and handout of 
DFUs can also be given at other visits during the study. Training is the responsibility of the 
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investigator or delegate. The investigator or designee must instruct the participant on how to 
manage the in-use time of the dispensed products. 
The investigator should remind participants of dosing instructions throughout the study, as 
applicable. A dose reminder card will be handed out to the participants from the first dispensing 
visit (visit 2) to visit 9, to remind the participant of the dose to be taken until next site visit. 
Approximately a week before the next scheduled visit, the investigator should contact the 
participant and remind them about when to administer the next dose according to Section 1.3 and a 
reminder for the same will be included in the participant’s diary as well (see flowchart; Section 1.2). 
Investigational medicinal products (IMP) 
The study interventions are listed in Table 6-1.  
Dosing instructions 
Participants will be instructed to inject the trial product subcutaneously once-weekly in the 
abdomen, thigh, or upper arm. The injection site can be changed without dose adjustment.  
Participants must be trained in handling the pen-injector when dispensed the first time and training 
must be repeated during the study as indicated in the flowchart (Section 1.2). The investigator may 
choose to observe the participant when administering the first dose. 
The injection can be administered at any time of the day irrespective of meals, but on the same day 
of the week. The day of weekly administration can be changed if necessary if the time between 
two doses is at least 2 days (≥48 hours) or in accordance with the local label. After selecting a new 
dosing day, once-weekly dosing should be continued. 
Visits with blood sampling for PK are planned with specific timing in connection with trial product 
administration. The timing of visits is optimised to ensure that the weekly fluctuation in PK can be 
characterised with population PK modelling. 
In order to ensure correct timing of PK sampling in relation to trial product administration, the visits 
after randomisation should be scheduled within the allowed visit window according to the PK 
flowchart (Section 1.3). Blood sampling should always be collected prior to trial product 
administration if the visit is planned on a dosing day. If blood sampling is not planned on a dosing 
day, it is important to perform the visit and the blood sampling within the allowed number of 
hours/days after dosing. Guidance for the timing of visits and blood sampling is outlined in 
Table 10-4. 
If the participant by mistake has administered trial product outside the ranges specified, the visit 
should be rescheduled (within the visit window). If this is not possible, Investigator should try to 
change the PK sample e.g. from a trough sample to a peak or a decline sample (whatever is feasible 
compared to when the dose was taken). 
Dose escalation 
Dose escalation to the target maintenance dose of semaglutide s.c. 1.0 mg should take place during 
the first 8 weeks after randomisation. All participants will initiate semaglutide s.c. 0.25 mg on the 
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day of randomisation (visit 2). Dose escalation of semaglutide s.c. should take place every 4 weeks 
after randomisation, as illustrated in Figure 4-1. The maintenance dose of 1.0 mg will be reached at 
week 8 and will continue for the remaining treatment duration. If a participant does not tolerate the 
designated target dose, the participant may stay at a lower dose level. This should only be allowed if 
the participant would otherwise discontinue trial product completely and if considered safe to 
continue trial product at a lower dose, as per the investigator’s discretion. 
Missed doses 
If a semaglutide s.c. dose is missed, it should be administered as soon as noticed, provided the time 
to the next scheduled dose is at least 2 days (≥48 hours). If a dose is missed and the next scheduled 
dose is less than 2 days (48 hours) away, the participant should not administer the missed dose. A 
missed dose should not affect the scheduled dosing day of the week. 
If ≥ 2 consecutive doses of trial product are missed, and if the participant does not meet any of the 
discontinuation criteria (Section 7.1), the participant should be encouraged to recommence the 
treatment if considered safe as per the investigator’s discretion. The trial product should be 
continued as early as the situation allows. The missed doses should not affect the scheduled dosing 
day of the week. The start dose for re-initiation of trial product is at the investigator’s discretion. In 
case of questions related to re-initiation of trial product, the investigator should consult 
Novo Nordisk global medical experts. If doses are missed, blood glucose should be more closely 
monitored if judged necessary by the investigator. 
Non-investigational medicinal products (NIMP) 
Antidiabetic background medication (metformin) and rescue medication are considered NIMP(s) 
and will not be supplied by Novo Nordisk.  
Auxiliary supplies including medical devices not under investigation 
Blood glucose (BG) meters will be provided by Novo Nordisk through a vendor while the other 
auxiliary supplies (Table 6-2) will be provided by Novo Nordisk. 
Table 6-2 
Auxiliary supplies 
Auxiliary supplies 
Details 
Needles 
Needles for PDS290 pen-injector. 
Details will be provided in the TMM.  
Only needles approved and provided by Novo Nordisk and with a maximum length of 
6 mm must be used for administration of trial product. 
DFU 
DFUs for PDS290 pen-injector. 
DFUs are not included in the dispensing unit and must be handed out separately. 
BG meter and related 
auxiliaries  
A FreeStyle Precision Neo/FreeStyle Optium Neo/Optium Xido Neo/Precision Xtra BG 
meter will be handed out at the randomisation visit (V2). Participants will be instructed in 
how to use the BG meter and the instructions will be repeated during the study as needed. 
Abbreviations: BG = blood glucose; DFU = direction for use; TMM = trial materials manual. 
The PDS290 pen-injector (device constituent) is used for administration of semaglutide and is a 
prefilled pen-injector which is not under investigation in this study. The PDS290 pen-injector is a 
dial-a-dose prefilled device integrated with a 1.5 mL cartridge (filled with 
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semaglutide 1.34 mg/mL). The PDS290 pen-injector for semaglutide 1.34 mg/mL can deliver the 
doses of 0.25 mg, 0.5 mg and 1.0 mg (dose dialled on pen-injector).  
Risk assessment has been conducted for the PDS290 pen-injector for semaglutide 1.34 mg/mL 
complying with EN International Organisation for Harmonisation (ISO) 14971:2019: Medical 
devices - Application of risk management to medical devices. A device risk assessment has been 
performed to ensure safe and accurate handling and dosing of semaglutide s.c. when using the 
PDS290 pen-injector in participants with T2D. All identified risks associated with using PDS290 
pen-injector for semaglutide 1.34 mg/mL 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 PDS290 pen-Injector for semaglutide 1.34 mg/mL in this study is 
therefore considered to be of nonsignificant risk. 
6.2 
Preparation, handling, storage and accountability 
Only participants enrolled in the study may use study intervention and only delegated site staff may 
supply study intervention. 
Each site will be supplied with sufficient study intervention for the study on an ongoing basis 
according to recruitment and randomisation. 
Instructions on how to use the PDS290 pen-injector will be provided in the DFU. 
For selected countries and if permitted by local regulations, the investigator may offer to send study 
intervention from the study site or pharmacy to the participant’s home by courier service. The 
process for sending study intervention from the study site or pharmacy to a participant’s home is 
described in the “Study site/pharmacy instruction for shipment of trial product to participant’s 
homes” document. This document contains detailed instructions for preparing, packaging, and 
setting up the pick-up of study intervention, handover of study intervention from the study site or 
pharmacy staff to the courier, required temperature monitoring of study intervention, delivery to 
and receipt of study intervention by the participant. The process for returning study intervention to 
the study site or pharmacy by courier is also described in this document. Investigators, study 
site/pharmacy staff and participants who will be involved in shipment of study intervention to the 
participant’s home will be adequately trained in this process. 
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that any discrepancies are reported and 
resolved before use of the trial products. 
All trial products must be stored in a secure, controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator and 
delegated site staff. 
The investigator must inform Novo Nordisk immediately if any trial product has been stored outside 
specified conditions. The trial product must not be dispensed to any 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 (TMM). 
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The investigator or designee is responsible for trial product accountability and record maintenance 
(i.e., receipt, accountability and final disposition records). Drug accountability must be performed 
by registering pen-injectors as returned either as used/partly used, unused or as lost. Drug 
accountability should also be performed in the RTSM/IWRS.  
The investigator or designee must instruct the participant in what to return at next visit. 
The investigator or designee must instruct the participant on how to manage the in-use time of the 
dispensed products. The in-use time can be found in the TMM and the labels of the trial products.  
 
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. 
Destruction of trial product must be documented in the RTSM/IWRS. 
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 by the site, 
and/or reconciled by the monitor, at the latest at closure of the site. 
Each single pen should be accounted for.  
 
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 TMM. 
6.3 
Measures to minimise bias: Randomisation and blinding 
Participants  will be screened and centrally randomised using an RTSM/IWRS and assigned to the 
next available treatment according to the randomisation schedule. Trial products will be allocated 
by the RTSM/IWRS and dispensed by the investigator at the study visits summarised in the 
flowchart (Section 1.2). Once the participant has been assigned a randomisation number, the 
number must not be re-assigned to another participant. 
This is a double-blind study in which participants, care providers and investigators are blinded to 
trial product allocation. 
To preserve the blinding of the current study in the event of interim evaluation, only a minimum 
number of Novo Nordisk personnel are allowed to see the randomisation table and treatment 
assignments before the study is completed. 
The RTSM/IWRS is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a participant’s trial product is warranted. Participant 
safety must always be the first consideration in making such a determination. 
If the investigator decides that unblinding is warranted, the investigator should make every effort to 
contact Novo Nordisk prior to unblinding a participant’s study intervention unless this could delay 
emergency treatment of the participant. 
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If a participant’s trial product is unblinded, Novo Nordisk (Global Safety department) must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation. The person breaking the blind must print the blind 
break confirmation notification generated by the RTSM/IWRS, sign and date the document. If 
RTSM/IWRS is not accessible at the time of blind break, the RTSM/IWRS helpdesk should be 
contacted. Contact details are listed in Attachment I. 
Unblinded participants may continue with trial product if there are no safety concerns at the 
discretion of the investigator. 
6.4 
Study intervention compliance 
Throughout the study, the investigator will remind the participants to follow the study procedures 
and requirements to encourage participant compliance. 
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 noncompliance 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; counting returned trial product, visual inspection of pens. 
 Review of diaries including self-measured plasma glucose (SMPG) profiles, semaglutide 
s.c. doses and hypoglycaemia. 
 Evaluating glycaemic control and adherence to the visit schedule. 
 Trial product start and stop dates will be recorded in the electronic case report form (eCRF). 
6.5 
Dose modification 
Deviations from the planned doses (see Table 6-1) are not allowed. Please refer to Section 6.1 for 
description of missed doses. 
In order to minimise the risk of gastrointestinal AEs the participants should follow the 
recommended dose escalation regimen described in Section 6.1. In case of tolerability issues, the 
dose of semaglutide s.c. can be adjusted as described in Section 6.1. 
6.6 
Continued access to study intervention after end of study 
When discontinuing study intervention, the participant should be transferred to a suitable marketed 
product at the discretion of the investigator. The long half-life of semaglutide must be taken into 
consideration when selecting antidiabetic treatment after discontinuation of study intervention.  
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/SAEs. 
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Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the participant. 
For more information on overdose, also consult the current version of the IB7 and any updates 
thereof. 
Overdoses of up to 4.0 mg of semaglutide s.c. in a single dose/in one week have been reported in 
clinical studies. The most commonly reported adverse reaction was nausea. All participants 
recovered without complications. In the event of overdose, appropriate supportive treatment should 
be initiated according to the participants’ clinical signs and symptoms. A prolonged period of 
observation and treatment for these symptoms may be necessary, taking into account the long 
half-life of semaglutide of approximately one week. 
Please consult the current version of the semaglutide (IB)7 and any updates thereof for more 
information on overdose of semaglutide s.c. 
6.8 
Concomitant therapy 
Any medication or vaccine that the participant is receiving at the time of screening visit (visit 1) or 
receives until end of study visit (visit 11) must be recorded along with: 
 Primary indication. 
 Dates of administration including start and stop dates and total daily dose. 
Changes in concomitant therapy must be recorded at each visit. If a change is due to an AE, then 
this must be reported according to Section 8.3. 
6.8.1 
Rescue medicine 
Intensification of background oral antidiabetic treatment and/or initiation of new 
antihyperglycaemic treatment, should be implemented at the discretion of the investigator in case of 
persistent hyperglycaemia. 
Rescue medication should be selected according to American Diabetes Association (ADA)/ 
European Association for the Study of Diabetes (EASD) guideline10,11 (excluding GLP-1 RAs, 
dipeptidyl peptidase-4 (DPP-4) inhibitors and amylin analogues). 
Participants that are prescribed rescue medication should continue to follow the protocol-specified 
visit schedule and stay on study intervention unless the investigator judge that it jeopardises 
participants’ safety. 
Rescue medication should be documented in medical records and reported on the concomitant 
medication form in the eCRF. 
The site will not supply any rescue medication but will be reimbursed, as long as the participant is 
participating in the study, if required, according to local requirements. 
 
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7 
Discontinuation of study intervention and participant 
discontinuation/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. 
If a participant discontinues study intervention, the participant should be transferred to a 
commercially available treatment, at the investigator’s discretion. 
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 study intervention.  
The study intervention must be discontinued, if any of the following applies for the participant: 
1. Safety concerns related to study intervention or unacceptable intolerability, as judged by the 
investigator. 
2. Confirmation of acute pancreatitis. 
3. Pregnancy. 
4. Intention of becoming pregnant. 
5. Simultaneous use of an approved or non-approved IMP in another clinical study. 
See the flowchart (Section 1.2) for data to be collected at the time of study intervention 
discontinuation (early discontinuation visit) and follow-up and for any further evaluations that need 
to be completed. 
The participants should continue with the remaining scheduled visits and assessments until the time 
of the originally scheduled ‘end of treatment’ visit (visit 10) and “end of study” visit (visit 11).  
All efforts should be made to have the participant attend at least the ‘end of treatment’ clinic visit 
containing the final data collection of primary and confirmatory secondary efficacy endpoints, and 
the “end of study” visit. 
If the participant does not wish to attend the scheduled clinic visits efforts should be made to have 
the remaining visits converted to phone contacts.  
The primary reason for discontinuation of study intervention must be specified in the eCRF, and 
final trial product accountability must be performed. Discontinuation of treatment must be made in 
the RTSM/IWRS. 
7.1.1 
Temporary discontinuation of study intervention 
The participant should adhere to the study intervention to the extent possible. Exceptions to this 
could be in the case of safety concerns or AEs, as judged by the discretion of the investigator. 
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In case of suspicion of acute pancreatitis, the study interventions should promptly be interrupted. 
Discontinuation of treatment should not be completed in RTSM/IWRS before diagnosis of acute 
pancreatitis is confirmed (according to the Atlanta criteria)12. Appropriate actions should be 
initiated. 
If acute pancreatitis is confirmed, the study interventions should not be restarted, and 
discontinuation of treatment must be made in RTSM/IWRS. If the Atlanta criteria are not fulfilled 
and thus, the suspicion of acute pancreatitis is not confirmed, study interventions may be resumed. 
If a participant has temporarily discontinued study interventions due to an AE or a safety concern, 
they are allowed to restart, unless any of the discontinuation criteria specified in Section 7.1 applies. 
The participant should follow the guide for missed doses in Section 6.1. Similarly, a participant who 
discontinues study interventions on their own initiative should be encouraged to resume the study 
interventions. 
Treatment discontinuation and treatment resume must be registered in RTSM/IWRS when a 
participant discontinues or resumes study intervention. 
7.1.2 
Rescue criteria 
Participants with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. To allow time for dose escalation to maximum dose and to observe the expected 
effect of treatment on glycaemic parameters, rescue criteria will be applied at week 12 and onwards. 
If any of the HbA1c values exceeds the limit outlined below and no intercurrent cause of the 
hyperglycaemia can be identified, a confirmatory HbA1c in the central laboratory should be 
obtained within 30 days. If the confirmatory HbA1c exceeds the value described below then the 
participant should be offered treatment intensification (rescue medication) at the discretion of the 
investigator and in accordance with the ADA/EASD guidelines10,11 (excluding GLP-1RAs, DPP-4 
inhibitors and amylin analogues). 
Rescue medication should be offered from week 12 to week 33 to: 
 Participants with persistent poor glycaemic control, as expressed by a stable HbA1c value 
above 8.5% (69 mmol/mol) that is confirmed within 30 days by the central laboratory and 
considered unacceptably high according to investigator’s assessment. Refer to Section 6.8.1 
for description of rescue medication. 
7.2 
Participant discontinuation/withdrawal from the study 
A participant may withdraw consent at any time at his/her own request. 
If a participant withdraws consent or is withdrawn by the investigator prior to randomisation, they 
will not be asked to have any follow-up assessments performed. The following data must be 
collected: Demography, 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 or is withdrawn by the investigator after randomisation, the 
investigator must ask the participant if they are willing, as soon as possible, to have assessments 
performed according to visit 10 and visit 11. See the flowchart (Section 1.2) for data to be collected. 
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Final trial product accountability must be performed even if the participant is not able to come to 
the site. Discontinuation of treatment must be made in RTSM/IWRS. The primary reason for 
discontinuation of study intervention should be specified in the end of IMP treatment form in the 
eCRF. 
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, they 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 their 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 eCRF. 
7.2.1 
Replacement of participants 
If a participant discontinues study intervention, withdraws consent or is withdrawn by the 
investigator, they will not be replaced. 
7.3 
Lost to follow-up 
A participant will be considered lost to follow-up if they repeatedly fail 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. 
 Should the participant continue to be unreachable, the participant will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’. 
 Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved 
in any attempts to collect vital status information. 
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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 assessments: 
 Blood sampling (especially when collection fasting blood samples) 
 Other assessments 
A visit-specific diary for collection of detailed hypoglycaemic episodes, dosing history and AEs 
must be handed out at each site visit from randomisation (visit 2) to end of treatment (visit 10) 
included. 
Review of diaries, laboratory reports, etc., must be documented in the source documents or the 
participant’s medical record. If clarification of entries or discrepancies in the diary 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. 
Repeat samples may be taken for technical issues and unscheduled samples or assessments may be 
taken for safety reasons. Please refer to Appendix 2 (Section 10.2) for further details on laboratory 
samples. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2). 
8.1.1 
Clinical efficacy assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart (Section 1.2) and the laboratory manual. 
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8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart (Section 1.2).  
Medical history is a medical event that the participant experienced prior to the time point from 
which AEs are collected.  
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. 
The following concomitant illness/medical history should be recorded in the eCRF: 
 T2D including date of diagnosis. 
 History of cardiovascular disorders and procedures. 
 History of dyslipidaemia. 
 History of kidney diseases. 
 History of eye diseases. 
 History of neuropathy. 
 History of gallbladder diseases and procedures. 
 History of pancreatic diseases. 
 Other relevant concomitant illness/medical history including malignant neoplasms and 
coronavirus disease 19 (COVID-19). 
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. 
8.2.1 
Physical examinations 
A physical examination will include assessments of the: 
 Head, ears, eyes, nose, throat, neck, 
 Respiratory system, 
 Cardiovascular system, 
 Gastrointestinal system including mouth, 
 Musculoskeletal system, 
 Central and peripheral nervous system, 
 Skin. 
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 AEs, see 
Appendix 3 (Section 10.3). 
Body measurements (e.g., height and weight) will also be measured and recorded as specified in the 
flowchart (Section 1.2). 
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Height will be measured and recorded at the screening visit (visit 1). Body weight will be measured 
and recorded according to the flowchart (Section 1.2).  
 Body weight should be measured in kilograms (kg) or pounds (lb) in participants wearing only 
light clothing. Body weight will be recorded to one decimal place, with a precision of 1/10 unit, 
(e.g. 45.2 kg / 137.2 lb). 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 ½ cm or ¼ inch. 
From the body weight and height, the BMI will be calculated in the eCRF at visit 1 and recorded in 
the participant’s medical records. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
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 the time points mentioned in the flowchart 
(Section 1.2).  
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 
eCRF. The eCRF will calculate the mean of the last 2 measurements. 
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 eCRF. The eCRF will 
calculate the mean of the last 2 measurements. 
8.2.3 
Eye examination 
Participants with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible (Section 5.2) as this indicates retinopathy that has recently progressed to a level that 
requires intervention or is approaching intervention but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist or another suitably qualified health 
care provider (e.g., optometrist) must be available and evaluated by the investigator before 
randomisation to assess eligibility. The eye examination should be performed as a fundus 
photography (e.g., 2-field 60 degree or better, colour or red-free) or by slit-lamp bio-microscopy 
examination (e.g., using a precorneal or corneal contact lens examination). Pharmacological 
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pupil-dilation is a requirement unless using a digital fundus photography camera specified for 
non-dilated examination. 
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. 
After randomisation an eye examination must be performed according to above at visit 10 as per 
protocol flowchart (Section 1.2). The investigator should indicate the outcome of each eye 
examination. 
Eye examinations required at visit 10 can be performed within 3 weeks prior to visit 10, provided 
no clinical symptoms suggestive of eye disease have occurred in the meantime. Results should be 
available for evaluation at visit 10. The investigator should indicate the outcome of each eye 
examination. Relevant findings prior to randomisation must be recorded as concomitant 
illness/medical history. Relevant findings occurring after randomisation should be reported as an 
AE, please refer to Section 8.3 and Appendix 3 (Section 10.3) for details. Participants who 
discontinued treatment should also have their eye examinations performed in relation to the end of 
treatment visit (visit 10). 
8.2.4 
Self-measured plasma glucose  
Plasma glucose (PG) should always be measured using a BG meter and recorded in the diary and 
eCRF when a hypoglycaemic episode is suspected. For more information on reporting of 
hypoglycaemic episodes, see Appendix 7 (Section 10.7). 
When using BG meters, the measurement is performed with capillary blood calibrated to plasma 
equivalent glucose values, i.e., the measurement is performed on blood while the value is reported 
as plasma; therefore ‘PG’ or ‘SMPG’ are the terms to use as descriptor for the value. 
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 record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
transcribed into the eCRF during or following the contact. If obtained via phone, and a discrepancy 
is later detected, the values in the eCRF must be corrected. If clarification of entries or 
discrepancies in the diary 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. 
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Occasional review by the investigator of the BG meter values stored in the memory of the BG meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the study database. 
8.2.5 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the protocol flowchart (Section 1.2) 
8.2.6 
Pregnancy testing  
Women of childbearing potential (WOCBP) should only be included after a negative, highly 
sensitive urine pregnancy test (refer to Appendix 2 (Section 10.2)) at visits 1 and 2. Urine 
pregnancy test will also be conducted at visit 10 and 11, according to flowchart (Section 1.2). 
Pregnancy testing should also be performed whenever a menstruation is missed or when pregnancy 
is otherwise suspected. The results of the urine pregnancy tests should be entered in the eCRF. 
Additional pregnancy testing should be performed during the treatment period, if required locally, 
refer to Appendix 9 (Section 10.9). 
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. Some AEs require additional data collection 
on a specific event form. The relevant events are listed below in Table 8-1, together with other 
events requiring collection of additional information. 
Table 8-1 
AEs requiring additional data collection and other events requiring additional 
data collection 
Event type  
AE requiring additional 
data collection 
Other event requiring collection of 
additional information 
Medication error  
X 
 
Misuse and abuse 
X 
 
Acute gallbladder disease 
X 
 
Hypersensitivity reactions 
X 
 
Hypoglycaemic episodes  
 
X 
 
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. 
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8.3.1 
Time period and frequency for collecting AE information 
All AEs and SAEs must be collected from the first administration of study intervention under 
clinical investigation and until the end of study 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 study intervention under clinical 
investigation, 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 or designee within 24 hours, and the investigator must 
submit any updated SAE data to Novo Nordisk or designee 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 IMP under investigation or related to study participation, the investigator must promptly 
notify Novo Nordisk. 
8.3.2 
Method of detecting AEs  
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 
nonleading verbal questioning of the participant is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs  
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 SAEs 
Prompt notification by the investigator to Novo Nordisk or designee 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, institutional review board (IRB)/institutional ethics committee 
(IEC), and investigators. This also includes suspected unexpected serious adverse reactions 
(SUSAR). 
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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 IB 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 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 and pharmacodynamics  
8.4.1 
Pharmacokinetics 
Plasma samples will be used to evaluate the pharmacokinetics of semaglutide J s.c. as well as 
semaglutide B s.c. The date, exact time and dose of all the administrations of trial product (dosing 
history) will be recorded in the diary along with the location of the injection site (see flowchart, 
Section 1.2). Site will transfer the information from the diary to the eCRF. The blood sampling for 
PK analyses will be collected in accordance with Section 1.3 and Table 10-4. 
 Single-blood samples for measuring plasma concentration of semaglutide J s.c. and 
semaglutide B s.c. will be drawn on visits specified in the flowchart.  
 The exact timing of obtaining the pharmacokinetic (PK) sample must be recorded on the 
laboratory form. 
 The purpose of measuring plasma semaglutide levels is to conduct exposure-response, to 
evaluate the dose response and the adherence to the treatment.  
 Blood samples for PK assessments must be collected, handled and shipped according to the 
description in the laboratory manual supplied by the central laboratory. The bioanalysis of 
semaglutide PK will be performed by a special laboratory. Semaglutide PK samples will be 
stored at the special laboratory responsible for PK until final clinical study report (CSR) in case 
Novo Nordisk requests further analysis of the PK samples. Details of the bioanalysis will be 
outlined in a bioanalytical study plan issued by the special laboratory. 
8.4.2 
Pharmacodynamics 
Not applicable for this study. 
8.5 
Genetics 
Not applicable for this study. 
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8.6 
Biomarkers 
Not applicable for this study. 
8.7 
Immunogenicity assessments  
Blood samples will be drawn pre-dosing for measurement of serum anti-semaglutide antibodies 
according to the flowchart (Section 1.2). For antibody samples collected at visit 2 and visit 11, the 
participant must be fasting (For details, see Section 5.3.1). 
The samples will be analysed by a special laboratory assigned by Novo Nordisk, please refer to 
Attachment I. Confirmed antibody positive samples will be further characterised for cross reactivity 
to native GLP-1 and titrated to estimate the magnitude of the response. Samples taken at visit 11 
which are positive for anti-semaglutide antibodies will be further characterised for in vitro 
neutralising effect towards semaglutide s.c. In addition, samples taken at visit 11 which are positive 
for cross reactivity to native GLP-1 will be further analysed for in vitro neutralising effect towards 
native GLP-1. The in vitro neutralising antibody assays will be performed by Novo Nordisk. 
The investigator will not be able to review the results of antibody measurement during the study as 
this may not be performed until after LPLV and the results will only be available after DBL. 
8.8 
Human biosamples for future research  
Not applicable for this study. 
8.9 
Health economics 
Not applicable for this study 
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9 
Statistical considerations  
The statistical analysis plan (SAP) will be finalized prior to the partial (interim) database lock 
(DBL) and it will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
9.1 
Statistical hypotheses 
Non-inferiority will be declared if the following two one-sided null hypothesis is rejected. Let the 
treatment difference of change from baseline to week 28 in HbA1c between semaglutide J s.c. and 
semaglutide B s.c. be defined as μ = “change in HbA1c for semaglutide J s.c.” minus “ change in 
HbA1c for semaglutide B s.c.”.  
 H0: µ ≥ 0.3%-points against Ha: µ < 0.3%-points.  
The non-inferiority margin of 0.3%-points is justified in Section 4.2.  
9.1.1 
Multiplicity adjustment 
The type 1 error probability will be controlled at 2.5% under the aforementioned one-sided null-
hypothesis, and as the study has only one primary analysis, and no confirmatory secondary 
analyses, adjustment for multiplicity is not applicable. 
9.2 
Analysis sets 
The following participant analysis sets are defined:  
Participant analysis set (PAS) 
Description 
Full analysis set (FAS) 
All randomised study participants. Participants will be included in the analyses 
according to the randomised intervention. 
Safety analysis set 
All participants who are exposed to study intervention. Participants will be 
included in the analyses according to the intervention they actually received for 
the majority of the period being treated. 
 
The following data points sets are defined: 
Defined data points set (DPS) 
Description 
DPS1 – in study 
All observed data points from randomisation until the first date of: 
end of study visit (visit 11) or 
death or 
withdrawal of informed consent or 
last contact as defined by investigator for participants that are lost to follow up. 
DPS2 – on treatment 
All observed data points from first drug date until the first date of: 
end of DPS1 – in study or 
the end of study visit (visit 11) or 
last trial product administration +42 days. 
DPS3 – on treatment without 
rescue 
All observed data points from first drug date until the first date of: 
initiation of rescue medication or 
last trial product administration +7 days 
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The FAS and DPS1 are used to estimate the primary estimand (defined in Section 3.1.1). 
The FAS and DPS3 are used to estimate the additional estimand (defined in Section 3.1.1). 
The safety analysis set and DPS2 are used to present safety data with a long lag-time (AEs, 
hypoglycaemic episodes, anti-semaglutide antibodies and eye examination). 
Safety analysis set and a modified DPS2 are used to present safety data with an acute onset (vital 
signs, laboratory assessments, physical examination). For these summaries, the DPS2 is modified 
by having an end date at date of last trial product administration +7 days or date of end of DPS1, 
whichever occurs first.  
9.3 
Statistical analyses 
9.3.1 
General considerations 
A baseline assessment will be defined as the most recent measurement at randomisation. Missing 
baseline values will be imputed by the average of the non-missing baseline values. 
The frequency and timing of intercurrent events as defined in Section 3.1.1 will be presented 
descriptively. 
9.3.2 
Primary endpoint analyses 
9.3.2.1 
Primary estimand analysis 
The primary estimand, presented in Section 3.1.2, will be estimated based on the FAS and DPS1. 
Missing end of treatment data will be imputed using multiple imputation (MI) assuming that 
missing data are missing at random (MAR). The imputation will be performed, under the non-
inferiority null-hypothesis, by imputing missing end of treatment data separately within each to the 
four groups defined by randomised treatment and treatment status at end of treatment: 
 semaglutide B s.c. and on-treatment at end of treatment, 
 semaglutide B s.c. and off-treatment at end of treatment, 
 semaglutide J s.c. and on-treatment at end of treatment, 
 semaglutide J s.c. and off-treatment at end of treatment. 
For each group an analysis of covariance (ANCOVA) with region as a factor and baseline HbA1c as 
a covariate will be fitted to the observed end of treatment values. The estimated location and 
dispersion parameters will then be used to impute 500 values for each participant with missing end 
of treatment data. Furthermore, for participants randomised to semaglutide J s.c. a penalty of 0.3, 
corresponding to the non-inferiority margin, is added to the imputed values. 
The 500 complete datasets will be analysed using an ANCOVA with randomised treatment and 
region as factors and baseline HbA1c as a covariate. Rubin’s rule13 will then be applied to combine 
these estimates and draw inference. 
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In case of sparse data, defined as less than 5 participants with available end of treatment data, in 
some groups, the imputation model will be thinned by region. If this is not sufficient the imputation 
will be based on participants randomised to the same treatment regardless of treatment status using 
the imputation model region as a factor and baseline HbA1c as a covariate. If this is still not 
sufficient, the imputation model may be thinned again in the aforementioned order. 
9.3.2.1.1 
Sensitivity analysis 
A two-way tipping point sensitivity analysis will be performed by repeating the ANCOVA 
described in Section 9.3.2.1. However, prior to analysis, penalties are added to the imputed end of 
treatment values in both intervention arms simultaneously. A range of penalties will be explored for 
both treatment groups, and the impact on the conclusion will be assessed through a contour plot of 
the p-values. This sensitivity analysis evaluates the robustness of the non-inferiority conclusions to 
violations in missing data assumptions in both intervention arms.  
9.3.2.2 
Additional estimand  
The additional estimand, presented in Section 3.1.1, will be estimated based on the FAS and DPS3. 
Missing end of treatment data will be imputed using multiple imputation (MI) assuming that 
missing data are missing at random (MAR). The imputation will be performed separately within 
each treatment group. First, intermittent missing values are imputed using a Markov Chain Monte 
Carlo (MCMC) method, to obtain a monotone missing data pattern, generating 500 complete data 
sets. Secondly, a sequential conditional linear regression approach for imputing monotone missing 
values will be implemented starting with the first visit after baseline and sequentially continuing to 
the last planned visit. The imputation model will include region as a factor and baseline and post-
baseline HbA1c values observed prior to the visit in question as covariates. 
The 500 complete datasets will be analysed using an ANCOVA with randomised treatment and 
region as factors and associated baseline HbA1c as a covariate. Rubin’s rule13 will then be applied to 
combine the estimates and draw inference. 
9.3.2.2.1 
Sensitivity analysis 
A two-way tipping point sensitivity analysis as described in Section 9.3.2.1.1 will be performed. 
9.3.3 
Secondary endpoint analyses 
9.3.3.1 
Secondary supportive endpoints 
9.3.3.1.1 
Change in body weight (kg) 
Primary estimand 
A similar analysis as described in Section 9.3.2.1 will be performed, but with values of body weight 
instead of HbA1c, and where no penalty (or rather a penalty of 0, corresponding to a superiority test) 
is added to imputed values for participants that are randomised to semaglutide J s.c. 
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Additional estimand 
A similar analysis as described in Section 9.3.2.2 will be performed, but with values of body weight 
instead of HbA1c. 
9.3.3.1.2 
Number of treatment-emergent AEs 
For details on analyses of number of treatment emergent AEs, please refer to the SAP. 
9.3.3.1.3 
Anti-semaglutide antibodies 
For details on analyses of anti-semaglutide antibodies, please refer to the SAP. 
9.3.4 
Exploratory endpoints analysis 
Not applicable for this study.  
9.3.5 
Safety analyses 
The AEs will be summarised by treatment arm by number of participants experiencing at least one 
event, proportion of participants in the safety analysis set experiencing at least one event, the 
number of events, and the rates of events (number of events per person-years of exposure). 
The occurrence of anti-semaglutide antibodies (positive/negative) will summarised descriptively. 
This will be supported by a listing on anti-semaglutide antibody levels. 
For further details on summaries of safety, please refer to the SAP. 
9.3.6 
Other analyses 
Pharmacokinetic and/or pharmacodynamic modelling 
The 8 PK samples for each participant will be used to fit a 1-compartment population PK model. In 
the visit schedule, 3 PK visit window types have been defined (see Table 10-4) ensuring that PK 
sampling times relative to dosing times are distributed across the weekly dosing interval, allowing 
for estimation of the absorption rate, the volume of distribution, and the clearance rate for each 
participant in the population PK model, and from this Cmax, Cmin and Cavg will be estimated for each 
participant. Lastly, a comparison of Cmax, Cmin and Cavg between semaglutide J s.c. and 
semaglutide B s.c. will be made. 
Additional population PK/PD exposure-response analyses may be included for exploratory 
pharmacodynamic analysis as needed. 
 
The modelling will include data from all enrolled participants that were exposed to semaglutide s.c. 
in this study and might be performed as a meta-analysis. Actual dose, date, time and injection site of 
all the administrations of trial product before PK sampling will be registered in the eCRF and used 
in the analysis, together with actual time point for PK sampling. The analysis will be further 
specified in a modelling analysis plan (MAP) that is to be prepared before unblinding at the partial 
(interim) database lock. The modelling analyses will be performed by Pharmacometrics at Novo 
Nordisk A/S and will be reported separately from the CSR. 
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9.4 
Interim analysis 
This study will be subject to a partial (interim) database lock (DBL) at the end of the treatment 
period for all participants, i.e. after the date of the last participant last treatment (LPLT) visit. A full 
DBL will be performed, as per the usual procedures, after last participant last visit. The partial DBL 
is implemented to allow for an early submission to Agency and thereby securing the stable supply 
of the semaglutide molecule to meet the current high demand. Novo Nordisk employees not 
involved in data cleaning will become unblinded to potentially both participant level data and 
comparative results at the time of the partial database lock, whereas participants and investigators 
will remain blinded until after last participant last visit (LPLV). All efficacy analyses will be 
performed based on the data from the partial DBL and analysis of safety will primarily be based on 
the full DBL. No efficacy assessments are collected after LPLT and in turn the efficacy results 
cannot be biased by the early unblinding. The potential impact on safety is considered negligible, as 
most participants will have completed the follow-up visit at the time of the partial DBL. 
9.5 
Sample size determination 
The study is designed to have a marginal power of at least 80% of confirming a non-inferior effect 
of semaglutide J s.c. against semaglutide B s.c. on change from baseline to week 28 in HbA1c 
(%-point). 
The power calculation is based on a 1-sided t-test with a significance level of 0.025, a 3:1 
randomisation, an expected treatment difference (TD) of 0%-points and standard deviation (SD) of 
0.9%-points. Under these assumptions 380 participants (285:95) are required to be randomised, and 
the actual power is 80.1%. 
The powers sensitivity to number of participants is show in Figure 9-1. The powers sensitivity to 
assumed treatment difference and standard deviation is sown in Table 9-1 
Figure 9-1 
Power sensitivity to number of participants 
 
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Table 9-1 
Power sensitivity to treatment effect and standard deviation assumptions 
TD\SD 
0.85 
0.9 
0.95 
1 
0.01 
0.867 
0.826 
0.784 
0.742 
0 
0.844 
0.801 
0.758 
0.714 
-0.01 
0.819 
0.774 
0.729 
0.685 
 
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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 
Helsinki14 and applicable International Council of Harmonisation (ICH) Good Clinical Practice 
(GCP) Guideline15 
 Applicable laws and regulations 
The protocol, informed consent form, IB (as applicable) and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC and reviewed and approved by the IRB/IEC 
before the 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 
For country specific requirements in US and Slovakia, please refer to Appendix 9 (Section 10.9). 
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. 
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For US sites: Verification under disclosures per Code of Federal Regulations (CFR) of Financial 
Conflict of Interest. 
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 
GCP15 guidelines, Declaration of Helsinki,14 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  
A separate informed consent form intended for a male partner of a female participant in case of an 
abnormal pregnancy or child born with health problem is available for this study 
(Appendix 4 (Section 10.4)). 
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. 
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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 
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 CSR. 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. 
10.1.7 
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,14 the International Committee of Medical Journal Editors (ICMJE),16 the FDAAA,17 
European Commission Requirements1, 18, 19 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 for transparency, some countries require public 
disclosure of investigator names and their affiliations. 
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10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
Novo Nordisk or designee is responsible for the data management of this 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. 
All participant data relating to the study will be recorded on eCRFs unless transmitted electronically 
to Novo Nordisk or designee (e.g., laboratory and diary 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 eCRF is revoked or the 
eCRF is temporarily unavailable:  
 AE forms  
 Safety information forms  
 Technical complaint forms  
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF 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 eCRF, the eCRF must be signed and dated again by the investigator. 
The investigator must ensure that data is recorded in the eCRF 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 
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 eCRF 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 GCP15, and all applicable regulatory requirements, evaluating the adequacy of 
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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 CSR. 
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the study database. 
10.1.9 
Source documents 
All data entered in the eCRF must be verifiable in source documentation other than the eCRF. 
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 
The original of the completed diaries must not be removed from the site, unless they form part of 
the CRF and a copy is kept at the site. 
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 from source documents must be consistent with the source 
documents, or the discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records. Also, current medical records must be available. 
It must be possible to verify 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 can be found in a source document agreement at each 
site. There will only be one source document defined at any time for any data element. 
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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, 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. 
For country specific requirements in Canada and US, please refer to Appendix 9 (Section 10.9). 
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. 
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 they have 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 
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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 they move or retire), 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. 
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. 
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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 investigator will be appointed by Novo Nordisk to review and sign the CSR (signatory 
investigator) 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 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the study concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.20 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication. 
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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, Table 10-2, Table 10-3 and Table 10-4 will be performed by the 
central laboratory, unless otherwise noted. 
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 lab will communicate to the investigator abnormal values of parameters not requested in 
the protocol but identified by the laboratory equipment and/or their processes according to their 
laboratory SOPs. 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. 
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 end of study or no later than at finalisation of 
the CSR. 
For haematology samples (differential count) where the test result is not normal, a part of the 
sample may be kept for up to two years or according to local regulations. 
Laboratory results that could unblind the study will not be reported to the sites until the study has 
been unblinded.  
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism  
 
Assessments performed at V1, V2, V3, 
V4, V5, V6, V7, V8, V9, and V10 
unless otherwise indicated 
 Fasting plasma glucosea (V2, V7, V10) 
 HbA1c  
Notes: 
V – visit 
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)). 
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Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory assessments 
Parameters 
Haematology 
 
Assessments performed at V1 and V10  
 Basophils  
 Eosinophils 
 Erythrocytes 
 Haematocrit 
 Haemoglobin 
 Leucocytes 
 Lymphocytes  
 Monocytes  
 Neutrophils  
 Thrombocytes 
Biochemistrya 
 
Assessments performed at V1 and V10  
 Alanine Aminotransferase (ALT) 
 Alkaline phosphatase 
 Amylase 
 Aspartate Aminotransferase (AST) 
 Bilirubin 
 Creatinine 
 Lipase 
 Potassium 
 Sodium 
 Urea 
Pregnancy 
 Testingb 
 
Assessments performed at V1, V2, V10 
and V11  
 Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test  
Other tests 
 
Assessment performed at V1 and V10 
 eGFR calculated by the central laboratory based on the creatinine value 
using the CKD-EPI equation 
Antibodiesc,d 
 
Assessments performed at V2, V4, V5, 
V6, V10 and V11 unless otherwise 
indicated 
 Anti-semaglutide Antibody Screening (% B/T) 
 Anti-Semaglutide Antibody Confirmation (Positive/Negative) 
 Anti-semaglutide Antibodies level (Titer)  
 Antibodies cross reacting with native GLP-1 (Positive/Negative) 
 Semaglutide AB (neutralising effect) (Positive/Negative) (only at V11) 
 Antibodies neutralising native GLP-1 (Positive/Negative) (only at V11) 
Notes: 
V – visit 
aDetails of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix 3 (Section 10.3) (Hy’s Law) and Protocol Section 7.1 ‘discontinuation of study 
intervention’.  
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 All the analyses will be performed by a laboratory contracted by Novo Nordisk, with the exception of neutralising 
antibodies assessment, which will be performed by Novo Nordisk laboratory.  
d Results will not be provided to the investigator, as these results will not be used for any clinical evaluation during 
the study. 
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Table 10-3 
Protocol-required PK assessments 
Laboratory assessments 
Parameters 
Pharmacokineticsa, b  
 
Assessments performed at V3, V4, V5, 
V6, V7, V8, V9, V10 and V11  
Semaglutide plasma concentrations 
Notes: 
V – visit 
a Analysis performed by special laboratory contracted by Novo Nordisk 
b Results will not be provided to the investigator, as these results will not be used for any clinical evaluation during the 
study. 
 
Table 10-4 
Timing of visits and PK blood sampling 
Visit 
Timing of visit 
3 
24 to 71 hours after dosing (from 1 to 3 days after dosing): Peak 
4 
Prior to treatment administration on a planned dosing day: Trough  
5 
24 to 71 hours after dosing (from 1 to 3 days after dosing): Peak 
6 
Prior to treatment administration on a planned dosing day: Trough  
7 
24 to 71 hours after dosing (from 1 to 3 days after dosing): Peak 
8 
96 to 144 hours after dosing (from 4 to 6 days after dosing): Decline 
9 
Prior to treatment administration on a planned dosing day: Trough 
10 
24 to 71 hours after dosing (from 1 to 3 days after dosing): Peak 
11 
No specific requirement. 
 
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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 AE 
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 AEs: 
 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 an SAE 
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. 
 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 
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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 ALT or aspartate aminotransferase (AST) >3x UNL 
and total bilirubin >2x UNL where no alternative aetiology exists (Hy’s law) 
10.3.3 
Description of AEs 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. 
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 dispensing unit number (DUN) is not considered a medication error 
unless it results in administration of wrong drug. 
 wrong route of administration, such as intramuscular instead of subcutaneous 
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 accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the 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. 
Acute gallbladder disease 
Events of symptomatic acute gallbladder disease (including gallstones and cholecystitis). 
Hypersensitivity reactions 
Events of hypersensitivity reactions. 
Other events requiring collection of additional information 
Hypoglycaemic episodes 
All hypoglycaemic episodes must be recorded on a hypoglycaemic episode form. If the 
hypoglycaemic episode fulfills the criteria for an SAE, then in addition to the hypoglycaemic 
episode form, an AE form and a safety information form must be filled in. One AE form and safety 
information form can cover several hypoglycaemic episode forms, if the participant has not 
recovered between the episodes. 
10.3.4 
Recording and follow-up of AE and/or SAE 
10.3.4.1 
AE and SAE recording 
The investigator will record all relevant AE/SAE information in the eCRF. 
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 
subject ID, must be redacted on the copies of the source documents before submission to Novo 
Nordisk. 
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For all nonserious 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: if an AE is considered to have a causal 
relationship with a Novo Nordisk marketed product used as 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 diseases, 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 IB for the assessment. For each AE/SAE, the investigator must 
document in the medical records that they have reviewed the AE/SAE and has provided an 
assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator always 
makes an assessment of causality for every event before the initial transmission of the SAE 
data. 
The investigator may change his/her opinion of causality, in light of follow-up information, and 
update the causality assessment in the eCRF. 
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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 they 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 AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g., severe hypersensitivity reactions, Hy’s 
law). This may include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
New or updated information should be recorded in the eCRF. 
10.3.5 
Reporting of SAEs  
AE and SAE reporting via eCRF 
Relevant forms must be completed in the eCRF. 
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 
 Both forms must be signed within 7 calendar days after first knowledge by the investigator 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
10.4.1 
Definitions 
Women 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 needed for male participants as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use methods 
of contraception consistently and correctly. Table 10-5 lists the highly effective methods of 
contraception allowed. Local regulations may apply, see Appendix 9 (Section 10.9). 
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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 10-5 
Highly effective contraceptive methods allowed21 
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 
 Vasectomised partner 
Vasectomised 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 (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
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. 
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 adverse event in connection with 
pregnancy or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. If relevant, consider adding ‘gestational’, ‘pregnancy-related’ or a similar term when 
reporting the AE/SAE. 
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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 
study intervention.  
 
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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 study interventions (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 eCRF within: 
 24 hours if related to an SAE 
 5 days calendar for all other technical complaints 
If the eCRF 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 eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF. 
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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 
Remaining PK samples (back-up samples and/or residual samples after PK analyses) may be 
retained for later re-analysis. The analyses will be performed by Novo Nordisk or a laboratory 
assigned by Novo Nordisk. The samples will be retained only until CSR finalisation after which 
they will be discarded.  
Residual antibody samples may be retained for later re-analysis and/or further characterisation of 
antibody responses towards drug if required by health authorities or for safety reasons. The analyses 
will be performed by Novo Nordisk or a laboratory assigned by Novo Nordisk. Results will be 
documented independently and reported separately from the CSR. The samples will be retained 
until marked authorisation, but no longer than 15 years. 
Novo Nordisk will ensure that third party collaborators live up the regulations on data protection, 
see Appendix 1 (Section 10.1.5). 
The participant may request the stored antibody samples to be destroyed by withdrawing the 
designated informed consent at any timepoint during and after the study. For antibody samples that 
have already been analysed, the results can still be used for scientific research and will not be 
removed from the datafile. 
 
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Repeated PG measurements and/or symptoms will by default be considered as one hypoglycaemic 
episode until a succeeding PG value is ≥ 3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved and should be reported as only one hypoglycaemic episode. In case of several low PG 
values within the hypoglycaemic episode, the lowest value is the one that will be reported as the PG 
value for the hypoglycaemic episode, but the start time of the episode will remain as the time for the 
first low PG value and/or symptom. The remaining values will be kept as source data. 
If the severity of a hypoglycaemic episode changes, only one hypoglycaemic episode will be 
reported, reflecting the most severe degree of hypoglycaemia. 
Regarding the question: “To feel better, did you need help to get a sugary drink, food, or 
medicine?” the investigator must instruct the 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.27 
Additional information (e.g., description of symptoms, alleviation of symptoms, seizure or coma) in 
relation to severe hypoglycaemic episodes must be recorded in the hypoglycaemic episode eCRF. 
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. 
For low PG values for hypoglycaemic episodes with incomplete reporting information: 
1. If a hypoglycaemic episode form in the diary is not completed by the participant within 7 
calendar days of the PG measurement, the episode should be described in the source documents 
and reported by the investigator on a hypoglycaemic episode eCRF with as much information as 
possible. If the participant did not need help to get a sugary drink, food, or medicine, Novo 
Nordisk will only ask for start date due to recall bias.28, 29 
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: Mitigations to ensure participant safety and data integrity during an 
emergency situation  
10.8.1 
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 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 10-7 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. 
Sites should comply with local regulations, requirements and/or guidelines if they are issued. 
10.8.2 
Visits 
Screening (visit 1) and randomisation/baseline (visit 2) 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 6, 10 and 11 should be performed as on-site visits, if in any way possible. If not, assessments 
can be conducted remotely (video, phone or similar) or as home or off-site visits. 
On-site visits (visits 3, 4, 5, 7, 8 and 9) can be converted to remote visits (video, phone or similar) 
or home or off-site visits. 
If the end of treatment visit (visit 10) cannot be performed on-site, using remote (video, phone or 
similar) or home or off-site visits within the given visit window, the visit window for the 
assessment can be extended for up to 3 months. 
At each visit, the investigator must indicate in the eCRF how the visit was performed and specify 
the reason for the preferred assessment method. 
10.8.3 
Assessments 
Assessments used for safety or the primary endpoints (i.e., HbA1c and treatment emergent AEs) 
should be prioritised. The preferred order for the method of assessment is: on-site, home, video, 
phone visit. Specifications regarding how to perform these assessments using remote visits or as 
home visits will be provided by Novo Nordisk. Specifications will include training for raters 
performing remote assessments and adoption of modifications for equivalent administration of 
assessments using remote visits (video, phone or similar). 
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Local laboratories or diagnostic facilities can be used for haematology, biochemistry, fasting plasma 
glucose, HbA1c and eye examination at the investigator’s discretion if on-site visits are not possible 
or in case of temporary lockdown of the central laboratory. Only findings meeting the definition for 
an AE (refer to Appendix 3 (Section 10.3)) should be reported in the eCRF.  
Home measurements of weight, vital signs and pregnancy test 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 eCRF.  
If the assessments indicated in Table 10-7 cannot be performed as on-site visits, remote visits or be 
analysed at a local laboratory or diagnostic facility, they should be performed at the first possible 
timepoint following the originally scheduled visit in agreement with Novo Nordisk. 
10.8.4 
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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10.9 
Appendix 9: Country-specific requirements 
For Canada: 
 5.1 Inclusion criteria: PK studies: Males must not have donated blood (450 mL) within 56 
days of PK draws totalling 450mL; Females 84 days. 
 10.01.10 Retention of clinical study documentation: Part C, Division 5 of the Food and Drug 
Regulations (C.05.012) requires a 25-year retention period 
For United States: 
 10.01 Appendix 1: Regulatory, ethical, and study oversight considerations:  
FDA form 1572: 
For US sites: 
 Intended for US sites 
 Conducted under the IND 
 All US investigators, as described above, will sign FDA Form 1572 
For sites outside the US: 
 Intended for participating sites outside of the US 
 Not conducted under the IND 
 All investigators outside of the US 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 study. 
10.01.10 Retention of clinical study documentation: In the US, 21 CFR 312.62(c) and 21 CFR 
812.140(d) require 2 years following the date a marketing application is approved for the drug for 
the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is discontinued 
and FDA is notified’. For Slovakia:  
 10.01.01 Regulatory and ethical considerations:  
The investigator will be responsible for: 
 notifying the IRB/IEC of SAEs – only death, as required by IRB/IEC procedures and local 
regulations 
 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 
 reporting any potential serious breaches to the sponsor immediately after discovery 
The sponsor 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 according to local 
 regulations and procedures established by the IRB/IEC and/or regulatory authorities  
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
ensuring submission of protocol, protocol amendments, ICF, investigator brochure, CSR
synopsis and other relevant documents to the IRB/IEC and/or regulatory authorities
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Status: 
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10.10 Appendix 10: Abbreviations  
ADA 
American Diabetes Association 
AE 
adverse event(s) 
 
ALT 
Alanine Aminotransferase 
ANDA 
Abbreviated New Drug Application 
AST 
Aspartate Aminotransferase  
BG 
blood glucose 
BMI 
body mass index 
Cavg 
Steady state average plasma concentration in a dosing interval  
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CMC 
Chemistry, Manufacturing, and Controls 
COVID 
coronavirus disease 
CRF 
case report form  
CSR 
clinical study report  
CTFG 
Clinical Trial Facilitation Group  
DBL 
database lock 
DFU 
directions for use 
DP 
drug product 
DPP-4 
dipeptidyl peptidase-4  
DPS 
data-point set 
DS 
drug substance 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
EASD 
European Association for the Study of Diabetes  
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
FAS 
full analysis set  
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendment Act 
FPG  
fasting plasma glucose 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GLP-1 
glucagon like peptide-1 
HbA1c 
glycosylated haemoglobin 
hCG 
human chorionic gonadotropin 
IB 
investigator’s brochure 
ICH 
International Council of Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
institutional ethics committee  
IHSG 
International Hypoglycaemia Study Group 
IMP 
investigational medicinal product 
IRB 
institutional review board  
ISO 
International Organisation for Harmonisation 
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Status: 
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IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IWRS 
Interactive Web Response System  
LPLT 
last participant last treatment 
LPLV 
last patient last visit 
MAP 
meta-analytic-predictive 
MCMC 
Markov Chain Monte Carlo 
MI 
myocardial infarction 
 
NDA 
New Drug Application 
NIMP 
non-investigational medicinal products  
NN 
Novo Nordisk 
NYHA 
New York Heart Association 
PAS 
participant analysis set  
PCD 
primary completion date 
PD 
pharmacodynamics 
PG 
plasma glucose 
PK 
pharmacokinetics 
QTL 
quality tolerance limits  
RA 
receptor agonist 
RTSM 
Randomisation and Trial Supply Management  
SAE 
serious adverse event(s) 
SAP 
statistical analysis plan  
s.c. 
subcutaneous(ly) 
SD 
standard deviation 
SMPG 
self-measured plasma glucose 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reactions 
T2D 
type 2 diabetes 
TMM 
trial materials manual  
UNL 
upper normal limit 
US 
United States 
WOCBP 
women of childbearing potential  
 
 
 
 
 
 
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Study ID: NN9535-4820 
Version: 
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Status: 
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Page: 
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10.11 Appendix 16: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version 2.0 (08 April 2022), global 
This amendment is considered 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.2 
Overall rationale for preparing protocol, version 2.0: 
This version of the protocol is prepared to include additional PK samples and analyses to allow PK 
comparability of semaglutide J s.c. and semaglutide B s.c., based on the Health Canada’s feedback. 
Population pharmacokinetics will be addressed in a modelling analysis plan and the totality of 
evidence from all PK assessments will be presented as a collective whole in a comprehensive 
modelling report. Therefore, secondary PK objective has been removed from the protocol. 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Removal of secondary PK objective. 
Since all PK assessments will be 
performed based on modelling 
analysis plan and will be presented in 
a comprehensive modelling report, the 
secondary PK objective has been 
removed from the protocol.  
Section 1.2 Flowchart  
 
Additional PK sampling visits at 
visit 7, 8 and 9. 
 
Additional row has been added to 
remind the participant about 
when the trial product should be 
administered . 
Additional PK samples are collected 
to allow PK comparability and a 
dosing reminder has been added to 
ensure correct PK sampling in relation 
to trial product administration. 
The terminology ‘administration of 
trial product’ has been replaced with 
‘dosing history’. 
To make it clear that we are recording 
the date, time, dose and injection site 
of trial product, the term 
‘administration of trial product’ has 
been replaced with ‘dosing history’. 
A footnote added to indicate that the 
race and ethnicity must be 
self-reported by the participants. 
To comply with FDA requirements on 
self-reporting of race and ethnicity. 
Section 1.3 Flow chart – PK sampling Introduced detailed flow chart for PK 
sampling. 
A detailed flowchart for PK sampling 
has been added to indicate when the 
trough, peak and decline samples will 
be collected. 
Section 3.1 Objectives and endpoints 
Removal of secondary objective and 
endpoint (Cavg), and addition of a 
statement that population PK will be 
reported in a comprehensive 
modelling report.  
Since all PK assessments will be 
performed based on modelling 
analysis plan and will be presented in 
a comprehensive modelling report, the 
secondary PK objective and endpoint 
has been removed from the protocol.  
Section 6.1 Study interventions 
administered 
Addition of reminders for dosing. 
This has been added to help the 
participants remember the dosing for 
PK sampling visits. 
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Section # and name 
Description of change 
Brief rationale 
A brief description on how blood 
sampling for PK assessments is 
planned for PK sampling visits. 
To provide more clarity on how and 
when the blood sampling for PK 
assessments are planned. 
Section 7 Discontinuation of study 
intervention and participant 
discontinuation/withdrawal  
RTSM language for recording 
treatment discontinuation has been 
updated across the section. 
The wording has been aligned with 
regards to RTSM language. 
Section 8.4.1 Pharmacokinetics 
Changed that the date, exact time and 
dose of all the administrations of trial 
product will be recorded in diary. 
This has been changed to provide 
more clarity that the dosing history for 
all trial product administrations will 
be recorded. 
Section 9.3.6 Other analyses  
A brief summary on the PK modelling 
has been added. 
This has been added to provide details 
on PK samples and assessments  
Section 10.2 Appendix 2: Clinical 
laboratory tests  
Additional table on ‘timing of visits 
and PK sampling’. 
This has been added to provide more 
clarity on how the timing of visits is 
planned for PK sampling 
Section 10.8 Appendix 8: Mitigations 
to ensure participant safety and data 
integrity during an emergency 
situation  
The flowchart in this section is 
updated in accordance with section 
1.2. 
To align with the flowchart in Section 
1.2. 
Section 10.9 Appendix 9: 
Country-specific requirements 
Country specific requirements for 
Slovakia has been added. 
This has been added based on the 
comments received from Regulatory 
Authority (RA) of Slovakia. 
Section 1.1 Synopsis and Section 4.1 
Study design 
Retaining ‘active-controlled’ study 
instead of ‘active, internal and 
historical controlled’ study to keep it 
simple. 
 
The changes have been made to 
provide more clarity that, we use 
historical information in the primary 
comparison which is not part of the 
study design but is rather a feature of 
the primary analysis. For this purpose, 
we have retained ‘active-controlled 
study’ wherever we are talking about 
study design. However, we have 
explained what internal and historical 
control is in further section.  
 
Protocol version 3.0 (05 October 2022) 
This amendment is considered 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 
Overall rationale for preparing protocol, version 3.0: 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Section 2.1 Study rationale 
Section 3 Objectives, 
endpoints and estimand 
Section 4 Study design 
Section 6.3 Measures to 
minimise bias: 
Randomisation and blinding 
The primary analysis has been changed 
from Bayesian comparability analysis 
utilizing historical data to a frequentist 
non-inferiority analysis based on data 
from participants enrolled in this study 
(concurrent data). 
 
This change has been made to increase the 
robustness and acceptability of the primary 
assessment and is based on recommendations 
from Health Authority. 
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Section # and name 
Description of change 
Brief rationale 
Section 9 Statistical 
considerations 
Section 1.1 Synopsis 
Section 4.1 Overall design 
Section 9.5 Sample size 
determination 
An additional 48 participants will be 
randomised in a 3:1 manner to receive 
either semaglutide J s.c. or semaglutide 
B s.c.  
This is to maintain 80% power under the 
non-inferiority analysis that does not utilize 
historical data. 
Section 6.1 Study 
intervention compliance 
A sentence has been modified to clarify 
that DFU will be given only at visit 2 
and verbal training will be given at visit 
2, 4 and 6. 
This has been done to simplify and provide 
more clarity. 
Section 10.10 Appendix 10: 
Abbreviations 
‘FAZ’ has been changed to ‘FAS’. 
 
‘SUSTAIN’ has been removed. 
This has been done to correct spelling 
mistake. 
This has been removed as it is no longer 
defined in the protocol. 
 
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Date: 
20 February 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
4.0 
     
Status: 
Final 
     
Page: 
88 of 89 
 
 
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. 
European Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis 
in clinical trials to the guideline on statistical principles for clinical trials. Step 5 
EMA/CHMP/ICH/436221/2017). 2020. 
3. 
Novo Nordisk A/S. Ozempic® (semaglutide), US prescribing Information (PI). Jan 2020. 
4. 
Novo Nordisk A/S. Ozempic® (semaglutide), EU Summary of product characteristics 
(SmPC). 27 Mar 2020. 
5. 
Food and Drug Administration. CDER. Guidance for Industry.  Changes to an Approved 
NDA or ANDA. April 2004. 
6. 
ICH Topic Q5E Comparability of Biotechnological/Biological Products.   NOTE FOR 
GUIDANCE ON BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO 
CHANGES IN THEIR MANUFACTURING PROCESS 
(CPMP/ICH/5721/03). CPMP/ICH/5721/03. June 2005. 
7. 
Novo Nordisk A/S. Abbreviated Investigator Brochure, Semaglutide s.c. (Ozempic), project 
NN9535 (edition 18). 30 July 2021. 
8. 
European Medicines Agency. Guideline on clinical investigation of medicinal products in 
the treatment or prevention of diabetes mellitus (CPMP/EWP/1080/00 Rev. 2). 29 Jan 2018. 
9. 
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products  (ENTR/F/2/AM/an D(2010) 
3374). 03 Feb 2010. 
10. 
Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, 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. 
Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 Update to: 
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. 2020;43(2):487-93. 
12. 
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification 
of acute pancreatitis-2012: revision of the Atlanta classification and definitions by 
international consensus. Gut. 2013;62(1):102-11. 
13. 
Little RJA, Rubin DB. Statistical analysis with missing data. New York: Wiley. 1987. xiv, 
278 p. p. 
14. 
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. 
15. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Current 
step 4 version. 09 Nov 2016. 
16. 
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. 
17. 
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. 
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Signature Page for VV-TMF-5985554 v1.0
Signature Page for VV-TMF-5985554 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 22-Feb-2023 10:50:01
GMT+0000
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9.1.1
Protocol Attachment
Protocol Attachment I is located in the Trial Master File.
If applicable, Protocol Attachment II is also located in the Trial Master File.
Content: Global key staff and Country key staff.
Date:
Novo Nordisk
Version:
Status:
Once weekly semaglutide
Study ID: NN9535-4820
Clinical Study Report
Appendix 9.1.1
01 December 2023
1.0
Final
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05478252  
Sponsor trial ID: 
NN9535-4820 
Official title of study: 
Investigation of Clinical Comparability of Semaglutide Drug 
Products Based on the Proposed and the Approved Drug Substance 
Manufacturing Processes in Participants with Type 2 Diabetes 
Document date*: 
08 September 2023 
 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content. 


Link
List of contents
Statistical analysis plan......................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Once weekly semaglutide
Study ID: NN9535-4820
Clinical Study Report
Appendix 9.1.9
01 December 2023
1.0
Final
9.1.9 Documentation of statistical methods
CONFIDENTIAL
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
1 of 17 
 
Statistical Analysis Plan
Protocol Title: Investigation of Clinical Comparability of 
Semaglutide Drug Products Based on the Proposed and the 
Approved Drug Substance Manufacturing Processes in 
Participants with Type 2 Diabetes 
Substance: semaglutide s.c. 
 
Biostatistics GLP-1 Diabetes 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
2 of 17 
 
Table of contents 
 
Page 
Table of contents ............................................................................................................................................... 2 
Table of tables ................................................................................................................................................... 3 
Version History ................................................................................................................................................. 4 
1 Introduction ................................................................................................................................................. 5 
1.1 
Objectives, Endpoints, and Estimands ................................................................................................ 5 
1.1.1 
Primary estimand ................................................................................................................. 6 
1.1.2 
Additional estimand ............................................................................................................. 6 
1.2 
Study Design ....................................................................................................................................... 7 
2 Statistical Hypotheses ................................................................................................................................. 8 
2.1 
Multiplicity Adjustment ...................................................................................................................... 8 
3 Analysis Sets ................................................................................................................................................ 9 
4 Statistical Analyses .................................................................................................................................... 10 
4.1 
General Considerations ..................................................................................................................... 10 
4.2 
Primary Estimand Analysis ............................................................................................................... 10 
4.2.1 
Main Analytical Approach ................................................................................................ 10 
4.2.1.1 
Sensitivity Analysis ........................................................................................ 10 
4.2.2 
Additional estimand Analysis ............................................................................................ 11 
4.2.2.1 
Sensitivity Analysis ........................................................................................ 11 
4.3 
Secondary Endpoints Analysis ......................................................................................................... 11 
4.3.1 
Confirmatory Secondary Endpoints .................................................................................. 11 
4.3.2 
Supportive Secondary Endpoints ....................................................................................... 11 
4.3.2.1 
Change in body weight .................................................................................. 11 
4.4 
Exploratory Endpoints Analyses ....................................................................................................... 11 
4.5 
Other Safety Analysis ....................................................................................................................... 12 
4.5.1 
Adverse Events .................................................................................................................. 12 
4.5.2 
Anti-semaglutide antibodies .............................................................................................. 12 
4.6 
Other Analysis .................................................................................................................................. 12 
4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling ..................................................... 12 
4.7 
Interim Analysis ................................................................................................................................ 13 
4.8 
Changes to Protocol-planned Analyses ............................................................................................. 13 
5 Sample size determination ........................................................................................................................ 14 
6 Supporting Documentation ...................................................................................................................... 15 
6.1 
Appendix 1: List of abbreviations ..................................................................................................... 15 
6.2 
Appendix 2: Definition and calculation of endpoints, assessments and derivations ........................ 15 
7 References .................................................................................................................................................. 17 
 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
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Table of tables 
Page 
Table 1-1 
Objectives and endpoints ............................................................................................................. 5
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
4 of 17 
 
Version History 
This Statistical Analysis Plan (SAP) for study NN9535-4820 is based on the protocol version 4.0 
dated 20-Feb-2023. 
SAP Version 
Date 
Change 
Rationale 
1.0 
8-SEP-2023
Not Applicable 
Original version 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
7 of 17 
 
 
 Remaining intercurrent events: No further events are identified. The three intercurrent events 
are addressed in the intervention condition attributes. Treatment discontinuation for any reason 
and initiation of rescue medication is handled with the hypothetical strategy. Changes to 
metformin dose is handled by the treatment policy strategy. 
1.2 
Study Design 
See protocol Section 4.1. 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
8 of 17 
 
 
2 
Statistical Hypotheses 
Non-inferiority will be declared if the following one-sided null hypothesis is rejected. Let the 
treatment difference of change from baseline to week 28 in HbA1c between semaglutide J s.c. and 
semaglutide B s.c. be defined as μ = “change in HbA1c for semaglutide J s.c.” minus “change in 
HbA1c for semaglutide B s.c.”. 
 H0: µ ≥ 0.3%-points against Ha: µ < 0.3%-points 
The non-inferiority margin of 0.3%-points is justified in the protocol Section 4.2. 
2.1 
Multiplicity Adjustment 
The type-1 error probability will be controlled at 2.5% under the aforementioned one-sided null-
hypothesis, and as the study has only one primary analysis, and no confirmatory secondary 
analyses, adjustment for multiplicity is not applicable. 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
9 of 17 
 
 
3 
Analysis Sets 
The following participant analysis sets are defined:  
Participant analysis set (PAS) 
Description 
Full analysis set (FAS) 
All randomised study participants. Participants will be included in the analyses 
according to the randomised intervention. 
Safety analysis set 
All participants who are exposed to study intervention. Participants will be 
included in the analyses according to the intervention they actually received for 
the majority of the period being treated. 
 
The following data points sets are defined: 
Defined data points set (DPS) 
Description 
DPS1 – in study 
All observed data points from randomisation until the first date of: 
 
end of study visit (visit 11) or 
 
death or 
 
withdrawal of informed consent or 
 
last contact as defined by investigator for participants that are lost to follow 
up. 
DPS2 – on treatment 
All observed data points from first drug date until the first date of: 
 
end of DPS1 – in study or 
 
the end of study visit (visit 11) or 
 
last trial product administration +42 days. 
DPS3 – on treatment without 
rescue 
All observed data points from first drug date until the first date of: 
 
initiation of rescue medication or 
 
last trial product administration +7 days 
 
The FAS and DPS1 are used to estimate the primary estimand (defined in Section 1.1.1). 
The FAS and DPS3 are used to estimate the additional estimand (defined in Section 1.1.2). 
The safety analysis set and DPS2 are used to present safety data with a long lag-time (AEs, 
hypoglycaemic episodes, anti-semaglutide antibodies and eye examination). 
Safety analysis set and a modified DPS2 are used to present safety data with an acute onset (vital 
signs, laboratory assessments, physical examination). For these summaries, the DPS2 is modified 
by having an end date at date of last trial product administration +7 days or date of end of DPS1, 
whichever occurs first.  
 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
10 of 17 
 
 
4 
Statistical Analyses 
4.1 
General Considerations 
A baseline assessment will be defined as the most recent measurement at randomisation. Missing 
baseline values will be imputed by the average of the non-missing baseline values. 
The frequency and timing of intercurrent events as defined in Section 1.1.1 will be presented 
descriptively. 
4.2 
Primary Estimand Analysis 
4.2.1 
Main Analytical Approach 
The primary estimand, presented in section 1.1.1, will be estimated based on the FAS and DPS1. 
Missing end of treatment data will be imputed using multiple imputation (MI) assuming that 
missing data are missing at random (MAR). The imputation will be performed, under the non-
inferiority null-hypothesis, by imputing missing end of treatment data separately within each to the 
four groups defined by randomised treatment and treatment status at end of treatment: 
 semaglutide B s.c. and on-treatment at end of treatment, 
 semaglutide B s.c. and off-treatment at end of treatment, 
 semaglutide J s.c. and on-treatment at end of treatment, 
 semaglutide J s.c. and off-treatment at end of treatment. 
For each group an analysis of covariance (ANCOVA) with region as a factor and baseline HbA1c as 
a covariate will be fitted to the observed end of treatment values. The estimated location and 
dispersion parameters will then be used to impute 500 values for each participant with missing end 
of treatment data. Furthermore, for participants randomised to semaglutide J s.c. a penalty of 0.3, 
corresponding to the non-inferiority margin, is added to the imputed values. 
The 500 complete datasets will be analysed using an ANCOVA with randomised treatment and 
region as factors and baseline HbA1c as a covariate. Rubin’s rule2 will then be applied to combine 
these estimates and draw inference. 
In case of sparse data, defined as less than 5 participants with available end of treatment data, in 
some groups, the imputation model will be thinned by region. If this is not sufficient the imputation 
will be based on participants randomised to the same treatment regardless of treatment status using 
the imputation model region as a factor and baseline HbA1c as a covariate. If this is still not 
sufficient, the imputation model may be thinned again in the aforementioned order. 
4.2.1.1 
Sensitivity Analysis 
A two-way tipping point sensitivity analysis will be performed by repeating the ANCOVA 
described in Section 4.2.1. However, prior to analysis, penalties are added to the imputed end of 
treatment values in both intervention arms simultaneously. A range of penalties will be explored for 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
11 of 17 
 
 
both treatment groups, and the impact on the conclusion will be assessed through a contour plot of 
the p-values. This sensitivity analysis evaluates the robustness of the non-inferiority conclusions to 
violations in missing data assumptions in both intervention arms.  
4.2.2 
Additional estimand Analysis 
The additional estimand, presented in section 1.1.2 will be estimated based on the FAS and DPS3. 
Missing end of treatment data will be imputed using multiple imputation (MI) assuming that 
missing data are missing at random (MAR). The imputation will be performed separately within 
each treatment group. First, intermittent missing values are imputed using a Markov Chain Monte 
Carlo (MCMC) method, to obtain a monotone missing data pattern, generating 500 complete data 
sets. Secondly, a sequential conditional linear regression approach for imputing monotone missing 
values will be implemented starting with the first visit after baseline and sequentially continuing to 
the last planned visit. The imputation model will include region as a factor and baseline and post-
baseline HbA1c values observed prior to the visit in question as covariates. 
The 500 complete datasets will be analysed using an ANCOVA with randomised treatment and 
region as factors and associated baseline HbA1c as a covariate. Rubin’s rule2 will then be applied to 
combine the estimates and draw inference. 
4.2.2.1 
Sensitivity Analysis 
A two-way tipping point sensitivity analysis as described in Section 4.2.1.1 will be performed. 
4.3 
Secondary Endpoints Analysis 
4.3.1 
Confirmatory Secondary Endpoints 
Not applicable for this study. 
4.3.2 
Supportive Secondary Endpoints 
4.3.2.1 
Change in body weight 
Primary estimand 
A similar analysis as described in Section 4.2.1 will be performed, but with values of body weight 
instead of HbA1c, and where no penalty (or rather a penalty of 0, corresponding to a superiority test) 
is added to imputed values for participants that are randomised to semaglutide J s.c. 
Additional estimand 
A similar analysis as described in Section 4.2.2 will be performed, but with values of body weight 
instead of HbA1c. 
4.4 
Exploratory Endpoints Analyses 
Not applicable for this study.  
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
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4.5 
Other Safety Analysis 
4.5.1 
Adverse Events 
The AEs will be summarised descriptively by treatment arm in terms of number of participants 
experiencing at least one event (N), proportion of participants in the safety analysis set experiencing 
at least one event (%), the number of events (E), and the event rate (R) per 100 PYE. 
Number of treatment-emergent AEs 
A treatment-emergent AE is defined as an AE with an onset date (or increase in severity) during the 
on-treatment observation period (see Section 3).  
Treatment-emergent AEs will be summarised descriptively by treatment arm in terms of number of 
participants experiencing at least one event (N), proportion of participants in the safety analysis set 
experiencing at least one event (%), the number of events (E), and the event rate (R) per 100 
person-years of exposure (PYE). 
4.5.2 
Anti-semaglutide antibodies 
The occurrence of antibodies (positive/negative): 
 In vitro neutralising anti-semaglutide antibodies 
 Anti-semaglutide binding antibodies cross-reacting with endogenous GLP-1 
o In vitro neutralising cross-reacting antibodies to endogenous GLP-1 
during the time from baseline visit (visit 2; week 0) to end of study visit (visit 11; week 33) will be 
summarised descriptively by treatment and visit and positive at any time in terms of number of 
participants with a positive result (N), the proportion of participants in the safety analysis set with a 
positive result (%). Only visits with one or more positive results will be displayed. To visualise the 
impact of antibodies on HbA1c (%), a spaghetti plot will be provided showing the change in HbA1c 
(%) levels for each subject throughout the trial with all antibodies negative and positive subjects 
being in two different colours. Similarly, a spaghetti plot will be produced showing semaglutide 
pharmacokinetic concentration by occurrence of anti-semaglutide antibodies. 
4.6 
Other Analysis 
4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling 
The 8 PK samples for each participant will be used to fit a 1-compartment population PK model. In 
the visit schedule, 3 PK visit window types have been defined ensuring that PK sampling times 
relative to dosing times are distributed across the weekly dosing interval, allowing for estimation of 
the absorption rate, the volume of distribution, and the clearance rate for each participant in the 
population PK model, and from this Cmax, Cmin and Cavg will be estimated for each participant. 
Lastly, a comparison of Cmax, Cmin and Cavg between semaglutide J s.c. and semaglutide B s.c. will 
be made. 
Additional population PK/PD exposure-response analyses may be included for exploratory 
pharmacodynamic analysis as needed. 
The modelling will include data from all enrolled participants that were exposed to semaglutide s.c. 
in this study and might be performed as a meta-analysis. Actual dose, date, time and injection site of 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
13 of 17 
 
 
all the administrations of trial product before PK sampling will be registered in the eCRF and used 
in the analysis, together with actual time point for PK sampling. The analysis will be further 
specified in a modelling analysis plan (MAP) that is to be prepared before unblinding at the partial 
(interim) database lock. The modelling analyses will be performed by Pharmacometrics at Novo 
Nordisk A/S and will be reported separately from the CSR. 
4.7 
Interim Analysis 
This study will be subject to a partial (interim) database lock (DBL) at the end of the treatment 
period for all participants, i.e. after the date of the last participant last treatment (LPLT) visit. A full 
DBL will be performed, as per the usual procedures, after last participant last visit. The partial DBL 
is implemented to allow for an early submission to Agency and thereby securing the stable supply 
of the semaglutide molecule to meet the current high demand.  Novo Nordisk employees not 
involved in data cleaning will become unblinded to potentially both participant level data and 
comparative results at the time of the partial database lock, whereas participants and investigators 
will remain blinded until after last participant last visit (LPLV). All efficacy analyses will be 
performed based on the data from the partial DBL and analysis of safety will primarily be based on 
the full DBL. No efficacy assessments are collected after LPLT and in turn the efficacy results 
cannot be biased by the early unblinding. The potential impact on safety is considered negligible, as 
most participants will have completed the follow-up visit at the time of the partial DBL. 
4.8 
Changes to Protocol-planned Analyses 
- 
The event rate of AEs will be calculated per 100 PYE rather than PYE. 
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
14 of 17 
 
 
5 
Sample size determination 
See protocol Section 9.5. 
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CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
15 of 17 
 
 
6 
Supporting Documentation 
6.1 
Appendix 1: List of abbreviations 
AE 
adverse event 
ANCOVA 
analysis of covariance 
DBL 
database lock 
DPS 
data point set 
FAS 
full Analysis set 
GLP-1 
glucagon-like peptide-1 
HbA1c 
glycated haemoglobin 
ICH 
International Council on Harmonization 
LPLT 
last participant last treatment 
MCMC 
Markov chain Monte Carlo 
PAS 
participant analysis set 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PYE 
person-years of exposure 
s.c. 
subcutaneous 
SAP 
statistical analysis plan 
T2D 
type 2 diabetes 
6.2 
Appendix 2: Definition and calculation of endpoints, assessments and derivations 
Type 
Title 
Time frame 
Unit 
Primary endpoint 
Change in glycosylated 
haemoglobin (HbA1c) 
From baseline (week 0) to week 28  %-points 
Supportive secondary 
endpoint 
Change in body weight 
From baseline (week 0) to week 28 
kg 
Supportive secondary 
endpoint 
Number of treatment 
emergent adverse events 
(AEs) 
From the time of first dosing to 
week 33 
count 
Supportive secondary 
endpoint 
Occurrence of anti-
semaglutide antibodies  
From baseline to week 33 
count of participant  
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
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Type 
Title 
Time frame 
Unit 
Supportive secondary 
endpoint 
Occurrence of 
anti-semaglutide binding 
antibodies cross-reacting 
with endogenous GLP-1 
From baseline to week 33 
count of participant  
Supportive secondary 
endpoint 
Occurrence of in vitro 
neutralising 
anti-semaglutide binding 
antibodies cross-reacting 
with endogenous GLP-1 
From baseline to week 33 
count of participant  
Supportive secondary 
endpoint 
Anti-semaglutide antibody 
level 
From baseline to week 33 
%B/T  
Supportive secondary 
endpoint 
Anti-semaglutide antibody 
level 
From baseline to week 33 
titre  
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Statistical Analysis Plan 
 
Date: 
08 September 2023 Novo Nordisk 
Study ID: NN9535-4820 
Version: 
1.0 
UTN: U1111-1266-2391 
Status: 
Final 
EudraCT: 2021-001501-69 
Page: 
17 of 17 
 
 
7 
References 
1. 
European Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis 
in clinical trials to the guideline on statistical principles for clinical trials. Step 5 
EMA/CHMP/ICH/436221/2017). 2020. 
2. 
Little RJA, Rubin DB.   Statistical analysis with missing data.   New York.:   Wiley.   1987. 
xiv, 278 p.p. 
 
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