Clinical trial NCT04707469
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2021-01-15; Completion date: 2023-03-08
Enrollment: 1606 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares three doses of once daily semaglutide tablets in people with type 2 diabetes who were previously treated with other oral anti-diabetic medicines. Participants will be initiated on the lowest starting dose of 3 mg and gradually increased until they reach the final trial dose of 14 mg, 25 mg or 50 mg once daily semaglutide tablets. The final three doses will be randomized (i.e., decided by chance). Participants will be administered one tablet per day for 68 weeks. Women cannot take part if they are pregnant, breast-feeding or planning to become pregnant during the study period. Women who can get pregnant will be checked for pregnancy via urine tests. Once daily semaglutide tablets (3 mg, 7 mg and 14 mg) are approved for the treatment of type 2 diabetes in the US, in the EU and in some other countries, under the brand name Rybelsus®.

Detailed description:

Arms: arm 1: Participants will receive once daily semaglutide tablets in a dose escalating manner for 68 weeks: 3 mg (week 1-4), 7 mg (week 5-8), 14 mg (week 9-12), 25 mg (week 13-16) and 50 mg (week 17-68). arm 2: Participants will receive once daily semaglutide tablets in a dose escalating manner for 68 weeks: 3 mg (week 1-4), 7 mg (week 5-8), 14 mg (week 9-12) and 25 mg (week 13-68). arm 3: Participants will receive once daily semaglutide tablets in a dose escalating manner for 68 weeks: 3 mg (week 1-4), 7 mg (week 5-8) and 14 mg (week 9-68).
Interventions: intervention 1: Oral semaglutide
Intervention descriptions: intervention 1: Participants will receive once daily semaglutide tablets (oral administration) in a dose escalating manner for 68 weeks.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04707469 
Sponsor trial ID: 
NN9924-4635 
Official title of study: 
Efficacy and safety of once-daily oral semaglutide 25 mg and 
50 mg compared with 14 mg in subjects with type 2 diabetes 
Document date: 
16 September 2022 
*Document date refers to the date on which the document was most recently updated. 
 


Protocol 
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Date: 
16 September 2022 Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
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Protocol 
PIONEER PLUS 
NN9924-4635 
Including: 
Amendment 1, dated 09 November 2020 
Amendment 2, dated 04 March 2021 
Amendment 3, Croatia and Germany, dated 28 April 2021 
Amendment 4, dated 04 June 2021 
Amendment 5, dated 01 February 2022 
Amendment 6, dated 16 September 2022 
Protocol title: 
Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in 
subjects with type 2 diabetes  
Substance: Semaglutide 
Universal Trial Number: U1111-1247-0210 
EudraCT Number: 2020-000299-39 
 
Trial phase: 3b 
 ;A523<99<D6;4%<C<%<?16@8	(.;16A@.33696.A2@D699/2@A.A21.@K%<C<%<?16@8L 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Trial ID: NN9924-4635 
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DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s) 
Protocol version 7.0 (including 
protocol amendment no. 1, 2, 3, 4, 5 
and 6) 
16 September 2022  
Global 
Protocol version 6.0 (including 
protocol amendment no. 1, 2, 3, 4 and 
5) 
01 February 2022 
Global 
Protocol version 5.0 (including 
protocol amendment no. 1, 2, 3 and 4) 
04 June 2021 
Global 
Protocol version 4.0 (including 
protocol amendment no. 1, 2 and 3) 
28 April 2021 
For Croatia and Germany only 
Protocol version 3.0 (including 
protocol amendment no. 1 and 2) 
04 March 2021 
Global 
Protocol version 2.0 (including 
protocol amendment no. 1) 
09 November 2020 
Global 
Original protocol version 1.0 
08 July 2020 
Global 
Protocol version 7.0 (16 September 2022) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union,1 because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 7.0: 
The overall rationale for the changes implemented in the amended protocol is to add a description 
of the existing possibility to go back and evaluate previous ECG data in case of unforeseen or 
abnormal observations that could indicate safety findings and specify content and impact of the 
planned partial database lock. Furthermore, a numerical error has been corrected in Table 9-2. 
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Section # and name 
Description of change 
Brief rationale 
8.2.3 Electrocardiograms 
Reason for central storage of ECG data has been 
provided. Bold text added in below paragraph: 
M)52@D699/20<9920A213<?02;A?.9@A<?.42
for potential future assessment. This is to have 
the possibility to go back and evaluate 
previous ECG data in case of unforeseen or 
abnormal observations that could indicate 
safety findings or for future scientific 
purposes related to semaglutide, T2D, CV 
outcome or related diseases.N 
To clarify and describe the 
purpose of the ECG collection 
with the possibility of future 
evaluation. 
9.2 Sample size determination 
The treatment difference (TD) for HbA1cS-
point) for the 50 mg dose has been corrected in 
the first five rows of the first column of 
Table 9-2. 
To accommodate feedback from 
FDA: The TD was incorrectly 
stated here as -0.53 
9.5 Interim analyses 
Added reference to Section 9.7. 
To accommodate feedback from 
FDA. 
9.7 Reporting of the main part 
of the trial 
Content and impact of the planned partial 
database lock have been specified before 
unblinding of data. 
To accommodate feedback from 
FDA. 
 
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  $$# 
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 4 
1 
Protocol summary ..................................................................................................................................... 7 
1.1 
Synopsis ........................................................................................................................................... 7 
1.2 
Flowchart ....................................................................................................................................... 10 
2 
Introduction ............................................................................................................................................. 12 
2.1 
Trial rationale ................................................................................................................................. 12 
2.2 
Background .................................................................................................................................... 12 
2.3 
Benefit-risk assessment .................................................................................................................. 13 
2.3.1 
Risk assessment ............................................................................................................... 13 
2.3.2 
Benefit assessment ........................................................................................................... 16 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 17 
3 
Objectives and endpoints ........................................................................................................................ 18 
3.1 
Primary and secondary objectives, and estimands ......................................................................... 18 
3.2 
Primary and secondary endpoints .................................................................................................. 22 
3.2.1 
Primary endpoint ............................................................................................................. 22 
3.2.2 
Secondary endpoints ........................................................................................................ 22 
3.2.2.1 
Confirmatory secondary endpoints ................................................................. 22 
3.2.2.2 
Supportive secondary endpoints ..................................................................... 22 
4 
Trial design .............................................................................................................................................. 23 
4.1 
Overall design ................................................................................................................................ 23 
4.2 
Scientific rationale for trial design ................................................................................................. 23 
4.3 
Justification for dose ...................................................................................................................... 24 
4.4 
End of trial definition ..................................................................................................................... 25 
5 
Trial population ....................................................................................................................................... 26 
5.1 
Inclusion criteria ............................................................................................................................ 26 
5.2 
Exclusion criteria ........................................................................................................................... 26 
5.3 
Lifestyle considerations ................................................................................................................. 27 
5.3.1 
Meals and dietary restrictions .......................................................................................... 27 
5.4 
Screen failures ................................................................................................................................ 28 
5.5 
Run-in criteria and randomisation criteria and dosing day criteria ................................................ 28 
6 
Treatments ............................................................................................................................................... 29 
6.1 
Treatments administered ................................................................................................................ 29 
6.2 
Preparation/handling/storage/accountability .................................................................................. 31 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 32 
6.4 
Treatment compliance .................................................................................................................... 33 
6.5 
Concomitant medication ................................................................................................................ 33 
6.5.1 
Rescue medication ........................................................................................................... 34 
6.6 
Dose modification .......................................................................................................................... 34 
6.7 
Treatment after end of trial ............................................................................................................ 34 
7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 35 
7.1 
Discontinuation of trial treatment .................................................................................................. 35 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 36 
7.1.2 
Rescue criteria ................................................................................................................. 36 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 36 
7.2.1 
Replacement of subjects .................................................................................................. 37 
7.3 
Lost to follow-up ........................................................................................................................... 37 
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8 
Trial assessments and procedures ......................................................................................................... 38 
8.1 
Efficacy assessments ...................................................................................................................... 39 
8.1.1 
Clinical efficacy laboratory assessments ......................................................................... 39 
8.1.2 
Body weight..................................................................................................................... 39 
8.1.3 
Waist circumference ........................................................................................................ 39 
8.2 
Safety assessments ......................................................................................................................... 39 
8.2.1 
Physical examinations ..................................................................................................... 40 
8.2.2 
Vital signs ........................................................................................................................ 40 
8.2.3 
Electrocardiograms .......................................................................................................... 40 
8.2.4 
Eye examination .............................................................................................................. 41 
8.2.5 
Clinical safety laboratory assessments ............................................................................ 41 
8.3 
Adverse events and serious adverse events .................................................................................... 42 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 42 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 43 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 43 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 43 
8.3.5 
Pregnancy ........................................................................................................................ 43 
8.3.6 
Cardiovascular and death events ..................................................................................... 43 
8.3.7 
Technical complaints ....................................................................................................... 44 
8.4 
Treatment of overdose ................................................................................................................... 44 
8.5 
Pharmacokinetics ........................................................................................................................... 44 
8.6 
Pharmacodynamics ........................................................................................................................ 44 
8.7 
Genetics ......................................................................................................................................... 45 
8.8 
Biomarkers ..................................................................................................................................... 45 
8.9 
Immunogenicity assessments ......................................................................................................... 45 
8.10 
Health economics ........................................................................................................................... 45 
9 
Statistical considerations ........................................................................................................................ 46 
9.1 
Statistical hypotheses ..................................................................................................................... 46 
9.2 
Sample size determination ............................................................................................................. 47 
9.3 
Populations for analyses ................................................................................................................ 49 
9.4 
Statistical analyses ......................................................................................................................... 51 
9.4.1 
General considerations .................................................................................................... 51 
9.4.2 
Primary endpoint ............................................................................................................. 52 
9.4.3 
Secondary endpoints ........................................................................................................ 53 
9.4.3.1 
Confirmatory secondary endpoint ................................................................... 53 
9.4.3.2 
Supportive secondary endpoints ..................................................................... 53 
9.4.4 
Other safety analyses ....................................................................................................... 54 
9.4.5 
Other analyse(s) ............................................................................................................... 54 
9.4.5.1 
Pharmacokinetic modelling ............................................................................. 54 
9.5 
Interim analyses ............................................................................................................................. 54 
9.6 
Data monitoring committee ........................................................................................................... 54 
9.7 
Reporting of the main part of the trial............................................................................................ 54 
10 Supporting documentation and operational considerations ............................................................... 56 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 56 
10.1.1 
Regulatory and ethical considerations ............................................................................. 56 
10.1.2 
Financial disclosure ......................................................................................................... 56 
10.1.3 
Informed consent process ................................................................................................ 56 
10.1.4 
Information to subjects during trial ................................................................................. 57 
10.1.5 
Data protection ................................................................................................................ 57 
10.1.6 
Committees structure ....................................................................................................... 58 
10.1.6.1 Novo Nordisk safety committee...................................................................... 58 
10.1.7 
Dissemination of clinical trial data .................................................................................. 58 
10.1.8 
Data quality assurance ..................................................................................................... 58 
10.1.8.1 Case report forms ............................................................................................ 58 
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10.1.8.2 Monitoring ...................................................................................................... 59 
10.1.8.3 Protocol compliance ........................................................................................ 59 
10.1.9 
Source documents ............................................................................................................ 59 
10.1.10 Retention of clinical trial documentation ........................................................................ 60 
10.1.11 Trial and site closure ....................................................................................................... 60 
10.1.12 Responsibilities................................................................................................................ 61 
10.1.13 Indemnity statement ........................................................................................................ 61 
10.1.14 Publication policy ............................................................................................................ 62 
10.1.14.1 Communication of results ............................................................................... 62 
10.1.14.2 Authorship ....................................................................................................... 62 
10.1.14.3 Site-specific publication(s) by investigator(s)................................................. 63 
10.1.14.4 Investigator access to data and review of results ............................................ 63 
10.2 
Appendix 2: Clinical laboratory tests ............................................................................................ 64 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-
up, and reporting ............................................................................................................................ 66 
10.3.1 
Definition of AE .............................................................................................................. 66 
10.3.2 
Definition of an SAE ....................................................................................................... 66 
10.3.3 
Description of AEs requiring additional data collection ................................................. 67 
10.3.4 
Recording and follow-up of AE and/or SAE ................................................................... 69 
10.3.5 
Reporting of SAEs ........................................................................................................... 70 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ............................ 72 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting ................................................................................................................. 76 
10.5.1 
Definition of technical complaint .................................................................................... 76 
10.5.2 
Recording and follow-up of technical complaints ........................................................... 76 
10.5.3 
Reporting of technical complaints ................................................................................... 77 
10.6 
Appendix 6: Hypoglycaemic episodes ........................................................................................... 78 
10.7 
Appendix 7: Retention of human biosamples ................................................................................ 80 
10.8 
Appendix 8: Country-specific requirements .................................................................................. 81 
10.9 
Appendix 9: Abbreviations ............................................................................................................ 83 
10.10 Appendix 10: Protocol amendment history ................................................................................... 86 
11 References ................................................................................................................................................ 92 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments. 
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1 
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1.1 
Synopsis 
Rationale 
The currently approved oral semaglutide maintenance doses are 7 mg and 14 mg2, and the approval 
was based on the comprehensive global clinical phase 3a development programme (the PIONEER 
programme). Although oral semaglutide provided clinically relevant benefits for subjects with type 
2 diabetes (T2D) at all disease stages in the PIONEER programme, approximately 20-40% of the 
subjects did not achieve the recommended level of glycaemic control (HbA1c <7%). Oral 
semaglutide dose levels higher than 14 mg may enable such subjects to achieve adequate glycaemic 
control. 
Dose-dependent effects of oral semaglutide at doses exceeding the currently maximum approved 
dose for the treatment of T2D (14 mg once daily), have been demonstrated in relation to glycaemic 
control and body weight (NN9924-3790). The 40 mg dose level reduced HbA1c by 1.9 %-points and 
body weight by 7 kg.  
To support the approval of higher dose levels of oral semaglutide in T2D, the present randomised 
controlled clinical trial is designed to compare the efficacy, safety and tolerability of oral 
semaglutide 14 mg, 25 mg and 50 mg in subjects with T2D.  
Objectives and endpoints 
Primary 
objective 
To confirm superiority of oral semaglutide 25 mg and 50 mg once daily versus oral 
semaglutide 14 mg once daily on HbA1c reduction in subjects with T2D on stable 
dose of 1-3 OADs. 
Secondary 
objectives 
To confirm superiority of oral semaglutide 25 mg and 50 mg once daily versus oral 
semaglutide 14 mg once daily on body weight reduction in subjects with T2D on a 
stable dose of 1-3 OADs. 
To compare the efficacy of oral semaglutide 25 mg and 50 mg once daily versus 
oral semaglutide 14 mg once daily on parameters related to glycaemic control in 
subjects with T2D on a stable dose of 1-3 OADs. 
To compare the efficacy of oral semaglutide 25 mg and 50 mg once daily versus 
oral semaglutide 14 mg once daily on parameters related to weight-related 
outcomes in subjects with T2D on a stable dose of 1-3 OADs. 
To compare the safety and tolerability of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily in subjects with T2D on stable 
dose of 1-3 OADs. 
Estimands 
For the primary and the confirmatory secondary objective, estimands of primary interest and 
additional estimands are defined. The estimands are used to address the trial objectives in terms of 
two different aspects of the treatment effect of oral semaglutide 14, 25 and 50 mg.  
The primary and secondary estimands address the primary questions of interest: What is the 
efficacy of oral semaglutide 25 and 50 mg versus oral semaglutide 14 mg on change from baseline 
to week 52 in HbA1c (primary objective) and body weight (confirmatory secondary objective) in 
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subjects with T2D on stable dose of 1-3 OADs regardless of treatment discontinuation, changes in 
dose and initiation of additional anti-diabetic medication. 
The additional estimands address additional questions of interest: What is the efficacy of oral 
semaglutide 25 and 50 mg versus oral semaglutide 14 mg on change from baseline to week 52 in 
HbA1c (primary objective) and body weight (confirmatory secondary objective) in subjects with 
T2D on stable dose of 1-3 OADs regardless of change in dose of trial treatment and if all subjects 
had remained on trial treatment without use of rescue medication.  
Similar estimands are defined for the other secondary efficacy objectives. 
Primary endpoint 
Endpoint title 
Timeframe 
Unit 
Change in glycated haemoglobin (HbA1c) 
From baseline (week 0) to week 52 
%-point 
Secondary confirmatory endpoint 
Endpoint title 
Timeframe 
Unit 
Change in body weight  
From baseline (week 0) to week 52 
kg 
Supportive secondary endpoints 
Endpoint title 
Timeframe 
Unit 
Change in fasting plasma glucose (FPG) 
From baseline (week 0) to week 52  
mmol/l 
Achievement of HbA1c <7% (Yes/No)  
At week 52 
Count of subjects 
Achievement of HbA1c H-2@	%< 
At week 52 
Count of subjects 
Relative change in body weight  
From baseline (week 0) to week 52 
Percentage (%) 
Change in waist circumference 
From baseline (week 0) to week 52 
cm 
0562C2:2;A<3D2645A9<@@I-2@	%< 
At week 52 
Count of subjects 
0562C2:2;A<3D2645A9<@@I
-2@	%< 
At week 52 
Count of subjects 
Adverse events 
From baseline (week 0) to follow-up visit 
(week 73) 
Count of events 
Overall design 
This is a 68-week, randomised, active-controlled, double-blinded, three-armed, multi-centre, 
multinational clinical trial comparing the efficacy, safety and tolerability of once-daily oral 
semaglutide 25 mg, 50 mg and 14 mg (the current maximum maintenance dose) in subjects with 
T2D, on stable doses of 1-3 oral anti-diabetic drugs (OADs) (metformin, sulfonylureas, SGLT2 
inhibitors, DPP-4 inhibitors). 
Subjects will be randomised to receive maintenance doses of either 14 mg, 25 mg or 50 mg oral 
semaglutide once daily. Randomisation will be stratified on baseline oral anti-diabetic medication 
and will include a total of 8 strata for combinations of sulfonylureas, SGLT2 inhibitors, and 
terminated DPP-4 inhibitors. Metformin is not included in the stratification. 
Key inclusion criteria 
 Male or female, age above or equal to 18 years at the time of signing informed consent. 
 6.4;<@21D6A5AF=216./2A2@:2996AB@I 180 days prior to the day of screening. 
 HbA1c of 8.0-
P::<9	:<9/<A56;09B@6C2 
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 $ I5 kg/m2. 
 Stable daily dose(s) for 90 days prior to the day of screening of: any of the following treatment 
regimens: 
- 
No more than 3 of the following oral anti-diabetic drugs and at least 1 marked with a *: 
o * $2A3<?:6;I

:4<?:.E6:B:A<92?.A21<?23320A6C21<@2 
o * (B93<;F9B?2.@(*I5.93<3A52:.E6:B:.==?<C211<@2.00<?16;4A<9<0.99./29
or maximum tolerated or effective dose). 
o * SGLT2 inhibitors (maximum tolerated dose). 
o DPP-4 inhibitors (maximally indicated dose as per local label). 
 Subjects, on treatment with stable dose of DPP-4 inhibitors at inclusion, must be willing to 
terminate DPP-4 inhibitor treatment at randomisation (with no wash-out).  
Key exclusion criteria 
 Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 90 days prior to the day of screening. However, short term 
insulin treatment for a maximum of 14 days prior to the day of screening is allowed. 
 Renal impairment measured as estimated glomerular filtration rate (eGFR) value of <30 
mL/min/1.73 m2 according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
creatinine equation as defined by KDIGO 2012 classification. 
 Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination. 
Number of subjects 
1620 subjects will be randomly assigned to trial treatment.  
Treatment groups and duration 
The planned total duration for each subject will be approximately 75 weeks. The trial includes a 
screening period of approximately two weeks followed by randomisation. Oral semaglutide will be 
dosed once daily starting with a dose escalation period of up to 16 weeks followed by a 
maintenance period of minimum 52 weeks. The duration of dose escalation period will depend on 
the maintenance dose to be reached, but the total dose escalation and maintenance period comprises 
68 weeks for all three treatment arms. All subjects will enter a 5-week follow-up period after the 
end-of-treatment visit. 
Tablets of oral semaglutide (3 mg, 7 mg, 14 mg, 25 mg, 50 mg) in dose packs and/or HDPE bottles 
will be provided by Novo Nordisk A/S. 
The trial products will not be available to subjects after the end of trial. 
Trial data monitoring committee: No 
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1.2 
Flowchart 
  
Protocol sections 
Screening 
Randomisation 
Dose escalation/ 
maintenance period 
Maintenance period 
End of treatment 
Follow-up 
Visit 
  
V1 V2 V3 V4 
V5 
P6 
V7 
P8 
V9 
V10 V11 V12 V13 V14 V15 V16 V17 
Timing of Visit 
  
-2W 0W 4W 8W 12W 14W 16W 18W 20W 26W 32W 38W 44W 52W 60W 68W 73W 
Visit Window (Days) 
  
±7 
±0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
  Informed Consent and Demography a 
10.1.3  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Eligibility Criteria 
 5.1,5.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Randomisation 
  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Discontinuation Criteria 
 7.1 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
  Concomitant Medication 
 6.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Medical History/Concomitant Illness 
 8.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Tobacco Use b 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Pregnancy Test c 
 8.3.5,10.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
  Height 
 8.2.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Body Weight 
 8.1.2 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Waist circumference 
 8.1.3 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
  ECG 
8.2.3 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
  Adverse Event 
 8.3,10.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Hypoglycaemic Episodes 
 10.6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Laboratory Assessments 
10.2 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Attend Visit Fasting 
5.3.1  
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
  PK Sampling 
 8.5 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
  Eye Examination 
8.2.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
  Physical Examination 
 8.2.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
  Vital Signs 
 8.2.2 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
  Dispensing Visit 
6.1, 6.3, 5.3.1 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 


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Protocol sections 
Screening 
Randomisation 
Dose escalation/ 
maintenance period 
Maintenance period 
End of treatment 
Follow-up 
Visit 
  
V1 V2 V3 V4 
V5 
P6 
V7 
P8 
V9 
V10 V11 V12 V13 V14 V15 V16 V17 
Timing of Visit 
  
-2W 0W 4W 8W 12W 14W 16W 18W 20W 26W 32W 38W 44W 52W 60W 68W 73W 
Visit Window (Days) 
  
±7 
±0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
  Drug Accountability 
6.4 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
  IWRS Session 
  
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Hand Out ID Card 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Hand Out and Instruct in Diary 
 8 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Hand Out and Instruct in BG-meter 
 10.6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Hand Out of Urine Kit d 
 10.2 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
  Hand Out of Pregnancy Test 
8.3.5, 10.4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnotes: 
a: Demography consists of year of birth, sex, race and ethnicity (according to local regulation) 
b: Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
c: For women of childbearing potential only. In addition to the planned assessment at screening, end of treatment and follow-up, urine dipstick pregnancy test should be performed at any 
time during the trial if a menstrual period is missed, or if pregnancy is suspected, or as required by local law. 
d: This urine kit can be handed out at an earlier visit for subjects who discontinue trial treatment prematurely and do not attend the V15 visit. 


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2 
$" %$  
Semaglutide is a potent glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a high degree of 
homology to human GLP-1. GLP-1 RAs are recommended for the treatment of patients with type 2 
diabetes (T2D) with inadequate glycaemic control and a need to minimize weight gain, promote 
weight loss or minimize hypoglycaemia.3 Guidelines have recently been updated to recommend 
GLP-1 RAs for patients with T2D and high cardiovascular (CV) risk, established cardiovascular 
disease (CVD), or chronic kidney disease (CKD).4 
Oral semaglutide (Rybelsus®) is the first peptide-based anti-diabetic therapy available for oral 
administration. Based on a comprehensive global clinical development programme (PIONEER), 
once-daily oral semaglutide at dose levels 3, 7 and 14 mg was recently approved as an adjunct to 
diet and exercise to improve glycaemic control in adults with T2D. 
In addition, semaglutide is approved as a subcutaneous (s.c.) formulation (Ozempic®, NN9535, 
based on the global clinical phase 3a programme SUSTAIN) for once-weekly administration for the 
treatment of T2D and reduction of CV risk in patients with T2D and established CV disease. 
2.1 
Trial rationale 
The currently approved oral semaglutide maintenance doses are 7 mg and 14 mg2. Although oral 
semaglutide provided clinically relevant benefits for subjects with T2D at all disease stages, 
approximately 20-40% of the subjects in the PIONEER programme did not achieve the 
recommended level of glycaemic control (HbA1c <7%). Oral semaglutide dose levels higher than 
14 mg may enable such subjects to achieve adequate glycaemic control. 
Dose-dependent effects of oral semaglutide, at doses exceeding the currently maximum 
maintenance dose for the treatment of T2D, have been demonstrated in relation to glycaemic 
control and body weight (trial NN9924-3790). 
To support the approval of higher dose levels of oral semaglutide in T2D, the present randomised 
controlled clinical trial is designed to compare the efficacy, safety and tolerability of oral 
semaglutide 14 mg, 25 mg and 50 mg in subjects with T2D. See Section 4.3 for details on the 
justification of dose. 
2.2 
Background 
The PIONEER programme was a comprehensive clinical programme and including 10 phase 
3a trials comprising 9,543 subjects with T2D, of whom 5,707 were exposed to oral semaglutide. 
The programme confirmed a favourable benefits/risk profile of oral semaglutide in a broad and 
representative population of subjects with T2D, ranging from treatment-naïve to insulin-requiring 
subjects, subjects with micro- and macrovascular disease and subjects with moderate renal 
impairment. Clinically relevant and sustained improvements in glycaemic control and reductions in 
body weight were demonstrated with the approved maintenance doses of oral semaglutide, and the 
safety and tolerability profiles of oral semaglutide were consistent with those of other GLP-1 RAs.5 
By week 26 in the PIONEER phase 3a programme, oral semaglutide 14 mg had reduced HbA1c by 
up to 1.4% and body weight by 4.4 kg and enabled around 60-80% of the subjects to achieve 
HbA1c <7%5. At week 52, the proportion of subjects who had achieved HbA1c <7% was similar to 
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that at week 26. Hence, 20-40% of subjects had not achieved the recommend glycaemic goal by 
week 26 or 52.  
Dose-dependent reductions in HbA1c and body weight with oral semaglutide at dose levels up to 
40 mg (i.e. around 3 times the currently approved maximum dose level) were demonstrated in the 
oral semaglutide dose-finding phase 2 trial (NN9924-3790). The 40 mg dose level reduced HbA1c 
by 1.9 %-points and body weight by 7 kg.  
The proportion of subjects with adverse events (AEs) and the number of AEs increased with 
increasing oral semaglutide dose in trial NN9924-3790. The proportion of subjects who 
discontinued treatment prematurely due to an AE was higher with oral semaglutide compared to 
placebo and appeared to increase with increasing dose of oral semaglutide. The AEs were mainly 
gastrointestinal (GI) AEs; however, most were transient and mild to moderate in severity. A low 
starting dose of oral semaglutide and slow dose escalation were associated with lower rates of 
GI AEs during dose escalation and hence lower treatment discontinuation J initiating treatment with 
a low dose of oral semaglutide had a greater effect on mitigating GI AEs than a slow dose 
escalation, which is why dose escalation at a starting dose of 3 mg was implemented in the 
PIONEER programme. The rate of SAEs was low across oral semaglutide groups, and no fatal 
events were reported in any treatment group in the NN9924-3790 trial. Thus, although the 
frequency of GI AEs also appeared to be dose dependent, all dose levels investigated in trial 
NN9924-3790 (including 40 mg) were found to be safe and well tolerated, and no unexpected safety 
concerns were identified.  
A comprehensive review of results from the nonclinical and clinical studies of oral semaglutide can 
/23<B;16;A520B??2;A216A6<;<3A526;C2@A64.A<?N@/?<05B?25, and any updates hereof. 
2.3 
Benefit-risk assessment 
Main benefits and risks are described in the below sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events (AEs) of oral 
semaglutide :.F/23<B;16;A526;C2@A64.A<?N@/?<05B?25, prescribing information2 or summary of 
product characteristics.6  
2.3.1 
Risk assessment 
Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Trial treatment (semaglutide) 
Gastrointestinal 
(GI) disorders 
Consistent with other GLP-1 RAs, the most 
frequent AEs with semaglutide are GI 
(nausea, vomiting and diarrhoea). In 
general, these reactions are mild or 
moderate in severity, of short duration, and 
dose dependent.   
 
In subjects treated with GLP-1 RAs, 
nausea, vomiting and diarrhoea may lead to 
significant dehydration. This should be 
considered when treating subjects with 
impaired renal function as it may cause a 
deterioration of renal function.  
Clinical trials have shown that a low starting 
dose and gradual dose escalation mitigate the 
risk of developing GI symptoms.  
 
Subjects with GI symptoms are recommended to 
drink plenty of fluids to avoid volume depletion. 
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Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Trial treatment (semaglutide) 
Hypoglycaemia 
There is a low risk of hypoglycaemic 
episodes when semaglutide is used as 
monotherapy. Subjects treated with 
semaglutide in combination with 
sulfonylurea or insulin may have an 
increased risk of hypoglycaemia.  
The risk of hypoglycaemia can be lowered by 
reducing the dose of sulfonylurea or insulin 
when initiating treatment with semaglutide. 
 
Diabetic 
retinopathy 
complications  
A 2-year clinical trial with s.c. semaglutide 
(NN9535-3744) investigating 3,297 
subjects with T2D, high CV risk, long 
duration of diabetes and poorly controlled 
blood glucose. In this trial, adjudicated 
events of diabetic retinopathy 
complications occurred in more subjects 
treated with s.c. semaglutide (3.0%) 
compared to placebo (1.8%). This was 
observed in insulin-treated subjects with 
known diabetic retinopathy. The treatment 
difference appeared early and persisted 
throughout the trial. Systematic evaluation 
of diabetic retinopathy complication was 
only performed in the CV outcomes trial 
with s.c. semaglutide. In clinical trials with 
oral semaglutide of up to 18 months 
duration involving 6,352 subjects with 
T2D, adverse event related to diabetic 
retinopathy were reported in similar 
proportions in subjects treated with 
semaglutide (4.2%) and comparators 
(3.8%).  
Rapid improvement in glucose control has been 
associated with a temporary worsening of 
diabetic retinopathy, but other mechanisms 
cannot be excluded. Long-term glycaemic 
control decreases the risk of diabetic retinopathy. 
These subjects should be monitored closely and 
treated according to clinical guidelines.  
 
Subjects with uncontrolled and potentially 
unstable diabetic retinopathy or maculopathy 
will not be enrolled in this trial. 
Allergic reactions 
As with all protein-based pharmaceuticals, 
treatment with semaglutide may evoke 
allergic reactions, including serious allergic 
reactions such as angioedema and 
anaphylactic reactions.  
As a precaution, subjects with known or 
suspected hypersensitivity to semaglutide or 
related products will not be enrolled in this trial. 
In addition, subjects will be instructed to contact 
the site staff as soon as possible for further 
guidance if suspicion of a hypersensitivity 
reaction to the trial product occurs. 
Acute pancreatitis 
Acute pancreatitis has been observed with 
the use of GLP-1 RAs. In the completed 
phase 3 trials with s.c. semaglutide and oral 
semaglutide, both the event rate and the 
proportion of subjects experiencing 
confirmed pancreatitis were similar with 
semaglutide and comparator. Few events 
were confirmed; the events occurred 
throughout the trial periods and the overall 
rates were similar to the rates reported in 
background populations. 
Subjects should be informed of the characteristic 
symptoms of acute pancreatitis and if 
pancreatitis is suspected, semaglutide should be 
discontinued. If confirmed, semaglutide should 
not be restarted. 
Neoplasms 
(malignant and 
non-malignant) 
Patients with T2D, as well as patients with 
overweight or obesity, have an increased 
risk of certain types of cancer. There is no 
evidence from clinical trials that GLP-1-
based therapies increase the risk of 
neoplasms. However, in the s.c. 
semaglutide as well as oral semaglutide 
phase 3a trials, the proportion of subjects 
with neoplasms (malignant and non-
Subjects with presence or history of malignant 
neoplasm within 5 years prior to the day of 
screening will not be enrolled in this trial. Basal 
and squamous cell skin cancer and any 
carcinoma in-situ is allowed 
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Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Trial treatment (semaglutide) 
malignant) were slightly higher with 
semaglutide than with comparator. The 
number of subjects exposed to s.c. 
semaglutide or oral semaglutide for a 
longer period is considered insufficient for 
a thorough assessment of the risk of 
neoplasms. 
Pancreatic cancer 
Patients with T2D have an increased risk of 
certain types of cancer such as pancreatic 
cancer. There is currently no support from 
non-clinical studies, clinical trials or post-
marketing data that GLP-1 based therapies 
increase the risk of pancreatic cancer. 
However, pancreatic cancer has been 
classified as a potential class risk for all 
marketed GLP-1 RAs by regulatory 
agencies. There is no indication of an 
increased relative risk in the semaglutide 
treatment groups vs. comparator, including 
placebo. The rates of EAC-confirmed 
events of pancreatic cancer were 
consistently low across trials. 
Subjects with presence or history of malignant 
neoplasm within 5 years prior to the day of 
screening will not be enrolled in this trial. 
Medullary thyroid 
cancer 
Thyroid C-cell tumours were seen in 
mouse and rat carcinogenicity studies after 
daily exposure to semaglutide for 2 years. 
The rodent C-cell tumours are caused by a 
non-genotoxic, specific GLP-1 receptor 
mediated mechanism to which rodents are 
particularly sensitive. No C-cell tumours 
were observed in monkeys after 52 weeks 
exposure up to 52-fold above the clinical 
plasma exposure at 14 mg/day. The GLP-1 
receptor is not expressed in the normal 
human thyroid, and therefore the clinical 
relevance of the findings is considered to 
be low. 
To mitigate this risk, subjects with a family or 
personal history of medullary thyroid carcinoma 
or multiple endocrine neoplasia type 2 (MEN2) 
are excluded from clinical trials with 
semaglutide. 
Risk of COVID-19 
infection in 
relation to trial 
treatment 
Available data does not suggest an 
increased risk of infection or a more severe 
progression of infection when treated with 
oral semaglutide.  
More detailed information about the known risks 
for oral semaglutide may be found in the 
6;C2@A64.A<?N@/?<05B?25, Prescribing 
information7 or Summary of product 
characteristics.6 
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Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Trial treatment (semaglutide) 
Trial procedures 
Risk of COVID-19 
infection in 
relation to 
participation in 
trial 
Subjects may be exposed to the risk of 
COVID-19 transmission and infection in 
relation to site visits if an outbreak is 
ongoing in the given country. 
The risk of COVID-19 transmission in relation 
to site visits is overall considered to be low, 
however this may vary between geographical 
area. To minimize the risk as much as possible, 
the following measures have been taken: 
 
Cautious subject recruitment planning 
ensures controlled subject enrolment in 
countries where the COVID-19 
pandemic is evaluated to be sufficiently 
under control, and at sites where health 
care resources are evaluated to be 
adequate. 
 
The number of physical on-site visits 
has been limited to the extent possible. 
Phone visits have to the extent possible 
replaced on-site visits. 
 
On-site visits will be well-prepared and 
as short as possible. Physical contact 
between subjects and site staff will be 
limited to the extent possible, and 
protective measures will be 
implemented. 
 
A COVID-19 mitigation plan has been 
developed for this trial which lists the 
additional actions to consider in case a 
site or country are locked down and 
subjects cannot attend on-site visits. 
Other 
Pregnancy and 
fertility 
Studies in animals have shown 
reproductive toxicity. There are limited 
data from the use of semaglutide in 
pregnant women. 
Semaglutide should not be used during 
pregnancy. Women of childbearing potential are 
required to use highly effective contraceptive 
methods when participating in this trial 
(Appendix 4 (Section 10.4), Table 10-3). If a 
subject wishes to become pregnant, or pregnancy 
occurs, semaglutide should be discontinued 
(please refer to Section 8.3.5 for further 
guidance). The effect of semaglutide on fertility 
in humans is unknown.  
2.3.2 
Benefit assessment 
Oral semaglutide has demonstrated clinically relevant and dose-dependent improvements in 
glycaemic control and body weight reduction in subjects with T2D. Also, the reduction in HbA1c 
was consistently greater with higher baseline HbA1c.8 Consequently, it is expected that oral 
semaglutide 25 mg and 50 mg will provide improved glycaemic and body weight control in subjects 
with T2D as compared to semaglutide 14 mg, the current maximum maintenance dose approved. 
All subjects will therefore be treated with a regimen expected to be more efficacious compared to 
the treatment they receive at trial entry. 
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In addition, it is expected that all subjects will benefit from participation through close contact with 
the trial site with close monitoring and treatment of T2D and a careful medical examination, all of 
which will most likely result in an intensified management of their diabetes. 
Investigators will ensure that subjects are treated according to recommended standard-of-care for 
T2D management. Safety and efficacy will be monitored regularly, and acceptable glycaemic 
control will be reinforced at all times during the trial. 
All subjects in this trial will receive trial product and auxiliary supplies free of charge. 
2.3.3 
Overall benefit-risk conclusion 
Necessary precautions have been implemented in the design and planned conduct of the trial in 
order to minimise the risks and inconveniences of participation in the trial. The safety profile for 
semaglutide generated from the clinical and non-clinical development programme has not revealed 
any safety issues that would prohibit administration of oral semaglutide doses up to 50 mg once 
daily. The results of the phase 2 trial (NN9924-3790) indicate a dose-dependent reduction of HbA1c 
and body weight following treatment with oral semaglutide. 
It is therefore concluded that the potential benefits from the trial will outweigh the potential risks 
for the subjects. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of oral @2:.49BA612:.F/23<B;16;A52 ;C2@A64.A<?N@?<05B?2 5 and 
any updates hereof. 
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3 
$&#! $# 
3.1 
Primary and secondary objectives, and estimands 
Primary objective 
To confirm superiority of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on HbA1c reduction in 
subjects with T2D on stable dose of 1-3 OADs. 
Secondary objectives 
To confirm superiority of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on body weight 
reduction in subjects with T2D on a stable dose of 1-3 OADs. 
To compare the efficacy of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on parameters related 
to glycaemic control in subjects with T2D on a stable dose of 1-3 
OADs. 
To compare the efficacy of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on parameters related 
to weight-related outcomes in subjects with T2D on a stable dose of 1-
3 OADs. 
To compare the safety and tolerability of oral semaglutide 25 mg and 
50 mg once daily versus oral semaglutide 14 mg once daily in subjects 
with T2D on stable dose of 1-3 OADs. 
Estimands 
For the primary and the confirmatory secondary objective, estimands of primary interest and 
additional estimands are defined. The estimands are used to address the trial objectives in terms of 
two different aspects of the treatment effect of oral semaglutide 14, 25 and 50 mg. Three 
intercurrent events are considered: Premature trial treatment discontinuation (due to any reason), 
change in dose and initiation of additional anti-diabetic medication. Intercurrent events are events 
occurring after treatment initiation that affect the interpretation or the existence of the 
measurements associated with the questions of interest.  
The estimands for the primary objective are introduced below and the attributes of the estimands are 
summarised in Table 3-1. Additional details are available in Section 9.  
Similar estimands are applied to the objective related to superiority in change in body weight. 
The primary estimand addresses the main question of interest: What is the efficacy of oral 
semaglutide 25 and 50 mg versus oral semaglutide 14 mg on change from baseline to week 52 in 
HbA1c in subjects with T2D on stable dose of 1-3 OADs regardless of premature trial treatment 
discontinuation, changes in dose and initiation of additional anti-diabetic medication.  
For this estimand, the treatment policy strategy is applied for all intercurrent events (Section 9.3 and 
Table 9-3). Data collection will continue after an intercurrent event and the collected data will be 
included in analyses regardless of the occurrence of the event. 
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Results based on the primary estimand are expected to mirror the clinical practice scenario because 
the estimand considers both the efficacy and tolerability of oral semaglutide. In addition, a similar 
estimand is represented in the label for Rybelsus®. 
The additional estimand addresses an additional question of interest: What is the efficacy of oral 
semaglutide 25 and 50 mg versus oral semaglutide 14 mg on change from baseline to week 52 in 
HbA1c in subjects with T2D on stable dose of 1-3 OADs regardless of change in dose of trial 
treatment and if all subjects had remained on trial treatment without use of rescue medication.  
For this estimand, a hypothetical strategy is applied for two of the intercurrent events (premature 
trial treatment discontinuation and initiation of rescue medication). The treatment policy strategy is 
used to handle any changes in trial treatment dose level because this intercurrent event is part of the 
pre-specified treatment regimen.  
The additional estimand is considered relevant because it quantifies the achievable treatment effect 
without potentially confounding effects of any rescue medication. Further, results obtained with the 
additional estimand allows for comparison with results from the oral semaglutide phase 3a 
programme (PIONEER), which applied a similar additional estimand.  
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Table 3-1 
Estimands 
Objective 
Estimand 
category 
Attributes 
Treatment condition 
Variable / 
endpoint 
Population of 
interest 
Intercurrent events and 
strategy 
Population-
level summary 
measure 
Primary objective: 
To confirm superiority of oral semaglutide 
25 mg and 50 mg once daily versus oral 
semaglutide 14 mg once daily on HbA1c 
reduction in subjects with T2D on stable 
dose of 1-3 OADs 
Primary  
 
The effect of high doses of oral semaglutide with 
or without additional anti-diabetic medication 
versus the effect of oral semaglutide 14 mg with or 
without additional anti-diabetic medication, both 
as add-on to stable dose of 1-3 OADs 
Change in 
HbA1c from 
baseline to 
week 52 
T2D subjects as 
defined by the 
protocol inclusion 
and exclusion criteria 
Treatment policy 
strategy for: 
 
Premature trial 
treatment 
discontinuation 
 
Dose change 
 
Initiation of 
additional anti-
diabetic medication 
Difference in 
means 
Additional*  
The effect of high doses of oral semaglutide 
without rescue medication versus the effect of oral 
semaglutide 14 mg without rescue medication, 
both as add-on to stable dose of 1-3 OADs 
Hypothetical strategy 
for: 
 
Premature trial 
treatment 
discontinuation 
 
Initiation of rescue 
medication 
Treatment policy 
strategy for: 
 
Dose change 


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Objective 
Estimand 
category 
Attributes 
Treatment condition 
Variable / 
endpoint 
Population of 
interest 
Intercurrent events and 
strategy 
Population-
level summary 
measure 
Secondary objective: 
To confirm superiority of oral semaglutide 
25 mg and 50 mg once daily versus oral 
semaglutide 14 mg once daily on body 
weight reduction in subjects with T2D on 
stable dose of 1-3 OADs 
Secondary  
The effect of high doses of oral semaglutide with 
or without additional anti-diabetic medication 
versus the effect of oral semaglutide 14 mg with or 
without additional anti-diabetic medication, both 
as add-on to stable dose of 1-3 OADs 
Change in body 
weight from 
baseline to 
week 52 
T2D subjects as 
defined by the 
protocol inclusion 
and exclusion criteria 
Treatment policy 
strategy for: 
 
Premature trial 
treatment 
discontinuation 
 
Dose change 
 
Initiation of 
additional anti-
diabetic medication 
Difference in 
means 
Additional*  
The effect of high doses of oral semaglutide 
without rescue medication versus the effect of oral 
semaglutide 14 mg without rescue medication, 
both as add-on to stable dose of 1-3 OADs 
Hypothetical strategy 
for: 
 
Premature trial 
treatment 
discontinuation 
 
Initiation of rescue 
medication 
Treatment policy 
strategy for: 
 
Dose change 
* Not related to the confirmatory hypotheses  
Similar estimands are defined for the other efficacy objectives.


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3.2 
Primary and secondary endpoints 
3.2.1 
Primary endpoint 
Endpoint title 
Timeframe 
Unit 
Change in glycated haemoglobin (HbA1c) 
From baseline (week 0) to week 52 
%-point 
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoints 
3.2.2.2 
Supportive secondary endpoints 
Endpoint title 
Timeframe 
Unit 
Change in fasting plasma glucose (FPG) 
From baseline (week 0) to week 52 
mmol/l 
Achievement of HbA1c <7% (Yes/No)  
At week 52 
Count of subjects 
Achievement of HbA1c H-2@	%< 
At week 52 
Count of subjects 
Relative change in body weight  
From baseline (week 0) to week 52 
Percentage (%) 
Change in waist circumference 
From baseline (week 0) to week 52 
cm 
0562C2:2;A<3D2645A9<@@I-2@	%< 
At week 52 
Count of subjects 
0562C2:2;A<3D2645A9<@@I
-2@	%< 
At week 52 
Count of subjects 
Adverse events 
From baseline (week 0) to follow-up visit 
(week 73) 
Count of events 
Endpoint title 
Timeframe 
Unit 
Change in body weight  
From baseline (week 0) to week 52 
kg 
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4
"#
4.1
Overall design
This is a 68-week, randomised, active-controlled, double-blinded, three-armed, multi-centre, 
multinational clinical trial. 
Eligible subjects will be randomised in a 1:1:1 manner to receive either: 

oral semaglutide 50 mg once daily

oral semaglutide 25 mg once daily

oral semaglutide 14 mg once daily
Randomisation will be stratified by baseline anti-diabetic medication: ± SU, ±SGLT2 inhibitor, 
±terminated DPP-4 inhibitor. Consequently, randomisation will comprise 8 strata for combinations 
of SU, SGLT2 inhibitor, and terminated DPP-4 inhibitor. Metformin is not included in the 
stratification. A 30% cap on DPP-4 inhibitor users will be implemented to equalise the 
representation of baseline background anti-diabetic medication across the population.
The trial comprises a 2-D228@0?22;6;4=2?6<1A<.@@2@@A52@B/720AN@29646/696AF3<99<D21/F.
randomisation visit (V2) and a 68-week treatment period. The treatment period is divided into a 
dose escalation period of 8-16 weeks and a maintenance period of 52-60 weeks. After the end-of-
treatment visit (V16), all subjects will enter a follow-up period of 5 weeks, ended by a follow-up 
visit (V17), which corresponds to the end of the trial. The planned total trial duration for the 
individual subject is approximately 75 weeks (including screening).
The trial design is illustrated in Figure 4-1
Figure 4-1
Trial design
4.2
Scientific rationale for trial design
The trial has been designed as an active-controlled, double-blinded, parallel, three-armed trial to 
ensure a direct comparison of oral semaglutide 25 mg, 50 mg, and 14 mg.
A randomised, double-blind trial design was chosen to minimise bias in the assessment of the 
efficacy and safety of oral semaglutide 25 and 50 mg. The formulation (shape and composition) of 
the tablets, used for the 25 mg and 50 mg dose levels, has been updated to improve bioavailability 
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as compared to the formulation of the tablets used for the 14 mg dose level. Consequently, the 
shape of the tablets will have a minor difference and will not be visually identical. However, the 
double-blind design is considered justified because: 1) identical primary and secondary packaging is 
used for all tablets in all treatment arms; 2) a third-party, who is only allowed to be involved in trial 
product handling will be responsible for drug accountability (see Section 6.3). Of note, a double-
dummy design was not considered feasible considering the dosing conditions for oral semaglutide.  
The planned treatment duration of the trial is 68 weeks, with an additional 5 weeks of follow-up to 
account for the exposure and long half-life of semaglutide. An evaluation of the efficacy-related 
parameters after a 52-week treatment period is considered appropriate and in line with regulatory 
guidance and with previous trials in T2D, including the PIONEER phase 3a trials. A total treatment 
duration of 68 weeks will ensure a robust safety and tolerability evaluation. 
Predictions based on PIONEER and SUSTAIN exposure-response modelling indicate stabilisation 
or minimal increase in the effect of semaglutide on HbA1c beyond 26 weeks of treatment. The 
exposure-response models indicate, however, additional weight benefit at week 52 compared to 
week 26 based on approximately 30 weeks on maintenance dose. The primary and confirmatory 
secondary endpoints are therefore defined after 52 weeks of treatment. 
Evaluation of the 20-40% of subjects failing to reach the glycaemic target of HbA1c <7% after 26 
weeks on oral semaglutide 14 mg in the PIONEER phase 3a programme suggests that the 
population likely to particularly benefit from a dose of oral semaglutide higher than 14 mg is 
characterised by high baseline HbA1c (>8%) and high baseline BMI (>25 kg/m2). Such patients with 
T2D in need of treatment intensification are very likely to receive a broader range of anti-diabetic 
medication at baseline; therefore, treatment with stable dose of 1-3 oral anti-diabetic drugs (OADs) 
at baseline is allowed (see Section 5.1).  
This population is considered to be clinically relevant, because it is likely to benefit both from the 
better glycaemic control and the additional body weight loss anticipated to be achievable with the 
higher doses of oral semaglutide. 
4.3 
Justification for dose 
The oral semaglutide doses of 25 mg and 50 mg are chosen to ensure that the increments between 
the doses provide clinically meaningful differentiation between their effects on glycaemic control 
while displaying a satisfactory safety and tolerability profile.  
Relative to formulation used for the currently approved doses of Rybelsus®, the formulation for oral 
semaglutide 25 mg and 50 mg has been changed with regards to excipient composition. This change 
in formulation is based on results from trial NN9924-4427, as it is anticipated that the new 
formulation will lead to improved bioavailability relative to the formulation for the currently 
approved doses of Rybelsus®. In trial NN9924-4427, exposure of healthy male subjects to once 
daily dosing of the new formulation of oral semaglutide (5 days on 3 mg and 5 days on 7 mg) 
resulted in an increase in semaglutide exposure by approximately 25% compared to the formulation 
of the currently marketed doses of oral semaglutide (Rybelsus®). 
Using pharmacokinetic (PK) simulations and assuming dose-proportionality, 25 mg and 50 mg 
semaglutide are expected to result in Cavg of 36.5 (90% range:11.4-92.3) nmol/L and 72.9 (90% 
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range:22.8-184.7) nmol/L, respectively. The simulated oral semaglutide concentrations are based on 
a population PK model developed on a trial population matching subjects on 14 mg oral 
semaglutide from PIONEER 1, 2, 8 and 9 (trials NN9924-4233, 4223, 4280 and 4281).  
An exposure level higher than the one potentially reached with steady-state treatment of 25 mg oral 
semaglutide has already been tested in previous trials with oral and s.c. semaglutide. In the oral 
semaglutide phase 2 trial (NN9924-3790), subjects with T2D received up to 40 mg oral 
semaglutide. In this trial, the highest Cavg observed in the highest dose arm (40 mg) was 
185 nmol/L.  
The semaglutide exposure level potentially reached with steady-state treatment of 50 mg oral 
semaglutide (Cavg of 72.9 [90% range: 22.8-184.7] nmol/L) are similar to or may be higher than 
dose levels previously tested. Approximately 5% of subjects on 50 mg are likely to achieve an 
exposure level above the maximum exposure level observed with oral semaglutide in trial NN9924-
3790 (highest Cavg observed was 185 nmol/L) where subjects were treated with doses up to 40 mg. 
In addition, s.c. semaglutide 0.3 mg and 0.4 mg once daily (corresponding to a weekly dose of 2.1 
mg and 2.8 mg, respectively) have been dosed to subjects with T2D or obesity in trials NN9535-
4191 and NN9536-4153, respectively. In the obese population, the highest observed Cavg for s.c. 
semaglutide 0.4 mg was 128 nmol/L (trial 4153). No unexpected safety or tolerability findings were 
observed in either of the trials. 
Based on prior experience with oral semaglutide (NN9924-3790 and the PIONEER programme) 
and other GLP-1 RAs, low starting dose and gradual dose escalation of oral semaglutide is expected 
to mitigate the risk of developing GI symptoms. To increase GI tolerability, possible dose 
reductions and extensions of dose-escalation periods will be introduced based on clinical evaluation 
made by the investigator (see Section 6.6). 
4.4 
End of trial definition 
A subject is considered to have completed the trial if he/she has completed all phases of the trial, 
including the follow-up visit (V17). 
The end of the trial is defined as the date of the last visit of the last subject in the trial globally. 
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5 
"! !%$  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
2. Male or female, age above or equal to 18 years at the time of signing informed consent. 
3. 6.4;<@21D6A5AF=216./2A2@:2996AB@I
1.F@=?6<?A<A521.F<3@0?22;6;4 
4. HbA1c of 8.0-
P:mol/mol) (both inclusive). 
5. $ I5.0 kg/m2. 
6. Stable daily dose(s) for 90 days prior to the day of screening of: any of the following treatment 
regimens: 
- 
No more than 3 of the following oral anti-diabetic drugs and at least 1 marked with a *: 
o * $2A3<?:6;I1500 mg or maximum tolerated or effective dose). 
o * (B93<;F9B?2.@(*I5.93<3A52:.E6:B:.==?<C211<@2.00<?16;4A<9<0.99./29
or maximum tolerated or effective dose). 
o * SGLT2 inhibitors (maximum tolerated dose). 
o DPP-4 inhibitors (maximally indicated dose as per local label). 
7. Subjects, on treatment with stable dose of DPP-4 inhibitors at inclusion, must be willing to 
terminate DPP-4 inhibitor treatment at randomisation (with no wash-out). 
Taiwan: for country-specific requirements, please see Appendix 8 (Section 10.8). 
5.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
1. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 90 days prior to the day of screening. However, short-term 
insulin treatment for a maximum of 14 days prior to the day of screening is allowed. 
2. Anticipated initiation or change in concomitant medications (for more than 14 consecutive days) 
known to affect body weight or glucose metabolism (e.g. treatment with orlistat, thyroid 
hormones, or systemic corticosteroids). 
3. Renal impairment measured as estimated glomerular filtration rate (eGFR) value of 
<30 mL/min/1.73 m2 according to CKD-EPI creatinine equation as defined by KDIGO 2012 
classification. 
4. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination. 
5. History of major surgical procedures involving the stomach potentially affecting absorption of 
drugs and/or nutrients, as judged by the investigator. 
6. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma. 
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7. Presence or history of pancreatitis (acute or chronic). 
8. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
9. Presently classified as being in New York Heart Association (NYHA) Class IV. 
10. Planned coronary, carotid or peripheral artery revascularisation. 
11. Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal 
and squamous cell skin cancer and any carcinoma in-situ is allowed. 
12. Known or suspected hypersensitivity to trial products or related products. 
13. Previous participation in this trial. Participation is defined as signed informed consent. 
14. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using a highly effective contraceptive method. 
15. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 3 months before screening*. 
16. Other subject(s) from the same household participating in any oral semaglutide trial 
17. ;F16@<?12?B;D6996;4;2@@<?6;./696AFD56056;A526;C2@A64.A<?N@<=6;6<;:645A72<=.?16@2
@B/720AN@@.32AF<?0<:=96.;02D6A5A52=?<A<0<9 
*Simultaneous participation in a trial with the primary objective of evaluating an approved or 
non-approved investigational medicinal product for prevention or treatment of COVID-19 disease 
or COVID-19 postinfectious conditions is allowed if the last dose of the investigational medicinal 
product has been received more than 30 days before screening. 
Croatia and Germany: for country-specific requirements, please see Appendix 8 (Section 10.8). 
5.3 
Lifestyle considerations 
To ensure alignment regarding performance of assessments across subjects and trial sites, the below 
restrictions apply. 
5.3.1 
Meals and dietary restrictions 
The trial product must: 
 be taken on an empty stomach in the morning at least 30 minutes before intake of food, liquids 
or other oral medicinal products. 
 waiting less than 30 minutes, or taking with food, beverages (other than water) or other oral 
medication will lessen the effect of oral semaglutide. 
 waiting more than 30 minutes might increase the absorption of oral semaglutide. 
 be taken with no more than a half a glass of water equivalent to 120 ml (4 ounces). 
 be swallowed whole. 
 not be split, crushed or chewed. 
Subjects must attend visits fasting according to the flowchart (Section 1.2). Fasting is defined as: 
 no food or liquid, except for water, for at least 6 hours prior to the visit. 
 no water 2 hours prior to the visit. 
Trial product and any medication which should be taken with or after a meal should be withheld on 
the day of the visit until blood samples have been obtained. 
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If the subject is not fasting as required, the subject must be called in for a new visit within the visit 
window to have the fasting procedures performed. 
5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes informed consent date, 
demography, screen failure details, eligibility criteria, completion of end-of-trial form and any 
serious adverse event (SAE). 
A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
5.5 
Run-in criteria and randomisation criteria and dosing day criteria 
Not applicable for this trial. 
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6 
"$$# 
6.1 
Treatments administered 
Investigational medicinal products  
The investigational medicinal products (IMP, trial products) provided by Novo Nordisk are listed in 
Table 6-1. 
Table 6-1 
Investigational medicinal products provided by Novo Nordisk 
Description Trial product (IMP) 
name 
Dosage form 
Route of 
administration 
Dosing instruction 
Packaging 1 
Semaglutide Semaglutide 3 mg 
Tablet 
Oral 
1 tablet in the morning as 
described in Section 5.3.1 
Dose pack 
Semaglutide Semaglutide 7 mg 
Tablet 
Oral 
1 tablet in the morning as 
described in Section 5.3.1 
Dose pack 
Semaglutide Semaglutide 14 mg 
Tablet 
Oral 
1 tablet in the morning as 
described in Section 5.3.1 
Dose pack 
HDPE bottle  
Semaglutide Semaglutide C 25 mg Tablet 
Oral 
1 tablet in the morning as 
described in Section 5.3.1 
HDPE bottle 
Semaglutide Semaglutide C 50 mg Tablet 
Oral 
1 tablet in the morning as 
described in Section 5.3.1 
HDPE bottle  
1: A dose pack contains one blister card with 7 tablets. A high density polyurethane (HDPE) bottle contains 30 tablets. 
Directions for use 
 
The investigator must document that directions for use (DFU) are given to the subject orally at the 
first dispensing visit (as specified in the flowchart in Section 1.2). The investigator should remind 
subjects of dosing instructions (as described in Section 5.3.1) ongoing throughout the trial, as 
applicable. 
Participants must be instructed to take oral semaglutide at least 30 min before the first food, 
beverage or other oral medications of the day with no more than 120 mL or 4 ounces of plain water. 
Waiting less than 30 minutes, or taking food, beverages (other than plain water) or other oral 
medications will lessen the effect of oral semaglutide. Waiting more than 30 minutes to eat may 
increase the absorption of oral semaglutide. The tablet must be swallowed whole. The tablet must 
not be cut, crushed or chewed.  
Dose escalation 
Dose escalation of oral semaglutide should take place during the first 8-16 weeks after 
randomisation as illustrated in Table 6-2. All subjects should aim at reaching the randomised target 
dose of oral semaglutide once daily. 
 
 
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Table 6-2 
Treatment overview 
 
 
Dose escalation/maintenance 
Maintenance 
Follow-up 
Trial periods 
Screening 
Randomisation/ 
Treatment-
period 1 
Treatment- 
period 2 
Treatment- 
period 3 
Treatment- 
period 4 
Treatment- period 5 End of treatment 
Duration of each 
period 
2 weeks 
4 weeks 
4 weeks 
4 weeks 
4 weeks 
52 weeks 
5 weeks 
Treatment arm 
Oral semaglutide  
50 mg 
Screening 
Oral  
semaglutide 
3 mg 
Dose pack 
Oral 
semaglutide 
7 mg 
Dose pack 
Oral 
semaglutide 
14 mg 
Dose pack 
Oral 
semaglutide 
25 mg 
HDPE bottle 
Oral semaglutide 
50 mg 
HDPE bottle 
Follow-up 
Oral semaglutide  
25 mg 
Screening 
Oral  
semaglutide  
3 mg  
Dose pack 
Oral 
semaglutide 
7 mg 
Dose pack 
Oral 
semaglutide 
14 mg 
Dose pack 
Oral 
semaglutide 
25 mg 
HDPE bottle 
Oral semaglutide 
25 mg 
HDPE bottle 
Follow-up 
Oral semaglutide  
14 mg 
Screening 
Oral  
semaglutide  
3 mg 
Dose pack 
Oral 
semaglutide 
7 mg 
Dose pack 
Oral 
semaglutide 
14 mg 
Dose pack 
Oral 
semaglutide 
14 mg 
HDPE bottle 
Oral semaglutide 
14 mg 
HDPE bottle 
Follow-up 
HDPE = High density polyurethane. 
Missed doses 
If a dose is missed, the missed dose should be skipped, and the next dose should be taken the 
following day.  
If consecutive doses of trial treatment are missed, the subject should be encouraged to re-commence 
A52A?2.A:2;A630<;@612?21@.32.@=2?A526;C2@A64.A<?N@16@0?2A6<;.;163A52@B/720A1<2@;<A:22A
any of the discontinuation criteria (Section 7.1). The trial treatment should be continued as early as 
the situation allows. If the subject has been off treatment for more than 10 consecutive days, the 
investigator should consult Novo Nordisk global medical experts for guidance regarding 
continuation of trial medication. 
Auxiliary supplies 
The following auxiliary supplies will be provided by Novo Nordisk: 
 Blood glucose (BG) meter and related auxiliaries 
Subjects will be instructed in how and when to use the BG meter and the instructions will be 
repeated during the trial as needed. 
Shipment of trial product to #%$)# home 
For selected countries and if permitted by local regulations, the investigator may offer to send trial 
product and auxiliaries from the trial site or pharmacy to the @B/720AN@home by courier service. 
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The process for sending trial product from the trial site or pharmacy to a @B/720AN@ home is 
12@0?6/216;A52K)?6.9@6A2	=5.?:.0F6;@A?B0A6<;3<?@56=:2;A<3A?6.9=?<1B0AA<=.A62;A@N5<:2@L
document. This document contains detailed instructions for preparing packaging and setting up the 
pick-up of trial product, handover of trial product from the trial site or pharmacy staff to the courier, 
required temperature monitoring of trial product, delivery to and receipt of trial product by the 
subject. The process for returning trial product to the trial site or pharmacy by courier is also 
described in this document. 
Investigators, trial site/pharmacy staff and subjects who will be involved in shipment of trial 
product to the @B/720AN@ home will be adequately trained in this process. 
Please note that the drug dispensing and accountability are handled by the third-party, as described 
in Section 4.2 and 6.3. 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply trial product. 
 Each site will be supplied with sufficient trial products for the trial on an ongoing basis. Trial 
products will be distributed to the sites according to screening and randomisation. 
 The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that any discrepancies are reported 
and resolved before use of the trial products. 
 All trial products must be stored in a secure, controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the investigator 
and delegated site staff. 
 The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. The trial product must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. Additional details regarding 
handling of temperature deviations can be found in the trial materials manual (TMM). 
 The investigator or designee is responsible for drug accountability and record maintenance (i.e. 
receipt, accountability and final disposition records). 
 The investigator or designee must instruct the subject in what to return at next visit. 
 Drug accountability must be performed in the IWRS by registering tablets as returned either un-
used or as lost. 
 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.  
Destruction of trial product must be documented in the IWRS. 
 All returned, un-used, expired or damaged trial products (for technical complaint samples, see 
Section 10.5) must be stored separately from non-allocated trial products. No temperature 
monitoring is required. 
 Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
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6.3 
Measures to minimise bias: Randomisation and blinding 
All subjects will be centrally screened and randomised using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Trial treatment will be dispensed/allocated 
at the trial visits summarised in the flowchart (Section 1.2). 
Subjects will be randomly assigned in a 1:1:1 ratio to receive trial treatment. 
At screening, each subject will be assigned a unique 6-digit subject number which will remain the 
same throughout the trial. Each site is assigned a 3-digit number and all subject numbers will start 
with the site number. 
Dose reduction to lower doses than 14 mg is not allowed (see Section 6.6). Consequently, the 
allowed dose reduction steps will not induce change of trial product packaging and therefore not 
compromise the double-blinded trial design. 
Investigators and site personnel are to remain blinded throughout the trial. Due to the minor 
differences in tablet shapes, the primary and secondary packaging are identical in all treatment arms 
to maintain the blinding (see Section 4.2). Further, a third-party will be responsible for drug 
accountability of all trial products and an unblinded monitor will be responsible for drug 
reconciliation (see Section 10.1.8.2). It will not be possible for the third-party or the unblinded 
monitor to see the actual treatment. The third-party will also be allowed to handle trial product 
arrival and temperature monitoring of trial product including handling of potential temperature 
deviations. The unblinded monitor will also be allowed to check documentation regarding potential 
temperature deviations. The unblinded monitor will also be allowed to check documentation 
regarding above tasks and be involved in trial product destruction according to local procedures. 
It is recommended that the third-party also is responsible for dispensing of all trial products, but in 
case site personnel and/or investigator needs to be responsible for dispensing of trial products, they 
are only allowed to handle trial product in its original packaging material (unbroken packaging). 
The third-party and the unblinded monitor will not be involved in any other trial procedures. 
The IWRS is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of .@B/720A@NA?2.A:2;A6@D.??.;A21(B/720A@.32AF
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 u;/96;16;4.@B/720A@NA?2.A:2;AB;92@@A56@0<B91129.F2:2?42;0F
A?2.A:2;A<3A52@B/720A 3.@B/720AN@A?2.A:2;A6@B;/96;121%<C<%<?16@89</.9(.32AF
department) must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation.  
The person breaking the blind must print the "code break confirmation" notification generated by 
the IWRS, sign and date the document. If IWRS is not accessible at the time of blind break, the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I. Subject will 
continue on trial treatment after blind break. 
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6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. Compliance is defined as taking between 
80%-120% of the dose as prescribed between visits.  
When subjects self-administer trial treatment at home, compliance with trial treatment will be 
assessed and the assessment documented in source documents at each visit where information is 
available. If any suspicion of non-compliance arises, the site must enter into a dialogue with the 
subject, 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 
 Questioning of subjects about missed doses 
Treatment start and stop dates will be recorded in the electronic case report form (eCRF). 
6.5 
Concomitant medication 
Any medication (including over-the-counter (OTC) or prescription medicines) other than the trial 
treatment that the subject is receiving at the time of the first visit or receives during the trial must be 
recorded along with: 
 Trade name or generic name 
 Indication 
 Dates of administration including start and stop dates 
 Dose (only to be recorded for anti-hyperglycaemic medication and levothyroxine) 
 Time of dosing (only to be recorded for levothyroxine) 
 Medication administered in relation to a clinical trial for COVID-19 prevention or treatment 
 Approved COVID-19 vaccine 
After signing the informed consent, subjects must continue their OADs (with the exception of 
DPP-4 inhibitors J see Section 4.1 and 5.1) at the same dose level and with the same dosing 
frequency throughout the entire treatment period unless safety concerns related to the use their 
OADs arise.  
To mitigate SU-induced hypoglycaemia, subjects treated with SU should, at the discretion of the 
investigator, reduce the SU dose at randomisation by approximately 50%. 
Apart from the initial dose reduction of SU, background medication dose should remain at the same 
dose level and with the same frequency during the entire treatment period unless glycaemic rescue 
treatment is needed (as described in Section 7.1.2) or safety concern related to the use of 
background medications arises. 
Investigators can switch OAD treatment within the same drug class, e.g. in case specific drugs 
become unavailable. 
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Changes in concomitant medication, including switch of OAD treatment within the same drug class, 
must be recorded at each visit. If a change is due to an AE, then this must be reported according to 
Section 8.3. 
Croatia and Germany: for country-specific requirements, please see Appendix 8 (Section 10.8). 
6.5.1 
Rescue medication 
Glycaemic rescue medication, i.e. intensification of background OAD treatment and/or initiation of 
new anti-hyperglycaemic treatment, should be implemented at the discretion of the investigator in 
case of persistent hyperglycaemia. Please see Section 7.1.2. 
Rescue medication should be selected according to American Diabetes Association 
(ADA)/European Association for the Study of Diabetes (EASD) guideline4 (excluding GLP-1 RAs, 
DPP-4 inhibitors and amylin analogues).  
Subjects that are started on rescue medication should continue to follow the protocol-specified visit 
schedule and stay on randomised treatment unless the investigator judge that it jeopardises sB/720AN@
safety. 
Rescue medication should be documented in medical records and reported on the concomitant 
medication form in the electronic case report form (eCRF). 
Rescue medication will not be supplied by Novo Nordisk. 
6.6 
Dose modification 
Subjects should be dose escalated as indicated in Table 6-2 and Figure 4-1. However, if treatment 
with oral semaglutide 25 mg and 50 mg are associated with unacceptable GI AEs (moderate to 
severe), dose reduction or extension of dose escalation intervals are allowed in treatment period 4 
and 5 (see Table 6-2) if the GI AEs are causally related to the trial treatment as judged by the 
investigator. This is to accommodate subject tolerability and safety. In these specific, expected rare 
cases dose adjustments are at the discretion of the investigator. It is recommended that the subject 
makes at least one attempt to re-escalate to the recommended target dose. 
Dose reduction to lower doses than 14 mg is not allowed.  
It is mandatory that the investigator consults Novo Nordisk in case of persistent deviations from the 
planned escalation regimen. 
6.7 
Treatment after end of trial 
When discontinuing trial treatment, the subject should be transferred to a suitable marketed product 
at the discretion of the investigator. 
Considering the long half-life of semaglutide and to avoid over-exposure to GLP-1 RAs and 
interference with safety data collection, initiating GLP-1 RA or DPP-4 inhibitor should be avoided 
between the end-of-treatment visit (V16) and the follow-up visit (V17). 
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7 
# $%$  $"$"$$#%$ 
# $%$ '$"' 
Treatment of a subject may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have subjects attend and complete all scheduled visit procedures. Only 
subjects who withdraw consent will be considered as withdrawn from the trial. Subjects must be 
educated about the continued scientific importance of their data, even if they discontinue trial 
treatment. 
7.1 
Discontinuation of trial treatment 
Discontinuation of treatment can be decided by both the investigator and the subject. 
Subjects who discontinue trial treatment should continue with the scheduled visits and assessments 
to ensure continued counselling and data collection. 
The trial treatment must be discontinued, if any of the following applies for the subject: 
1. Safety concern 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 investigational medicinal product in another 
clinical trial* 
*Simultaneous participation in a trial with the primary objective of evaluating an approved or 
non-approved investigational medicinal product for prevention or treatment of COVID-19 disease 
or COVID-19 postinfectious conditions is allowed at the investigator discretion without 
discontinuing trial product. 
The subjects should continue with the remaining scheduled visits and assessments until the time of 
the originally scheduled end-of-treatment visit (V16) and follow-up visit (V17). 
All efforts should be made to have the subject attend at least visit V10, V14, the end-of-treatment 
visit (V16) and the follow-up visit (V17). If the subject does not wish to attend the scheduled clinic 
visits, efforts should be made to have the remaining visits converted to phone contacts. If a subject 
is unwilling to attend any of the remaining visits, information about the attempts to follow up with 
A52@B/720A:B@A/21<0B:2;A216;A52@B/720AN@:2160.9?20<?1 
The primary reason for discontinuation of trial treatment must be specified in the end-of-treatment 
form in the eCRF, and final drug accountability must be performed. A treatment discontinuation 
session must be made in the IWRS. 
Croatia and Germany: for country-specific requirements, please see Appendix 8 (Section 10.8). 
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7.1.1 
Temporary discontinuation of trial treatment 
If a subject has discontinued trial treatment due to temporary safety concern not related to trial 
product and treatment with trial product is allowed to be resumed, the guide for missed doses 
(Section 6.1) should be followed. In such cases a treatment discontinuation session should not be 
made in the IWRS. 
In case of suspicion of acute pancreatitis, the trial treatment should promptly be interrupted 
(treatment discontinuation session should not be made in IWRS before diagnosis of acute 
pancreatitis is confirmed). Appropriate actions should be initiated, including local measurement of 
amylase and lipase (see Appendix 3 (Section 10.3) for reporting). 
If acute pancreatitis is confirmed, treatment with trial product should not be restarted, and a 
treatment discontinuation session should be made in IWRS. If the Atlanta criteria9 are not fulfilled 
and thus, the suspicion of acute pancreatitis is not confirmed, treatment with trial product may be 
resumed. 
7.1.2 
Rescue criteria 
Subjects 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 26 and onwards. 
If the HbA1c exceeds the value described below, and no unexpected discrepancies are found in the 
trend of the subjects previous HbA1c values, then the subject should be offered treatment 
intensification (rescue medication) at the discretion of the investigator and in accordance with the 
ADA/EASD guidelines10 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues). 
Rescue medication should be offered from week 26 (V10) to week 68 (V16) to: 
 subjects with persistent poor glycaemic control, as expressed by a stable HbA1c value above 
::<9	:<9.;10<;@612?21B;.002=A./9F5645.00<?16;4A<6;C2@A64.A<?N@
assessment. 
Refer to Section 6.5.1 for description of rescue medication. 
7.2 
Subject discontinuation/withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request. 
If a subject withdraws consent, the investigator must make every effort to collect AEs from last visit 
to withdrawal.  
Final drug accountability must be performed even if the subject is not able to come to the site. A 
treatment discontinuation session must be made in the IWRS. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. 
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Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the CRF. 
7.2.1 
Replacement of subjects 
Subjects who discontinue trial treatment or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the trial. 
 Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
 Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
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8 
"####$#!" %"# 
 The following sections describe the assessments and procedures, while their timing is 
summarised in the flowchart (Section 1.2) and in Appendix 2 (Section 10.2). 
 Informed consent must be obtained before any trial related activity, see Section 10.1.3. 
 All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all inclusion criteria and none of the exclusion criteria. 
 The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
 At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant site staff that can be contacted in case of emergency.  
 Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct.  
 The investigator must ensure to keep regular contact with each subject throughout the entire 
trial, and always have updated contact information. Even if a visit is missed and it is not 
possible to reschedule, every effort must be made to have all subjects followed for the primary 
endpoint and AEs. 
 It is the responsibility of the investigator to schedule the visits and contacts as per the protocol 
flowchart (Section 1.2) and to ensure they take place. See Section 6.4 for treatment compliance. 
 Suggested order of assessments: 
 electrocardiogram (ECG) and vital signs 
 blood samples 
 other assessments 
 Diaries will include the following in relation to the visit they support: 
 Reminders: 
o to attend visit fasting (see flowchart in Section 1.2) 
o to collect first morning urine on day prior to visit and on the day of the visit (see 
Table 10-1) 
o to return trial product at next site visit 
o to return diary at next site visit 
 Instruction on how to use the diary 
 Information to be collected: 
o date of first dose of trial product 
o date and time of last dose prior to PK visit 
o hypoglycaemic events (according to Appendix 6 in Section 10.6) 
o health issues 
 Review of diaries, ECG and laboratory reports must be documented either on the documents or 
in the subject's source documents. If clarification of entries or discrepancies in the diary is 
needed, the subject must be questioned, and a conclusion made in the subject's source 
documents. Care must be taken not to bias the subject. 
 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. 
 Source data of clinical assessments performed and recorded in the CRF must be available and 
D699B@B.99F/2A52@B/720AN@:2160.9?20<?1@Additional recordings to be considered source data 
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include but are not limited to laboratory reports, ECG, diary recordings and clinical outcome 
assessments. Ensure to transcribe the following into the CRF: 
o All information from the diary 
o Evaluations of ECGs 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2) and in 
Appendix 2 (Section 10.2). 
8.1.1 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.1.2 
Body weight 
Body weight will be measured and recorded as specified in the flowchart (Section 1.2).  
Body weight should be measured without shoes and only wearing light clothing and recorded in the 
eCRF in kilogram [kg] or pound [lb] with a precision of 1/10 unit (e.g. 62.2 / 137.2 lb). BMI will be 
calculated in the eCRF. 
8.1.3 
Waist circumference 
Waist circumference will be measured and recorded as specified in the flowchart (Section 1.2). 
Waist circumference is defined as the minimal abdominal circumference located midway between 
the lower rib margin and the iliac crest and will be measured using a non-stretchable measuring 
tape. The measurement of waist circumference should be performed and recorded in the eCRF to 
the nearest ½ cm or ¼inch. The waist circumference should be measured in a standing position with 
an empty bladder and wearing light clothing with accessible waist. The subject should be standing 
with arms down their side and feet together. The measuring tape should touch the skin but not 
compress soft tissue. The subject should be asked to breathe normally, and the measurement should 
be taken when the subject is breathing out gently. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart (Section 1.2).  
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product.  
Medical history is a medical event that the subject experienced prior to the time point from which 
AEs are collected. 
Only relevant and significant medical history including COVID-19 as judged by the investigator 
should be recorded in the eCRF at the screening visit. Findings of specific medical history (diabetes 
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history, comorbidities and history of cardiovascular disease) should de described in designated 
forms. 
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form in the eCRF. 
Any new finding fulfilling the AE definition (see Appendix 3 (Section 10.3)) during the trial and 
any clinically significant worsening from baseline must be reported as an AE (see Section 8.3). 
8.2.1 
Physical examinations 
 A physical examination will include assessments of the following: General appearance, thyroid 
gland, cardiovascular system, respiratory system, gastrointestinal system incl. mouth, central 
and peripheral nervous system, and musculoskeletal system. 
 Investigators should pay special attention to clinical signs related to previous serious illnesses. 
 Height will be measured and recorded as specified in the flowchart (Section 1.2). 
 Height should be measured without shoes in centimetres or inches and recorded to nearest ½ cm 
or ¼ inch. 
8.2.2 
Vital signs 
 Pulse rate as well as systolic and diastolic blood pressure will be assessed as specified in the 
flowchart (Section 1.2). 
 Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest for 
the subject in a quiet setting without distractions (e.g. no use of television, cell phones). 
 Blood pressure and pulse rate measurements will be assessed sitting with a completely 
automated device. Manual techniques must be used only if an automated device is not available. 
 Blood pressure 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.  
Only the last 2 systolic and last 2 diastolic blood pressure readings must be recorded in the 
eCRF. The eCRF will then calculate the mean for systolic and diastolic blood pressure. 
 Pulse rate will be measured in connection to the blood pressure measurements. Record the pulse 
rate for the last 2 blood pressure measurements in the eCRF. The pulse rate is to be recorded as 
the mean of the last 2 measurements. 
8.2.3 
Electrocardiograms 
12-lead ECG will be obtained as outlined in the flowchart (Section 1.2) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals.  
The ECGs will be collected for central storage for potential future assessment. This is to have the 
possibility to go back and evaluate previous ECG data in case of unforeseen or abnormal 
observations that could indicate safety findings or for future scientific purposes related to 
semaglutide, T2D, CV outcome or related diseases.  
Local review for clinically significant abnormal findings must be performed by the investigator. 
ECG must be performed according to the manual from the supplier. 
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8.2.4 
Eye examination 
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention but has yet to be brought under control. 
Results of an eye examination performed by an ophthalmologist or another suitably qualified health 
care provider (e.g. optometrist) must be available and evaluated by the investigator before 
randomisation to assess eligibility. The eye examination should be performed as a fundus 
photography (e.g. 2-field 60 degree or better, colour or red-free) or by slit-lamp biomicroscopy 
examination (e.g. using a pre-corneal or corneal contact lens examination). Pharmacological 
pupil-dilation is a requirement unless using a digital fundus photography camera specified for 
non-dilated examination. 
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her evaluation upon the results of that examination. The examination must 
be repeated before randomisation if the subject has experienced worsening of visual function since 
the last examination. If the applicable eye examination was performed before the subject signed the 
informed consent form, it must be documented that the reason for performing the examination was 
not related to this trial. 
After randomisation, an eye examination performed according to the above must be completed as 
per the flowchart (Section 1.2). An eye examination performed within 2 weeks prior to the 
applicable visits is acceptable, provided that no clinical symptoms suggestive of eye disease have 
occurred in the meantime in case of which a new examination must be completed. The investigator 
should indicate the outcome of each eye examination in the CRF. 
The fundus photography or slit-lamp biomicroscopy examination should be used for evaluation of 
retinopathy or maculopathy. Additional examinations (e.g., optical coherence tomography and/or 
best corrected visual acuity) can be performed as a supplement for further evaluation. However, in 
this trial, additional eye examinations including the optical coherence tomography and/or best 
corrected visual acuity, cannot replace the fundus photography or slit-lamp biomicroscopy 
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). 
Germany and United States of America: for country-specific requirements, please see Appendix 8 
(Section 10.8). 
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. 
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8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on events* 
that meet the definition of an AE or SAE. 
*including AEs of COVID-19, irrespective of seriousness. Note: Suspected COVID-19 should be 
reported if the clinical presentation is suggestive of COVID-19, even in the absence of a COVID-19 
test or without a positive COVID-19 test result. In the absence of clinical symptoms, a positive 
COVID-19 test (antigen or antibody) should be reported, if available. 
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. This always includes 
medication error, misuse and abuse of IMP. The relevant event(s) are listed below in Table 8-1. 
Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs) 
Event type  
Diabetic retinopathy 
Gallbladder disease 
Hepatic Event 
Neoplasm 
Acute pancreatitis 
Acute kidney injury 
Medication error, misuse and abuse 
A detailed description of the events mentioned in the above table can be found in Appendix 3 
(Section 10.3). 
Hypoglycaemic episodes 
Hypoglycaemic episodes require additional data collection on a hypoglycaemic episode form. As 
opposed to AEs requiring additional data collection (Table 8-1), non-serious hypoglycaemic 
episodes do not require an AE form to be filled in. If the hypoglycaemic episode fulfils the criteria 
for an SAE, then, in addition to the hypoglycaemic episodes form, an AE form and a safety 
information form must be filled in, please refer to Appendix 3 (Section 10.3). For more information 
on hypoglycaemic episodes, please refer to Appendix 6 (Section 10.6). 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs must be collected from the screening visit and until the follow-up visit (V17) at 
the time points specified in the flowchart (Section 1.1).  
Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3 (Section 10.3). All SAEs must be recorded and reported to Novo 
Nordisk 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. 
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Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
subject is lost to follow-up as described in Section 7.3. Further information on follow-up and final 
outcome of events is given in Appendix 3 (Section 10.3).  
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk or designee of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/ Independent Ethics Committee (IEC), and 
investigators. This also includes suspected unexpected serious adverse reactions (SUSAR). 
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it along 
with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy 
Details of pregnancies in female subjects will be collected after first exposure to trial product and 
until pregnancy outcome. 
If a female subject becomes pregnant, the investigator should inform Novo Nordisk within 14 
calendar days of learning of the pregnancy and should follow the procedures outlined in Appendix 4  
(Section 10.4). 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3. 
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8.3.7 
Technical complaints 
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5 (Section 10.5). 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form.  
8.4 
Treatment of overdose 
There are no specific antidotes to semaglutide. Effects of overdose with semaglutide may be 
associated with GI disorders. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities, and appropriate supportive treatment should be initiated 
according to the subject@N096;60.9@64;@.;1@F:=A<:@=?<9<;421=2?6<1<3</@2?C.A6<;.;1
treatment for these symptoms may be necessary, taking into account the long half-life of oral 
semaglutide of approximately one week. 
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. 
For more information on overdose, also consult the current version of the oral semaglutide 
investigator's brochure. 
8.5 
Pharmacokinetics 
 Single blood samples for measuring plasma concentration of semaglutide will be drawn on 
visits specified in the flowchart (Section 1.2) and in Appendix 2 (Section 10.2). 
 Subject must be instructed to withhold their trial treatment in the morning of the clinic visit until 
blood sampling has been performed. 
 The exact timing (date and time) of obtaining the pharmacokinetic (PK) sample must be 
recorded on the laboratory form. 
 The exact timing (data and time) of last oral semaglutide dose must be recorded in the eCRF in 
relation to the PK sample 
 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 Trial Report (CTR) 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. Bioanalysis of plasma 
samples for semaglutide will be carried out using a validated LC-MS/MS assay. 
8.6 
Pharmacodynamics 
Not applicable for this trial. 
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8.7 
Genetics 
Not applicable for this trial. 
8.8 
Biomarkers 
Not applicable for this trial. 
8.9 
Immunogenicity assessments 
Anti-semaglutide antibodies 
Blood samples for measurements of binding antibodies against semaglutide will be collected at pre-
specified time points according to Appendix 2 (see Section 10.2) and must be completed pre-dose at 
V2. Blood samples will be collected, but anti-semaglutide antibodies will only be analysed by Novo 
Nordisk or a special lab appointed by Novo Nordisk if deemed necessary for clarification of 
unexpected drug exposure or other safety issues that may be related to antibody formation. If anti-
semaglutide binding antibodies are measured, data as well as assay method description will be 
reported outside the CTR for this trial.  
Procedures for sampling, handling, storage, labelling and shipment of samples must be performed in 
accordance with the laboratory manual. 
Residual antibody samples will be retained (please refer to Appendix 7, Section 10.7). 
8.10 
Health economics 
Not applicable for this trial. 
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9 
$$#$ #"$ # 
9.1 
Statistical hypotheses 
Four confirmatory hypotheses will be evaluated based on the primary and secondary estimand. For 
the primary endpoint, change in HbA1c from baseline to week 52, the following confirmatory one-
sided hypothesis of superiority will be tested for both oral semaglutide 50 mg and 25 mg versus oral 
semaglutide 14 mg. Let the mean treatment difference (higher dose of oral semaglutide - oral 
@2:.49BA612:4/21236;21.@R)52;B99 (H0) and alternative (HA) hypotheses to be tested are: 
H0RI
-point against HAR
-point 
For the confirmatory secondary endpoint, change in body weight from baseline to week 52, the 
following confirmatory one-sided hypothesis of superiority will be tested for both oral semaglutide 
50 mg and 25 mg versus oral semaglutide 14 mg: 
H0RI
84.4.6;@AAR
84 
Operationally, the hypotheses will be evaluated by two-sided tests. 
Multiplicity adjustment 
Adjustment for multiplicity associated with the testing of the four confirmatory hypotheses will be 
done using the weighted Bonferroni-based closed testing procedure described in Bretz et al.11 and 
outlined in Figure 9-1. The type I error will be preserved in the strong sense at a nominal two-sided 
5% level. The first hypothesis to be tested is superiority of oral semaglutide 50 mg vs 14 mg on 
change from baseline in HbA1c. It will be tested at the overall significance level (5%) while 
allocating 0% local significance level to the remaining of the hypotheses. For this hypothesis, and in 
general, if a hypothesis is confirmed, then the significance level will be reallocated according to the 
weight and the direction of the arrows going from the confirmed hypothesis to the next hypotheses 
as specified in Figure 9-1. Each of the four hypotheses will be tested at their updated local 
@64;6360.;0292C29Q-local). This process will be repeated until no further hypotheses can be 
confirmed.  
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding alternative hypothesis and the two-sided p-value from the primary analysis is strictly 
below its local two-sided significance level as defined by the closed testing procedure. This is 
equivalent to using a one-sided p-C.9B2;<:6;.9Q

.;1.<;2-sided 2.5% overall 
significance level in the closed testing procedure. 
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Figure 9-1
Graphical illustration of the closed testing procedure
)52<C2?.99@64;6360.;0292C29<3Q

AD<-sided) is initially allocated to the hypothesis of superiority of oral 
semaglutide 50 mg vs 14 mg on change from baseline in HbA1c (top left box). If a hypothesis is confirmed, the local 
@64;6360.;0292C29Q-local) will be reallocated according to the weight given by the directed edges between boxes 
(hypotheses).
9.2
Sample size determination
The sample size calculation was made considering the power for jointly confirming the superiority 
hypotheses with respect to HbA1c for both oral semaglutide 50 mg and 25 mg versus oral 
semaglutide 14 mg for the primary estimand and to ensure a sufficient number of subjects will be 
exposed to assess safety and tolerability of the higher dose levels.
The sample size is calculated using the calcPower function in the R package, gMCP12 using 10000 
simulations. All of the four pre-specified confirmatory tests are assumed to be independent. 
Because some of the tests are positively correlated, the assumption of independence is viewed as 
conservative.
For change from baseline in HbA1c, exposure-response modelling indicates a treatment difference 
vs 14 mg oral semaglutide of -0.52%-point and -0.33%-point for oral semaglutide 50 mg and 
25 mg, respectively, in the population with baseline HbA1c between 8.0% and 10.5% and baseline 
$ I5kg/m2 assuming that all subjects remain on trial treatment and do not initiate rescue 
medication. For change from baseline in body weight, treatment differences versus 14 mg oral 
semaglutide are predicted to be below -3.6 kg and -1.8 kg for oral semaglutide 50 mg and 25 mg, 
respectively.
In the sample size calculation, the assumed treatment effect will be adjusted for the anticipated 
premature trial treatment discontinuation, change in dose and use of rescue medication during 52
weeks. Across the PIONEER phase 3a trials, 15% to 20% of the subjects had discontinued trial 
treatment by week 52 with oral semaglutide 14 mg. Based on data from the PIONEER phase 3a 
trials for subjects with baseline HbA1c /2AD22;
.;1
.;1/.@296;2$ I5kg/m2,
similar to the inclusion criteria in this trial, it is anticipated that approximately 12% of subjects 
randomised to oral semaglutide 14 mg will prematurely discontinue trial treatment and that 12% 
will initiate rescue medication. Data from the 20 mg and 40 mg dose arms in the phase 2 trial 
(NN9924-3790) suggest that with oral semaglutide 25 and 50 mg, an additional 10-15% of the 
subjects may discontinue trial treatment, however, this was based on another dose escalation 
approach with a higher initial dose level. The procedures described in Section 6.6 are anticipated to 
Body weight (kg)
Superiority
αlocal=0
HbA1c (%-point)
Superiority
αlocal=0
Body weight (kg)
Superiority
αlocal=0
HbA1c (%-point)
Superiority
αlocal=0.05
Oral semaglutide 25 mg
vs. Oral semaglutide 14 mg
Oral semaglutide 50 mg
vs. Oral semaglutide 14 mg
½
½
1
1
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reduce the proportion of subjects prematurely discontinuing trial treatment with the higher dose 
levels. The proportion of subjects initiating rescue medication for the higher dose levels is assumed 
to be less than with the 14 mg dose.  
It can be assumed that subjects discontinuing on oral semaglutide 14 mg would also do so if 
randomised to 25 mg or 50 mg. For the 12% of subjects expected to discontinue already at 14 mg, a 
treatment difference of zero is therefore assumed. For the remaining subjects discontinuing on 
25 mg and 50 mg, a residual benefit of the higher dose could be expected depending on time of 
discontinuation. On the other hand, if discontinuing, subjects may initiate another treatment inferior 
to oral semaglutide 14 mg. As described in Section 6.6, dose reduction is allowed to accommodate 
subject tolerability. Collectively, a treatment difference of zero is assumed for the excess proportion 
of subjects assumed to reduce dose or prematurely discontinue treatment with the higher dose levels 
as well. The treatment difference is assumed to be reduced by 75% for subjects initiating rescue 
medication.  
The sample size calculation is based on the assumptions that 20% of the subjects reduce dose or 
discontinue trial treatment prematurely with the higher dose levels and that 12% initiate rescue 
medication with 14 mg oral semaglutide. Hereby, the adjusted treatment difference (TD) will be: 
ܶܦൌͲǤ͸ͺ ڄ ܶܦ൅ͲǤͳʹ ڄ ͲǤʹͷ ڄ ܶܦ൅ͲǤʹͲ ڄ Ͳ ڄ ܶܦ 
The adjusted TD are -0.38 %-point and -0.23 %-point for HbA1c and of -2.6 kg and -1.3 kg for body 
weight for oral semaglutide 50 and 25 mg, respectively. The power to jointly confirm HbA1c 
superiority for both dose levels will be 89% with 1620 subjects randomised and a randomisation 
ratio of 1:1:1. The assumed common standard deviations for the change from baseline endpoints are 
based on data from subjects with baseline HbA1c between 8.0% and 10.5% and baseline BMI 
I5kg/m2 in PIONEER 2 (trial NN9924-4223) and 3 (trial NN9924-4222). Calculated powers for 
individual hypotheses are presented in Table 9-1. 
Table 9-1 
Calculated powers for individual hypotheses 
 
 
HbA1c superiority 
Body weight superiority 
Treatment dose 
50 mg 
25 mg 
50 mg 
25 mg 
Power  
>99% 
89% 
>99% 
86% 
Table 9-2 shows the sensitivity of the power under different deviations from the above assumptions 
with a fixed sample size of 1620 subjects. 
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Table 9-2 
Power for jointly confirming HbA1c superiority under various assumptions 
TD HbA1cS  
(%-=<6;AS  
),S  
84S  
&?<=<?A6<;S  
16@0<;A6;B21S  
Adj. TD HbA1cS  
(%-=<6;AS  
17),S  
84S  
Standard 
12C6.A6<;S  
&<D2?S  

:4S  :4S  
:4S  :4S  
Both 1<@2@S  

:4S  :4S  
:4S  :4S  
HbA1cS  
,S  
S  
-0.52 
-0.33 
-3.6  
-1.8  
S  
-0.36 
-0.22  
-2.4  
-1.2  
S  
S  
84 S 
-0.52  
-0.33  
-3.6  
-1.8  

S  
-0.38  
-0.23 
-2.6 
-1.3 
S  

S  
S 
-0.52  
-0.33  
-3.6 
-1.8 
*  
-0.38 
-0.23  
-2.6  
-1.3  
*  
*  
	
* 
-0.52  
-0.33  
-3.6  
-1.8  

S  
-0.38 
-0.23  
-2.6  
-1.3  
S  

S  
S 
-0.52 
-0.33  
-3.6  
-1.8  
S  
-0.39  
-0.24 
-2.6  
-1.3  
S  
S  
S 
-0.50  
-0.30  
-3.3  
-1.5  
S  
-0.33  
-0.20  
-2.2 
-1.0  
S  
S  
77 % 
-0.50 
-0.30  
-3.3  
-1.5  

S  
-0.36  
-0.21  
-2.3  
-1.1  
S  
S  
83 % 
-0.50  
-0.30  
-3.3  
-1.5 
S  
-0.37  
-0.22  
-2.4 
-1.1  
S  
S  
85 % 
Assuming 12% on rescue medication with 14 mg oral semaglutide. The highlighted scenario has been chosen for the 
sample size calculation. 
1620 subjects will be randomly assigned to trial treatment.  
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Full analysis set (FAS) 
All subjects randomised. Subjects contribute to a treatment group based on the 
trial treatment they were randomised to receive. 
Safety analysis set (SAS) 
All subjects who receive at least 1 dose of trial treatment. Subjects contribute to 
a treatment group based on the trial treatment they actually received. 
The FAS will be used in the evaluation of the efficacy endpoints, the SAS will be used for the 
evaluation of the safety endpoints, exclusively. 
Data selections and observation periods 
Unless subjects withdraw their informed consent, data collection will continue for the planned full 
duration of the trial for the individual subject. The full duration of the trial is defined as up to and 
including the follow-up visit (V17) for subjects completing trial treatment and subjects who have 
discontinued trial treatment prematurely. 
As described in Section 3.1 the trial objectives relating to efficacy will be addressed using two 
different types of estimands. The primary and secondary estimands applying a treatment policy 
strategy to all intercurrent events and the additional supportive estimands applying a hypothetical 
strategy to the intercurrent events of premature trial treatment discontinuation and initiation of 
additional anti-diabetic medication. The handling of the intercurrent events with respect to data 
collection and analysis is specified in Table 9-3. 
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Table 9-3 
Handling of intercurrent events for the estimands 
Intercurrent event 
 Primary and secondary estimands 
Additional supportive estimands 
Premature trial treatment 
discontinuation 
Data collected after the intercurrent 
event is used in analysis in line with a 
treatment-policy strategy, i.e. 
disregarding the occurrence of the 
intercurrent event 
Data collected after the intercurrent 
event will be excluded and treated as 
missing in analysis, i.e. using a 
hypothetical strategy 
Initiation of additional anti-diabetic 
medication 
Change of dose 
Data collected after the intercurrent 
event and used in analysis in line with 
a treatment-policy strategy, i.e. 
disregarding the occurrence of the 
intercurrent event 
Additional anti-diabetic medication is defined as new anti-diabetic medication and/or intensification 
of anti-diabetic medication initiated at or after randomisation and before planned end of treatment. 
Rescue medication is used to designate additional anti-diabetic medication initiated while on trial 
treatment, i.e. before last dose of trial product. 
Observation periods will be used to select data for analyses in line with the strategies applied for the 
intercurrent events. Subjects and data to be used in an analysis will be selected in a two-step 
manner: 
 First, subjects will be selected based on the specified analysis set. 
 Second, data points on the selected subjects from the first step will be selected based on the 
specified observation period. 
For the efficacy and safety evaluations, three different observation periods will be defined: 
 The in-trial observation period J the time period from when a subject is randomised until the 
final scheduled visit, including any period after initiation of additional anti-diabetic medication 
or discontinuation of trial treatment. 
 The on-treatment observation period J the time period when a subject is on trial treatment, 
including any period after initiation of rescue medication. 
 The on-treatment without rescue medication observation period J the time period when a 
subject is on trial treatment, excluding any period after initiation of rescue medication. 
The in-trial observation period begins at the date of randomisation and ends at the final scheduled 
visit, which can be one of the below: 
 the follow-up visit (V17) for subjects who complete treatment and for subjects who discontinue 
trial treatment prematurely 
 the last contact for subjects who withdraw from trial, are lost to follow-up or die 
The on-treatment observation period begins at the date of first dose of trial treatment; the end date 
depends on the assessment being evaluated: 
 For all efficacy assessments and certain safety assessments (laboratory assessments, physical 
examination and vital signs), a plus-3-day window (i.e. the 3-day visit window) is used and the 
period ends at the first of the following time points:  
 last dose of trial treatment plus a 3-day window  
 end of the in-trial observation period 
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 For the remaining safety assessments (eye examination categories, AEs, and hypoglycaemic 
episodes), a plus-38-day window (i.e. the 5-week follow-up period plus the 3-day visit window) 
is used and the period ends at the first of the following time points: 
 the follow-up visit (V17) 
 the last dose of trial treatment +38 days  
 end of the in-trial observation period 
The on-treatment without rescue medication observation period begins at the date of the first 
dose of trial treatment and ends at the first of the following time points: 
 end of the on-treatment observation period 
 initiation of rescue medication (if any) 
For the efficacy endpoints, the primary and secondary estimands will be evaluated based on data 
from the in-trial observation period and the additional supportive estimands will be evaluated based 
on data from the on-treatment without rescue medication observation period thereby selecting data 
in line with the strategies applied for the intercurrent events as shown in Table 9-3. The safety 
evaluation will primarily be based on the on-treatment observation period, except for deaths and AE 
types with potentially long latency between onset and diagnosis, for which the in-trial observation 
period will be used. The observation period determines what data subjects contributes with to a 
specific analysis. Baseline values are by definition included in all observation periods; other data 
points collected outside the observation period used for an analysis will be considered missing. 
Before data are locked for statistical analysis, a review of all data will take place. Exclusion of data 
from analyses should be used restrictively, and normally no data should be excluded from the FAS. 
The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented before unblinding. The subjects and observations excluded from analysis sets, and the 
reason for this, will be described in the clinical trial report. 
9.4 
Statistical analyses 
The statistical analysis plan (SAP) will be finalised prior to database lock or potential partial 
database lock, and it will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints, including the primary and confirmatory secondary endpoints. 
9.4.1 
General considerations 
Data from all sites will be analysed and reported together. 
In statistical analyses where stratification is accounted for, the background medication at screening 
will be included based on the actual information collected through the eCRF. In case of missing 
eCRF information, the information collected from the IWRS system will be used.  
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.  
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Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for each high dose vs. 14 mg oral semaglutide with associated two-sided 95% confidence 
intervals and p-values corresponding to two-sided tests of no difference. 
Missing data 
The amount of missing data when estimating the primary and secondary estimands (i.e. data that are 
not available even though all efforts were made to ensure that subjects stayed in the trial regardless 
of premature discontinuation of trial treatment or initiation of additional anti-diabetic treatment) is 
expected to be low. At week 52, the proportion of subjects with missing data was 5-7% across trials 
in the PIONEER programme. Missing data will be missing mainly be due to subjects withdrawing 
consent or being lost to follow-up. In the statistical analyses, missing data will be handled in line 
with the strategies applied for the pre-defined intercurrent events. 
9.4.2 
Primary endpoint 
The primary endpoint is the change in HbA1c (%-point) from baseline (week 0) to week 52. 
Primary analysis for the primary estimand 
The primary estimand defined in Section 3.1 will be estimated based on the FAS using week 52 
measurements from the in-trial observation period. The primary statistical analysis will be a pattern 
mixture model using multiple imputation to handle missing data assuming that the missing data 
mechanism is missing at random (MAR) within the groups used for imputation. Imputation of 
missing week-52 data will be done within 6 groups of subjects defined by randomised treatment 
arm, and whether subjects at week 52 (i) are still on treatment and have not initiated rescue 
medication or (ii) have discontinued treatment or initiated rescue medication. It is hereby assumed 
that the likely values of what the missing data would have been if available are best described by 
information from subjects who at week 52 are similar in terms of randomised treatment arm and 
trial treatment discontinuation/rescue medication status. For each imputation group, an analysis of 
covariance model (ANCOVA) with stratification factor and region as factors and baseline HbA1c as 
covariate will be used to impute 1000 values for each subject with missing week 52 data. For the 
imputation groups where the subjects have discontinued treatment or initiated rescue medication the 
time (days) from randomisation until discontinuation or initiation of rescue medication will also be 
included as a covariate. The 1000 complete data sets will be analysed using an ANCOVA with 
treatment, stratification factor and region as factors and baseline HbA1c as covariate. The results 
</A.6;213?<:.;.9F@6;4A521.A.@2A@D699/20<:/6;21B@6;4'B/6;N@?B9213 to draw inference. 
Sensitivity analysis for the primary estimand  
In line with ICH E9 (R1), sensitivity analyses will be performed investigating the robustness of the 
conclusions made on the basis of the primary analyses towards the impact of missing data. 
Tipping-point multiple imputation analysis: A two-dimensional tipping point sensitivity analysis 
will be used to address the assumption of MAR within imputation groups. Subjects with missing 
data will be assumed to have a worse outcome in the 25 mg and 50 mg treatment arms and a better 
outcome in the 14 mg arm compared to the imputations in the primary analysis. Missing data will 
first be imputed as in the primary analysis. Secondly, penalties will be added to or subtracted from 
the imputed week-52 values. The approach is to gradually increase these penalties independently in 
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the treatment arms until the confirmed HbA1c conclusion from the primary analysis is changed. For 
each hypothesis tested, the values of the penalties that changes the conclusion will be used to 
evaluate the robustness of the primary analysis results.    
Return to baseline multiple imputation analysis: subjects with missing data at week 52 will have 
their change from baseline value imputed as 0 plus a random error. The error is randomly drawn 
from a normal distribution with a mean of 0 and a variance equal to the residual variance estimated 
from the MMRM for observed values of change from baseline in HbA1c, adjusted for the same 
covariates and factors as in the primary analysis. For missing values from patients who are still on 
treatment, it will be assumed that those data are missing at random and they will be imputed based 
on the observed data from the subjects who completed the trial on treatment in the same treatment 
arm. 
Analysis for the additional estimand 
The additional estimand (Section 3.1) will be estimated based on the FAS using post-baseline 
measurements up to and including week 52 from the on-treatment without rescue medication 
observation period. The analysis for the additional estimand will be a Mixed Model for Repeated 
Measurements (MMRM). A restricted maximum likelihood will be used. The model will include all 
post baseline HbA1c measurements collected at scheduled visits up to and including week 52 as 
dependent variables. The independent effects included in the model will be treatment, stratification 
factor and region as categorical fixed effects and baseline HbA1c as a covariate, all nested within 
visit. An unstructured covariance matrix for HbA1c measurements within the same subject will be 
employed, assuming measurements from different subjects are independent. 
9.4.3 
Secondary endpoints 
9.4.3.1 
Confirmatory secondary endpoint 
The confirmatory secondary endpoint is the change in body weight (kg) from baseline (week 0) to 
week 52. 
Analysis for the secondary estimand  
The secondary estimand will be estimated in the same way as for the primary endpoint with 
baseline HbA1c replaced by baseline body weight as the covariate. 
Sensitivity analysis for the secondary estimand 
Sensitivity analyses similar to the ones performed for the primary endpoint will be performed.  
Analysis for the additional estimand  
The additional estimand will be estimated in the same way as for the primary endpoint with baseline 
HbA1c replaced by baseline body weight as the covariate.  
9.4.3.2 
Supportive secondary endpoints 
For details on analyses of additional supportive secondary endpoints, please refer to the SAP, which 
will be completed prior to database lock or potential partial database lock. 
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9.4.4 
Other safety analyses 
All safety analyses will be made on the safety analysis set. The standard safety assessments (AEs, 
safety laboratory parameters, vital signs, etc.) will be reported descriptively; including any notable 
changes of clinical interest in laboratory parameters. 
9.4.5 
Other analyse(s)  
For other analyse(s), please refer to the SAP.  
9.4.5.1 
Pharmacokinetic modelling 
Population PK modelling and exposure-response analyses may be included to support dose 
selection and to explore the benefits of high versus lower doses of semaglutide in subjects with 
T2D.  
The modelling will include data from all randomised subjects that were exposed to semaglutide in 
this trial and might be performed as a meta-analysis including data from historical trials. Actual 
dose and date of administration of last dose before PK sampling will be registered in the CRF and 
used in the analysis, together with actual time point for PK sampling.  
A modelling analysis plan will be prepared before database lock or potential partial database lock 
for the trial, outlining details of the analysis. The results will be reported separately from the CTR. 
9.5 
Interim analyses 
See Section 9.7 for details regarding partial database lock. 
9.6 
Data monitoring committee  
Not applicable for this trial. 
9.7 
Reporting of the main part of the trial 
A partial database lock will be performed at the end of the treatment period for all subjects, i.e., 
after the date of the last subject last treatment visit. A partial database lock is implemented to 
support potential earlier access of oral semaglutide 25 and 50 mg to the patient population expected 
to benefit from higher doses.  
All efficacy analyses will be performed based on the data from the partial database lock. No 
efficacy assessments are collected after last subject last treatment, and so unblinding of Novo 
Nordisk staff will be after all subjects have completed treatment. Therefore, efficacy results cannot 
be biased by the early unblinding. Impact on PK and safety evaluation after partial database lock is 
considered minor as most subjects will have completed the follow-up visit, and subjects and 
investigators remain blinded. Full analysis of PK and safety will be performed after the full 
database lock.  
The SAP will be finalised prior to partial database lock. A detailed plan for data handling, blinding, 
data analysis, and operational aspects of the partial database lock and the database update will be 
finalised before the partial database lock.  
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The result of the evaluation at partial database lock will not be shared with investigators or subjects 
before the full database lock, and only a minimum number of Novo Nordisk staff will know the 
randomisation code at subject level. There will be no change in study design regardless of the 
outcome of the evaluation at partial database lock.  
The database will be updated after the partial database lock to include the remaining data. The full 
database lock will be performed, as per the usual procedures, after the date of the last subject last 
visit.  
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10 %!! "$ %$$  !"$  #"$ # 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
 This trial will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki14 and applicable ICH Good Clinical Practice (GCP) Guideline15 
 Applicable laws and regulations 
 )52=?<A<0<96;3<?:210<;@2;A3<?:6;C2@A64.A<?N@/?<05B?2.@.==960./92.nd other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
 Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the CTR according to national requirements. 
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects. 
 Before a site is allowed to start screening subjects, written notification from Novo Nordisk must 
be received. 
 The investigator will be responsible for: 
 providing written summaries of the status of the trial annually or more frequently in accordance 
with the requirements, policies, and procedures established by the IRB/IEC and/or regulatory 
authorities. 
 notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
 providing oversight of the conduct of the trial at the site and adherence to requirements of ICH 
guidelines, the IRB/IEC, and all other applicable local regulations. 
 ensuring submission of the CTR synopsis to the IRB/IEC. 
 reporting any potential serious breaches to the sponsor immediately after discovery. 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
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 trial to the subject and 
answer all questions regarding the trial. 
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 The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
 Subjects must be informed that their participation is voluntary. 
 Subjects must be informed about their privacy rights.  
 Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines15, Declaration of Helsinki14 and the IRB/IEC 
or site. 
 The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial related activity. 
 The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
 Subjects must be re-consented to the most current version of the informed consent form during 
their participation in the trial. 
 A copy of the informed consent form must be provided to the subject.  
10.1.4 
Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive .KD290<:2A<A52A?6.992AA2?L.;1.KA5.;8F<B3<?F<B?=.?A606=.A6<;92AA2?L
after completion of the trial. Further, the subject may receive other written information during the 
trial.  
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
10.1.5 
Data protection 
 Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the subject are transferred to Novo Nordisk. 
 The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements.  
 The subject must be informed about his/her privacy rights, including that his/her personal trial 
related data will be used by Novo Nordisk in accordance with local data protection law. The 
disclosure of the data must also be explained to the subject.  
 The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
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10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal trial independent ad hoc 
group will be established in order to maintain the blinding of the trial personnel. 
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov, clinicaltrialsregister.eu and 
novonordisk-trials.com. It will also be disclosed according to other applicable requirements, such as 
those of the International Committee of Medical Journal Editors (ICMJE)16, the Food and Drug 
Administration Amendment Act (FDAAA)17, European Commission Requirements1, 18, 19 and other 
relevant recommendations or regulations. If a subject requests to be included in the trial via the 
Novo Nordisk e-:.690<;A.0A.AA52@2D2/@6A2@%<C<%<?16@8:.F16@09<@2A526;C2@A64.A<?N@
contact details to the subject. As a result of increasing requirements for transparency, some 
countries require public disclosure of investigator names and their affiliations. 
The primary completion date (PCD) is the last assessment of the primary endpoint, and is for this 
trial last subject first treatment (LSFT) + 52 weeks corresponding to visit V14. If the last subject is 
withdrawn early, the PCD is considered the date when the last subject would have completed visit 
V14. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
FDAAA. 
10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
 Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data. 
 All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory 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 (also to be used to report complaints on trial product not yet 
allocated to a subject) 
 <??20A6<;@A<A52'1.A.:.F/2:.12/FA526;C2@A64.A<?<?A526;C2@A64.A<?N@12924.A21
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
?2.@<;3<?A520<??20A6<; 30<??20A6<;@.?2:.12/FA526;C2@A64.A<?N@12924.A21@A.33.3A2?A52
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date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator. 
 The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.  
10.1.8.2 
Monitoring 
 The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the trial. If the electronic 
medical record does not have a visible audit trail, the investigator must provide the monitor with 
signed and dated printouts. In addition, the relevant site staff should be available for discussions 
at monitoring visits and between monitoring visits (e.g. by telephone).  
 Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 
 Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
 $<;6A<?@D699?2C62DA52@B/720AN@:2160.9?20<?1@.;1<A52?@<B?02 data, e.g. the diaries to 
ensure consistency and/or identify omissions compared to the CRF.  
 An unblinded monitor will be responsible for the reconciliation process set up for this trial. 
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database.  
10.1.9 
Source documents 
 All data entered in the CRF must be verifiable in source documentation other than the CRF. 
 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 trial 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 subject and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
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 Data reported on the paper CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available.  
  A:B@A/2=<@@6/92A<C2?63F@B/720AN@:2160.956@A<?F6;@<B?021<0B:2;A@@B05.@@B/720AN@
medical record.  
 The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested, and who was contacted. 
 Definition of what constitutes source data can be found in a source document agreement at each 
site. There will only be one source document defined at any time for any data element. 
10.1.10 
Retention of clinical trial documentation 
 Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk.  
 The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF (eCRF) and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems supplied 
by Novo Nordisk. Site-specific CRFs and other subject data (in an electronic readable format or 
as paper copies or prints) must be retained by the site. A copy of all data will be stored by Novo 
Nordisk. 
 (B/720AN@:2160.9?20<?1@:B@A/282=A3<?A52:.E6:B:=2?6<1=2?:6AA21/FA525<@=6A.9
institution or private practice. 
Canada: for country-specific requirements, please see Appendix 8 (Section 10.8). 
10.1.11 
Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the investigator must 
inform the subjects promptly and ensure appropriate therapy and follow-up. The investigator and/or 
Novo Nordisk must also promptly inform the regulatory authorities and IRBs/IECs and provide a 
detailed written explanation. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
 failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines 
 inadequate recruitment of subjects by the investigator 
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 discontinuation of further trial product development. 
10.1.12 
Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
@A.33=.?A606=.A6;46;A520<;1B0A<3A52A?6.9 A6@A526;C2@A64.A<?N@?2@=<;@6/696AFA<@B=2?C6@2A52
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. 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 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
10.1.13 
Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.  
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10.1.14 
Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One (or two) investigator(s) will be appointed by Novo Nordisk to review and sign the CTR 
(signatory investigator) on behalf of all participating investigators. The signatory investigator(s) 
will be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications.20 
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
0<;A2;A<3.;F=B/960.A6<;/<A5A526;C2@A64.A<?@N.;1%<C<%<?16@8<=6;6<;@D699/23airly and 
sufficiently represented in the publication. 
10.1.14.2 
Authorship 
Novo Nordisk will work with one or more investigators and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications. 
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Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors.20 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database.  
Individual investigators will have their own research subjects' data and will be provided with the 
randomisation code after results are available. 
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10.2 
Appendix 2: Clinical laboratory tests 
 The tests detailed in Table 10-1 and Table 10-2 will be performed by the central laboratory, 
unless otherwise specified. 
 Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is needed, 
e.g. to follow up on AEs, this must be done at a local laboratory. 
 The central laboratory will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab SOPs. These data will not be transferred to the trial database. The 
investigator should review such values for AEs and report these according to this protocol. 
 The investigator must review all laboratory results for concomitant illnesses and AEs. 
 Laboratory samples will be destroyed no later than at finalisation of the CTR.  
 For haematology samples (differential count) where the test result is not normal, then a part of 
the sample may be kept for up to two years or according to local regulations.  
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Visit 
Glucose 
metabolism  
 Fasting plasma glucose1 
V2, V5, V7, V10, V14, V16 
 HbA1c 
V1, V2, V3, V4, V5, V7, V9, V10, V11, V12, 
V13, V14, V15, V16 
Lipids 
 High density lipoprotein (HDL) cholesterol 
 Low density lipoprotein (LDL) cholesterol 
 Triglycerides 
 Total cholesterol 
V2, V10, V14, V16 
Urinanalysis2 
 Urinary albumin to creatinine ratio (UACR) 
V2, V5, V10, V14, V16 
NOTES: 
1An FPG result H3.9 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 (see Appendix 3 (Section 10.3). 
2 Subjects should collect a first morning urine sample both on the day prior to the visit and on the day of the visit. 
Samples should be stored in the fridge at home and brought to the site 
Table 10-2 
Protocol-required safety laboratory assessments 
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Laboratory 
assessments 
Parameters 
Visit 
Haematology 
 Eosinophils 
 Lymphocytes 
 Basophils 
 Monocytes 
 Neutrophils 
 Erythrocytes 
 Haematocrit 
 Haemoglobin 
 Leucocytes 
 Thrombocytes 
V1, V10, V14, V16 
Biochemistry1 
 Alanine Aminotransferase (ALT)  
 Alkaline phosphatase 
 Aspartate Aminotransferase (AST) 
 Creatinine 
 Potassium 
 Sodium 
 Amylase 
 Lipase 
 Total bilirubin 
V1, V10, V14, V16 
Hormones 
 Calcitonin2 
V2 
Pregnancy 
Testing 
 Urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of 
childbearing potential)3 
V1, V16, V17 
Pharmacokinetics 
 Semaglutide plasma concentration 
V3, V5, V7, V10, V14, V16 
Antibodies 
 Anti-semaglutide antibodies 
V2, V3, V5, V7, V10, V14, V16, V17 
Other tests 
 eGFR calculated by the central laboratory 
based on the creatinine value using the 
CKD-EPI equation 
V1, V10, V14, V16 
Notes: 
1 Details of required actions and follow-up assessments for increased liver parameters including any discontinuation 
criteria are given in Appendix 3 (Section 10.3) (HyNs Law) and Section 7.1. 
2 Calcitonin will be measured once at baseline. Not intended for screening. The investigator must evaluate need for 
further measurements during the trial.  
3 Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
All trial-required laboratory assessments will be performed by a central laboratory, with the 
exception of:  
 urine pregnancy testing, which will be performed locally at site or at home 
 semaglutide plasma concentrations, which will be performed at a specialised laboratory  
 anti-semaglutide antibodies (if deemed necessary for clarification of unexpected drug exposure 
or other safety issues that may be related to antibody formation), which will be performed at a 
specialised laboratory  
Laboratory/analyte results that could unblind the trial will not be reported to the sites until the trial 
has been unblinded.
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10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting 
10.3.1 
Definition of AE 
AE definition 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated 
with the use of an investigational medicinal product (IMP), whether or not considered related to 
the IMP. 
An AE can therefore be any unfavourable and unintended sign, including an abnormal laboratory 
finding, symptom or disease (new or exacerbated) temporally associated with the use of an IMP. 
 
Events meeting the AE definition 
 Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgment of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected 
 Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected  
 Exacerbation/worsening of a chronic or intermittent condition including either an increase in 
frequency and/or intensity of the condition 
 Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction 
 Signs, symptoms or the clinical sequelae of a suspected overdose of IMP regardless of intent 
A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfil the definition. 
Events NOT meeting the AE definition  
 Conditions present prior to the time point from which AEs are collected and anticipated day-to-
day fluctuations of these conditions, including those identified during screening or other trial 
procedures performed before exposure to IMP.  
 Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
 Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads to the 
procedure is the AE. 
 Medical or surgical procedures not preceded by an AE or worsening of a known condition. 
10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
3<?</@2?C.A6<;.;1	<?A?2.A:2;AA5.AD<B91;<A5.C2/22;.==?<=?6.A26;A52=5F@606.;N@<33602
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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 
1<B/A.@A<D52A52?K5<@=6A.96@.A6<;L<00B??21<?D.@;202@@.?FA52@5<B91/20<;@612?21
serious. 
 Hospitalisation for elective treatment (e.g. elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note:  
 Hospitalisations for administrative, trial related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs.  
 Hospital admissions for medical or surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs.  
d. Results in persistent or significant disability/incapacity 
 )52A2?:16@./696AF:2.;@.@B/@A.;A6.916@?B=A6<;<3.=2?@<;N@./696AFA<0<;1B0A;<?:.99632
functions. 
 This definition is not intended to include experience of relatively minor medical significance, 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g. sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the subject 
or may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious and reported as SAEs 
using the important medical event criterion. 
 The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable: 
 Suspicion of transmission of infectious agents via the IMP  
 Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x ULN (upper limit of normal) and total bilirubin >2 x ULN where no alternative 
aetiology exists (Hy's law) 
10.3.3 
Description of AEs requiring additional data collection  
Description of AEs requiring additional data collection (on specific event form)  
Adverse events requiring additional data collection 
AEs requiring additional data collection (Table 8-1) are AEs where the additional data will benefit 
the evaluation of the safety of the trail product. The selection of these events is based on the non-
clinical and clinical data with semaglutide, knowledge from the GLP-1 RA drug class as well as 
regulatory requirements. 
Diabetic retinopathy 
New onset or worsening of diabetic retinopathy. 
Gallbladder disease 
Events of symptomatic gallbladder disease, including gallstones and cholecystitis. 
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Hepatic event 
Hepatic event defined as: 
 disorders of the liver including cholestatic conditions and liver related signs and symptoms 
 ALT or AST > 3x ULN and total bilirubin > 2x ULN* 
 ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
&92.@2;<A2A5.A6;0.@2<3@B05.52=.A602C2;AD52?2;<.9A2?;.A6C2.2A6<9<4F2E6@A@FN@9.D
the event must be reported as an SAE using the important medical event criterion if no other 
seriousness criteria are applicable. 
Neoplasms 
All confirmed neoplasms (both malignant and non-malignant) by histology or other substantial 
clinical evidence. 
Acute pancreatitis 
The diagnosis of acute pancreatitis requires two of the following three features: 
 abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, 
epigastric pain often radiating to the back). 
 serum lipase activity (and/or amylase activity) at least three times greater than the upper limit 
of normal. 
 characteristic findings of acute pancreatitis imaging. 
Acute kidney injury 
Event of an abrupt or rapid decline in renal filtration function. This condition is usually marked 
by a rise in serum creatinine concentration or by azotemia (a rise in blood urea nitrogen (BUN) 
concentration). 
Medication error 
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the subject, such as:  
 administration of wrong drug 
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.  
 wrong route of administration 
 accidental administration of a higher dose than intended. The administered dose must deviate 
from the intended dose to an extent where clinical consequences for the trial subject were 
likely to happen as judged by the investigator, although they did not necessarily occur. 
Misuse and abuse 
 Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g. overdose to maximise effect) 
 Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm) 
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence (e.g. hypoglycaemia or other), this must be reported on an additional AE 
form. 
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10.3.4 
Recording and follow-up of AE and/or SAE 
AE and SAE recording 
 The investigator will record all relevant AE/SAE information in the CRF. 
 The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) related to the 
event. 
 There may be instances when copies of source documents (e.g. medical records) for certain 
cases are requested by Novo Nordisk. In such cases, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the source documents before 
submission to Novo Nordisk. 
 For all non-serious AEs, the applicable forms should be signed when the event is resolved or at 
the end of the trial at the latest. For sign-<33<3(?29.A213<?:@?232?A<K.;1(
?2=<?A6;4C6.=.=2?'L9.A2?6;A56@@20A6<; 
 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 trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report 
this adverse event to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess severity for each event reported during the trial and assign it to one of 
the following categories:  
 Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with a SAE. Both AEs and 
SAEs can be assessed as severe.  
 
Assessment of causality 
 The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. 
 Relationship between an AE/SAE and the relevant IMP(s) should be assessed as:  
 Probable - Good reason and sufficient documentation to assume a causal relationship. 
 Possible - A causal relationship is conceivable and cannot be dismissed. 
 Unlikely - The event is most likely related to aetiology other than the IMP. 
 Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
 )526;C2@A64.A<?@5<B91B@2A526;C2@A64.A<?N@/?<05B?2for the assessment. For each AE/SAE, 
the investigator must document in the medical records that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator 
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always makes an assessment of causality for every event before the initial transmission of 
the SAE data. 
 The investigator may change his/her opinion of causality, in light of follow-up information, 
and update the causality assessment in the CRF. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Final outcome 
The investigator will select the most appropriate outcome: 
 Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented 
 Recovering/resolving: The condition is improving, and the subject is expected to recover from 
the event. This term may be applicable in cases of chronic conditions, cancer or AEs ongoing 
at time of death (where death is due to another AE).  
 Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
 Recovered/resolved with sequelae: The subject has recovered from the condition but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
 Not recovered/not resolved: The condition of the subject has not improved, and the symptoms 
are unchanged, or the outcome is not known.  
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE).  
 Fatal: This term is only applicable if the subject died from a condition related to the reported 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed as 
K?20<C2?21	?2@<9C21LK?20<C2?6;4	?2@<9C6;4LK?20<C2?21	?2@<9C21D6A5@2>B29.2L<?K;<A
recovered/not resolvedL;D6A5.3.A.9<BA0<:2:B@A/2?2=<?A21.@.;( 
 Unknown: This term is only applicable if the subject is lost to follow-up. 
 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions). 
This may include additional laboratory tests (e.g. skin prick test) or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a subject dies during participation in the trial or during a recognised follow-up period, the 
investigator should provide Novo Nordisk with a copy of autopsy report including 
histopathology, if available. 
New or updated information will be recorded in the CRF. 
10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
 Relevant forms (AE and safety information form) must be completed in the eCRF.  
 For reporting and sign-off timelines, see Figure 10-1 below. 
 If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form, and 
if the CRF is unavailable for more than 5 calendar days, then the site will use the safety 
information form (see box below). 
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 The site will enter the SAE data into the eCRF as soon as it becomes available.
 After the trial is completed, the trial database will be locked, and the CRF will be 
decommissioned to prevent the entry of new data or changes to existing data. If a site receives 
a report of a new SAE from a subject or receives updated data on a previously reported SAE 
after CRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone.
AE and SAE reporting via paper CRF
 Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk in 
an encrypted manner in accordance with Section 10.1.5.
 For SAEs, initial notification via telephone is acceptable, although it does not replace the need 
for the investigator to complete the AE and safety information form within the designated 
reporting timelines (as illustrated in the figure below):
 AE form within 24 hours
 Safety information form within 5 calendar days
 Both forms must be signed within 7 calendar days after first knowledge by the investigator.
 The specific event form for AEs requiring additional data collection within 14 calendar days
AE identified
AE form ≤  24 hours
SIF ≤5 calendar days
Sign off ≤ 7 calendar days
Is the AE serious, or
non-serious?
Does the AE require 
additional data 
collection?
Non-serious
Serious
No
Specific event form
For SAE: 
≤14 calendar days
Yes

Timelines are from the awareness of an AE.

Queries and follow-up requests to be resolved ≤14 calendar days.

Non-serious AEs: Data must be recorded in the CRF as soon as possible, 
preferably within 5 working days (see Appendix 1)
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
AE Form
No additional 
action
NOTE: The collection of AEs includes the collection of COVID-19 or suspected COVID-19 AEs.
Figure 10-1
Decision tree for determining the event type and the respective forms to
complete with associated timelines
Contact details for SAE reporting can be found in the investigator trial master file.
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
If fertility is unclear (e.g. amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of trial treatment, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
 Documented total hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
Females with permanent infertility due to an alternate medical cause other than the above (e.g. 
Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in determining 
trial enrolment. 
3. Postmenopausal female: 
 A postmenopausal state is defined as amenorrhoea for 12 months without an alternative medical 
cause.  
 Females I
F2.?@<3.420.;/20<;@612?21=<@A:2;<=.B@.96??2@=20A6C2<3A?2.A:2;AD6A5.
hormonal contraception or hormone replacement therapy (HRT)) if they have both: 
 Amenorrhoea and 
 Documentation of 2 high follicle stimulating hormone (FSH) measurements in the 
=<@A:2;<=.B@.9?.;42.;1<;2<3A52@2D.@</@2?C21IF2.?=?6<?A<@0?22;6;4 
 2:.92@I
F2.?@<3.420.;/20<;@612?21=<@A:2;<=.B@.9 
Females on HRT 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-0.;0<:23?<:A52@6A2@A.33N@?2C62D<3@B/720AN@
medical records, medical examination or medical history interview. 
Contraception guidance 
Male subjects  
No contraception measures are required for male subjects, because the risk of 
teratogenicity/fetotoxicity caused by transfer of semaglutide in seminal fluid is unlikely. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table below: 
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Table 10-3 
Highly effective contraceptive methods 
 
CONTRACEPTIVES a ALLOWED DURING THE TRIAL INCLUDE: 
 Highly effective methods b, d that have low user dependency (Failure rate of <1% per year 
when used consistently and correctly): 
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS)b 
 Bilateral tubal occlusion 
 Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is 
the sole sexual partner of the woman of childbearing potential, and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
 
 Highly effective methods b,d that are user dependent (Failure rate of <1% per year when used 
consistently and correctly): 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation c 
o oral 
o intravaginal 
o transdermal 
o injectable 
 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 trial treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the trial 
and the preferred and usual lifestyle of the subject.) 
NOTES 
a) Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical trials. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates 
differ from those when used consistently and correctly. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines,  
contraceptive methods are limited to those which inhibit ovulation as the primary mode of 
action. 
d) Contraception should be utilised during the treatment period and for at least 35 days 
(corresponding to time needed to eliminate trial product) after the last dose of trial treatment. 
In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with: 
1. known intolerance to the highly effective methods mentioned in Table 10-3 or where the use of 
any of the listed highly effective contraceptive measures are contraindicated in the individual 
subject, and/or 
2. if the risk of initiating treatment with a specific highly effective method outweighs the benefit 
for the female. 
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Justification for accepting double barrier method should be at the discretion of the investigator, 
A.86;46;A<0<;@612?.A6<;56@	52?8;<D92142./<BAA5232:.92N@:2160.956@A<?F0<;0<:6A.;A699;2@@
concomitant medication and observed AEs. The justification must be stated in the medical records. 
Czech Republic, and Germany: For country-specific requirements, please see Appendix 8 (Section 
10.8). 
Pregnancy testing 
 WOCBP should only be included after a negative highly sensitive urine pregnancy test (refer to 
Appendix 2, Section 10.2) 
 Additional pregnancy testing should be performed according to the flowchart (Section 1.2). 
 Pregnancy testing should be performed whenever a menstruation is missed or when pregnancy 
is otherwise suspected. 
 Pregnancy testing is advised 5 weeks after premature discontinuation of trial treatment. 
 Additional pregnancy testing should be performed during the treatment period, if required 
locally (Appendix 8, Section 10.8). 
Collection of pregnancy information  
Female subjects who become pregnant  
 Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this trial. 
 Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a subject's pregnancy (see Figure 10-2). 
 Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate which will be forwarded to Novo Nordisk 
within 14 calendar days. Generally, follow-up will not be required for longer than 1 month 
beyond the delivery date. 
 Any termination of pregnancy will be reported, regardless of 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 
<?( 3?292C.;A0<;@612?.116;4M42@A.A6<;.9NM=?24;.;0F?29.A21N<?.@6:69.?A2?:
when reporting the AE/SAE. 
 Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. 
 Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the IMP by the investigator will be reported to Novo Nordisk as described in 
Section 10.3. While the investigator is not obligated to actively seek this information in former 
subjects, he or she may learn of an SAE through spontaneous reporting. 
 
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Maternal form 1b 
≤ 14 calendar days after birth
Maternal form 1a
≤ 14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2 ≤ 14 calendar days
Paternal form*1 ≤ 14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
Figure 10-2 Decision tree for determining the forms to complete with associated timelines 
for pregnancy.  
Any female subject who becomes pregnant while participating in the trial will discontinue IMP.  
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10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.5.1 
Definition of technical complaint 
Technical complaint definition  
 A technical complaint is any written, electronic or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE but does 
not concern the AE itself. 
Examples of technical complaints: 
 Problems with the physical or chemical appearance of trial products (e.g. discoloration, particles 
or contamination) 
 Problems with packaging material including labelling 
Time period for detecting technical complaints  
All technical complaints which occur from the time of receipt of the product at site until the time 
of the last usage of the product must be collected for products predefined on the technical 
complaint form.  
10.5.2 
Recording and follow-up of technical complaints 
Reporting of technical complaints to Novo Nordisk 
Contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN. 
2. If DUN is not available, a technical complaint form for each batch, code or lot number must 
be completed. 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
 24 hours if related to an SAE (or could have led to an SAE) 
 5 days calendar for all other technical complaints  
If the CRF is unavailable, or when reporting a technical complaint on a trial product that is not 
yet allocated to subject , the information must be provided on a paper form to Customer 
Complaint Center, Novo Nordisk, within the same timelines as stated above. When the CRF 
becomes available again, the investigator must enter the information on the technical complaint 
form in the CRF. 
 
Follow-up of technical complaints  
The investigator is responsible for ensuring that new or updated information will be recorded on 
the originally completed form. 
 
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Collection, storage and shipment of technical complaint samples 
The investigator must collect the technical complaint sample and all associated parts that were 
packed in the same DUN and notify the monitor within 5 calendar days of obtaining the sample at 
site. The sample and all associated parts must be sent as soon as possible to Customer Complaint 
Center, Novo Nordisk, together with a copy of the completed technical complaint form. The 
technical complaint sample should contain the batch, code or lot number and, if available, the 
DUN. If the technical complaint sample is unobtainable, the reason must be stated on the 
technical complaint form. If several samples are shipped in one shipment, the sample and the 
corresponding technical complaint form should be kept together. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
10.5.3 
Reporting of technical complaints 
Reporting of technical complaints for Novo Nordisk products not included in technical 
complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form 
should be reported to local Novo Nordisk. 
 
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10.6 
Appendix 6: Hypoglycaemic episodes 
Table 10-4 
Classification of hypoglycaemia 
Classification of hypoglycaemia 
Level 
Glycaemic criteria 
Description 
Hypoglycaemia alert value 
(level 1) 
H 3.9 mmol/L (70 mg/dL) and  
I
::<9	#:4	1# 
Sufficiently low for treatment with fast-acting 
carbohydrate and dose adjustment of glucose-lowering 
therapy 
Clinically significant 
hypoglycaemia (level 2) 
< 3.0 mmol/L (54 mg/dL) 
Sufficiently low to indicate serious, clinically 
important hypoglycaemia 
Severe hypoglycaemia 
(level 3) 
No specific glucose threshold 
1Hypoglycaemia associated with severe cognitive 
impairment requiring external assistance for recovery 
Notes: The Novo Nordisk terms are adapted from IHSG21, ADA22, ISPAD23, type 1 diabetes outcomes program24, 
ATTD25. Severe hypoglycaemia as defined by Seaquist26 and ISPAD23. 
Severe hypoglycaemia 
1Severe hypoglycaemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be 
available during an event, but neurological recovery following the return of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.26 
Nocturnal hypoglycaemia 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive. 
Reporting of hypoglycaemic episodes 
Reporting of hypoglycaemic episodes by BG meters: 
Plasma glucose (PG) should always be recorded in the diary/eCRF when a hypoglycaemic episode 
is suspected.  
Hypoglycaemic episodes should be reported according to the instructions below. When a subject 
experiences a hypoglycaemic episode, the subject should record the general information in relation 
to the hypoglycaemia (timing, PG measurements, symptoms etc.) as described in the diary. The 
investigator should ensure correct reporting of the hypoglycaemic episode and report the 
hypoglycaemic episode to the eCRF. In case a subject is not able to fill in the diary (e.g. in case of 
hospitalisation), the investigator should still report the hypoglycaemic episode on the 
hypoglycaemic episodes form in the eCRF.  
If the hypoglycaemic episode fulfils the criteria for an SAE, then in addition to the above, an AE 
form and a safety information form must also be filled in. One AE form and safety information 
form can cover several hypoglycaemic episode forms, if the subject has not recovered between the 
episodes. 
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 
15 minutes until the PG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance with current guidelines.26 
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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. 
'24.?16;4A52>B2@A6<;K)<3229/2AA2?161F<B;221529=A<42A.@B4.?F1?6;83<<1<?
:21606;2LA526;C2@A64.A<?:B@A6;@A?B0AA52@B/720A@A<.;@D2?K-2@L63A522=6@<12D.@.;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.26 
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 subject 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:  
 If a hypoglycaemic episode form in the diary is not completed by the subject 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 (e)CRF with as much information as 
possible. If the subject did not need help to get a sugary drink, food, or medicine, Novo Nordisk 
will only ask for start date due to recall bias.27, 28 
Re-training of subjects 
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low PG values not reported as hypoglycaemic episodes. The training should be documented by the 
investigator in source documents. 
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10.7 
Appendix 7: Retention of human biosamples 
Remaining and residual antibody samples already collected (Sections 8.5 and 8.9) may be retained 
after end of the trial. 
 The samples will be stored at Novo Nordisk or a biorepository assigned by Novo Nordisk after 
end of trial and until marketing authorisation approval or until the research project terminates, 
but no longer than 15 years from the end of the trial after which they will be destroyed. 
 Samples might be transferred to other countries, to a laboratory assigned by Novo Nordisk. 
 The retained samples may be used to: 
 evaluate safety or efficacy aspects that address concerns arising during or after the trial. 
 further characterise the antibody responses towards the drug, if required by health authorities or 
for safety reasons. 
 conduct further analytical method development and validation of antibody assays. 
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10.8 
Appendix 8: Country-specific requirements  
Section 5.1 Inclusion criteria 
For Taiwan: 
Inclusion criteria 2: I
years at the time of signing informed consent. 
Section 5.2 Exclusion criteria 
For Croatia and Germany: 
Exclusion criterion 15: K*Simultaneous participation in a trial with the primary objective of 
evaluating an approved or non-approved investigational medicinal product for prevention or 
treatment of COVID 19 disease or COVID-19 postinfectious conditions is allowed if the last dose 
of the investigational medicinal product has been received more than 30 days before screening.Lis 
not applicable for Croatia and Germany. 
Section 6.5 Concomitant medication 
For Croatia and Germany: 
KMedication administered in relation to a clinical trial for COVID-19 prevention or treatmentL6@
not applicable for Croatia and Germany. 
Section 7.1 Discontinuation of trial treatment 
For Croatia and Germany: 
6@0<;A6;B.A6<;<3A?6.9A?2.A:2;A0?6A2?6<;K*Simultaneous participation in a trial with the 
primary objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or COVID-19 postinfectious conditions is allowed at 
the investigator discretion without discontinuing trial product.L6@;<A.==960./92 for Croatia and 
Germany. 
Section 8.2.3 Eye examination 
For Germany: 
Fundus photography have to be performed by an ophthalmologist. Performance of fundus 
photography by an optimetrist or another qualified health care provider is not allowed. 
For United States of America: 
Fundus photography will be performed by the Investigator or a local Ophthalmologist/Optometrist 
according to local practice. 
Appendix 1, Section 10.1.10 Retention of clinical trial documentation 
For Canada: 
Retention period is 25 years. 
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Appendix 4 Contraceptive guidance and collection of pregnancy information 
For Czech Republic and Germany: 
Contraceptive measures considered adequate include highly effective contraceptive methods in 
.00<?1.;02D6A5A52)@K'20<::2;1.A6<;@?29.A21A<0<;A?.02=A6<;.;1=?24;.;0FA2@A6;46;
clinical trialsLas listed in Table 10-3. 
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10.9 
Appendix 9: Abbreviations  
ADA 
American Diabetes Association 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
BMI 
body mass index 
BUN 
blood urea nitrogen  
CFR 
Code of Federal Regulations  
CKD 
chronic kidney disease  
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
case report form 
COVID-19 
Coronavirus disease 2019 
CTFG 
Clinical Trial Facilitation Group 
CTR 
clinical trial report 
CV 
cardiovascular 
CVD 
cardiovascular disease 
DFU 
directions for use 
DPP-4 
dipeptyl peptidase-4 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
EASD 
European Association for the Study of Diabetes 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
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HbA1c 
glycated haemoglobin 
HCG 
human chorionic gonadotropin  
HDL 
high-density lipoprotein 
HDPE 
High density polyurethane 
HF 
heart failure 
HRT 
hormone replacement therapy 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IUD 
Intrauterine device  
IUS 
Intrauterine device  
IWRS 
interactive web response system 
KDIGO 
kidney disease improving global outcomes 
LDL 
low-density lipoprotein 
LSFT 
last subject first treatment  
MAR 
missing at random  
MEN2 
multiple endocrine neoplasia type 2  
MMRM 
mixed model for repeated measurement 
NYHA 
New York Heart Association 
OAD 
oral anti-diabetic drug 
OTC 
over-the-counter 
PCD 
primary completion date 
PG 
plasma glucose 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Safety analysis set 
s.c. 
subcutaneous 
SGLT2 
sodium-glucose co-transporter 2 
SU 
sulphonylurea 
SUSAR 
suspected unexpected serious adverse reaction 
TD 
treatment difference 
T2D 
type 2 diabetes 
TMM 
trial materials manual 
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ULN 
upper limit of normal 
UACR 
urinary albumin to creatinine ratio  
WOCBP 
woman of child bearing potential 
 
 
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10.10 Appendix 10: 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, including protocol amendment no. 1: 09 November 2020, global 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for preparing protocol, version 2.0 
Due to the COVID-19 pandemic, the exclusion and discontinuation criteria have been amended to 
allow for simultaneous participation in trials with the primary objective of evaluating an approved 
or non-approved investigational medicinal product for prevention or treatment of COVID-19 
disease or COVID-19 postinfectious conditions. 
This amendment also addresses clarifications for missed doses and treatment compliance, as well as 
administrative changes. 
Section # and name 
Description of change 
Brief rationale 
Section 1.2 Flowchart 
<?+.;1+C6@6AD6;1<D0<??20A213?<:MN
A<MGN 
For correctness 
Section 1.2 Flowchart 
For V17, visit window corrected from 0/3 to +3 
For correctness 
Section 1.2 Flowchart 
For Laboratory Assessments, added X under the 
visit columns 
For correctness 
Section 5.2 Exclusion 
criteria 
Addition to exclusion criterion 15 
*Simultaneous participation in a trial with the 
primary objective of evaluating an approved or 
non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or 
COVID-19 postinfectious conditions is allowed if 
the last dose of the investigational medicinal 
product has been received more than 30 days before 
screening. 
To allow for co-participation in 
COVID-19 trials 
Section 6.1 Missed 
doses 
Text modified with regards to guidance on missed 
doses 
To clarify that if the subject has 
been off treatment for more than 10 
consecutive days, the investigator 
should consult Novo Nordisk 
global medical experts for guidance 
regarding continuation of trial 
medication. 
Section 6.4 Treatment 
compliance 
Definition of treatment compliance added 
To clarify that compliance is 
defined as taking between 
80%-120% of the dose as 
prescribed between visits. 
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Section # and name 
Description of change 
Brief rationale 
Section 6.5 
Concomitant 
medication 
Text included for collection of COVID-19 
concomitant medication 
To specify that medication(s) in 
relation to a clinical trial for 
COVID-19 prevention or treatment 
as well as approved COVID-19 
vaccine must be recorded. 
Section 7.1 
Discontinuation of 
trial treatment 
Text added to discontinuation criterion 5 
*Simultaneous participation in a trial with the 
primary objective of evaluating an approved or 
non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or 
COVID-19 postinfectious conditions is allowed at 
the investigator discretion without discontinuing 
trial product. 
To allow for co-participation in a 
COVID-19 trial 
Section 8.2 Safety 
assessments 
Addition of COVID-19 in text  
To include COVID-19 to the 
concomitant illness/medical history 
that should be reported in relevant 
forms 
Section 8.3 Adverse 
events 
Text regarding COVID-19 AEs included 
*including AEs of COVID-19, irrespective of 
seriousness. Note: Suspected COVID-19 should be 
reported if the clinical presentation is suggestive of 
COVID-19, even in the absence of a COVID-19 
test or without a positive COVID-19 test result. In 
the absence of clinical symptoms, a positive 
COVID-19 test (antigen or antibody) should be 
reported, if available. 
To describe the procedure for 
collection of COVID-19 AEs 
Appendix 2 
Bilirubin removed from the list of Biochemistry test 
parameters 
For correctness 
Appendix 3, Figure 
10-1 
Text regarding COVID-19 AEs included 
To describe the procedure for 
collection of COVID-19 AEs 
 
Protocol version 3.0, including protocol amendment no. 1 and 2: 04 March 2021, global 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for preparing protocol, version 3.0 
The exposure-response modelling has been updated based on data that have become available after 
the completion of the first version of the protocol. The new predicted treatment differences for 50 
mg and 25 mg compared to 14 mg are less than previously predicted and therefore, the sample size 
has been increased to maintain the power. 
This amendment also addresses few additional changes such as third-party responsibility and user 
credentials for IT systems. 
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Section # and name 
Description of change 
Brief rationale 
Protocol amendment 
summary of changes 
table 
Substantial amendment as per the 
European Parliament and the Council of 
the European Union 
Reference added for information 
Section 1.1 Synopsis 
Number of subjects changed from 1224 
to 1620. 
To ensure sufficient power given the lower 
expected treatment differences 
Section 2.3.1 Risk 
assessment 
Allergic reactions and neoplasms 
New information added to align with the 
current risk assessment of semaglutide 
Section 2.3.1 Risk 
assessment 
COVID-19 related mitigation plan 
To develop a COVID-19 mitigation plan for 
this trial 
Section 4.2 Scientific 
rationale for trial design 
Third-party responsibility  
To clarify that a third-party, who is only 
allowed to be involved in trial product 
handling, will be responsible for drug 
accountability 
Section 6.3 Measures to 
minimise bias: 
Randomisation and 
blinding 
Blinding and trial product handling 
To clarify the third-party responsibilities in 
relation to trial product handling 
Section 6.3 Measures to 
minimise bias: 
Randomisation and 
blinding 
Quality Assurance audit at site(s) 
To follow GCP advice agreement, text 
regarding Quality Assurance audit at site(s) 
and allowing them access to unblinded trial 
treatment records at the site(s) has been 
removed 
Section 8.2.4 Eye 
examination 
Fundus photography or slit-lamp 
biomicroscopy  
To clarify that fundus photography or slit-
lamp biomicroscopy examination should be 
used for evaluation of retinopathy or 
maculopathy. Additional examinations (e.g., 
optical coherence tomography and/or best 
corrected visual acuity) can be performed as 
a supplement for further evaluation. 
However, in this trial, additional eye 
examinations including the optical 
coherence tomography and/or best corrected 
visual acuity, cannot replace the fundus 
photography or slit-lamp biomicroscopy 
examination 
Section 9.2 Sample size 
determination 
Updated sample size assumption 
To ensure sufficient power given the lower 
expected treatment differences 
Section 9.4.2 Primary 
endpoint 
Updated tipping point sensitivity analysis 
and added an extra sensitivity analysis 
To accommodate feedback from FDA 
Section 9.4.3.1 
Confirmatory 
secondary endpoint 
Updated with similar sensitivity analyses 
as for the primary endpoint 
To accommodate feedback from FDA 
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Section # and name 
Description of change 
Brief rationale 
Section 10.1.12 
Responsibilities 
Sharing of user credentials for IT 
systems 
To emphasize that the investigator will 
ensure that IT equipment will not be shared 
with others in a way where user credentials 
have the possibility of being shared 
Appendix 2 (Section 
10.2) Clinical 
laboratory tests 
In Table 10-1, V15 removed for fasting 
plasma glucose  
For correctness 
Appendix 2 (Section 
10.2) Clinical 
laboratory tests 
In Table 10-1 footnote, FPG of 
<3.9 ::<9	#05.;421A<H mmol/L  
For correctness 
Appendix 6 (Section 
10.6) Hypoglycaemic 
episodes 
In Table 10-4, Hypoglycaemia alert 
value (level 1) <3.9 mmol/L changed to 
H mmol/L 
For correctness 
Appendix 6 (Section 
10.6) Hypoglycaemic 
episodes 
&C.9B2I::<9	#05.;421A<
>3.9 mmol/L 
For repeated PG measurements, 
succeeding PG value changed from 
I mmol/L to >3.9 mmol/L 
For correctness 
Appendix 9 (Section 
10.9) Abbreviations 
Added COVID-19 
For clarification 
Section 11 References 
The European Parliament and the 
Council of the European Union 
Reference added for information 
 
Protocol version 4.0, including protocol amendment no. 1, 2 and 3: 28 April 2021, Croatia and 
Germany 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union,1 because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
For Croatia and Germany, co-participation in COVID-19 trials is not allowed due to local 
requirements, and not allowing co-participation in COVID-19 trials does not affect patient safety. 
Overall rationale for preparing protocol, version 4.0: 
The overall rationale for the changes implemented in the amended protocol is to address local 
requirements in Croatia and Germany. 
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Section # and name 
Description of change 
Brief rationale 
5.2 Exclusion criteria 
Updated to include a reference to 
country-specific requirements for 
Croatia and Germany 
Co-participation in COVID-19 trials 
is not allowed in Croatia and 
Germany due to local requirements. 
6.5 Concomitant medications 
Updated to include a reference to 
country-specific requirements for 
Croatia and Germany 
Co-participation in COVID-19 trials 
is not allowed in Croatia and 
Germany due to local requirements. 
7.1 Discontinuation of trial treatment 
Updated to include a reference to 
country-specific requirements for 
Croatia and Germany 
Co-participation in COVID-19 trials 
is not allowed in Croatia and 
Germany due to local requirements. 
10.8 Appendix 8: Country-specific 
requirements 
Requirements for Croatia and 
Germany updated to disallow co-
participation in clinical trials 
evaluating approved or non-
approved investigational medicinal 
products for the prevention or 
treatment of COVID-19 disease or 
COVID-19 postinfectious 
conditions. Accordingly, exclusion 
criterion #15, use of concomitant 
medications related to COVID-19 
and discontinuation of trial treatment 
criterion #5 are not applicable for 
Croatia and Germany.  
Co-participation in COVID-19 trials 
is not allowed in Croatia and 
Germany due to local requirements. 
 
Protocol version 5.0, including protocol amendment no. 1, 2, 3 and 4: 04 June 2021, global 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union,1 because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 5.0: 
The overall rationale for the changes implemented in the amended protocol is to include an 
unblinded monitor. 
Section # and name 
Description of change 
Brief rationale 
6.3 Measures to minimise bias: 
Randomisation and blinding 
Addition of an unblinded monitor 
To clarify monitoring responsibilities 
10.1.8.2 Monitoring 
Addition of an unblinded monitor 
To clarify monitoring responsibilities 
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Protocol version 6.0, including protocol amendment no. 1, 2, 3, 4 and 5: 01 February 2022 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union,1 because 
it neither significantly impacts the safety nor physical/mental integrity of subjects nor the scientific 
value of the trial. 
Overall rationale for preparing protocol, version 6.0: 
The overall rationale for the changes implemented in the amended protocol is to include the 
possibility of performing partial DBL and to update the text related to reconciliation process to 
include risk based reconciliation. 
Section # and name 
Description of change 
Brief rationale 
9.4 statistical analysis, 9.4.3.2 supportive 
secondary endpoints, 9.4.5.1 
pharmacokinetic modelling, 9.7 reporting 
of the main part of the trial 
 
Addition of partial DBL text 
The possibility of performing a 
partial DBL is implemented to 
support potential earlier access of 
oral semaglutide 25 and 50 mg to 
the patient population expected to 
benefit from higher doses.  
6.2 
preparation/handling/storage/accountability 
Text with respect to reconciliation 
process is updated as below: 
"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 IWRS."  
Deleted bold text from the above 
bullet point 
This text was misleading in 
relation to the reconciliation 
process set up for PIONEER 
PLUS as risk based reconciliation 
is used for this trial. 
10.1.8.2 Monitoring 
The last bullet text regarding 
reconciliation process has been 
updated i.e.  "An unblinded 
monitor will reconcile trial 
product accountability" was 
updated to "An unblinded monitor 
will be responsible for the 
reconciliation process set up for 
this trial." 
This text was misleading in 
relation to the reconciliation 
process set up for PIONEER 
PLUS as risk based reconciliation 
is used for this trial. 
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11 "# 
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. 
Novo Nordisk A/S. Rybelsus® (semaglutide tablets), US Prescribing Information. September 
2019. 
3. 
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. 
4. 
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. 
5. 
Novo Nordisk A/S. Investigator's Brochure, Oral semaglutide for Type 2 Diabetes, Project 
NN9924 (ed. 11). 31 July 2019. 
6. 
Novo Nordisk A/S. Rybelsus® (oral semaglutide), EU Summary of Product Characteristics 
(SmPC). 03 Apr 2020. 
7. 
Novo Nordisk A/S. Rybelsus® (oral semaglutide), US Prescribing Information (PI). 20 Sep 
2019. 
8. 
Meier J. Efficacy of oral semaglutide according to baseline HbA1c: an exploratory subgroup 
analysis of the PIONEER trial programme [Internet]. EASD Barcelona 2019, virtual 
meeting, oral presentation #51, Session: Semaglutide: ingested or injected. 2019 [cited 2020 
21 Apr]. 
9. 
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. 
10. 
.C62@$N92@@6<?.186;!"2?;.;,$.A562B$6;4?<;22A.9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. 
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biometrical Journal. 2011;53(6):894-913. 
12. 
Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 10/3/2014 2014. 
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. 
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Trial ID: NN9924-4635 
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17. 
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. 
18. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
19. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
20. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org. 
21. 
International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/l 
(54 mg/dl) should be reported in clinical trials: a joint position statement of the American 
Diabetes Association and the Europian Association for the Study of Diabetes. Diabetologia. 
2017;60(1):3-6. 
22. 
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64. 
23. 
Abraham MB, Jones TW, Naranjo D, Karges B, Oduwole A, Tauschmann M, et al. ISPAD 
Clinical Practice Consensus Guidelines 2018: Assessment and management of 
hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2018;19 Suppl 
27:178-92. 
24. 
Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. 
Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 
Diabetes: A Consensus Report of the American Association of Clinical Endocrinologists, 
the American Association of Diabetes Educators, the American Diabetes Association, the 
Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable 
Trust, the Pediatric Endocrine Society, and the T1D Exchange. Diabetes Care. 
2017;40(12):1622-30. 
25. 
Danne T, Nimri R, Battelino T, Bergenstal RM, Close KL, DeVries JH, et al. International 
Consensus on Use of Continuous Glucose Monitoring. Diabetes Care. 2017;40(12):1631-40. 
26. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95. 
27. 
US Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome 
Measures: Use in Medical Product Development to Support Labeling Claims. December 
2009. 
28. 
Stull DE, Leidy NK, Parasuraman B, Chassany O. Optimal recall periods for patient-
reported outcomes: challenges and potential solutions. Curr Med Res Opin. 2009;25(4):929-
42. 
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04707469 
Sponsor trial ID: 
NN9924-4635 
Official title of study: 
Efficacy and safety of once-daily oral semaglutide 25 mg and 
50 mg compared with 14 mg in subjects with type 2 diabetes 
Document date* 
23 December 2022 
*Document date refers to the date on which the document was most recently updated. 
 


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
1 of 27 
Statistical Analysis Plan
NN9924-4635 
PIONEER PLUS 
Biostatistics 
Redacted VWDWLVWLFDODQDO\VLVSODQ
Includes redaction of personal identifiable information only. 
. 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
2 of 27 
 
 
 
 
	
 
 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 4 
Table of tables ................................................................................................................................................... 4 
Version history .................................................................................................................................................. 5 
 
Introduction ............................................................................................................................................... 6 
Objectives and endpoints ............................................................................................................................ 6 
Primary and secondary objectives, and estimands ...................................................................................... 6 
Estimands .................................................................................................................................................... 6 
Primary and secondary endpoints ............................................................................................................... 9 
Primary endpoint ............................................................................................................................ 9 
Secondary endpoints ...................................................................................................................... 9 
Confirmatory secondary endpoints .............................................................................. 9 
Supportive secondary endpoints .................................................................................. 9 
Trial design ................................................................................................................................................ 10 
 
Statistical hypotheses .............................................................................................................................. 11 
Multiplicity Adjustment ............................................................................................................................ 11 
 
Sample size determination ...................................................................................................................... 12 
 
Analysis sets ............................................................................................................................................. 13 
 
Statistical analyses ................................................................................................................................... 14 
General considerations .............................................................................................................................. 14 
Subject disposition .................................................................................................................................... 17 
Primary endpoint analysis ......................................................................................................................... 17 
Definition of endpoint .................................................................................................................. 17 
Main analytical approach ............................................................................................................ 17 
Sensitivity analysis ....................................................................................................................... 18 
Supplementary analyses ............................................................................................................... 18 
Secondary endpoints analysis .................................................................................................................... 19 
Confirmatory secondary endpoints .............................................................................................. 19 
Definition of endpoints ............................................................................................... 19 
Main analytical approach .......................................................................................... 19 
Sensitivity analysis ..................................................................................................... 19 
Supplementary analyses ............................................................................................. 19 
Supportive secondary endpoints .................................................................................................. 19 
Exploratory endpoints analysis ................................................................................................................. 23 
Safety analyses .......................................................................................................................................... 23 
Adverse events ............................................................................................................................. 23 
Hypoglycaemia ............................................................................................................................ 23 
Other safety endpoints ................................................................................................................. 25 
Interim analyses .............................................................................................................................................. 25 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
3 of 27 
 
 
 
 
 
Supporting documentation ..................................................................................................................... 27 
Appendix 1 List of abbreviations .............................................................................................................. 27 
 
References ................................................................................................................................................ 27 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
4 of 27 
 
 
 
 
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Page 
Figure 1 
Trial design ................................................................................................................................. 10 
Figure 2 
Graphical illustration of the closed testing procedure ........................................................... 12 
 
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Page 
Table 1 
Overview of estimands and their attributes .............................................................................. 8 
Table 2 
Overview of defined populations .............................................................................................. 13 
Table 3  
Handling of intercurrent events for the estimands ................................................................. 15 
 
CONFIDENTIAL


Statistical Analysis Plan 
UTN:U1111-1247-0210 
Date: 
23 December 2022 
Status: 
Trial ID: NN9924-4635 
EudraCT No:2020-000299-39 
Version: 
3.0 
Page: 
 
 
 
 
 
This Statistical Analysis Plan (SAP) for trial NN9924-4635 is based on the protocol version 
7.0 dated 16SEP2022.   
SAP 
Version Date 
Change 
Rationale 
1.0 
03Oct2022 
Not Applicable 
Original version 
2.0 
04Oct2022 
Minor corrections 
 
3.0 
23Dec2022 
Specification the how to 
handle region Australia 
and strata variable in the 
imputation models 
To avoid potential 
estimation problems 
Clarification that in the 
week 68 analyses the 
treatment 
discontinuation/rescue 
medication during the 68 
weeks period will used 
when defining imputation 
groups 
Clarification 
Analysis that mimics a 2-
stage randomisation 
design 
Investigate potential 
effect if 25 mg or 50 mg 
is used as intensification. 
Added time to event 
analyses of rescue 
medication 
To investigate the use of 
rescue medication 
Correction of typos in the 
section describing the 
hypoglycaemia analyses 
Correction of typos 
 


Statistical Analysis Plan 
UTN:U1111-1247-0210 
Date: 
23 December 2022 
Status: 
Trial ID: NN9924-4635 
EudraCT No:2020-000299-39 
Version: 
3.0 
Page: 
 
 
 
 
 
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Objectives and endpoints 
Primary and secondary objectives, and estimands  
Primary objective  
To confirm superiority of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on HbA1c reduction 
in subjects with T2D on stable dose of 1-3 OADs.  
Secondary objectives  
To confirm superiority of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on body weight 
reduction in subjects with T2D on a stable dose of 1-3 OADs.  
To compare the efficacy of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on parameters 
related to glycaemic control in subjects with T2D on a stable dose 
of 1-3 OADs.  
To compare the efficacy of oral semaglutide 25 mg and 50 mg once 
daily versus oral semaglutide 14 mg once daily on parameters 
related to weight-related outcomes in subjects with T2D on a stable 
dose of 1-3 OADs.  
To compare the safety and tolerability of oral semaglutide 25 mg 
and 50 mg once daily versus oral semaglutide 14 mg once daily 
in subjects with T2D on stable dose of 1-3 OADs.  
Estimands  
For the primary and the confirmatory secondary objective, estimands of primary interest and 
additional estimands are defined. The estimands are used to address the trial objectives in 
terms of two different aspects of the treatment effect of oral semaglutide 14, 25 and 50 mg. 
Three intercurrent events are considered: Premature trial treatment discontinuation (due to any 
reason), change in dose and initiation of additional anti-diabetic medication. Intercurrent 
events are events occurring after treatment initiation that affect the interpretation or the 
existence of the measurements associated with the questions of interest.   
The estimands for the primary objective are introduced below and the attributes of the 
estimands are summarised in Table 1. Additional details are available in Section 0.   
Similar estimands are applied to the objective related to superiority in change in body weight.  
The primary estimand addresses the main question of interest: What is the efficacy of oral 
semaglutide 25 and 50 mg versus oral semaglutide 14 mg on change from baseline to week 52 
in HbA1c in subjects with T2D on stable dose of 1-3 OADs regardless of premature trial 
treatment discontinuation, changes in dose and initiation of additional anti-diabetic 
medication.   


Statistical Analysis Plan 
UTN:U1111-1247-0210 
Date: 
23 December 2022 
Status: 
Trial ID: NN9924-4635 
EudraCT No:2020-000299-39 
Version: 
3.0 
Page: 
 
 
 
 
For this estimand, the treatment policy strategy is applied for all intercurrent events (Table 3). 
Data collection will continue after an intercurrent event and the collected data will be 
included in analyses regardless of the occurrence of the event.  
Results based on the primary estimand are expected to mirror the clinical practice scenario 
because the estimand considers both the efficacy and tolerability of oral semaglutide. In 
addition, a similar estimand is represented in the label for Rybelsus®.  
The additional estimand addresses an additional question of interest: What is the efficacy of 
oral semaglutide 25 and 50 mg versus oral semaglutide 14 mg on change from baseline to 
week 52 in HbA1c in subjects with T2D on stable dose of 1-3 OADs regardless of change in 
dose of trial treatment and if all subjects had remained on trial treatment without use of rescue 
medication.   
For this estimand, a hypothetical strategy is applied for two of the intercurrent events 
(premature trial treatment discontinuation and initiation of rescue medication). The treatment 
policy strategy is used to handle any changes in trial treatment dose level because this 
intercurrent event is part of the pre-specified treatment regimen.   
The additional estimand is considered relevant because it quantifies the achievable treatment 
effect without potentially confounding effects of any rescue medication. Further, results 
obtained with the additional estimand allows for comparison with results from the oral 
semaglutide phase 3a programme (PIONEER), which applied a similar additional estimand.  
Similar estimands are defined for the other efficacy objectives.  
 
 
 


Statistical Analysis Plan 
UTN:U1111-1247-0210 
Date: 
23 December 2022 
Status: 
Trial ID: NN9924-4635 
EudraCT No:2020-000299-39 
Version: 
3.0 
Page: 
 
 
 
 
Table 1 
Overview of estimands and their attributes 
Objective  
Estimand 
category  
Attributes  
Treatment condition  
Variable / 
endpoint  
Population of 
interest  
Intercurrent events 
and strategy  
Population
-level 
summary 
measure  
Primary objective:  
To confirm 
superiority of oral 
semaglutide 25 mg 
and 50 mg once 
daily versus oral 
semaglutide 14 mg 
once daily on 
HbA1c reduction 
in subjects with 
T2D on stable dose 
of 1-3 OADs  
Primary   
㻌 
The effect of high doses of oral 
semaglutide with or without additional 
anti-diabetic㻌medication versus the effect 
of oral semaglutide 14 mg with or 
without additional anti-
diabetic㻌medication, both as add-on to 
stable dose of 1-3 OADs  
Change in 
HbA1c fro
m baseline 
to 
week 52  
T2D subjects a
s defined by 
the protocol 
inclusion and 
exclusion 
criteria  
Treatment 
policy strategy for:  
 
Premature 
rial treatment 
discontinuation 㻌
 
Dose 
change 㻌
 
Initiation 
of additional anti-
diabetic medication 㻌
Difference 
in means  
Additional*
   
The effect of high doses of oral 
semaglutide without rescue medication ver
sus the effect of oral semaglutide 14 mg 
without rescue medication, both as add-on 
to stable dose of 1-3 OADs  
Hypothetical strateg
y for:  
 
Premature 
rial treatment 
discontinuation 㻌
 
Initiation 
of rescue medication
㻌
Treatment 
policy strategy for:  
 
Dose 
change 㻌
Secondary objective
:  
To confirm 
superiority of oral 
semaglutide 25 mg 
and 50 mg once 
daily versus oral 
semaglutide 14 mg 
once daily on body 
weight reduction 
in subjects with 
T2D on stable dose 
of 1-3 OADs  
Secondary   The effect of high doses 
of oral semaglutide with 
or without additional anti-
diabetic㻌medication versus the effect of 
oral semaglutide 14 mg with 
or without additional anti-
diabetic㻌medication, both as add-on to 
stable dose of 1-3 OADs  
Change in 
body 
weight 
from 
baseline to 
week 52  
T2D subjects a
s defined by 
the protocol 
inclusion and 
exclusion 
criteria  
Treatment 
policy strategy for:  
 
Premature 
rial treatment 
discontinuation 㻌
 
Dose 
change 㻌
 
Initiation 
of additional anti-
diabetic medication 㻌
Difference 
in means  
Additional*
   
The effect of high doses of oral 
semaglutide without rescue medication ver
sus the effect of oral semaglutide 14 mg 
without rescue medication, both as add-on 
to stable dose of 1-3 OADs  
Hypothetical strateg
y for:  
 
Premature 
rial treatment 
discontinuation 㻌
 
Initiation 
of rescue medication
㻌
Treatment 
policy strategy for:  
 
Dose 
change 㻌
* Not related to the confirmatory hypotheses   
 
 


Statistical Analysis Plan 
UTN:U1111-1247-0210 
Date: 
23 December 2022 
Status: 
Trial ID: NN9924-4635 
EudraCT No:2020-000299-39 
Version: 
3.0 
Page: 
 
 
 
 
Primary and secondary endpoints  
Primary endpoint 
Endpoint title  
Timeframe  
Unit  
Change in glycated haemoglobin 
(HbA1c)  
From baseline (week 0) to week 52  %-point  
Secondary endpoints 
Confirmatory secondary endpoints 
Endpoint title  
Timeframe  
Unit  
Change in body weight   
From baseline (week 0) to week 52 kg  
Supportive secondary endpoints 
Endpoint title  
Timeframe  
Unit  
Change in fasting plasma glucose (FPG)  
From baseline (week 0) to week52   
mmol/l  
Achievement of HbA1c <7% (Yes/No)   
At week 52 
Count of subjects  
Achievement of HbA1c 6#0-  
At week 52 
Count of subjects  
Relative change in body weight   
From baseline (week 0) to week 52 
Percentage (%)  
Change in waist circumference  
From baseline (week 0) to week 52 
cm  
!&'#3#+#,1-$4#'%&1*-007#0-  At week 52  
Count of subjects  
!&'#3#+#,1-$4#'%&1*-007	#0-   At week 52 
Count of subjects  
Adverse events  
From baseline (week 0) to follow-
up visit (week 73)  
Count of events  
The endpoints specified at week 52 will also be analysed at week 68. 
 


Statistical Analysis Plan
Date:
23 December 2022
Novo Nordisk
Trial ID: NN9924-4635
Version:
3.0
UTN:U1111-1247-0210
Status:
Final
EudraCT No:2020-000299-39
Page:
10 of 27
Trial design
This is a 68-week, randomised, active-controlled, double-blinded, three-armed, multi-centre, 
multinational clinical trial.  
Eligible subjects will be randomised in a 1:1:1 manner to receive either:  

oral semaglutide 50 mg once daily 

oral semaglutide 25 mg once daily 

oral semaglutide 14 mg once daily 
Randomisation will be stratified by baseline anti-diabetic medication: ± SU, ±SGLT2 inhibitor, 
±terminated DPP-4 inhibitor. Consequently, randomisation will comprise 8 strata for combinations 
of SU, SGLT2 inhibitor, and terminated DPP-4 inhibitor. Metformin is not included in the 
stratification. A 30% cap on DPP-4 inhibitor users will be implemented to equalise the 
representation of baseline background anti-diabetic medication across the population. 
The trial comprises a 2-4##)0!/##,',%.#/'-"1-00#001&#02 (#!1:0#*'%' '*'15$-**-4#" 5
randomisation visit (V2) and a 68-week treatment period. The treatment period is divided into a 
dose escalation period of 8-16 weeks and a maintenance period of 52-60 weeks. After the end-of-
treatment visit (V16), all subjects will enter a follow-up period of 5 weeks, ended by a follow-up 
visit (V17), which corresponds to the end of the trial. The planned total trial duration for the 
individual subject is approximately 75 weeks (including screening). 
Figure 1
Trial design
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
11 of 27 
 
 
 
 
 
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 
Four confirmatory hypotheses will be evaluated based on the primary and secondary estimand. For 
the primary endpoint, change in HbA1c from baseline to week 52, the following confirmatory one-
sided hypothesis of superiority will be tested for both oral semaglutide 50 mg and 25 mg versus oral 
semaglutide 14 mg. Let the mean treatment difference (higher dose of oral semaglutide - oral 
semaglutide 14 mg) be "#$',#"0<&#,2**0) and alternative (HA) hypotheses to be tested are:  
H0<7-point against HA<-point  
For the confirmatory secondary endpoint, change in body weight from baseline to week 52, the 
following confirmatory one-sided hypothesis of superiority will be tested for both oral semaglutide 
50 mg and 25 mg versus oral semaglutide 14 mg:  
H0<7)%%',01A<)% 
Operationally, the hypotheses will be evaluated by two-sided tests.   
 
Multiplicity Adjustment 
Adjustment for multiplicity associated with the testing of the four confirmatory hypotheses will be 
done using the weighted Bonferroni-based closed testing procedure described in Bretz et al.1 and 
outlined in Figure 2. The type I error will be preserved in the strong sense at a nominal two-sided 
5% level. The first hypothesis to be tested is superiority of oral semaglutide 50 mg vs 14 mg on 
change from baseline in HbA1c. It will be tested at the overall significance level (5%) while 
allocating 0% local significance level to the remaining of the hypotheses. For this hypothesis, and in 
general, if a hypothesis is confirmed, then the significance level will be reallocated according to the 
weight and the direction of the arrows going from the confirmed hypothesis to the next hypotheses 
as specified in Figure 2. Each of the four hypotheses will be tested at their updated local 
0'%,'$'!,!#*#3#*;-local). This process will be repeated until no further hypotheses can be 
confirmed.   
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding alternative hypothesis and the two-sided p-value from the primary analysis is strictly 
below its local two-sided significance level as defined by the closed testing procedure. This is 
equivalent to using a one-sided p-3*2#,-+',*;
,"-,#-sided 2.5% overall 
significance level in the closed testing procedure.  
 
CONFIDENTIAL


Statistical Analysis Plan
Date:
23 December 2022
Novo Nordisk
Trial ID: NN9924-4635
Version:
3.0
UTN:U1111-1247-0210
Status:
Final
EudraCT No:2020-000299-39
Page:
12 of 27
Figure 2
Graphical illustration of the closed testing procedure
&#-3#/**0'%,'$'!,!#*#3#*-$;14--sided) is initially allocated to the hypothesis of 
superiority of oral semaglutide 50 mg vs 14 mg on change from baseline in HbA1c (top left box). If 
&5.-1&#0'0'0!-,$'/+#"1&#*-!*0'%,'$'!,!#*#3#*;-local) will be reallocated according to the 
weight given by the directed edges between boxes (hypotheses).


Please refer to section 9.2 in the protocol.
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
13 of 27 
 
 
 
 
 
 
The following populations are defined:  
 
Table 2 
Overview of defined populations  
 
Population  
Description  
Full analysis set (FAS)  
All subjects randomised. Subjects contribute to a treatment group based on the 
trial treatment they were randomised to receive.  
Safety analysis set (SAS)  
All subjects who receive at least 1 dose of trial treatment. Subjects contribute to a 
treatment group based on the trial treatment they actually received.  
The FAS will be used in the evaluation of the efficacy endpoints, the SAS will be used for 
the evaluation of the safety endpoints, exclusively.  
 
 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
14 of 27 
 
 
 
 
 
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 
General considerations 
Data from all sites will be analysed and reported together.  
 
In statistical analyses where stratification is accounted for, the background medication at screening 
will be included based on the actual information collected through the eCRF. In case of missing 
eCRF information, the information collected from the IWRS system will be used.   
The latest available measurement, at or prior to the randomisation visit, will be used as the baseline 
measurement. If no measurement(s) have been obtained, at or prior to randomisation, the baseline 
value will be left missing.   
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for each high dose vs. 14 mg oral semaglutide with associated two-sided 95% confidence 
intervals and p-values corresponding to two-sided tests of no difference.  
 
 
Missing data  
The amount of missing data when estimating the primary and secondary estimands (i.e. data 
that are not available even though all efforts were made to ensure that subjects stayed in the trial 
regardless of premature discontinuation of trial treatment or initiation of additional anti-diabetic 
treatment) is expected to be low. At week 52, the proportion of subjects with missing data was 5-
7% across trials in the PIONEER programme. Missing data will be missing mainly be due to 
subjects withdrawing consent or being lost to follow-up. In the statistical analyses, missing data will 
be handled in line with the strategies applied for the pre-defined intercurrent events.  
 
Data selections and observation periods  
Unless subjects withdraw their informed consent, data collection will continue for the planned full 
duration of the trial for the individual subject. The full duration of the trial is defined as up to and 
including the follow-up visit (V17) for subjects completing trial treatment and subjects who have 
discontinued trial treatment prematurely.  
As described in Section 0 the trial objectives relating to efficacy will be addressed using two 
different types of estimands. The primary and secondary estimands applying a treatment policy 
strategy to all intercurrent events and the additional supportive estimands applying a hypothetical 
strategy to the intercurrent events of premature trial treatment discontinuation and initiation of 
additional anti-diabetic medication. The handling of the intercurrent events with respect to data 
collection and analysis is specified in Table 3.  
 
 
 
 
 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
15 of 27 
 
 
 
 
Table 3  
Handling of intercurrent events for the estimands 
 
Intercurrent event  
 Primary and secondary estimands  Additional supportive estimands  
Premature trial treatment 
discontinuation  
Data collected after the intercurrent 
event is used in analysis in line with a 
reatment-policy strategy, i.e. 
disregarding the occurrence of the 
intercurrent event  
Data collected after the intercurrent 
event will be excluded and treated as 
missing in analysis, i.e. using a 
hypothetical strategy  
Initiation of additional anti-diabetic 
medication  
Change of dose  
Data collected after the intercurrent 
event and used in analysis in line with a 
treatment-policy strategy, i.e. 
disregarding the occurrence of the 
intercurrent event  
 
Additional anti-diabetic medication is defined as new anti-diabetic medication and/or intensification 
of anti-diabetic medication initiated at or after randomisation and before planned end of treatment. 
Rescue medication is used to designate additional anti-diabetic medication initiated while on trial 
treatment, i.e. before last dose of trial product.  
Observation periods will be used to select data for analyses in line with the strategies applied for 
the intercurrent events. Subjects and data to be used in an analysis will be selected in a two-
step manner:  
 
First, subjects will be selected based on the specified analysis set.  
 
Second, data points on the selected subjects from the first step will be selected based on the 
specified observation period.  
For the efficacy and safety evaluations, three different observation periods will be defined:  
 
The in-trial observation period 8 the time period from when a subject is randomised until 
the final scheduled visit, including any period after initiation of additional anti-
diabetic medication or discontinuation of trial treatment.  
 
The on-treatment observation period 8 the time period when a subject is on trial treatment, 
including any period after initiation of rescue medication.  
 
The on-treatment without rescue medication observation period 8 the time period when a 
subject is on trial treatment, excluding any period after initiation of rescue medication.  
The in-trial observation period begins at the date of randomisation and ends at the 
final scheduled visit, which can be one of the below:  
 
the follow-up visit (V17) for subjects who complete treatment and for subjects who 
discontinue trial treatment prematurely  
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
16 of 27 
 
 
 
 
 
the last contact for subjects who withdraw from trial, are lost to follow-up or die  
The on-treatment observation period begins at the date of first dose of trial treatment; the end 
date depends on the assessment being evaluated:  
For all efficacy assessments and certain safety assessments (laboratory assessments, physical 
examination and vital signs), a plus-3-day window (i.e. the 3-day visit window) is used and the 
period ends at the first of the following time points:   
 
last dose of trial treatment plus a 3-day window   
 
end of the in-trial observation period  
For the remaining safety assessments (eye examination categories, AEs, and hypoglycaemic 
episodes), a plus-38-day window (i.e. the 5-week follow-up period plus the 3-day visit window) is 
used and the period ends at the first of the following time points:  
 
the follow-up visit (V17)  
 
the last dose of trial treatment +38 days   
 
end of the in-trial observation period  
The on-treatment without rescue medication observation period begins at the date of 
the first dose of trial treatment and ends at the first of the following time points:  
 
end of the on-treatment observation period  
 
initiation of rescue medication (if any)  
For the efficacy endpoints, the primary and secondary estimands will be evaluated based on data 
from the in-trial observation period and the additional supportive estimands will be evaluated based 
on data from the on-treatment without rescue medication observation period thereby selecting data 
in line with the strategies applied for the intercurrent events as shown in Table 3. The safety 
evaluation will primarily be based on the on-treatment observation period, except for deaths and AE 
types with potentially long latency between onset and diagnosis, for which the in-trial observation 
period will be used. The observation period determines what data subjects contributes with to a 
specific analysis. Baseline values are by definition included in all observation periods; other data 
points collected outside the observation period used for an analysis will be considered missing.  
Before data are locked for statistical analysis, a review of all data will take place. Exclusion of data 
from analyses should be used restrictively, and normally no data should be excluded from the FAS. 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
17 of 27 
 
 
 
 
The subjects or observations to be excluded, and the reasons for their exclusion must be 
documented before unblinding. The subjects and observations excluded from analysis sets, and the 
reason for this, will be described in the clinical trial report.  
 
Subject disposition 
Subject disposition will be summarised by treatment arm using descriptive statistics. 
Primary endpoint analysis 
Definition of endpoint 
The primary endpoint is the change in HbA1c (%-point) from baseline (week 0) to week 52. 
Main analytical approach 
Primary analysis for the primary estimand  
The primary estimand defined in Table 3 will be estimated based on the FAS using week 52 
measurements from the in-trial observation period. The primary statistical analysis will be a pattern 
mixture model using multiple imputation to handle missing data assuming that the missing data 
mechanism is missing at random (MAR) within the groups used for imputation. Imputation of 
missing week-52 data will be done within 6 groups of subjects defined by randomised treatment 
arm, and whether subjects at week 52 (i) are still on treatment and have not initiated rescue 
medication or (ii) have discontinued treatment or initiated rescue medication. It is hereby assumed 
that the likely values of what the missing data would have been if available are best described by 
information from subjects who at week 52 are similar in terms of randomised treatment arm and 
trial treatment discontinuation/rescue medication status. For each imputation group, an analysis of 
covariance model (ANCOVA) with stratification factor and region as factors and baseline HbA1c as 
covariate will be used to impute 1000 values for each subject with missing week 52 data. For the 
imputation groups where the subjects have discontinued treatment or initiated rescue medication the 
time (days) from randomisation until discontinuation or initiation of rescue medication will also be 
included as a covariate.  
 
The 1000 complete data sets will be analysed using an ANCOVA with treatment, stratification 
factor and region as factors and baseline HbA1c as covariate. The results obtained from analysing 
1&#"10#104'** #!-+ ',#"20',%2 ',:0/2*#2 to draw inference. 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
18 of 27 
 
 
 
 
The regions to be used in the statistical analyses are defined as Europe, North America, Australia 
and Asia. When addressing the treatment policy estimand, the imputation is to be done within 
groups defined by randomised treatment and treatment adherence at time of evaluation. Due to the 
low number of subjects in region Australia the region variable included in the imputation model 
will be reduced in levels avoiding estimation problems due to sparse data. The regions to be used in 
these imputations are defined as Europe, North America and Asia with Australia included in region 
Asia.  
 
Similarly, if estimation issues are encountered due to low number of subjects in some of the strata 
levels, then the smallest group will be merged with the next smallest. This process will be continued 
until the estimation issue is no longer present. 
Sensitivity analysis 
In line with ICH E9 (R1), sensitivity analyses will be performed investigating the robustness of the 
conclusions made on the basis of the primary analyses towards the impact of missing data. 
  
Tipping-point multiple imputation analysis: The assumption of MAR within groups used for 
imputation will be evaluated by a tipping point sensitivity analysis. Missing data will first be 
imputed as for the primary analysis. Secondly, for each of the 25 mg and 50 mg oral semaglutide 
treatment arms, a penalty will be added to the imputed week-52 values. The approach is to 
gradually increase this penalty until the confirmed HbA1c conclusion from the primary analysis is 
changed. For each hypothesis tested, the specific value of the penalty that changes the conclusion 
will be used to evaluate the robustness of the primary analysis results.   
 
Return to baseline multiple imputation analysis: subjects with missing data at week 52 will have 
their change from baseline value imputed as 0 plus a random error. The error is randomly drawn 
from a normal distribution with a mean of 0 and a variance equal to the residual variance estimated 
from the MMRM for observed values of change from baseline in HbA1c, adjusted for the same 
covariates and factors as in the primary analysis. For missing values from patients who are still on 
treatment, it will be assumed that those data are missing at random and they will be imputed based 
on the observed data from the subjects who completed the trial on treatment in the same treatment 
arm. 
Supplementary analyses 
Analysis for the additional estimand  
The additional estimand will be estimated based on the FAS using post-baseline measurements up 
to and including week 52 from the on-treatment without rescue medication observation period. The 
analysis for the additional estimand will be a Mixed Model for Repeated Measurements (MMRM). 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
19 of 27 
 
 
 
 
A restricted maximum likelihood will be used. The model will include all post baseline HbA1c 
measurements collected at scheduled visits up to and including week 52 as dependent variables. The 
independent effects included in the model will be treatment, stratification factor and region as 
categorical fixed effects and baseline HbA1c as a covariate, all nested within visit. An unstructured 
covariance matrix for HbA1c measurements within the same subject will be employed, assuming 
measurements from different subjects are independent. 
Secondary endpoints analysis 
Confirmatory secondary endpoints 
Definition of endpoints 
The confirmatory secondary endpoint is the change in body weight (kg) from baseline (week 0) to 
week 52. 
Main analytical approach 
The secondary estimand will be estimated in the same way as for the primary endpoint with 
baseline HbA1c replaced by baseline body weight as the covariate. 
Sensitivity analysis 
A tipping-point multiple imputation analysis similar to the one performed for the primary endpoint 
will be performed.  
Supplementary analyses 
Analysis for the additional estimand  
The additional estimand will be estimated in the same way as for the primary endpoint with 
baseline HbA1c replaced by baseline body weight as the covariate. 
Supportive secondary endpoints 
.1.1.1 
Efficacy endpoints 
The below supportive secondary efficacy endpoints will be evaluated for 
 
similar to the primary estimand based on FAS using the  in-trial observation period 
 
similar to the additional estimand based on FAS using the on-treatment without rescue 
medication observation period 
No sensitivity analyses are planned for these. 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
20 of 27 
 
 
 
 
Continuous efficacy endpoints 
Change from baseline to week 68 in: 
 
HbA1c 
 
Body weight (kg) 
Change from baseline to week 52 and 68 in: 
 
Body weight (%) 
 
FPG 
 
BMI 
 
Waist circumference 
 
Fasting lipid profiles (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) 
The above continuous endpoints will be analysed separately using similar model approaches as for 
the primary endpoint with the associated baseline response as a covariate (for both primary 
estimand and additional estimand).  
Fasting lipid profile endpoints will be log-transformed prior to analysis with the associated log-
transformed baseline value as a covariate. 
For the analyses for estimand similar to the primary estimand at week 68 the imputation groups will 
be defined by randomised treatment and whether the subject had discontinued randomised treatment 
or initiated rescue at week 68. 
Additionally an analysis of Body weight (%) after 68 weeks will analysed separately using similar 
model approaches as for the primary endpoint with the associated baseline response as a covariate 
only including subjects with a baseline BMI>=27.  
 
To investigate the potential effect of intensification with 25 mg or 50 mg for subjects in need of 
intensification an analysis that mimics 2-stage randomisation design will be performed for HbA1c 
and body weight.  
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
21 of 27 
 
 
 
 
The analysis of HbA1c will only include subjects who at week 12 are still on treatment and have 
not reached the glycaemic target of HbA1c < 7. The change from week 12 to week 52 will be 
analysed using similar model approaches as for the primary analysis. Week 12 HbA1c will be 
included in the model as a covariate instead of baseline HbA1c. 
The analysis of body weight will be similar but only include subject who are still on treatment and 
have not reached a body weight loss of at least 5% at week 12 and include week 12 body weight as 
a covariate instead of HbA1c. 
Binary efficacy endpoints 
Subjects who after 52 weeks of treatment achieve (yes/no): 
 
HbA1c < 7.0 % (53 mmol/mol) (ADA) target* 
 
HbA1c 6++-*+-*1/%#1 
 
#'%&1*-007 
 
#'%&1*-007	 
The above four endpoints will be evaluated after week 68 as well. 
Missing data  
Missing data for the above binary endpoints will be accounted for using multiple imputation 
techniques. For the estimand similar to the primary estimand the binary endpoints will be calculated 
as dichotomisations of the 1000 multiple imputations underlying the MI analysis of the 
corresponding continuous endpoint. For the additional estimand the model will be implemented 
using a sequential imputation approach assuming MAR. The imputation will be done as described 
below: 
 
Intermittent missing values in the on-treatment without rescue observation period will be 
imputed using a Markov Chain Monte Carlo (MCMC) method, in order to obtain a monotone 
missing data pattern. This imputation is done for each treatment group separately and a 
1000 copies of the data set will be generated. 
 
A sequential regression approach for imputing monotone missing values at planned visits will 
be implemented starting with the first visit after baseline and sequentially continuing to the 
planned end of treatment visit. For each treatment group an analysis of covariance model will 
be used to impute missing values at each planned visit. The model will include strata and 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
22 of 27 
 
 
 
 
region as categorical effect and baseline and post-baseline values prior to the visit in question 
as covariates. 
The binary endpoints will be derived as dichotomisations of the 1000 multiple imputations from the 
sequential imputation. 
For both estimands, each of the 1000 data sets will be analysed using a logistic regression model 
with treatment, strata and region as fixed effects and baseline value as covariate (i.e. baseline HbA1c 
for binary HbA1c endpoints, baseline body weight for body weight endpoints and both HbA1c and 
baseline body weight for the composite endpoints that comprises both parameters). The results will 
 #!-+ ',#"20',%2 ',:0/2*#1-"/4',$#/#,!# 
Time to event endpoint 
Definition of additional anti-diabetic medication: New anti-diabetic medication and/or 
intensification of anti-diabetic medication initiated at or after randomisation and before (planned) 
end-of-treatment. 
Definition of rescue medication: New anti-diabetic medication and/or intensification of anti-
diabetic medication initiated at or after randomisation and before last date on trial product. This is a 
subset of the additional anti-diabetic medication.  
The following rules will be applied based on the concomitant medication data reported by the 
investigator, to determine whether or not the recorded anti-diabetic medication is 1. New anti-
diabetic medication or 2. Intensification of anti-diabetic medication  
1. New anti-diabetic medication: Anti-diabetic medication (4th-level ATC code) that is 
initiated at or after randomisation and is new compared to the anti-diabetic background 
medication at randomisation (see above) and with a dosing duration of more than 21 days  
2. Intensification of anti-diabetic medication: A more than 20% increase in the dose of anti-
diabetic medication at or after randomisation as compared to the anti-diabetic medication 
dose at randomisation (5th-level ATC code not changed) and with a dosing duration of more 
than 21 days. 
More than 21 days is chosen as a minimum duration for the medication t- #!-,0'"#/#"09,1'-
"' #1'!+#"'!1'-,:&'01&/#0&-*"'00#11-#,02/#1&11&#0&-/1-1#/+"2/1'-,0'#6
	"50-$
anti-diabetic medication (e.g. in connection with concurrent illnesses) are not included because such 
intensifications are not likely to affect the effect endpoints. 
 
CONFIDENTIAL






Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
25 of 27 
 
 
 
 
will be analysed using a logistic regression model with treatment, stratification factor and region as 
fixed factors and baseline HbA1c as covariate. 
Other safety endpoints 
Change from baseline to week 52 and 68 in: 
 
Pulse 
 
Systolic blood pressure 
 
Diastolic blood pressure 
The above safety endpoints will be evaluated using the primary analysis for the primary estimand 
based on SAS using the in-trial observation period and using the primary analysis for the additional 
estimand based on SAS using the on-treatment observation period. Endpoints will be analysed 
separately as described above for continuous efficacy endpoints. Results will be presented at week 
52 and 68.  
Safety endpoints not mentioned above and assessments will be summarised descriptively by 
treatment arm and visit. Categorical safety endpoints will be summarised as counts and relative 
frequencies.  
 
 
A partial database lock will be performed at the end of the treatment period for all subjects, i.e., 
after the date of the last subject last treatment visit. A partial database lock is implemented to 
support potential earlier access of oral semaglutide 25 and 50 mg to the patient population expected 
to benefit from higher doses.  
All efficacy analyses will be performed based on the data from the partial database lock. No 
efficacy assessments are collected after last subject last treatment, and so unblinding of Novo 
Nordisk staff will be after all subjects have completed treatment. Therefore, efficacy results cannot 
be biased by the early unblinding. Impact on PK and safety evaluation after partial database lock is 
considered minor as most subjects will have completed the follow-up visit, and subjects and 
investigators remain blinded. Full analysis of PK and safety will be performed after the full 
database lock.  
A detailed plan for data handling, blinding, data analysis, and operational aspects of the partial 
database lock and the database update will be finalised before the partial database lock.  
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
26 of 27 
 
 
 
 
The result of the evaluation at partial database lock will not be shared with investigators or subjects 
before the full database lock, and only a minimum number of Novo Nordisk staff will know the 
randomisation code at subject level. There will be no change in study design regardless of the 
outcome of the evaluation at partial database lock.  
The database will be updated after the partial database lock to include the remaining data. The full 
database lock will be performed, as per the usual procedures, after the date of the last subject last 
visit. 
The early DBL will not impact the analyses as the analyses described in this SAP will not be 
modified after the early DBL and the results reported in the CSR will be based on all collected data. 
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
23 December 2022 
Novo Nordisk 
Trial ID: NN9924-4635 
Version: 
3.0 
UTN:U1111-1247-0210 
Status: 
Final 
EudraCT No:2020-000299-39 
Page: 
27 of 27 
 
 
 
 

 
Appendix 1 List of abbreviations 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
BMI 
Body mass index 
CSR 
Clinical Study Report 
DBL 
Database Lock 
FAS 
Full Analysis Set 
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed Model for Repeated Measurements 
PK 
Pharmacokinetic 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
 
 

 
1. Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches 
for multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. 
Biometrical Journal. 2011;53(6):894-913.  
2. Little RJA, Rubin DB. Statistical analysis with missing data. New York: Wiley. 1987. xiv, 278 
p. p.  
 
 
CONFIDENTIAL